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Risankizumab (Skyrizi): CADTH Reimbursement Review: Therapeutic area: Crohn disease [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Aug.
An overview of the submission details for the drug under review is provided in Table 1.
Submitted for Review.
Crohn disease (CD) is a chronic form of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal (GI) tract, but commonly affects the ileum (i.e., small intestine), colon (i.e., beginning of the large intestine), and rectum. Common symptoms experienced by patients with CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.1,2 Complications associated with CD can include malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, and intra-abdominal and other abscesses and ulcers.1,3 In addition, patients with colonic CD have been shown to have an increased risk of developing colon cancer.1 Smoking, a family history of IBD, infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs have been identified as risk factors.4 For many patients with CD, symptoms are chronic and intermittent, and disease activity and severity can vary widely over time. The predicted prevalence of CD in 2018 was 368 per 100,000 population, which translates to approximately 135,000 people in Canada living with CD.5,6
Currently, there is no cure for CD. Therapeutic goals include inducing and maintaining clinical and endoscopic remission. Pharmaceutical treatments for CD include aminosalicylates, immunosuppressants, corticosteroids, tumour necrosis factor (TNF) alpha antagonists, interleukin (IL) inhibitors, and integrin inhibitors. Medical management is based on a stepwise approach, with treatments used sequentially and escalated to either newer therapies or higher doses as patients fail to respond to each step of treatment. Not all patients respond to available treatments and their disease may become refractory to the current treatment regimens.
Risankizumab (Skyrizi) is a humanized immunoglobulin G1 monoclonal antibody that binds to the p19 subunit of human interleukin-23 (IL-23) cytokine and inhibits IL-23 signalling, including the release of the proinflammatory cytokine interleukin-17 (IL-17).7 Risankizumab is indicated for the treatment of adults with moderately to severely active CD who have had an inadequate response, intolerance, or demonstrated dependence to corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.7 The sponsor-submitted reimbursement criteria of risankizumab is the same as the Health Canada–approved indication. The recommended dose for CD is 600 mg IV infusion at week 0, week 4, and week 8 as induction therapy, followed by 360 mg subcutaneous (SC) injection at week 12 and every 8 weeks thereafter as maintenance therapy.7
The objective of this systematic review is to assess the beneficial and harmful effects of risankizumab (60 mg/mL) IV infusion as induction therapy and SC injection (150 mg/mL) as maintenance therapy for the treatment of adults with moderately to severely active CD who have an inadequate response, intolerance, or demonstrated dependence to corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.
The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from 1 clinical expert consulted by CADTH for the purpose of this review.
Two patient groups, Crohn’s and Colitis Canada (CCC) and the Gastrointestinal (GI) Society, provided input for this review. CCC’s input was informed by its Impact of Inflammatory Bowel Disease in Canada 2018 report, a survey involving 687 respondents with moderate to severe CD, and interviews with 3 patients with CD who participated in the risankizumab clinical trial. The GI Society’s input was informed by 5 patient surveys involving more than 1,000 participants; interviews with 2 patients with CD who participated in the risankizumab trial; a focus group; a patient round table; phone, email, and social media interactions; and story submissions.
From the patients’ perspective, the inability to predict when the next urgent bowel movement would occur and the inability to control flare-ups had a significant negative impact on the personal and social lives of patients with CD. Both patient groups emphasized the importance of relieving symptoms, achieving remission, improving quality of life, minimizing chronic steroid use, and having access to a variety of effective treatment options.
The clinical expert noted the following unmet needs of patients with CD: some patients do not respond to available treatments and some become refractory over time, access to biologic drugs is challenging or limited, and there is a lack of treatment options for fibrostenotic strictures and perianal or fistulizing CD.
The clinical expert noted that risankizumab is not expected to cause a shift in the treatment paradigm; they indicated it would be used in a similar fashion as other biologic treatments for CD, and likely prescribed alone or with a steroid taper or immunomodulator. The expert also noted that risankizumab could be used as first-line treatment or as a later treatment. However, the expert noted that due to a lack of data for fistulizing CD, these patients should try other treatments such as anti-TNF therapy before risankizumab.
The clinical expert commented that patients who are most in need are those with moderate to severe disease who have failed other biologic therapies, although those who are bionaive may have an even better response. Patients best suited should have an established diagnosis of CD based on an ileocolonoscopy with active disease.
The clinical expert noted that the following outcomes are used to determine patient response to treatment: clinical response and/or remission (e.g., improvement in symptoms such as pain, diarrhea), improvement in biomarkers, mucosal healing (e.g., endoscopic improvement), and improved health-related quality of life (HRQoL). The clinical expert noted that discontinuation of treatment should be based on primary or secondary loss of response, or adverse events (AEs) or symptoms that cannot be managed. It was noted by the expert that a gastroenterologist should be required to diagnose, treat, and monitor patients who might receive risankizumab, either in a community or hospital setting.
One clinician group that provided input was the Pan-Canadian Inflammatory Bowel Disease Specialist Group, which consists of specialists in gastroenterology caring for patients with CD. Their input was informed by 16 specialists.
The clinician group noted that the goal of treatment should focus on improving clinical symptoms, endoscopic response, and endoscopic remission. The clinician group stated there is a lack of safe and effective treatments for rapidly improving endoscopic outcomes of CD and maintaining improvement in the long term. It was suggested that risankizumab be used in patients with moderate to severe CD as first-line therapy, as well as second-line therapy for patients experiencing flares or inadequate response to biologics. The clinician group indicated that risankizumab is not suitable for patients with perianal or fistulizing CD, severe peripheral arthritis, uveitis, or a concomitant immune-mediated disease.
The clinician group indicated that administration of risankizumab during the induction phase should occur in a clinic under the supervision of a gastroenterologist. For maintenance therapy, the clinician group indicated patients could self-administer SC injections after training. Aligning with the opinion of the clinical expert consulted by CADTH, the clinician group proposed the following outcomes to determine treatment response with risankizumab: improvements in symptoms (e.g., stool frequency [SF], abdominal pain), a reduction in biomarkers (e.g., C-reactive protein, fecal calprotectin) of inflammatory activity by 3 months of therapy, symptomatic remission, discontinuation of corticosteroids by 6 months of treatment, and improvements in HRQoL. The clinician group indicated risankizumab should be discontinued when symptoms worsen or when there is inadequate response. Drug program input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for risankizumab:
The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Four phase III randomized controlled trials (RCTs) submitted by the sponsor were included in this systematic review: the M15-991 (MOTIVATE) induction study (N = 413), the M16-006 (ADVANCE) induction study (N = 559), the M16-000-substudy 1 (FORTIFY) maintenance substudy 1 (N = 363), and the M20-259 part 1 (SEQUENCE) induction and maintenance ongoing study, || |||. The objectives of the MOTIVATE, ADVANCE, and FORTIFY trials were to evaluate the efficacy and safety of risankizumab in patients with moderately to severely active CD who had an inadequate response, had a loss of response, or were intolerant to either conventional therapy (denoted as non-bio-IR) or biologic therapy (denoted as bio-IR). SEQUENCE aimed to evaluate the comparative efficacy and safety of risankizumab compared to ustekinumab in the same population. Both induction trials were of similar design, except the MOTIVATE study enrolled patients who were bio-IR, and the ADVANCE study enrolled patients who were bio-IR or non-bio-IR. In these 2 trials, eligible patients were randomized to receive risankizumab 600 mg IV administered at week 0, week 4, and week 8 or matching placebo, in a double-blind manner. Patients without clinical response to risankizumab at week 12 entered an additional exploratory open-label 12-week induction period (period 2) and were rerandomized to risankizumab 1,200 mg IV, risankizumab 360 mg SC, or risankizumab 180 mg SC. Clinical responders from the induction trials were eligible to enter the maintenance trial (FORTIFY), as were patients from induction period 2 who achieved clinical response at week 24. Patients who entered the maintenance study were rerandomized to receive blinded risankizumab 360 mg SC or matching placebo every 8 weeks for 52 weeks. The induction and maintenance trials included treatment groups (1,200 mg IV induction and 180 mg SC maintenance doses of risankizumab) that were not aligned with the Health Canada–approved dose; for this reason, these treatment groups were not included in this review. To meet regional regulatory requirements, all 3 trials included 2 protocols denoted as US and outside the US (OUS) that were identical in design but specified different coprimary and key ranked secondary outcomes. Clinical remission and endoscopic response were coprimary outcomes in both protocols; however, the definition of clinical remission in the US protocol was defined as Crohn’s Disease Activity Index (CDAI) score being less than 150, whereas in the OUS protocol, it was defined as SF and abdominal pain score (APS) (together, referred to as SF/APS) clinical remission (defined as average daily SF ≤ 2.8 and not worse than baseline and average daily APS ≤ 1 and not worse than baseline). Key secondary outcomes were similar in both protocols but ranked differently. These included clinical remission, clinical response, enhanced SF/APS clinical response and endoscopic response, endoscopic remission, ulcer-free endoscopy, corticosteroid-free clinical remission, the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score, the Inflammatory Bowel Disease Questionnaire (IBDQ) total score, the Short Form (36) Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores, and safety outcomes.
In the SEQUENCE study, patients were randomized to receive blinded risankizumab 600 mg IV induction at week 0, week 4, and week 8, then risankizumab 360 mg SC maintenance at week 12 and every 8 weeks thereafter or ustekinumab weight-based IV induction dose at week 0 and then ustekinumab 90 mg SC maintenance every 8 weeks thereafter, over 48 weeks. In the SEQUENCE study, part 1, the primary objective was to assess the noninferior rate of clinical remission based on a prespecified interim data lock that was powered by approximately 50% of planned patients (n = 272) who completed their week 24 visit or were prematurely discontinued before week 24. Other exploratory outcomes included clinical response, endoscopic remission, mucosal healing, deep remission, biologic remission, SF-36 PCS and MCS scores, and IBDQ total score.
Patients in the trial populations were predominantly white (77% to 91%), with an approximate mean age of 40 years and a mean CD duration of approximately 8 years to 12 years. In the MOTIVATE study, approximately 48% and 52% of patients were bio-IR of 1 and greater than 1, respectively. In the ADVANCE study, 23% to 30% of patients were bio-IR, 28% to 32% of patients were bio-IR greater than 1, and 42% to 45% of patients were non-bio-IR. Between 29% and 36% of patients across treatment groups were on concomitant corticosteroids and about 19% to 28% of patients were on immunomodulators. In the maintenance trial (FORTIFY), patients’ baseline characteristics were generally comparable to those in the induction trials. In the SEQUENCE study, ||| || ||| || |||||||| ||| |||||| |||||||| ||||||| || |||| |||| || ||||| || | ||| ||| || ||| ||| |||||| ||||||| |||| |. All other key baseline characteristics were generally comparable to the other trials.
The key efficacy results from the MOTIVATE, ADVANCE, and FORTIFY studies are summarized in Table 2 and Table 3. The primary outcome for the SEQUENCE study is described in the text.
In both induction trials (MOTIVATE and ADVANCE), the coprimary outcome of clinical remission at week 12 for both the US and OUS protocols favoured risankizumab versus placebo. In the MOTIVATE US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab versus placebo was 22.1% (95% confidence interval [CI], 13.1% to 31.0%; P < 0.001). For the OUS protocol, the adjusted between-group difference in the SF/APS clinical remission rate was 15.2% (95% CI, 6.4% to 24.0%; P = 0.001). In the ADVANCE US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab versus placebo was 20.7% (95% CI, 12.4% to 29.0%; P < 0.001). For the OUS protocol, the adjusted between-group difference in SF/APS clinical remission was 21.9% (95% CI, 13.8% to 29.9%; P < 0.001). In both trials and protocols, all secondary ranked multiplicity-controlled outcomes — including SF and APS remission at week 12, CDAI clinical remission at week 4, and SF/APS clinical remission at week 4 — favoured risankizumab versus placebo. The results of subgroup analyses by bio-IR status were consistent with the main analysis. The findings were robust to sensitivity analyses using different methods to account for missing data.
In the maintenance trial (FORTIFY), the coprimary outcome of clinical remission at week 52 in both protocols favoured risankizumab versus placebo. For the US protocol, the adjusted between-group difference in the CDAI clinical remission rate with risankizumab was 14.6% (95% CI, 4.3% to 25.0%; P = 0.005). For the OUS protocol, the adjusted between-group difference in the SF/APS clinical remission rate was 15.2% (95% CI, 4.9% to 25.4%); P = 0.004). In both protocols, almost all secondary remission outcomes — including SF and APS remission, maintenance of SF/APS or CDAI clinical remission, SF/APS or CDAI clinical remission with endoscopic response, and SF/APS or CDAI deep remission — favoured risankizumab versus placebo. The evidence was too imprecise to show a difference for corticosteroid-free CDAI or SF/APS clinical remission. However, except for SF/APS clinical remission (US protocol), the secondary outcomes are at an increased risk of type I error (false-positive results) because they were tested after failure of the statistical hierarchy.
In the ongoing SEQUENCE trial, the primary outcome of CDAI clinical remission at week 24 in the intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1 (ITT1H), and the per-protocol population for the interim lock analysis ||||||| risankizumab versus ustekinumab. However, this was based on only ||| of the planned population and the findings are at risk of overestimating the efficacy of |||||||||||| |||||| |||||||||||, although the potential presence and magnitude of the overestimation is unclear.
In both induction trials and protocols, all the secondary ranked multiplicity-controlled clinical response outcomes favoured risankizumab versus placebo. The between-group adjusted difference in CDAI clinical response at week 12 for risankizumab versus placebo was 23.1% (95% CI, 14.2% to 31.9%) in the ADVANCE study and 29.4% (95% CI, 19.9% to 39.0%) in the MOTIVATE study. The between-group adjusted difference for CDAI clinical response and endoscopic response combined at week 12 for risankizumab versus placebo was 24.5% (95% CI, 18.5% to 30.5%) in the ADVANCE study and 15.0% (95% CI, 8.5% to 21.5%) in the MOTIVATE study. Results of the sensitivity analysis for all outcomes were consistent with the primary analysis.
In the maintenance trial (FORTIFY), the secondary outcomes of CDAI clinical response and SF/APS enhanced clinical response at week 52 were not formally tested due to failure of the statistical hierarchy, although they were supportive of the primary outcomes.
In the induction trials, the coprimary outcome of endoscopic response and secondary outcomes of endoscopic remission and ulcer-free endoscopy at week 12 favoured risankizumab versus placebo. In the MOTIVATE study, the adjusted between-group difference in endoscopic response rate with risankizumab versus placebo was 17.7% (95% CI, 9.9% to 25.4%; P < 0.001). In the ADVANCE study, the adjusted between-group difference in endoscopic response rate was 28.3% (95% CI, 21.2% to 35.4%; P < 0.001). In both trials, results of the sensitivity analysis were consistent with the primary analysis.
In the maintenance trial (FORTIFY), the adjusted between-group difference in the coprimary outcome of endoscopic response at week 52 with risankizumab versus placebo was 27.8% (95% CI, 18.7% to 37.0%; P < 0.001). The ranked secondary outcomes of ulcer-free endoscopy and endoscopic remission were not formally tested due to failure of the statistical hierarchy, but were supportive of the primary outcomes.
Summary of Key Results From Induction Trials MOTIVATE and ADVANCE.
Summary of Key Results From Maintenance Trial FORTIFY.
Evidence from the pivotal trials showed induction therapy (600 mg IV) and maintenance therapy (360 mg SC) with risankizumab seemed generally safe and well tolerated. In the MOTIVATE study, treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation were higher in the placebo group than in the risankizumab group, mainly due to worsening CD. In the ADVANCE induction study, TEAEs occurred with similar frequency in both treatment groups while SAEs and AEs leading to study drug discontinuation occurred with higher frequency in the placebo group. The most common TEAEs with risankizumab (> 2% of patients) during the 12-week induction period were headache, arthralgia, and nasopharyngitis, whereas with placebo, they were worsening CD, headache, and arthralgia. In both induction trials, the most frequently reported TEAE leading to study drug discontinuation was worsening CD. Two deaths were reported, both of which occurred in the ADVANCE study’s placebo group. In the maintenance trial (FORTIFY), TEAEs, SAEs, and AEs leading to discontinuation were similar between treatment groups and induction trials. Across the 3 trials, the incidence of notable harms in treatment groups was comparable and infrequent. In the SEQUENCE study, || |||||||| |||| ||||||| ||||||| |||||||||||| ||| |||||||||||| || |||||||| ||| ||||||||| || ||||||| ||||| || |||| ||||||||| |||||| |||| ||||||||| |||| |||| ||| |||| |||||| || |||| |||||| ||||| ||||||| |||||| |||||||||||||| ||||| |||||||||||| |||||| || |||||| |||| ||||||||.
The trials used appropriate methods of randomization and allocation concealment via interactive response technology. In general, baseline characteristics of patients appeared balanced between trial groups, indicating that randomization was successful.
There are some concerns related to risk of bias due to deviation from the intended interventions. This is primarily due to performing the analysis on the intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies (ITT1A); this population included randomized patients who received at least 1 dose of the study drug. As this was not a true intention-to-treat (ITT) population, some concerns for bias were introduced in the ADVANCE and MOTIVATE trials (about 10% of patients were not included), and a high risk of potential bias may have been present for the FORTIFY trial (21% of the risankizumab group and 11% of the placebo group were not included). The magnitude and direction of the potential bias cannot be predicted.
For most outcomes, there was minimal concern for missing outcome data. In the induction trials, there was a higher number of discontinuations of the study drug in the placebo groups (10% in the MOTIVATE study and 12% in the ADVANCE study) compared to the risankizumab groups (2% in both the MOTIVATE and ADVANCE studies). In the maintenance trial, discontinuations were similar and just over 10% across groups. For the primary outcomes, acceptable methods were used to impute missing data, and the findings were robust to sensitivity analyses using different methods to account for missing data. There is concern for bias due to large and imbalanced amounts of missing data for the HRQoL and fatigue outcomes, particularly at the 12-week time point. The direction and magnitude of the potential bias is unclear.
Across all trials, most outcomes were subjective (e.g., SF/APS or CDAI clinical remission or response, FACIT-F, IBDQ, SF-36) and collected from patient diaries, except for endoscopic outcomes, which were read centrally by a blinded reviewer. Although the subjective outcomes are prone to risk of bias, the double-blind design of the trials mitigated this risk. There is some risk of unblinding that could have affected the subjective outcomes since dropout rates were higher in the placebo groups, which could allow investigators and patients to make inferences on treatment assignment regardless of blinding. However, the extent of the potential bias is unclear.
Statistical analyses in the 3 trials were prespecified. A hierarchical testing procedure was appropriately used in all 3 trials to account for multiplicity in coprimary and key secondary outcomes. The exploratory outcomes of Crohn’s Symptom Severity (CSS) and 5-Level EQ-5D (EQ-5D-5L) were not adjusted for multiplicity, which limited the ability to draw conclusions regarding these outcomes. In the FORTIFY study, early failure of the statistical hierarchy precluded formal statistical testing of most secondary outcomes. This lack of adjustment for multiplicity may have increased the likelihood of type I error and as such, P values for these outcomes should be considered supportive and not meant as a basis for drawing conclusions.
In the ongoing SEQUENCE trial, there were 2 key limitations with the interim results that are at risk of overestimating the treatment effect in |||||| || ||||||||||||, although the potential presence and magnitude of the overestimation is unclear. There was a considerable amount of missing data for all outcomes since this was an interim analysis where only 50% of patients had reached the time point of interest. There was also bias in the selection of reported results, as the statistical analyses presented for all exploratory outcomes were not described in the statistical analysis plan. The analysis plan only aimed to describe the outcomes descriptively. Because of these limitations, the interim results cannot support definitive conclusions about the efficacy of risankizumab compared to ustekinumab.
According to the clinical expert consulted by CADTH, the inclusion and exclusion criteria of the pivotal trials were generally aligned with selection criteria that would be adopted by most clinicians in Canada when identifying suitable candidates for risankizumab. The relative efficacy of risankizumab to other active treatments was not known, given the trial data available. In the MOTIVATE, ADVANCE, and FORTIFY studies, placebo was the comparator while in the SEQUENCE study, ustekinumab was the comparator. Since ustekinumab is not used frequently in Canada, it’s not considered as the most relevant active treatment. The trials included outcomes that were important to patients and clinicians. All outcomes were considered appropriate by the clinical expert, although the Harvey-Bradshaw Index was noted as a more commonly used tool to assess clinical remission in patients with CD in Canada. The clinical expert noted that the time frames used in the trials were appropriate to determine short-term treatment effects with risankizumab; however, they may not be considered sufficient to fully understand the long-term safety for rare events and those that take longer to develop, such as malignancy.
The sponsor-submitted indirect treatment comparison (ITC) was a network meta-analysis (NMA)11 assessing the efficacy and safety of risankizumab relative to vedolizumab, ustekinumab, adalimumab, infliximab, and placebo in patients diagnosed with moderately to severely active CD.
The 2 published ITCs identified from the CADTH literature search12,13 were also NMAs. Barberio et al. evaluated the efficacy of all biologic therapies and small molecules that have been investigated in phase III clinical trials in luminal CD, compared to placebo or each other. Singh et al. determined the relative efficacy and safety of infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab, and risankizumab (either alone or in combination with immunosuppressants) for the treatment of moderate to severe CD in patients with or without previous biologic exposure.
||||| || ||| ||||||| ||||||||| |||| ||| ||||||| || |||||||| |||||||| |||||| |||| |||||||| |||||||||| |||||||| |||||||| ||||||||| |||||||||| ||||||||| |||||||||| |||||||||| |||||||||||| ||||||||| |||| |||||||||||| ||| |||||||| || ||||||| ||||| |||| |||||||| ||| ||| |||||||||| |||||||||||| |||| ||||||| ||||| ||| ||||| ||| ||| |||||||||| |||||||| ||||||| |||| || |||| ||||||||| ||| ||||||||||| ||||||| |||||||| || |||||||||| ||||||||||| || ||||||||||| ||||| || ||||||||||| |||| ||||||| || ||| |||||||| |||||||| || |||||||||||| || ||||| |||||| |||||||||| ||||||||| |||||||||||| |||||||||||| ||||||||||| ||| ||||||||||| ||| || ||||||| ||||||||||| || |||| |||||||||| ||||||||| ||| |||| |||||||| |||| ||||||||| |||||||||| |||||||||| ||||||||||| ||||| ||| |||||| || |||||||||||| |||||| ||||||| || ||||| |||||| |||||||||| || |||| || ||| ||||| ||||||||.
As for the NMA conducted by Barberio et al., in the induction phase, both patients naive to biologic therapies and patients exposed to biologic therapies previously who were treated with risankizumab had a lower risk of failing to achieve clinical remission or clinical response compared to placebo and some of the active treatments (e.g., ustekinumab, adalimumab). During the maintenance phase, in most cases the effect estimates were too imprecise to draw conclusions about the efficacy of risankizumab versus placebo or any other active treatments in patients naive to biologic therapies or those exposed to biologic therapies previously. With respect to harms outcomes, the evidence was insufficient to show a difference between risankizumab 600 mg IV versus placebo or other active treatments in the incidence of any AEs or any infection at the induction phase.
As for the NMA conducted by Singh et al., patients naive to biologic therapies and patients with previous biologic exposure who were treated with risankizumab were more likely to achieve clinical remission or clinical response compared to placebo in the induction phase. Risankizumab was also superior to vedolizumab in achieving clinical remission in patients with previous biologic exposure in the induction phase. The effect estimates for efficacy outcomes in the maintenance phase were too imprecise to draw conclusions about the comparison of risankizumab versus placebo or any active treatment. No NMA comparative estimates for harms outcomes were available for risankizumab because they were not connected in the evidence networks.
There were several notable sources of heterogeneity across RCTs included in the sponsor-submitted NMA (e.g., differences in patient characteristics, differences in disease duration in the ||| |||||||||||, differences in the time at which primary outcomes across individual induction trials were accessed). These increase uncertainty in the effect estimates because it is likely that the assumption of exchangeability was violated. The causes of heterogeneity were not explored ||| ||||||||||||| |||||||| |||||||| || ||||||||||||||| || ||| ||||||||||||||||| ||||||. In addition, ||||||||| ||||||||| || ||| ||||| ||||||| |||| ||||| || ||| |||, which does not incorporate heterogeneity across included studies and implied that heterogeneity across included trials had no impact on the magnitude of effect, might yield biased NMA estimates given the notable heterogeneity. Many of the estimates of treatment effects were affected by imprecision. Finally, ||| |||| || |||| |||||||||| || ||| |||||||||| ||||| ||||| ||| ||| ||||||||| |||||| on the internal validity of the NMA effect estimates at the outcome level were not explicitly discussed in the sponsor-submitted NMA.
Given the overlap in the included studies, the potential sources of heterogeneity across included studies are likely to be similar between the sponsor-submitted NMA and the 2 published NMAs identified from the CADTH literature search (i.e., Barberio et al. and Singh et al.). However, neither of the 2 published NMAs adequately discussed or accounted for the heterogeneity issue. Therefore, there was considerable uncertainty in the effect estimates from both studies, and no definitive conclusions could be made.
No other relevant evidence was submitted by the sponsor or identified from the literature.
Evidence from 3 double-blind randomized trials (MOTIVATE, ADVANCE, and FORTIFY) showed that compared to placebo, treatment with risankizumab resulted in clinically important improvements in clinical remission and endoscopic response at a 12-week induction period (600 mg IV) and a 52-week maintenance period (360 mg SC) in adults with moderate to severe CD who had inadequate response or were intolerant to prior conventional or biologic therapies. These results addressed key treatment outcomes noted as important by both patients and clinicians. The clinical expert consulted by CADTH considered the benefits of risankizumab on clinical remission and endoscopic response, as well as the resolution of clinical symptoms (e.g., SF and APS remission) and disease activity (e.g., CDAI clinical response), and reductions in endoscopic inflammation (e.g., endoscopic remission, ulcer-free endoscopy) to be clinically meaningful. In the maintenance trial, the secondary outcomes were generally supportive of the induction trials; however, there is some risk of false-positive conclusions due to the outcomes being tested outside the statistical testing hierarchy and/or after failure. In the induction trials, risankizumab treatment was also associated with improvement in HRQoL outcomes that met most identified minimal important differences (MIDs); however, these findings were affected by bias and the CIs include the potential for effects that are not clinically important. The evidence was insufficient to show a difference for change in HRQoL compared to placebo in the maintenance trial. In general, risankizumab seemed safe and well tolerated compared to placebo, but long-term data are needed to further evaluate its efficacy and safety profile. Due to limitations of the preliminary data from the SEQUENCE trial comparing risankizumab to ustekinumab and ITCs, no firm conclusions can be drawn on the relative efficacy and safety of risankizumab compared to other active treatments.
CD is a chronic form of IBD that can affect any part of the GI tract, but most commonly affects the ileum (i.e., small intestine), colon (i.e., beginning of the large intestine), and rectum. CD has 3 phenotypes: inflammatory, stricturing, and penetrating (fistulas and abscesses).14 Common symptoms of CD include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.1,2 Inflammation associated with CD can also manifest outside the GI tract, affecting the joints, eyes, and skin.15 Complications associated with CD can include malnutrition, weight loss, anemia, bowel obstructions, fistulas, anal fissures, and intra-abdominal and other abscesses and ulcers.1,3 In addition, patients with colonic CD have an increased risk of developing colon cancer.1 Smoking, a family history of IBD, infectious gastroenteritis, and frequent use of nonsteroidal anti-inflammatory drugs have been identified as risk factors for CD.4
The diagnosis of CD is based on a combination of clinical evaluation and endoscopic, histological, radiological, and/or biochemical investigations.4 An ileocolonoscopy with multiple biopsy specimens is the first-line procedure for diagnosing CD.4 The endoscopic hallmark of CD is the patchy distribution of inflammation, with skip lesions, defined as areas of inflammation interposed between normal-appearing mucosa.4 Cross-sectional imaging using MRIs and CT enterography and transabdominal ultrasonography are complementary to endoscopy and offer the opportunity to detect and stage inflammatory, obstructive, and fistulizing CD.4 The classification of disease severity in CD suggested by the American College of Gastroenterology is provided in Table 4.
For many patients with CD, symptoms are chronic and intermittent, and disease activity and severity can vary widely over time. Some patients may have a continuous and progressive course of active disease, while approximately 20% of patients experience prolonged remission after initial presentation.15 For patients in remission, relapse rates at 1 year, 2 years, 5 years, and 10 years are estimated at 20%, 40%, 67%, and 76%, respectively.16 Based on patient group input for this review, CD has a profound effect on physical, emotional, and social well-being.
According to the Canadian Gastro-Intestinal Epidemiology Consortium, the predicted prevalence of CD in 2018 was 368 per 100,000 population, which translates to approximately 135,000 people in Canada living with CD.5,6 Age groups most likely to be diagnosed with CD are adolescents and those between the ages of 20 years and 30 years.1
Classification of Disease Severity in Crohn Disease.
The selection of treatment regimens for CD is based on location, extent, phenotype, and severity of disease.3 According to the clinical expert consulted by CADTH, the therapeutic goals of CD treatment are to induce and maintain clinical remission and reduce the need for long-term corticosteroid use while minimizing side effects. Long-term goals include endoscopic healing, the absence of disability, and the normalizing of HRQoL. Short to intermediate goals include normalizing biomarkers of disease activity (e.g., C-reactive protein, fecal calprotectin). These goals described by the clinical expert are consistent with Canadian and American published clinical practice guidelines.14,18 Several drug classes are used in the treatment of CD, including aminosalicylates, immunosuppressants (e.g., azathioprine, cyclosporine, methotrexate, 6-mercaptopurine), corticosteroids (e.g., prednisone), TNF alpha antagonists (e.g., infliximab, adalimumab), IL inhibitors, and integrin inhibitors (e.g., vedolizumab).3,19 With the exception of the TNF alpha antagonists, IL inhibitors, and vedolizumab, all are commonly referred to as conventional therapies. Medical management is based on a stepwise approach, with treatments used sequentially and escalating to either newer therapies or higher doses as patients fail to respond to each step of treatment.20 Most drugs have important adverse effects that may have short-term or long-term consequences.1,19 Surgery, including total colectomy and ileostomy, may be considered for patients with serious complications or for those who do not respond to medical management.3
The clinical expert consulted by CADTH noted the following unmet needs for patients with CD: not all patients respond to available treatments and their disease may become refractory to the current treatment regimens; to gain access to biologics, patients need to first be refractory to, or have side effects from, less expensive approved medications and assume the risks of these medications (e.g., corticosteroids, immunomodulators); treatment options for perianal or fistulizing CD are lacking; overall response and remission rates in clinical trials are not very high; and medications mostly target moderate to severe CD.
Risankizumab (Skyrizi) is a humanized immunoglobulin G1 monoclonal antibody that binds to the p19 subunit of human IL-23 cytokine and inhibits IL-23 signalling, including the release of the proinflammatory cytokine IL-17.7
Risankizumab has been approved by Health Canada for the treatment of adults with moderately to severely active CD who have had an inadequate response, intolerance, or demonstrated dependence to corticosteroids, or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.7 The sponsor-submitted reimbursement request for risankizumab is the same as the Health Canada indication. Risankizumab has been previously approved by Health Canada for the treatment of adult patients with plaque psoriasis,7 and was reviewed by CADTH for this indication.
The recommended dose for CD is 600 mg IV infusion at week 0, week 4, and week 8 as induction therapy, followed by 360 mg SC injection at week 12 and every 8 weeks thereafter as maintenance therapy.7 Key characteristics of risankizumab and commonly used medical treatments for CD are presented in Table 5.
Key Characteristics of Risankizumab, Ustekinumab, Vedolizumab, Infliximab, and Adalimumab.
This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.
Two patient groups, CCC and the GI Society, provided input for this review. The CCC gathered the information from a report published in 2018 (Impact of Inflammatory Bowel Disease in Canada), a 2022 survey involving 687 respondents with moderate to severe CD, and interviews with 3 patients with CD who participated in a risankizumab clinical trial. The patient input provided by the GI Society was based on surveys and interviews, including a 2015 survey on biologics and biosimilars involving 423 patients with IBD living in Canada; a 2018 survey on unmet needs involving 432 patients with IBD living in Canada; a 2020 survey on the unmet needs of IBD involving 579 respondents; a 2020 survey on biosimilars completed by 145 respondents (most of whom had IBD); a 2022 survey on the IBD patient journey completed by 54 patients with IBD living in Canada; interviews with 2 patients with CD who participated in the risankizumab trial; a 2022 focus group with patients with CD; as well as 1-on-1 conversations with patients with IBD; a patient round table; phone, email, and social media interactions; and story submissions.
Both the CCC and GI Society agreed that being unable to predict when the next urgent bowel movement would occur and the inability to control the flare had a significant negative impact on the personal and social lives of patients with CD. The CCC found that 6 in 10 respondents felt isolated because of having CD.
In terms of experiences with currently available treatments, the CCC stated that there were fewer treatment options available for patients with CD in Canada than in other Western countries, and 6 in 10 respondents feared that their treatment options were running out. Respondents were also expecting more effective treatments to manage their CD. More than 7 out of 10 respondents from the CCC input experienced diarrhea, bloating, and an unpredictable feeling of urgency to use the washroom at least some days, despite being on treatments. In a survey carried out by the GI Society, about 56% of IBD patients thought that the available medications were only somewhat adequate and 20% of IBD patients felt they were not at all adequate.
In terms of experiences with risankizumab, 5 patients with CD who participated in a risankizumab clinical trial valued its effectiveness for relieving symptoms. Furthermore, 3 favoured risankizumab for its convenience, ease of administration, and lack of side effects.
Symptom relief or remission and a subsequent improvement in quality of life were perceived by patients as being important. Specifically, 8 in 10 patients from the CCC input listed unpredictable and frequent bowel movements, pain, and fatigue as the most important factors in CD management. Taking fewer medications and minimizing chronic steroid use were also rated by the respondents from the CCC as important aspects of treatment options.
All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of CD.
The clinical expert noted unmet needs of patients with CD include that not all patients respond to available treatments and patients become refractory to available treatments. The clinical expert highlighted that overall response and remission rates are not very high. The clinical expert reported that to gain access to biologics, patients need to first be refractory to or experience side effects from less expensive medications and assume the risks of these medications (e.g., corticosteroids, immunomodulators). In addition, the clinical expert noted that there are unmet needs in the treatment of fibrostenotic strictures as medications generally target inflammation, not fibrosis, and treatment options for perianal or fistulizing CD. Lastly, medications in clinical trials mostly target moderate to severe disease.
The clinical expert noted that risankizumab is not expected to cause a shift in the treatment paradigm; it would be used in a similar manner to other biologic treatments for CD. Risankizumab is a monoclonal antibody against IL-23; similar to other biologics, it targets the underlying disease process and not just symptoms. Ustekinumab similarly blocks interleukin-12 as well as IL-23 through the shared p40 subunit. IL-23 is a key regulator in the inflammatory pathway in CD. The mechanism of action of risankizumab would likely be similar to ustekinumab. Risankizumab would likely be prescribed alone or with a steroid taper or immunomodulator. The clinical expert believed that further studies are needed to assess if risankizumab would be beneficial in combination with other biologics or for use specifically in fistulizing disease.
The clinical expert also noted that, in their opinion, this medication could be used as first-line treatment or as a later treatment; it would not need to be reserved for those who are intolerant or have contraindications for other biologics. For moderate to severe CD, the clinical expert indicated that patients would not need to try other biologic treatments first. However, due to a lack of data for fistulizing CD, the clinical expert believed that patients with fistulizing CD should try other treatments (namely anti-TNF) before risankizumab.
The clinical expert noted that patients who are most likely to respond to risankizumab are those with moderate to severe luminal CD, and patients who are in most need are those with moderate to severe disease who have failed other biologic therapies, although those who are bionaive may have an even better response. The clinical expert highlighted that patients best suited for treatment with risankizumab would be those who have an established diagnosis of CD based on an ileocolonoscopy with active disease (misdiagnosis is uncommon).
The clinical expert indicated that in their clinical opinion, earlier treatment with biologics may reduce cost, surgery, and hospitalization.
The clinical expert noted the following outcomes are used to determine response to treatment:
The clinical expert noted that discontinuation of treatment should be based on primary or secondary loss of response, and AEs or symptoms that cannot be managed.
The clinical expert noted that a specialist (i.e., gastroenterologist) should be required to diagnose, treat, and monitor patients who might receive risankizumab, either in a community or hospital setting.
This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section at the end of this report.
The clinician group input was provided by the Pan-Canadian Inflammatory Bowel Disease Specialist Group, which consists of specialists in gastroenterology from across Canada caring for patients with CD. The clinician group input was based on a discussion held by the Pan-Canadian Inflammatory Bowel Disease Specialist Group involving 16 experts in September 2022. The group reviewed the safety and efficacy data from the risankizumab trial, described the CD burden in Canada, and discussed the unmet treatment needs of CD, and how access to risankizumab could benefit patients and society in the short term and long term.
In addition to relieving clinical symptoms, the clinician group emphasized that the goal of treatment should focus on improvements in endoscopic response, endoscopic remission, and mucosal healing. However, the group stated that such a goal might not be achievable in most patients due to a lack of safe and effective treatments that could rapidly improve endoscopic appearance and maintain improvement in the long term. The group claimed that there is a high rate of surgery and postoperative recurrence in CD despite current available treatment options, such as corticosteroids, immunomodulators, and biologics.
The clinician group recognized and valued the potential of risankizumab to improve both clinical and endoscopic outcomes in patients with CD. They suggested the use of risankizumab in patients with moderate to severe CD as the first-line biologic, as well as in patients still experiencing flares or inadequate response on other existing biologics as a second-line drug. Furthermore, the use of risankizumab was considered not suitable by the clinician group for patients with perianal or fistulizing CD, severe peripheral arthritis, uveitis, or a concomitant immune-mediated disease for which an anti-TNF biologic drug would be more suitable.
The clinician group indicated that the administration of risankizumab during the induction phase should occur in a clinic under the supervision of a gastroenterologist. For maintenance therapy, patients could self-administer the on-body injector after receiving training. Aligning with the opinion of the clinical expert consulted by CADTH, the clinician group proposed several outcomes with which to determine the efficacy of risankizumab in patients with CD, including improvements in symptoms (e.g., SF, abdominal pain), accompanied by a decrease in biomarkers of inflammatory activity (e.g., C-reactive protein, fecal calprotectin) by 3 months of therapy, as well as symptomatic remission and being off corticosteroids by 6 months of treatment. In addition, the group highlighted that HRQoL should also be taken into consideration. If there is a worsening of symptoms or an inadequate response, risankizumab should be discontinued as per the clinician group.
The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 6.
Summary of Drug Plan Input and Clinical Expert Response.
The clinical evidence included in the review of risankizumab is presented in 2 sections. The first section, the systematic review, includes the pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well studies selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence from the literature that met the selection criteria specified in the review. No additional relevant studies were identified that were considered to address important gaps in the evidence included in the systematic review.
To perform a systematic review of the beneficial and harmful effects of risankizumab (60 mg/mL) IV infusion (induction) and SC injection (maintenance) for the treatment of adults with moderately to severely active CD who have an inadequate response, intolerance, or demonstrated dependence to corticosteroids, or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.
Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 7. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.
Inclusion Criteria for the Systematic Review.
The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.26
Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was risankizumab and its synonyms. Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.
No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.
The initial search was completed on November 23, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on March 22, 2022.
Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.27 Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy. These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts.
Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.
A total of 7 reports of 4 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 8.
Flow Diagram for Inclusion and Exclusion of Studies.
Details of Included Studies.
Studies MOTIVATE,8 ADVANCE,9 FORTIFY part 1,10 and SEQUENCE part 131 are pivotal trials submitted by the sponsor.
MOTIVATE and ADVANCE were both multicentre, randomized, double-blind, placebo-controlled, 12-week, phase III induction trials that aimed to assess the efficacy and safety of risankizumab in adult patients with moderately to severely active CD. Both trials were of similar design, except the MOTIVATE trial enrolled patients who were denoted as bio-IR, whereas the ADVANCE trial enrolled patients who were denoted as non-bio-IR or bio-IR. Clinical responders from the MOTIVATE and ADVANCE studies were eligible to enrol in FORTIFY substudy 1, a multicentre, randomized, placebo-controlled, 52-week, phase III maintenance trial that aimed to evaluate the efficacy and safety of continued risankizumab use versus the withdrawal of risankizumab (i.e., switched to placebo) in patients with moderately to severely active CD. Patients completing the FORTIFY study were eligible to continue in an open-label extension phase that is currently ongoing and not included in this review. The SEQUENCE study is an ongoing, multicentre, randomized, efficacy assessor-blinded, 48-week parallel-group, phase III trial designed to compare the efficacy and safety of risankizumab versus ustekinumab in adult patients with moderate to severe CD who have failed anti-TNF therapy. Only results for the SEQUENCE study, part 1, are included in this review, which consists of an interim data lock that was predetermined to occur when approximately 50% of patients in the risankizumab group had reached week 24 or discontinued the study. Part 2 is an open-label extension to evaluate the long-term safety of risankizumab for up to 220 weeks in patients who received risankizumab during part 1 and completed the week 48 visit. The SEQUENCE study is scheduled to be completed by September 2023.
The primary objective of both the MOTIVATE and ADVANCE study was to assess the efficacy and safety of IV risankizumab 600 mg administered at week 0, week 4, and week 8 versus IV placebo as induction therapy in adult patients with moderately to severely active CD (Figure 2). The MOTIVATE trial enrolled patients who were bio-IR, meaning they had inadequate response or intolerance to 1 or more biologic drugs including infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab (the percentage of patients with exposure to ustekinumab capped at 20% of the study population). The ADVANCE trial enrolled patients who were bio-IR as described in MOTIVATE or were non-bio-IR, meaning they had an inadequate response or were intolerant to conventional therapy including budesonide, beclomethasone, systemic corticosteroids, or immunomodulators, but not to biologic therapy. Each trial included a screening period of up to 35 days, a 12-week induction period (induction period 1), an additional exploratory blinded 12-week prolonged induction period (induction period 2) for patients who did not achieve clinical response at week 12, and a 140-day follow-up period for patients who did not continue in the FORTIFY maintenance trial. Clinical evaluations occurred at baseline and at week 4, week 8, and week 12, or at premature discontinuation. Both trials included treatment groups not aligned with the Health Canada–approved dose (refer to Table 7); these trials are not included in this review.
Enrolled patients were randomly assigned using interactive response technology 1:1 in the MOTIVATE trial (N = 413 patients across 214 sites, including Canada) or 2:1 in the ADVANCE trial (N = 559 patients across 297 sites, including Canada) to receive risankizumab 600 mg IV or placebo IV. There was a total of 17 Canadian sites and a total of 110 patients living in Canada enrolled. Randomization in both trials was stratified by the number of prior biologics failed (1, more than 1 in the MOTIVATE trial or 0, 1, more than 1 in the ADVANCE trial), corticosteroid use at baseline (yes, no), and Simple Endoscopic Score for Crohn’s Disease (SES-CD) score (original, alternative). Patients without clinical response to risankizumab at week 12 entered induction period 2 and were rerandomized 1:1:1 to risankizumab 1,200 mg IV, risankizumab 360 mg SC, or risankizumab 180 mg SC. Patients who did not have a clinical response to placebo at week 12 received risankizumab 1,200 mg IV. During the 12-week or 24-week induction period, initiation or dose changes of concomitant CD medications (e.g., aminosalicylates, oral locally acting steroids, systemic corticosteroids, immunomodulators) was prohibited. Since induction period 2 in both trials was exploratory and did not include the Health Canada–approved dose for induction, only results from the first 12-week induction period are reported in this review.
To meet regional regulatory requirements, both trials included 2 protocols denoted as US and OUS that were identical in design but specified different coprimary and key secondary outcomes. Clinical remission and endoscopic response were coprimary outcomes at week 12 in both the US and OUS protocols; however, the definition of clinical remission differed. In the US protocol, clinical remission was defined as CDAI less than 150 whereas in the OUS protocol, SF/APS clinical remission (defined as having average daily SF ≤ 2.8 and not worse than baseline and average daily APS ≤ 1 and not worse than baseline) was used. The secondary outcomes were similar in both protocols but ranked differently. They included clinical remission, clinical response, fatigue (FACIT-F score), HRQoL (SF-36 PCS score, IBDQ total score), enhanced SF/APS clinical response and endoscopic response, endoscopic remission, and ulcer-free endoscopy. Exploratory outcomes included CSS and EQ-5D-5L scores.
A detailed breakdown of secondary outcomes per protocol is provided in Table 8.
The primary objective of FORTIFY substudy 1 was to evaluate the efficacy and safety of risankizumab SC as maintenance therapy versus placebo (i.e., risankizumab was withdrawn) in patients with moderately to severely active CD who responded to risankizumab IV induction treatment in the MOTIVATE or ADVANCE study (Figure 2). The FORTIFY trial enrolled patients who achieved clinical response at the last visit of either induction period 1 or induction period 2 of the MOTIVATE or ADVANCE study (i.e., achieved SF/APS clinical response defined as ≥ 30% decrease in average daily SF and/or APS and both not worse than baseline of the induction study). Patients were required to have had a baseline of induction eligibility SES-CD score of 6 or more (≥ 4 for isolated ileal disease). The trial included a 52-week maintenance period with a 140-day follow-up (for those not entering the open-label extension), and an open-label extension lasting for up to 220 weeks or until study discontinuation. Only results from the rerandomized portion are reported in this review.
Enrolled patients were rerandomized in a 1:1 ratio using interactive response technology to continue receiving risankizumab 360 mg SC every 8 weeks or to have risankizumab treatment withdrawn (i.e., patients continued to receive placebo SC every 8 weeks to maintain the blind and are hereafter referred to as the placebo SC group). Rerandomization was stratified by endoscopic response (yes, no), SF/APS clinical remission status at last visit of induction (yes, no), and last IV risankizumab dose taken during induction. Similar to the induction trials, the FORTIFY study included a US protocol and an OUS protocol that included the same coprimary outcomes and similar secondary outcomes, ranked differently. A detailed breakdown of secondary outcomes per protocol are provided in Table 8.
Part 1 of the SEQUENCE study consists of a 35-day screening period, a 48-week treatment period, and a 140-day follow-up period for patients not participating in part 2. The primary objective of the SEQUENCE study, part 1, interim data lock analysis was to evaluate the noninferiority of risankizumab compared to ustekinumab in inducing clinical remission (defined as CDAI less than 150) at week 24. Patients were randomized 1:1 to risankizumab (600 mg IV at week 0, week 4, and week 8, and then at week 12 to 360 mg SC and every 8 weeks thereafter) or to ustekinumab (weight-based IV induction dose followed by a 90 mg SC maintenance dose at week 8 and every 8 weeks thereafter). Randomization was stratified by the number of anti-TNF failures (1 or fewer, more than 1) and corticosteroid use at baseline (yes, no). Secondary exploratory outcomes included clinical response, clinical remission, endoscopic remission, mucosal healing, deep remission, biologic remission, SF-36 PCS and MCS scores, and IBDQ total score.
Study Design of the MOTIVATE, ADVANCE, and FORTIFY Studies.
Study Design of the SEQUENCE Study, Part 1.
A detailed description of the inclusion and exclusion criteria for each study is provided in Table 8.
In both trials, eligible patients were aged 18 years to 80 years (where locally permissible, patients 16 years to younger than 18 years were enrolled) with a confirmed diagnosis of CD for at least 3 months before baseline, and moderately to severely active disease defined by a CDAI score of 220 to 450 at baseline, average daily SF greater than or equal to 4 and/or an average daily APS greater than or equal to 2, and endoscopic evidence of mucosal inflammation documented by an SES-CD score of 6 or more (or 4 or more for isolated ileal disease). In both the MOTIVATE and ADVANCE studies, a limited number of patients with an SES-CD score of 3 to less than 6 were enrolled. In the MOTIVATE study, patients must have been bio-IR for CD, and in the ADVANCE study, patients must have been non-bio-IR or bio-IR for CD.
Patients were eligible to enter the FORTIFY trial if they demonstrated clinical response to IV risankizumab induction therapy at week 12 of induction period 1 or at week 24 of induction period 2 in the ADVANCE or MOTIVATE trial. Clinical response was defined as at least a 30% decrease in mean SF of daily values reported for 7 days before the scheduled assessment visit or at least a 30% decrease in mean daily APS, both not worse than baseline of the induction study.
Eligible patients were aged 18 to 80 years with a confirmed diagnosis of CD for at least 3 months before baseline, and with moderately to severely active disease defined by a CDAI score of 220 to 450 at baseline, average daily SF greater than and/or equal to 4 or an average daily APS greater than or equal to 2, and endoscopic evidence of mucosal inflammation documented by an SES-CD score of 6 or more (or 4 or more for isolated ileal disease), and had failed 1 or more anti-TNF therapy.
A summary of baseline patient demographics and disease characteristics of ITT1A populations are in Table 9 and Table 10. Overall, key baseline characteristics were generally balanced between treatment groups and trials. Patients in the trial populations were predominantly white (77% to 91%), with an approximate mean age of 40 years, and a mean CD disease duration of approximately 8 years to 12 years. Between 29% and 36% of patients across treatment groups were on concomitant corticosteroids and about 19% to 28% of patients were on immunomodulators. The baseline mean CDAI score was about 310 to 320; however, the proportion of patients with moderate versus severe disease was not reported.
All of the patients in the MOTIVATE study (100%) and almost all of the patients in the ADVANCE study (approximately 99%) had previously taken at least 1 CD-related medication. The most frequently reported prior CD-related medications in the MOTIVATE and ADVANCE studies were adalimumab, infliximab, and vedolizumab. In the MOTIVATE study, approximately 48% and 52% of patients were bio-IR to 1 biologic therapy or greater than 1 biologic therapy, respectively. In the ADVANCE study, 23% to 30% of patients were bio-IR to 1 biologic therapy, 28% to 32% of patients were bio-IR to greater than 1 biologic therapy, and 42% to 45% of patients were non-bio-IR. Across the trials, 12% to 22% of patients had a history of ustekinumab failure and the majority of patients had failed 1 or more anti-TNF therapy (0 to 11% had not failed anti-TNF therapy).
A summary of baseline patient demographics and disease characteristics of the ITT1H population are shown in Table 11.
Demographic characteristics were generally balanced between the treatment groups. Most patients were white and the mean age was approximately 39 years. Disease characteristics were also relatively similar between the treatment groups.
Summary of Baseline Characteristics — MOTIVATE, ADVANCE, and FORTIFY Studies, ITT1A Population.
In both trials, patients received risankizumab 600 mg IV or matched placebo IV infusion administered at week 0, week 4, and week 8 as induction therapy, in a double-blinded manner. During the induction period, concomitant CD medications (e.g., aminosalicylates, oral locally acting steroids, systemic corticosteroids, immunomodulators) were allowed but initiating doses, increasing doses, or decreasing doses was prohibited.
Patients received either risankizumab 360 mg SC or placebo (i.e., 4 90 mg injections) at week 0, week 8, week 16, week 24, week 32, week 40, and week 48. Each scheduled dose was administered within plus or minus 7 days. Patients who did not respond adequately received open-label risankizumab rescue therapy defined as 1 single 1,200 mg IV infusion followed by 360 mg SC injection, starting at the week 16 visit on the basis of increased symptom activity and confirmation with objective markers of inflammation.
Patients received the risankizumab 600 mg IV induction dose administered at baseline, week 4, and week 8, and then at week 12, received a 360 mg SC maintenance dose and every 8 weeks thereafter and completed their last visit at week 24, or received a ustekinumab weight-based IV induction dose at week 0 (a patient weight of 55 kg or less = 260 mg dose; a patient weight of more than 55 kg to 85 kg = 390 mg dose; or a patient weight of more than 85 kg = 520 mg) and then a 90 mg SC maintenance dose at week 8 and every 8 weeks thereafter. Aminosalicylates, immunomodulators, and/or CD-related antibiotics at baseline were allowed but initiating doses, increasing doses, or decreasing doses was prohibited.
Summary of Week 0 Disease Characteristics — FORTIFY Study, ITT1A Population.
Summary of Baseline Characteristics — SEQUENCE Study, Part 1, ITT1H Population.
A list of efficacy outcomes identified in the CADTH review protocol that were assessed in the included clinical trials is summarized in Table 12. A detailed description and critical appraisal of the outcome measures is provided in Appendix 2, Table 37.
Summary of Outcomes of Interest Identified in the CADTH Review Protocol.
Change from baseline in HRQoL was assessed via generic or disease-specific instruments: IBDQ total score and SF-36 PCS and MCS. These are detailed in Appendix 2.
The power calculation for the MOTIVATE and ADVANCE studies was based on the expected number needed to detect a difference in the coprimary end points of clinical remission and endoscopic response at week 12 between risankizumab and placebo. This approach used historical data from the phase II Study 1311.6 that showed slightly lower event rate and similar treatment difference versus placebo for the endoscopic response rate than the clinical remission rate at week 12. Based on the assumption of a 23.5% clinical remission rate for the risankizumab group and 10% for the placebo group, in the MOTIVATE study, a sample size of 193 patients in each group would have 89% power to detect a difference between groups at week 12 using 2-sided Fisher’s exact test at a significance level of 0.025. Based on the assumption that the week 12 endoscopic response rate would be 17% for the risankizumab group and 5% for the placebo group, this sample size would have 93% power to detect the treatment difference for endoscopic response between the risankizumab group and the placebo group at week 12 using a Fisher’s exact test with a 2-sided alpha of 0.025.
In the ADVANCE study, to detect a clinical remission rate of 27.8% for the risankizumab group and 12% for the placebo group, a sample size of 342 patients for the risankizumab group and 171 patients for the placebo group would have 97% power to detect a treatment difference between groups at week 12 using a Fisher’s exact test at a 2-sided alpha of 0.025. Based on the assumption that the week 12 endoscopic response rate would be 25.5% for the risankizumab group and 8% for the placebo group, this sample size would have 99% power to detect the treatment difference between the risankizumab group and the placebo group at week 12 using a Fisher’s exact test at a 2-sided alpha of 0.025. In addition, the ADVANCE study would have approximately 80% power for the failed biologic therapy subgroup to detect the treatment difference between the risankizumab and placebo groups in clinical remission rates at week 12, with the assumption that the week 12 clinical remission rate would be 24.2% for the risankizumab group and 10% for the placebo group. For the failed conventional therapy subgroup, there would be 72% power to detect the treatment difference for clinical remission rates at week 12 between the risankizumab group and the placebo group, with the assumption that the week 12 clinical remission rate would be 35% for the risankizumab group and 15% for the placebo group.
In FORTIFY substudy 1, for the US protocol, assuming a 46% CDAI clinical remission rate for the risankizumab group and a 28% CDAI clinical remission rate for the placebo group at week 52, a sample size of 150 patients for each group would have 87% power to detect a difference between groups using the Fisher’s exact test at a 2-sided alpha of 0.05. For the OUS protocol, assuming a 38.7% clinical remission rate for the risankizumab group and a 20% clinical remission rate for the placebo group at week 52, a sample size of 150 patients for each group would have 93% power to detect a difference in SF/APS clinical remission rate. Based on the assumption that the week 52 endoscopic response rate would be 32.6% for the risankizumab group and 10% for the placebo group, this sample size would have approximately 95% power to detect the treatment difference between groups for endoscopic response rates at week 52.
In the SEQUENCE study, part 1, the power calculation was based on the assumption of a CDAI clinical remission (less than 150) rate of 45% for the risankizumab group and 29% for the ustekinumab group at week 24, based on phase III trials for ustekinumab and risankizumab. Based on this assumption, a sample size of 129 patients per group would have at least 95% power to determine noninferiority based on a noninferiority margin of 10% at the 0.05, 2-sided significance level. Clinical remission rate assumptions were informed by published results from phase III trials for ustekinumab and the MOTIVATE study. Noninferiority was met if the lower bound of the 95% CI of the adjusted risk difference between risankizumab and ustekinumab was above –10%. The margin of 10% was selected based on the physician’s perspective of the clinical meaningfulness of IBD trial results as per an International Organization for the Study of Inflammatory Bowel Disease survey.38
In the MOTIVATE and ADVANCE studies, testing for the difference between treatment groups across the coprimary and secondary end points was performed using a graphical multiplicity adjustment to control the familywise type I error rate at a 2-sided significance level of 0.05. The coprimary end points were first tested, each using a 2-sided significance level of 0.025. If those end points both reached statistical significance, the alpha was allocated to the ranked secondary end points, which were tested sequentially. If these reached statistical significance, the final group of ranked secondary end points was tested using the Holm procedure. All other efficacy end points were tested without control for type I error. The same multiplicity control procedure was used in the FORTIFY trial. The ranked secondary outcomes are described in Table 12.
In the SEQUENCE study, part 1, a single end point was tested (achievement of clinical remission); other end points were intended to be presented descriptively without formal statistical testing.
In the MOTIVATE and ADVANCE studies, the comparisons between risankizumab versus placebo for the coprimary outcomes were performed using the Cochran-Mantel-Haenszel (CMH) test, adjusted by the randomization factors of the number of prior biologics failed (1, greater than 1 in the MOTIVATE study or 0, 1, greater than 1 in the ADVANCE study) and baseline steroid use (yes, no) in the ITT1A population. A CMH-based, 2-sided, 95% CI for the difference between treatment groups was determined. Each primary end point was assigned a 2-sided alpha of 0.025.
In the FORTIFY study, the comparisons between risankizumab and placebo for the coprimary outcomes were performed using the CMH test, adjusted by the week 0 SF/APS clinical remission status and week 0 endoscopic response status (per central review), and the last risankizumab induction dose. A CMH-based, 2-sided, 95% CI for the difference between groups was constructed. Each primary end point was assigned a 2-sided alpha of 0.025.
In the SEQUENCE study, part 1, at interim lock 1 the primary outcome of CDAI clinical remission at week 24 was tested based on the ITT1H population using the CMH test stratified by the number of prior anti-TNF therapy failures (less than or equal to 1, greater than 1) and steroid use at baseline (yes, no). Point estimates and proportions for the difference in proportions between groups were calculated and the CI for the common difference was constructed based on the CMH estimate adjusting for stratification factors.
In the MOTIVATE, ADVANCE, and FORTIFY studies, the primary approach for handling missing data for the coprimary outcomes was the nonresponder imputation (NRI) approach incorporating multiple imputation for missing data due to COVID-19 infection or logistical restrictions. Patients with missing data for all other reasons were counted as nonresponders. In the FORTIFY trial, patients who received rescue therapy were also counted as nonresponders for categorical outcomes.
In the SEQUENCE study, the primary approach for handling missing data for the primary analysis was also NRI while incorporating multiple imputation to handle missing data due to COVID-19 infection or logistical restrictions due to pandemic and/or geopolitical conflict. Patients with missing data for all other reasons were counted as nonresponders.
In the MOTIVATE, ADVANCE, and FORTIFY studies, the subgroup analysis of interest for this review was bio-IR status (bio-IR less than or equal to 1 or greater than 1 in the MOTIVATE study and bio-IR or non-bio-IR in the ADVANCE and FORTIFY studies). This was a prespecified subgroup analysis conducted for the coprimary outcomes using the ITT1A population. Results are shown as the point estimate and 95% CI for treatment differences between the risankizumab group and placebo, without formal statistical testing. No subgroup analyses were reported for the SEQUENCE study, part 1.
Sensitivity analyses for the coprimary outcomes were conducted to provide insight on the robustness of the findings regarding the use of different data imputation methods. First, hybrid multiple imputation was used, where patients who discontinued before week 12 (in the MOTIVATE and ADVANCE studies) and week 52 (in the FORTIFY study) due to lack of efficacy, AEs or received rescue therapy were considered as “not achieved” for the clinical remission or endoscopic response, and patients who discontinued for other reasons were categorized according to multiple imputations. Next, an analysis of observed cases was performed, which excluded those patients with missing data at scheduled assessment visits. In the MOTIVATE and ADVANCE trials, the pattern-mixture model was also used for sensitivity analyses.
In the SEQUENCE study, sensitivity analyses using NRI and multiple imputation separately were conducted as well as an analysis using observed events, which did not impute values for missing evaluations.
Multiplicity-controlled ranked secondary outcomes of the MOTIVATE, ADVANCE, and FORTIFY studies are summarized in Table 13 and graphical testing procedures are in Appendix 4. In the MOTIVATE and ADVANCE studies, the coprimary and key secondary outcomes were controlled for type I error rate at a 2-sided significance level of 0.05 based on a prespecified hierarchical testing procedure, except for CSS and EQ-5D-5L, which were tested without multiplicity control. Continuous secondary efficacy outcomes with repeat measurements were analyzed using a mixed model of repeated measures (MMRM) model including factors for treatment group, visit, visit by treatment interaction, stratification variables, and the continuous fixed covariates of baseline measurement. The MMRM analysis was considered primary for inferential purposes. Continuous secondary efficacy variables that were collected at only 1 postbaseline visit were analyzed using an analysis of covariance approach based on observed data. Categorical secondary efficacy outcomes were analyzed using the CMH test controlling for stratification variables (i.e., prior biologics failed [1, greater than 1 in the MOTIVATE study or 0, 1, greater than 1 in the ADVANCE study]) and baseline steroid use [yes, no]). A CMH-based, 2-sided, 95% CI for the difference between the risankizumab group and placebo group was determined. In the FORTIFY study, continuous secondary efficacy outcomes with repeated measures were analyzed by an MMRM model whereas outcomes collected at only 1 post–week 0 visit were analyzed using an analysis of covariance model including treatment, stratification factors, and measurements at both induction baseline and week 0. In all trials, the methods of handling missing data were the same as the primary analysis of the coprimary outcomes.
Coprimary and Ranked Secondary Outcomes in the MOTIVATE, ADVANCE, and FORTIFY Studies, by Protocol.
In the SEQUENCE trial, all secondary outcomes were considered exploratory and statistical testing was not preplanned or controlled for multiplicity. Categorical variables were analyzed using the CMH test stratified by the number of prior anti-TNF therapy failures (≤ 1, > 1) and steroid use at baseline (yes, no). Continuous variables were analyzed using MMRM. The methods of handling missing data were the same as the primary analysis of the primary outcome.
In all trials, safety analyses were carried out using the corresponding safety analysis described in the Analysis Populations section. In all safety analyses, patients were analyzed according to treatment received regardless of randomization.
The primary efficacy analysis population for the 12-week induction period was the ITT1A population (N = 378 for the MOTIVATE study; N = 511 for the ADVANCE study), which included all randomized patients who received at least 1 dose of study drug and who had a baseline-eligible SES-CD score of 6 or more (4 or more for isolated ileal disease). The safety population was denoted as SA1 (N = 413 for the MOTIVATE study; N = 580 for the ADVANCE study). It included all patients who received at least 1 dose of study drug during induction period 1.
The primary efficacy analysis for the 52-week maintenance period was the ITT1A population (N = 305), which included rerandomized patients (i.e., patients who received at least 1 dose of study drug) who met eligibility criteria of an SES-CD score of 6 or more (4 or more for isolated ileal disease) at baseline of the induction study and received risankizumab IV for only 1 period of 12 weeks in the induction study. The SA1 population (N = 363) included all patients who received at least 1 dose of study drug in FORTIFY substudy 1.
The primary efficacy population for the 24-week interim lock analysis was a subset of all randomized patients (ITT1 population) — the ITT1H population (N = 265). The ITT1H population included approximately 50% of patients in the ITT1 population who reached week 24 (or discontinued) by the time of the interim lock 1. The per-protocol population denoted as PP1H (|| |||) excluded patients from the ITT1H population with major protocol deviations. The SA1 population (|||||) included all patients who received at least 1 dose of study drug by the predefined enrolment cut-off date of January 5, 2022.
A summary of patient disposition for the MOTIVATE, ADVANCE, and FORTIFY studies is in Table 14, and in Table 15 for the SEQUENCE study. Details of the screening period were not reported for all trials.
In the MOTIVATE study, 98.1% of patients who received risankizumab 600 mg IV and 89.9% of patients who received placebo completed the 12-week induction period. In the ADVANCE study, 97.9% of patients who received risankizumab 600 mg IV and 87.6% of patients who received placebo completed the 12-week induction period. In both trials, a higher proportion of patients in the placebo group discontinued the study drug during the 12-week induction period. The most common reasons for discontinuation in the placebo groups were due to AEs followed by lack of efficacy, whereas in the risankizumab group, discontinuations were generally low with no 1 primary reason. In the placebo groups, the most frequently reported AE that led to discontinuation of the study drug was worsening CD (6.3% in the MOTIVATE trial and 3.8% in the ADVANCE trial).
In the FORTIFY study, a similar proportion of patients (87.0% to 89.4%) completed the study drug across the 2 treatment groups. The most common reason for discontinuation was lack of efficacy in the withdrawal placebo SC group. In the risankizumab group, lack of efficacy and “other” accounted for 6.8% of the reasons for discontinuation.
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Patient Disposition in the MOTIVATE, ADVANCE, and FORTIFY Studies.
Patient Disposition in SEQUENCE Study, Part 1a.
Details of the extent of exposure to the study drug in the MOTIVATE, ADVANCE, and FORTIFY studies are reported in Table 16, and in Table 17 for the SEQUENCE study.
In the MOTIVATE and ADVANCE trials, mean exposure to risankizumab 600 mg IV and placebo IV was approximately 83.0 days for the 12-week induction period.
In the FORTIFY trial, mean exposure to risankizumab 360 mg SC was 328 days and 309 days for the withdrawal placebo SC group.
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Extent of Exposure — MOTIVATE, ADVANCE, and FORTIFY Studies.
Extent of Exposure — SEQUENCE Trial, ITT1H Population.
Only those efficacy outcomes and subgroup analyses identified in the review protocol are reported as follows.
The coprimary and secondary clinical remission outcomes in the ITT1A population (primary analysis) for both trials and protocols are summarized in Table 18 and Table 21, respectively. In both trials, the coprimary outcome of clinical remission at week 12 for both the US and OUS protocols favoured risankizumab versus placebo. In the MOTIVATE study’s US protocol, the CDAI clinical remission rate with risankizumab was 42.0% versus 19.8% with placebo, with a between-group adjusted difference of 22.1% (95% CI, 13.1% to 31.0%; P < 0.001). For the OUS protocol, the SF/APS clinical remission rate with risankizumab was 34.6% versus 19.3% with placebo, with a between-group adjusted difference of 15.2% (95% CI, 6.4% to 24.0%; P = 0.001). In the ADVANCE study’s US protocol, the CDAI clinical remission rate with risankizumab was 45.2% versus 24.6% with placebo, with a between-group adjusted difference of 20.7% (95% CI, 12.4% to 29.0%; P < 0.001). For the OUS protocol, the SF/APS clinical remission rate with risankizumab was 43.5% versus 21.7% with placebo, with a between-group adjusted difference of 21.9% (95% CI, 13.8% to 29.9%; P < 0.001). In both trials and protocols, all secondary ranked multiplicity-controlled remission-related outcomes — including SF and APS remission at week 12, CDAI clinical remission at week 4, and SF/APS clinical remission at week 4 — favoured risankizumab versus placebo (Table 18).
The results of the bio-IR subgroup analyses for the coprimary outcome of clinical remission were compatible with the primary analysis, and similar between trials. In both trials, results of the sensitivity analysis were consistent with the primary analysis.
The coprimary and secondary clinical remission outcomes in the ITT1A population (i.e., primary analysis of patients who were clinical responders at the end of the MOTIVATE or ADVANCE study) are summarized in Table 19 and Table 22, respectively. In both protocols, the coprimary outcome of clinical remission at week 52 favoured risankizumab versus placebo. For the US protocol, the CDAI clinical remission rate with risankizumab 360 mg SC was 52.2% versus 40.9% with placebo SC, with a between-group adjusted difference of 14.6% (95% CI, 4.3% to 25.0%; P = 0.005). For the OUS protocol, the SF/APS clinical remission rate was 51.8% versus 39.6%, respectively, with a between-group adjusted difference of 15.2% (95% CI, 4.9% to 25.4%; P = 0.004).
In both protocols, SF and APS remission, maintenance of SF/APS or CDAI clinical remission, SF/APS or CDAI clinical remission with endoscopic response, and SF/APS or CDAI deep remission favoured risankizumab versus placebo. The evidence was insufficient to show a between-group difference for CDAI or SF/APS clinical remission with discontinuation of corticosteroid use for 90 days in patients taking steroids at the baseline of the induction study (Table 19). However, due to the adjusted treatment difference for the comparison of risankizumab 180 mg SC versus placebo SC for the coprimary outcome of SF/APS clinical remission (OUS protocol) not achieving statistical significance, the hierarchical testing strategy prevented formal statistical testing of the significance of all subsequent secondary outcomes, including all secondary clinical remission outcomes (i.e., the findings for these outcomes are at increased risk of being false positives). In the US protocol, with the exception of SF/APS clinical remission, the hierarchical testing strategy prevented formal statistical testing of the significance of all subsequent secondary outcomes.
The results of the bio-IR subgroup analyses for the coprimary outcome of clinical remission were consistent with the primary analysis. The results of the sensitivity analysis were consistent with the primary analysis.
The SEQUENCE study, part 1 (induction and maintenance ongoing),|||| ||||||| ||||||| || |||| |||||||| ||||||||| || |||| || || ||| ||||| |||||||||| |||||||| ||||||||| ||| ||| |||||||| |||||||||| |||||||| || ||||| ||| ||| ||||||| |||| |||||||| || ||||| || Table 20| || ||| ||||| |||| |||||||| ||||||||| |||| |||||||||||| ||| || |||||| || || ||| ||||| ||| ||||| |||| ||||||||||| |||||||||||| ||||||||| |||| ||||| || ||| |||| | ||||||| ||||| |||||||| |||||||||| || ||||| |||| ||| |||| || ||||||| | ||||| ||| |||||||||| || ||| |||| |||| |||||||| ||||||||| ||| ||||| ||| |||||| ||||||||||||| |||| | ||||||| ||||| |||||||| |||||||||| || ||||| |||| ||| |||| || |||||| | ||||| ||| |||||||||| ||| ||||| ||||| || ||| ||| || |||| |||||||||| ||| ||||||| |||| ||| |||||||||||||| |||||| || |||| || |||| ||| ||||| ||| |||| |||||||| ||||| |||||||||| |||||||||||||| ||||||| |||||| || |||||||| |||||||||| ||| ||||||||||| |||||||| || |||||| ||||||||| |||| ||| |||||||| ||||||||| || |||| || ||| ||||| || Table 23.
The results of the sensitivity analyses were consistent with the primary analysis.
Coprimary Efficacy Outcomes, Clinical Remission — MOTIVATE and ADVANCE Induction Trials, ITT1A Population.
Coprimary Efficacy Outcomes, Clinical Remission — FORTIFY Maintenance Trial, ITT1A Population.
Clinical Remission at Week 24 — SEQUENCE Study.
The secondary outcome of clinical response in the ITT1A population (primary analysis) is summarized in Table 21. In both trials and protocols, all of the following secondary ranked multiplicity-controlled clinical response outcomes favoured risankizumab compared with placebo:
Results of the sensitivity analysis for all outcomes were consistent with the primary analysis.
The secondary outcomes of CDAI clinical response (US and OUS protocols) and SF/APS enhanced clinical response (OUS protocol) at week 52 in the ITT1A population favoured risankizumab versus placebo (Table 22). However, the hierarchical testing strategy prevented formal statistical testing of the significance of these outcomes, and they can be considered to be at increased risk of type I error (false-positive conclusions).
||| ||||||||||| ||||||| || |||| |||||||| |||||||| || |||| || || ||| ||||| |||||||||| ||| ||||| |||| |||||||||||| ||| ||||| |||| ||||||||||| ||| |||| ||| ||| || |||||| (Table 23).
In both trials, the ranked multiplicity-adjusted secondary outcome FACIT-F scores (US and OUS protocols) at week 12 in the ITT1H population favoured risankizumab versus placebo (Table 26). In the MOTIVATE study, patients in the risankizumab group reported FACIT-F scores that were 2.8 points higher than placebo (95% CI, 0.4 points to 5.1 points; P = 0.02) and in the ADVANCE study, 5.2 points higher than placebo (95% CI, 3.2 points to 7.2 points; P < 0.001), which indicate less fatigue. In the ADVANCE study, patients in the risankizumab group also reported favourable FACIT-F scores at week 4. In the MOTIVATE trial, the evidence was insufficient to show a difference in FACIT-F scores.
In the MOTIVATE and ADVANCE studies, the exploratory outcome of the CSS score in the ITT1A population favoured risankizumab compared to placebo. In the MOTIVATE trial, the least squares mean (LSM) change from baseline at week 12 in the CSS score was –11.0 (standard error [SE] = 0.66) points in the risankizumab group, and –7.5 (SE = 0.70) points in the placebo group, with a between-group adjusted difference in LSM of –3.5 points (95% CI, –5.4 points to –1.6 points). In the ADVANCE trial, the LSM change from baseline at week 12 in CSS score was –11.5 (SE = 0.47) points in the risankizumab group, and –6.0 (SE = 0.69) points in the placebo group, with a between-group adjusted difference in LSM of –5.5 points (95% CI, –7.1 points to –3.9 points).
The evidence was insufficient to show a difference between risankizumab and placebo for ranked secondary outcome FACIT-F (US and OUS protocols) scores change from baseline induction at week 52 in the ITT1H population (Table 27).
Secondary Clinical Outcomes — MOTIVATE and ADVANCE Induction Trials, ITT1A Population.
Secondary Clinical Outcomes — FORTIFY Maintenance Trial, ITT1A Population.
Exploratory Outcomes — SEQUENCE Study, ITT1H Population.
The coprimary outcome of endoscopic response and the secondary outcomes of endoscopic remission and ulcer-free endoscopy in the ITT1A population are summarized in Table 24 and Table 21, respectively. In both trials, the coprimary outcome of endoscopic response at week 12 favoured risankizumab versus placebo. In the MOTIVATE study, the endoscopic response rate with risankizumab was 28.8% versus 11.2% with placebo, with a between-group adjusted difference of 17.7% (95% CI, 9.9% to 25.4%; P < 0.001). In the ADVANCE study, the endoscopic response rate with risankizumab was 40.3% versus 12.0% with placebo, with a between-group adjusted difference of 28.3% (95% CI, 21.2% to 35.4%; P < 0.001). In both trials, the secondary ranked multiplicity-controlled outcomes of endoscopic remission and ulcer-free endoscopy at week 12 favoured risankizumab compared with placebo (Table 24).
The results of subgroup analyses for the coprimary outcome of endoscopic response by bio-IR status was consistent with the primary analysis, and similar across trials. In both trials, results of the sensitivity analysis were consistent with the primary analysis.
The coprimary outcome of endoscopic response and the secondary outcomes of ulcer-free endoscopy and endoscopic remission in the ITT1A population are summarized in Table 25 and Table 22, respectively. At week 52, the coprimary outcome of endoscopic response in the risankizumab 360 mg SC group was 46.5% and 22.0% in the withdrawal placebo SC group, with a between-group adjusted difference of 27.8% (95% CI, 18.7% to 37.0%; P < 0.001). The ranked secondary outcomes of ulcer-free endoscopy and endoscopic remission also favoured risankizumab versus placebo (Table 25). However, the hierarchical testing strategy prevented formal statistical testing of all secondary outcomes.
The results of the bio-IR subgroup analysis for the coprimary outcome of endoscopic response were compatible with the primary analysis. In both trials, results of the sensitivity analysis were consistent with the primary analysis.
The exploratory outcomes of endoscopic remission and mucosal healing in the ITT1H population are summarized in Table 23. || |||| ||| ||| |||||||| ||||||||||||| |||||||||| ||| |||||||||||| ||| ||||||||||| ||| ||||| ||||| || |||||| ||| |||||||||| ||||||||| ||| ||||| ||||| || |||||| ||| ||||||| |||||||.
Endoscopic Response — MOTIVATE and ADVANCE Induction Trials, ITT1A Population.
Endoscopic Response — FORTIFY Maintenance Trial, ITT1A Population.
In both trials, scores for ranked multiplicity-adjusted secondary outcomes IBDQ (OUS protocol) and SF-36 PCS (OUS) at week 12 in the ITT1A population favoured risankizumab versus placebo (Table 26). The IBDQ total score in the MOTIVATE study was 12.4 points higher with risankizumab than placebo (95% CI, 5.0 points to 19.8 points; P = 0.001) and in the ADVANCE study, 20.7 points higher with risankizumab than placebo (95% CI, 14.3 points to 27.1 points; P < 0.001), which indicate better HRQoL. The SF-36 PCS score in the MOTIVATE study was 2.22 points higher with risankizumab than placebo (95% CI, 0.58 points to 3.87 points; P = 0.008) and in the ADVANCE study, 2.91 points higher with risankizumab than placebo (95% CI, 1.51 points to 4.31 points; P < 0.001), which indicate better physical health status. In the ADVANCE trial, patients in the risankizumab group also reported favourable HRQoL outcomes at week 4. In the MOTIVATE trial, IBDQ and SF-36 PCS favoured risankizumab versus placebo at week 4. In both trials, results of the SF-36 MCS score at week 12 favoured risankizumab versus placebo; however, it was not adjusted for multiplicity. In both trials, the exploratory outcome EQ-5D-5L score also favoured risankizumab (Table 26).
The evidence was insufficient to show a difference between risankizumab and placebo for ranked secondary outcomes IBDQ (OUS protocol), FACIT-F (US and OUS protocols), and SF-36 PCS (OUS) scores change from baseline induction at week 52 in the ITT1H population (Table 27). For the exploratory outcome EQ-5D-5L score, the evidence was insufficient to show a difference between groups.
The exploratory outcomes of IBDQ total score and SF-36 PCS and MCS scores in the ITT1H population are summarized in Table 23. At week 24, ||| |||| |||| ||||| ||||| |||| |||||||| |||| |||||||||||| ||| ||||| ||| ||||| |||| |||||||||||| || |||| ||| ||| |||| ||||| ||| ||| |||||| |||||||||| |||||| |||| |||||||| || ||| |||||||||||| ||||| ||| |||| ||| |||| |||||| |||| ||| |||| || ||| ||||||||||| |||||| ||||||||||||| |||||||| |||||||||| ||| |||| |||||| |||| ||| ||||||||.
Secondary and Exploratory Symptom and HRQoL Outcomes — MOTIVATE and ADVANCE Induction Trials, ITT1A Population.
Sources: MOTIVATE and ADVANCE Clinical Study Reports.8,9
Secondary and Exploratory HRQoL Outcomes — FORTIFY Maintenance Trial, ITT1A Populationa.
Only those harms identified in the review protocol are reported as follows. The key harms results in the SA1 safety population for all trials are summarized in Table 28.
In the MOTIVATE study, the proportion of patients experiencing at least 1 TEAE was higher in the placebo group (66.2%) than the risankizumab group (47.6%); this was primarily attributable to a higher incidence of worsening CD in the placebo group (15.9%) compared to the risankizumab group (3.9%). Similar trends were observed for SAEs (placebo = 12.6%; risankizumab = 4.9%) and AEs leading to study drug discontinuation (placebo = 8.2%; risankizumab = 1.0%). The most frequently reported SAE in the placebo group was worsening CD (9.7% versus 0.5% in the risankizumab group) and anemia in the risankizumab group (1.0% versus 0% in the placebo group). In the ADVANCE trial, TEAEs occurred with similar frequency in both treatment groups (placebo = 56.5%; risankizumab = 56.3%), while SAEs and AEs leading to study drug discontinuation occurred with higher frequency in the placebo group (15.1% and 7.5%, respectively) than in the risankizumab group (7.1% and 2.4%, respectively). The most frequently reported SAE in both groups was worsening CD (placebo = 8.1%; risankizumab = 1.3%).
In the MOTIVATE and ADVANCE studies, the most common TEAEs with risankizumab (≥ 2% of patients) during the 12-week induction period were headache (MOTIVATE study = 5.3% in both groups; ADVANCE study = 6.4% with risankizumab versus 4.3% with placebo), arthralgia (MOTIVATE study = 3.9% with risankizumab versus 4.3% with placebo; ADVANCE study = 4.0% with risankizumab versus 3.8% with placebo), and nasopharyngitis (MOTIVATE study = 3.9% with risankizumab versus 5.3% with placebo; ADVANCE study = 5.9% with risankizumab versus 2.7% with placebo), whereas the most frequently reported TEAE with placebo was worsening CD (MOTIVATE study = 15.9% with placebo versus 3.9% with risankizumab; ADVANCE study = 13.4% with placebo versus 2.7% with risankizumab), headache, and arthralgia. In both trials, the most frequently reported TEAE leading to study drug discontinuation was worsening CD, which was more common with placebo and infrequent with risankizumab (MOTIVATE study = 6.3% versus 0.5%, respectively; ADVANCE study = 3.8% versus 0.5%, respectively). Two deaths were reported, both of which occurred in the ADVANCE placebo group.
In general, the incidence of notable harms in both treatment groups across the 2 trials was similarly low.
In the 52-week maintenance trial, the proportion of patients experiencing at least 1 TEAE was similar between the risankizumab (72.1%) and placebo withdrawal (73.4%) groups. The most common TEAEs with risankizumab (≥ 2% of patients) and placebo were worsening CD, nasopharyngitis, and arthralgia. Worsening CD was reported by 11.7% of patients and 17.4% of patients in the risankizumab and placebo groups, respectively. Similar proportions of patients experienced SAEs (placebo group = 12.5%; risankizumab group = 13.4%) and AEs leading to discontinuation of the study drug (placebo group = 3.3%; risankizumab group = 3.4%) across the treatment groups. The most frequently reported SAE in the risankizumab and placebo groups was worsening CD (2.1% and 2.2%, respectively). The event reported in more than 1 patient in both treatment groups leading to discontinuation of the study drug was worsening CD: 1.1% in the risankizumab group and 1.6% in the placebo group. There were no deaths reported.
The rates of notable harms in both treatment groups were generally comparable and similarly low. The 2 notable harms experienced by the highest proportion of patients in each group were hypersensitivity, of which most were injection-site reactions (risankizumab group = 6.1%; placebo group = 4.9%), and serious infections (risankizumab group = 4.5%; placebo group = 3.8%).
|| ||| ||| |||| ||||||| ||| |||||||||| || |||||||||||| ||||||| ||| ||||||||||| ||||||| ||||||| ||||||| ||||||||||| || |||||||| ||||||||||| |||| |||||||||||||| ||||| |||||||||||| |||||| ||| ||| ||||||| || ||||||||||||||| || ||||| |||| |||||||||||||| ||||| ||||||||||| ||||| |||||| ||| ||||||||| ||||||| ||| |||| |||||||||| |||||||| ||||| || |||| ||||||||| |||||| ||| |||||||| |||||||||||||| |||||| |||||||||||| ||||||| ||||| |||||| |||| |||||||| || |||| |||||||||| |||| || |||| || |||||||| |||||| ||| ||||||| ||||| ||| |||||||| || |||| || |||||||| || ||| |||||||||||| ||||| |||| |||| || |||||||||||| ||| || ||||| ||| |||||||| || |||| || |||||||| || ||| ||||||||||| ||||| |||| |||| || |||||||||||||| || |||||||| ||| ||||||||| || ||||||| ||||| || |||| ||||||||| |||||| |||| ||||||||| |||| ||| |||| |||||| ||||||| |||| || |||| |||||| ||| ||||||| |||||| |||||||||||||| ||||| |||||||||||| |||||| || |||||| |||| ||||||||.
The MOTIVATE, ADVANCE, and FORTIFY studies were phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre trials. The risk of bias arising from the randomization was low in all 3 trials. A stratified computerized randomizations scheme was used, and the allocation was concealment via the use of interactive response technology. In general, baseline characteristics of patients appeared balanced between trial groups across studies, indicating that randomization was successful.
There are some concerns related to risk of bias due to deviation from the intended interventions. In the MOTIVATE study, adherence to the intended interventions was high (at least 98%). Overall, protocol deviations occurred in 12% of patients, were balanced across the treatment groups, and seemed unlikely to have arisen due to trial context. Excluded concomitant treatments were received by few (4%) patients (this was slightly higher in the placebo group). This risk of bias due to deviation from the intended interventions was similar in the ADVANCE and FORTIFY studies. The analysis for all trials was based on the ITT1A population, which included randomized patients who received at least 1 dose of the study drug. As this is not a true ITT population, some concerns for bias were introduced in the ADVANCE and MOTIVATE trials (about 10% of patients were not included), and a high risk of potential bias may have been present for the FORTIFY trial (21% of the risankizumab group and 11% of the placebo group were not included). It is not clear whether those who were excluded from the analysis were different in an important way from those included; therefore, the magnitude and direction of the potential bias cannot be predicted.
Summary of Harms — Induction and Maintenance Trials, SA1 Population.
Concerns related to missing outcome data are low for most outcomes. In the induction trials, there was a higher number of discontinuations of the study drug in the placebo groups (10% in the MOTIVATE trial and 12% in the ADVANCE trial) compared to the risankizumab groups (2% in both the MOTIVATE and ADVANCE trials). In the maintenance trial (FORTIFY), discontinuations were similar and just over 10% across groups. The most common reasons for discontinuation in the placebo groups were AEs followed by lack of efficacy, whereas in the risankizumab group, discontinuations were generally low with no single primary reason. In the placebo groups, the most frequently reported AE that led to discontinuation of the study drug was worsening CD. Missing data pertaining to the primary and secondary outcomes were addressed using appropriate methods. NRI while incorporating multiple imputation to handle missing data due to COVID-19 was the primary approach for the coprimary outcomes. This approach is considered appropriate and would be conservative. Appropriate sensitivity analyses were conducted using different imputation methods. The results of these analyses were comparable to the primary analysis. There is concern for bias due to missing outcome data for the HRQoL and fatigue outcomes, due to large and imbalanced amounts of missing data, particularly at the 12-week time point. The direction and magnitude of the potential bias is unclear.
Across trials, most outcomes were subjective (e.g., SF/APS or CDAI clinical remission or response, FACIT-F, IBDQ, SF-36) and were collected from patient diaries, except for endoscopic outcomes, which were read centrally by a blinded reviewer. Although the subjective outcomes were prone to risk of bias, the double-blind design of the trials mitigated this risk. There is some risk of unblinding that could have affected the subjective outcomes since dropout rates were higher in the placebo groups, which could allow investigators and patients to make inferences on treatment assignment regardless of blinding. However, the extent of the potential bias is unclear. In general, reported outcomes across trials were validated in patients with CD; however, MIDs for clinical remission and response, FACIT-F, and EQ-5D-5L were not identified in the literature search conducted by CADTH.
A hierarchical testing procedure was appropriately used in all 3 trials to account for multiplicity in coprimary and key secondary outcomes. The exploratory outcomes of CSS and EQ-5D-5L were not adjusted for multiplicity; therefore, there is a risk of false-positive conclusions. In the FORTIFY study, due to the adjusted treatment difference for the comparison of risankizumab 180 mg SC (not included in this review) versus placebo SC for the coprimary outcome of SF/APS clinical remission (OUS protocol) not achieving statistical significance, the hierarchical testing strategy prevented formal statistical testing of the significance of all subsequent secondary outcomes in the hierarchy, including SF and APS remission, maintenance of SF/APS or CDAI clinical remission, SF/APS or CDAI clinical remission with endoscopic response, and SF/APS or CDAI deep remission. This lack of adjustment for multiplicity may increase the likelihood of type I error.
In the ongoing SEQUENCE trial, there were 2 key limitations with the interim results that are at risk of overestimating the treatment effect in favour of risankizumab, although the potential presence and magnitude of the overestimation is unclear. There were missing data for all outcomes given that data were only available for 50% of patients. There was also bias in the selection of reported results, as the statistical analyses presented for all exploratory outcomes were not described in the statistical analysis plan. The analysis plan only aimed to describe the outcomes descriptively. Similar to the other trials, the analysis was based on an ITT population that included randomized patients who received at least 1 dose of the study drug. Although this is not a true ITT population, the risk of bias would be low because almost all included patients received the study drug. Overall, the interim results from the SEQUENCE trial cannot support definitive conclusions about the efficacy of risankizumab compared to ustekinumab.
In the MOTIVATE, ADVANCE, and FORTIFY studies, the details of the screening period were not reported; therefore, the proportion of patients who may have been excluded is unknown. According to the clinical expert consulted by CADTH, the inclusion and exclusion criteria of the pivotal trials were generally aligned with selection criteria that they anticipated would be adopted by most Canadian clinicians when identifying suitable candidates for risankizumab.
The dosing and administration of risankizumab in all the trials were consistent with the product monograph. Based on the available trial data, the relative efficacy of risankizumab to other active treatments was not available. In the MOTIVATE, ADVANCE, and FORTIFY trials, placebo was the comparator while in the SEQUENCE study, ustekinumab was the comparator. Since ustekinumab is not used frequently in Canada, it is not considered the most relevant active treatment.
The trials included outcomes that were important to patients. Patient groups indicated that symptom relief, HRQoL, and clinical remission were important to them. The coprimary outcomes assessed in the MOTIVATE, ADVANCE, and FORTIFY studies were clinical remission and endoscopic response, defined by CDAI or SF/APS and SES-CD, respectively. Key secondary outcomes included the resolution of clinical symptoms (e.g., SF and APS remission), disease activity (e.g., CDAI clinical remission and response), and reductions in endoscopic inflammation (e.g., endoscopic remission, ulcer-free endoscopy). These outcomes were considered appropriate by the clinical expert, although the Harvey-Bradshaw Index was noted as a more common tool to assess clinical remission in patients with CD living in Canada.
The MOTIVATE and ADVANCE studies included 12 weeks of induction therapy and the FORTIFY study included 52 weeks of maintenance therapy. The clinical expert noted that these time frames were appropriate to determine short-term treatment effects with risankizumab; however, they may not be considered sufficient to fully understand the long-term safety for rare events and those events that take longer to develop, such as malignancy.
The patient population in the maintenance trial (FORTIFY) was likely enriched due to the study design of including clinical responders from the induction trials. As such, the maintenance withdrawal placebo group is not a true placebo group since patients are affected by residual drug exposure from the induction period.
A focused literature search for ITCs dealing with either risankizumab or CD was run in MEDLINE All (1946–) on November 23, 2022. No limits were applied to the search. Titles, abstracts, and full-text articles were screened for inclusion based on the population, intervention, comparator, and outcome criteria outlined in accordance with the protocol for the CADTH review. Two eligible ITCs12,13 were included from the CADTH literature search.
The objective of this section is to summarize and critically appraise the sponsor-submitted ITC as well as the 2 published ITCs conducted by Barberio et al.12 and Singh et al.13
The sponsor-submitted ITC was an NMA11 assessing the efficacy and safety of risankizumab relative to vedolizumab, ustekinumab, adalimumab, infliximab, and placebo in patients diagnosed with moderately to severely active CD.
The 2 published ITCs12,13 identified from the CADTH literature search were also NMAs. Barberio et al. evaluated the efficacy of all biologic therapies and small molecules that have been investigated in phase III clinical trials in luminal CD, compared to placebo or each other. Singh et al. determined the relative efficacy and safety of infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab, and risankizumab (either alone or in combination with immunosuppressants) for the treatment of moderate to severe CD in patients with or without previous biologic exposure.
The objective of the sponsor-submitted ITC11 was to evaluate the relative efficacy and safety of risankizumab to vedolizumab, ustekinumab, adalimumab, infliximab, and placebo in 2 groups of patients with moderately to severely active CD, including patients who had previously failed conventional care and those who had previously failed a biologic treatment. CD |||||||| |||| ||| |||||||| || ||||| ||| |||| |||||||| ||| |||||||||||| |||| ||| |||| |||||||||| || || ||| |||||| ||| ||||| |||||||| | |||| || | || ||| ||| ||| |||||| || |||| |||||||||| || ||||| || |||||||| |||| || |||| ||||||| || ||||| ||| ||||||||||| |||||| | ||||||| ||||||| |||||| |||||| || ||||||| || ||||||||| ||||||||||| ||||||||| ||||||| |||||| |||| |||||||| || ||||||||||| ||||||||| || |||| |||||||||| || ||||| |||||||| |||||||||.
A systematic literature review (SLR)32 conducted by the sponsor served as the evidence base, on which eligible studies were identified for the ITC according to the eligibility criteria as outlined in Table 29. The literature searches, last updated on May 10, 2022, were conducted in multiple electronic databases for published primary studies, clinical trial registries for unpublished trials, relevant proceedings for conference abstracts, and regulatory and health technology agency websites for relevant documents. Bibliographies of key studies and systematic reviews were also scanned. The study screening and selection process was conducted by 2 independent reviewers, with disagreement resolved by consultation with a third reviewer. Data were extracted by 1 reviewer and verified by a second reviewer. Risk of bias assessment was carried out at the study level. The methods by which risk of bias appraisal was accomplished were not reported.
In addition to the RCTs identified from the SLR, 3 sponsor-conducted RCTs, including the ADVANCE, MOTIVATE, and FORTIFY trials, were also included in the ITC.
The sponsor conducted an NMA using the |||||||| ||||||||| ||| ||||||| |||| ||||||| || ||| ||||||| || ||| ||| ||| ||||| || Table 30.
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Study Selection Criteria and Methods for Indirect Treatment Comparisons.
Indirect Treatment Comparison Analysis Methods.
Characteristics of Included Studies in the Sponsor-Submitted Network Meta-Analysis.
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Redacted.
Network Diagram for CDAI Outcomes in the BF Population — Induction Phase (Redacted).
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Redacted.
Network Diagram for Endoscopic Outcomes in the BF Population — Induction Phase (Redacted).
Network Meta-Analysis Estimates of Efficacy Outcomes in the Induction Phase.
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Network Diagram for CDAI Outcomes in the CCF Population — Maintenance Phase (Redacted) .
Network Diagram for CDAI Outcomes in the BF Population — Maintenance Phase (Redacted) .
Network Meta-Analysis Estimates of Efficacy Outcomes in the Maintenance Phase.
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Network Diagram for Harms Outcomes in the CCF and BF Populations Combined — Induction Phase (Redacted) .
Network Diagram for Harms Outcomes in the CCF and BF Populations Combined — Maintenance Phase (Redacted) .
Network Meta-Analysis Estimates of Harms Outcomes in the Induction Phase.
Overall, the SLR conducted by the sponsor to identify relevant studies for the NMA was methodologically sound. The sponsor adopted a comprehensive literature search strategy, performed study selection and data extraction in duplicate, described the characteristics of the included studies in adequate detail, and assessed the risk of bias within individual studies. |||||||| || ||| ||||||| ||||||| ||| |||| || |||| |||||||||| ||| ||||||| ||| || | |||||| || |||||||| |||||||||| |||| |||||||||||| ||| |||| || |||| |||||||||| ||| |||| ||||||||| || ||| |||||||||| ||||| |||||| |||||||| ||| |||| || |||| |||||||||| ||||||| |||||| |||||||||| ||||||| |||| ||| |||||||||||| |||| ||| ||| || ||||| ||||||||| ||||||| || ||| ||| |||||| ||||||||| |||| ||| |||||||||| ||||||||| || ||| ||||||| ||||||||| |||. There were several notable sources of heterogeneity in the sponsor-submitted NMA, which increase CADTH’s uncertainty in the NMA estimates. |||||| ||||||||||||| |||| ||||| || ||| ||||| |||||||||| ||||||||||| |||||||| |||||| |||||||| |||| |||| ||||||| || ||| ||| || ||||||||||||| | |||||||| ||||||| |||||| |||||||| || ||| |||| ||| |||||||||| |||||||| |||||||| | || ||||| || |||| | ||||||| ||||||||| |||||||| |||||| |||||| |||||||| |||||||| ||| |||||||| |||||||| |||||||| | || ||||| || |||| ||| ||| ||||||||| || |||||| |||||||| |||||||| | || ||||| || |||| || ||||||||| ||| ||||| || ||||||| |||||||| || ||| ||| ||||||||||| |||| || |||| ||||||| ||| ||||| || |||||||| ||||| |||||||||||| || ||| ||| ||||||||||| |||| || |||| ||||||| || |||| || ||| ||||| || |||||||| ||||| |||||||||||| || ||| || ||||||||||| |||| || |||| |||||| |||||| ||| |||||||| ||||||||| |||| |||| ||||||||| ||||||| || ||||||||||||| |||| ||||| |||||| ||| ||||||||| |||||| ||| ||||||||||| || ||| |||| || ||||| ||||||| |||||||| |||||| |||||||||| ||||||||| |||||| |||| |||||||| |||| |||||| ||||||| ||| |||||||||||||| ||| |||||||| || ||| |||| |||| ||||||||| |||||||| ||||||||| ||| |||||||| || |||| | || |||||||| ||||||| |||| ||||||||||| ||||| |||||||| ||||||||| ||| |||||||| || |||| || || |||||||| ||||||| |||| ||||||||||||| ||||||| |||||||| ||||| ||||| || |||||||| ||| |||||| |||||||| |||||| |||||||| ||||| ||||| || ||| |||||||||||| |||||||| || ||| ||||||| ||||||| |||||| |||||| |||||| ||| |||||||| ||||| ||| ||||||||| |||||||| ||||||||| || ||| |||||||| || ||| ||| || ||||||||| |||||||||| ||| ||||| ||||| || ||| |||||||||||| ||||||| |||| ||||||| |||||| |||| || || |||| |||||| ||||||||||| ||||||||||| |||| ||||| || ||| ||||||||||| || |||| |||||||| || |||||||| |||||| |||||||| |||||||| ||| |||||||| ||| |||||||| || |||||||| |||| ||||||| |||||||| |||||||| |||||||| || | |||||||| || ||||| |||| ||||| || ||| || |||| |||||| |||| ||||||||| ||||||| ||| ||||||| ||| ||||||| |||||| ||||||| |||||||| |||||||| |||||||| || | |||||||| || ||||| |||| ||||| || ||| || |||| |||||| |||| |||||||| || | ||||| |||| ||||| |||| |||| |||| |||||||| ||| |||||||| |||||| |||| ||||||||| |||||| | |||| |||| ||||| |||||| ||||| |||||||| || |||| || |||||| || |||| ||||||| ||| |||||||| ||| |||||| || |||| |||||| |||||||||||| |||||||||| || ||| |||||||||| ||||||| |||||||||| ||| |||||| || ||||||||||||| |||| ||| |||||||| ||||| ||||||||||||| |||||||| |||||||| || ||||||||||||||| || ||| ||||||| ||||||||| ||||||.
Network Meta-Analysis Estimates of Harms Outcomes in the Maintenance Phase.
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The NMA conducted by Barberio et al. aimed to examine the relative efficacy and safety between biologic therapies and small molecules licensed for luminal CD. Specifically, the NMA included phase III RCTs involving adults (≥ 18 years) with luminal CD, who were treated with infliximab, adalimumab, certolizumab, vedolizumab, etrolizumab, ustekinumab, risankizumab, tofacitinib, filgotinib, or upadacitinib. The population was further classified into 2 subgroups: patients naive to biologic therapies and those exposed to biologic therapies previously. In terms of efficacy outcomes in the induction phase, the NMA assessed failure to achieve clinical remission (defined as CDAI ≥ 150) and failure to achieve clinical response (defined as a reduction in CDAI ≥ 70). For the efficacy outcomes in the maintenance phase, the authors assessed the occurrence of the relapse of disease activity (defined as CDAI ≥ 150). AEs (including the total numbers of AEs, SAEs, infections, and AEs leading to study withdrawal) were also assessed in the NMA. Relative risk (RR) along with a 95% CI were used as the effect measure.
There was no information on whether the protocol of the NMA was published or registered a priori. To identify potentially relevant studies, Barberio et al. searched MEDLINE (1946 to July 1, 2022), Embase and Embase Classic (1947 to July 1, 2022), and the Cochrane Central Register of Controlled Trials (CENTRAL). The authors also searched conference proceedings and the bibliographies of all eligible articles. There were no language restrictions. Two reviewers independently conducted study screening and selection (agreement between investigators for study eligibility was reported; kappa statistic = 0.85), data extraction, and the assessment of risk of bias for individual studies using the Cochrane risk of bias tool (version not reported) at the study level. Disagreements were resolved by discussion. The NMA was carried out with the frequentist approach. In total, 23 articles reporting on 25 separate induction RCTs and 15 articles reporting on 15 separate maintenance trials, all of which were funded by pharmaceutical companies, were included for the NMA. For risankizumab, the NMA conducted by Barberio et al. incorporated the published results from the ADVANCE, MOTIVATE, and FORTIFY trials.28,29
All 25 induction trials reported data with respect to clinical remission at between 4 weeks and 16 weeks. Patients who were diagnosed with moderate to severe luminal CD and treated with risankizumab 600 mg IV had a lower risk of failing to achieve clinical remission compared to those treated with placebo (RR = 0.73; 95% CI, 0.66 to 0.80), ustekinumab 6 mg/kg (RR = 0.86; 95% CI, 0.77 to 0.97), ustekinumab130 mg (RR = 0.81; 95% CI, 0.72 to 0.92), adalimumab 80 mg/40 mg (RR = 0.82; 95% CI, 0.69 to 0.96), and vedolizumab 300 mg (RR = 0.79; 95% CI, 0.70 to 0.89). In the subgroup of patients naive to biologic therapies, those treated with risankizumab 600 mg had a lower risk of failing to achieve clinical remission than those treated with placebo (RR = 0.66; 95% CI, 0.52 to 0.85). In the subgroup of patients previously exposed to biologic therapies, the risk of experiencing failure to achieve clinical remission was lower in those treated with risankizumab 600 mg than those treated with placebo (RR = 0.74; 95% CI, 0.67 to 0.82), ustekinumab 6 mg/kg (RR = 0.84; 95% CI, 0.75 to 0.94) and 130 mg (RR = 0.82; 95% CI, 0.73 to 0.92), adalimumab 80 mg/40 mg (RR = 0.75; 95% CI, 0.60 to 0.94), or vedolizumab 300 mg (RR = 0.77; 95% CI, 0.69 to 0.86). There were 15 maintenance trials reporting clinical remission at between 22 weeks and 60 weeks. The evidence was insufficient to show a difference between risankizumab 360 mg every 8 weeks and placebo or any other active treatments in all patients diagnosed with moderate to severe luminal CD, in patients naive to biologic therapies, or in patients previously exposed to biologic therapies.
Data with respect to clinical response was reported by 24 induction trials at between 4 weeks and 16 weeks. In patients who were diagnosed with moderate to severe luminal CD, those treated with risankizumab 600 mg had a lower risk of failing to achieve clinical response compared to those treated with placebo (RR = 0.54; 95% CI, 0.41 to 0.70), ustekinumab 130 mg (RR = 0.72; 95% CI, 0.53 to 0.98), vedolizumab 300 mg (RR = 0.62; 95% CI, 0.46 to 0.84), or infliximab 10 mg/kg (RR = 0.67; 95% CI, 0.46 to 0.99). In the subgroup of patients naive to biologic therapies, the risk of failing to achieve clinical remission was lower in those treated with risankizumab 600 mg compared to those treated with placebo (RR = 0.51; 95% CI, 0.37 to 0.71), vedolizumab 300 mg (RR = 0.62; 95% CI, 0.42 to 0.90), or infliximab 10 mg/kg (RR = 0.64; 95% CI, 0.41 to 0.99). In the subgroup of patients previously exposed to biologic therapies, those treated with risankizumab 600 mg had a lower risk of experiencing failure to achieve clinical remission compared with those treated with placebo (RR = 0.58; 95% CI, 0.48 to 0.69), ustekinumab 6 mg/kg (RR = 0.77; 95% CI, 0.62 to 0.95) and ustekinumab 130 mg (RR = 0.874; 95% CI, 0.58 to 0.74), adalimumab 160 mg/80 mg (RR = 0.73; 95% CI, 0.56 to 0.95), and vedolizumab 300 mg (RR = 0.65; 95% CI, 0.52 to 0.80).
Based on available harms results provided by Barberio et al., the evidence was insufficient to show a difference between risankizumab 600 mg and placebo or other active treatments in the incidence of any AEs or any infection at the induction phase. However, in the induction phase, risankizumab 600 mg led to a lower risk of developing serious AEs compared to placebo (RR = 0.42; 95% CI, 0.29 to 0.62), ustekinumab 6 mg/kg (RR = 0.47; 95% CI, 0.27 to 0.84), and vedolizumab 300 mg (RR = 0.43; 95% CI, 0.24 to 0.77). In the induction phase, patients treated with risankizumab 600 mg had a lower risk of withdrawing from the study due to AEs compared to placebo (RR = 0.25; 95% CI, 0.13 to 0.48). Yet the evidence was insufficient to show a difference between risankizumab 360 mg every 8 weeks and placebo or other active treatments in the incidence of withdrawal due to AEs at the maintenance phase.
One of the key limitations that concerned CADTH’s certainty in the NMA results was heterogeneity across included studies along with the statistical method used to examine it. First, potential sources of heterogeneity across included studies were not narratively assessed in detail; however, they are likely to be similar to those mentioned in the sponsor-submitted NMA due to overlap in the included studies. For instance, the authors failed to discuss the heterogeneity in the event rates of the participants treated with placebo from across maintenance trials. Second, the authors relied on the network heat plot method54 to determine inconsistency between direct and indirect evidence. According to the authors, the heat plots showed no “hotspots” for efficacy networks signifying inconsistency. However, recent evidence suggested that the network heat plot might not be reliable in terms of signalling inconsistency. Applied to a network assessing overall survival in 7,531 lung cancer patients, the network heat plot method did not indicate evidence of inconsistency while other methods such as the Bucher approach, Cochran's Q statistic, node-splitting, and the inconsistency parameter approach did.55
Taken together, there was a high uncertainty in the effect estimates from the NMA conducted by Barberio et al. mainly due to the inadequately addressed heterogeneity issue and serious imprecision of some estimates. As a result, no definitive conclusions could be drawn.
The NMA conducted by Singh et al. included phase II and phase III RCTs and assessed the relative efficacy and safety of infliximab, adalimumab, certolizumab pegol, vedolizumab, ustekinumab, and risankizumab (either alone or in combination with immunosuppressants) for the treatment of moderate to severe CD in adult patients (≥ 18 years) with or without previous biologic exposure. Efficacy outcomes for induction trials included clinical remission (defined as CDAI < 150) as well as clinical response (defined as a reduction in the CDAI of ≥ 100 points compared to baseline). Efficacy outcomes for maintenance trials included clinical remission (defined as CDAI < 150). Safety outcomes for maintenance trials were serious AEs and infections, whereas those for induction trials were not assessed. Odds ratio (OR) and 95% CI were used as the effect measure.
No information was provided on whether the protocol of the NMA was published or registered a priori. A literature search was conducted in MEDLINE, Embase, and CENTRAL from inception to June 3, 2021, with no language restrictions. Conference proceedings and unpublished data were also searched. Study screening and selection, data extraction, and assessment of the risk of bias at the individual study level using the Cochrane risk of bias tool were carried out by 2 reviewers independently. Disagreements were resolved by consensus or in consultation with a third reviewer. The NMA was conducted using a multivariate consistency model random effects meta-regression under the frequentist approach. The NMA conducted by Singh et al. identified 15 induction RCTs in patients naive to biologic therapies, 10 induction RCTs in patients with previous biologic exposure, and 15 maintenance trials for patients with moderate to severe CD. For risankizumab, results come from a phase II induction trial,56 the ADVANCE and MOTIVATE trials (a conference abstract),57 and the FORTIFY trial (an AbbVie press release).58
In terms of the efficacy of risankizumab in the induction phase, patients naive to biologic therapies who were treated with risankizumab were more likely to achieve clinical remission compared to placebo (OR = 2.98; 95% CI, 1.33 to 6.64). However, the CIs surrounding estimates for clinical remission were too wide to draw conclusions for the comparison between risankizumab and any active treatment. No data with respect to the efficacy of risankizumab on clinical response were available for patients naive to biologic therapies. For patients with previous biologic exposure, those treated with risankizumab were more likely to achieve clinical remission (OR = 2.64; 95% CI, 1.89 to 3.68) and clinical response (OR = 3.31; 95% CI, 1.86 to 5.90) compared to placebo. For risankizumab versus active treatments, risankizumab was superior only to vedolizumab in terms of achieving clinical remission in patients with previous biologic exposure (OR = 2.10; 95% CI, 1.12 to 3.92). Estimates for comparisons to other treatments were imprecise.
In terms of the efficacy of risankizumab in the maintenance phase, all estimates of comparisons between risankizumab and placebo or any active treatment were affected by important imprecisions that precluded firm conclusions. In addition, no NMA estimates for harms outcomes (i.e., serious AEs or infections) were available for risankizumab, which was not involved in the evidence networks.
CADTH considered the NMA results regarding risankizumab to be of considerable uncertainty and no definitive conclusions could be made. There were several important reasons. First, the ADVANCE, MOTIVATE, and FORTIFY trial data came from a conference abstract and a press release, which were unlikely to provide adequate details to inform the evidence networks. Second, a lack of adequate details on how the NMA was carried out hindered CADTH’s ability to determine the methodological quality of the NMA. Little information was found on how model fit was assessed; how convergence was evaluated; how feasibility assessment, including connectivity and heterogeneity across included studies, was conducted; and how assessment for inconsistency was carried out.
No other relevant evidence was submitted by the sponsor or identified from the literature.
Four phase III RCTs submitted by the sponsor were included in the systematic review: the MOTIVATE induction study (N = 413); the ADVANCE induction study (N = 559); the FORTIFY substudy 1, maintenance (N = 363); and the SEQUENCE study, part 1, induction and maintenance ongoing (N = 272). The objectives of all 4 trials were to evaluate the efficacy and safety of risankizumab in patients with moderately to severely active CD who had an inadequate response, loss of response, or were intolerant to either non-bio-IR therapy or bio-IR therapy. Both induction trials were of similar design, except that the MOTIVATE trial enrolled patients who were bio-IR, and the ADVANCE trial enrolled patients who were bio-IR or non-bio-IR. In these 2 trials, eligible patients were randomized to receive risankizumab 600 mg IV administered at week 0, week 4, and week 8 or matching placebo, in a double-blind manner. Patients without clinical response to risankizumab at week 12 entered an additional exploratory open-label 12-week induction period (period 2) and were rerandomized to risankizumab 1,200 mg IV, risankizumab 360 mg SC, or risankizumab 180 mg SC. Clinical responders from the induction trials were eligible to enter the maintenance study (FORTIFY), as were patients from induction period 2 who achieved clinical response at week 24. Patients who entered the maintenance study were rerandomized to receive blinded risankizumab 360 mg SC or matching placebo every 8 weeks for 52 weeks. Clinical remission (a CDAI score of less than 150 or SF/APS clinical remission) and endoscopic response were coprimary outcomes. Key secondary outcomes included clinical remission, clinical response, fatigue (FACIT-F score), HRQoL (SF-36 PCS score, IBDQ total score), enhanced SF/APS clinical response and endoscopic response, endoscopic remission, ulcer-free endoscopy, and corticosteroid-free clinical remission.
In the ongoing trial SEQUENCE, patients were randomized to receive blinded risankizumab 600 mg IV induction at weeks 0, 4, and 8, then risankizumab 360 mg SC maintenance every 8 weeks thereafter or an ustekinumab weight-based IV induction dose at week 0 and then ustekinumab 90 mg SC maintenance every 8 weeks thereafter. The results of the SEQUENCE study, part 1, which consist of an interim data lock that includes approximately 50% of planned patients (n = 272), included exploratory outcomes of clinical remission, clinical response, endoscopic remission, mucosal healing, deep remission, biologic remission, SF-36 PCS and MCS scores, and IBDQ total score.
Patients in the trial populations were predominantly white (77% to 91%), with an approximate mean age of 40 years and a mean CD disease duration of approximately 8 years to 12 years. In the MOTIVATE trial, approximately 48% and 52% of patients were bio-IR of 1 and greater than 1, respectively. In the ADVANCE trial, 23% to 30% of patients were bio-IR, 28% to 32% of patients were bio-IR greater than 1, and 42% to 45% of patients were non-bio-IR. Between 29% and 36% of patients across treatment groups were on concomitant corticosteroids and about 19% to 28% of patients were on immunomodulators. In the maintenance trial, patients’ baseline characteristics were generally comparable to those in the induction trials. In the SEQUENCE study, demographic characteristics were generally balanced between the treatment groups. Most patients were white and the mean age was approximately 39 years. Disease characteristics were also relatively similar between the treatment groups.
Indirect evidence from 3 NMAs was included in this review; the NMAs comprised 1 sponsor-submitted NMA and 2 NMAs12,13 published in academic journals that were identified by CADTH through a literature search. ||| ||||||| ||||||||| ||| |||||||| ||| |||||||| ||| |||||| || |||||||||||| |||||||| || |||||||||||| |||||||||||| ||||||||||| ||||||||||| ||| ||||||| || || |||||||| |||| ||| ||| ||||| |||| ||| ||||||||| ||| |||||||| |||||| |||||||| ||| |||||||||| |||||||| |||| |||||||| || ||| ||||||| ||||||||| ||| ||| |||||||| ||||||||| ||||| |||| ||||||| |||| ||||||| ||||||||||| ||| ||||||||||||||| ||| || ||| |||| |||||||| ||| ||||| ||||||||.
Evidence from 3 pivotal trials supported a clinically meaningful superiority of risankizumab over placebo for the coprimary outcomes of clinical remission and endoscopic response at a 12-week induction period and a 52-week maintenance period in adults with moderate to severe CD who had inadequate response or were intolerant to prior conventional or biologic therapies. There is some potential for bias in these results due to the selection of the analysis population, which included only those who had received at least 1 dose of the study drug (i.e., this was not a true ITT population). These findings were consistent in prespecified subgroup analyses based on prior exposure to biologics and addressed key treatment outcomes noted to be important by both patients and clinicians. Patient groups indicated that symptom relief, HRQoL, and clinical remission are important to them. The clinical expert consulted by CADTH considered the benefits of risankizumab on the key secondary outcomes in the induction trials that evaluated the resolution of clinical symptoms (e.g., SF and APS remission), disease activity (e.g., CDAI clinical response), and reductions in endoscopic inflammation (e.g., endoscopic remission, ulcer-free endoscopy) to be clinically meaningful. In the induction trials, compared to placebo, higher rates of clinical response and remission were observed as early as week 4. Risankizumab treatment was also associated with improvement in symptoms (fatigue measured using FACIT-F) and HRQoL (measured with IBDQ and SF-36), although in general these improvements could have been affected by bias due to the subjective nature of the outcomes and the fact that CIs include the potential for effects that are not clinically important. In addition, MIDs for clinical remission and response, FACIT-F, and EQ-5D-5L were not identified in the literature search conducted by CADTH.
In the maintenance trial (FORTIFY), key secondary outcomes including clinical symptoms, disease activity, and reductions in endoscopic inflammation favoured risankizumab, except for corticosteroid-free clinical remission and HRQoL measures. However, except for SF/APS clinical remission (US protocol), these were tested after failure of the statistical hierarchy; therefore, there is a risk of false-positive conclusions.
Overall, the evidence from the 3 pivotal trials did not address the long-term efficacy of risankizumab, given the approximately 1-year study duration.
In the SEQUENCE trial, preliminary data from a 24-week interim lock analysis showed ||||||||||||||| || |||||||||||| |||||||| |||| ||||||||||| ||||| || ||| |||||||||| || |||||||| ||| |||||||| |||||||| |||||||||. However, these interim results are at risk of overestimating the treatment effect as they represent only ||| of the patients participating in the ongoing trial; therefore, these interim results cannot support definitive conclusions about the efficacy of risankizumab compared to ustekinumab.
Based on the sponsor-submitted ITC, the results of efficacy outcomes (i.e., CDAI clinical remission, a 100-point CDAI reduction clinical response, endoscopic response, and endoscopic remission) consistently indicated that risankizumab was superior to placebo among both conventional care failure patients and biologic failure patients in both the induction and maintenance trials. However, no consistent superiority or inferiority could be established with respect to the relative efficacy of risankizumab to other active treatments including vedolizumab, ustekinumab, adalimumab, and infliximab, due to serious imprecision in most estimates. Overall, no definitive conclusions could be drawn due to several limitations. Most importantly, there were several notable sources of heterogeneity across included RCTs, making it likely that the assumption of exchangeability underlying the NMA was violated.
High uncertainty was found in the results of both published NMAs due to limitations such as inadequately addressed heterogeneity and the lack of details on how the NMA was carried out. As a result, no definitive conclusions could be drawn.
Evidence from the pivotal trials showed induction therapy (600 mg IV) and maintenance therapy (360 mg SC) with risankizumab in patients with CD was generally safe and well tolerated. No new safety risks were observed and overall, the safety profile of risankizumab in CD was similar to its known safety profile in other approved indications, based on the Health Canada–approved product monograph.7 In MOTIVATE (induction study), TEAEs, SAEs, and AEs leading to study drug discontinuation were higher in the placebo group than in the risankizumab group, primarily due to worsening CD. In ADVANCE (induction study), TEAEs occurred with similar frequency in both treatment groups, while SAEs and AEs leading to study drug discontinuation occurred with higher frequency in the placebo group. In both induction trials, the most common TEAEs with risankizumab during the 12-week induction period (> 2% of patients) were headache, arthralgia, and nasopharyngitis. In both induction trials, the most frequently reported TEAE leading to study drug discontinuation was CD worsening. Two deaths across all pivotal trials were reported, both of which occurred in the ADVANCE placebo group. In the maintenance trial (FORTIFY), TEAEs, SAEs, and AEs leading to discontinuation were similar between treatment groups and induction trials. Across the 3 trials, the incidence of notable harms in treatment groups was comparable and infrequent. In the FORTIFY trial, the 2 notable harms experienced by the highest proportion of patients in each group were hypersensitivity, of which most were injection-site reactions (risankizumab group = 6.1%; placebo group = 4.9%), and serious infections (risankizumab group = 4.5%; placebo group = 3.8%). In the SEQUENCE study, | |||||||| |||| ||||||| ||||||| |||||||||||| || |||||||||||. In general, the incidence of notable harms in both treatment groups was similarly low, with the most common in both groups being hepatic events (risankizumab group = ||||; ustekinumab group = ||||). No deaths were reported.
The clinical expert noted that most AEs of biologic therapies used to treat CD are generally mild in their clinical experience. However, the clinical expert noted that the duration of follow-up in these trials may not be sufficient to fully understand the long-term safety for rare events and those events that take longer to develop, such as malignancy.
Due to the limitations in the sponsor-submitted ITC, credible conclusions regarding the relative safety of risankizumab to placebo and other active treatments cannot be drawn. While there may be expectations that risankizumab has a comparable safety profile with other biologic drugs based on its mechanism of action, currently there is insufficient evidence to determine its relative safety to active comparators.
Evidence from 3 double-blind randomized trials (the MOTIVATE, ADVANCE, and FORTIFY trials) showed that compared to placebo, treatment with risankizumab resulted in clinically important improvements in clinical remission and endoscopic response at a 12-week induction period (600 mg IV) and a 52-week maintenance period (360 mg SC) in adults with moderate to severe CD who had inadequate response or were intolerant to prior conventional or biologic therapies. These results addressed key treatment outcomes noted as important by both patients and clinicians. The clinical expert consulted by CADTH considered the benefits of risankizumab on clinical remission and endoscopic response, as well as the resolution of clinical symptoms (e.g., SF and APS remission) and disease activity (e.g., CDAI clinical response), and reductions in endoscopic inflammation (e.g., endoscopic remission, ulcer-free endoscopy) to be clinically meaningful. In the maintenance trial, the secondary outcomes were generally supportive of the induction trials; however, there is some risk of false-positive conclusions due to the outcomes being tested outside the statistical testing hierarchy and/or after failure. In the induction trials, risankizumab treatment was also associated with improvement in HRQoL outcomes that met most identified MIDs; however, these findings were affected by bias and the CIs included the potential for effects that are not clinically important. The evidence was insufficient to show a difference for change in HRQoL compared to placebo in the maintenance trial. In general, risankizumab seemed safe and well tolerated compared to placebo, but long-term data are needed to further evaluate its efficacy and safety profile. Due to limitations of the preliminary data from the SEQUENCE trial comparing risankizumab to ustekinumab and ITCs, no conclusions can be drawn on the relative efficacy and safety of risankizumab compared to other active treatments.
adverse event
abdominal pain score
inadequate response to biologic therapy
Crohn’s and Colitis Canada
Crohn disease
Crohn’s Disease Activity Index
confidence interval
Cochran-Mantel-Haenszel
Crohn’s Symptom Severity
5-Level EQ-5D
Functional Assessment of Chronic Illness Therapy–Fatigue
gastrointestinal
Gastrointestinal Society
health-related quality of life
inflammatory bowel disease
Inflammatory Bowel Disease Questionnaire
interleukin
interleukin-17
interleukin-23
indirect treatment comparison
intention-to-treat
intention-to-treat population, the primary efficacy analysis for the MOTIVATE, ADVANCE, and FORTIFY studies
intention-to-treat population, the primary efficacy analysis for the SEQUENCE study, part 1
least squares mean
mental component summary
minimal important difference
mixed model of repeated measures
network meta-analysis
inadequate response to conventional therapy
nonresponder imputation
odds ratio
outside the US
physical component summary
randomized controlled trial
relative risk
safety population
serious adverse event
subcutaneous
standard error
Simple Endoscopic Score for Crohn’s Disease
stool frequency
Short Form (36) Health Survey
stool frequency and abdominal pain score
systematic literature review
treatment-emergent adverse event
tumour necrosis factor
Note that this appendix has not been copy-edited.
Interface: Ovid
Databases:
Date of search: November 23, 2022.
Alerts: Biweekly search updates until project completion.
Search filters applied: none.
Limits: No language or date limits. Conference abstracts excluded.
Syntax Guide.
Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.
Strategy: (Other terms: Skyrizi OR risankizumab OR ABBV-066 OR ABBV066 OR BI-655066 OR BI655066 OR 655066 to 01 OR L04AC18 OR 90ZX3Q3FR7 OR 1612838 to 76 to 2) AND (Condition: Crohn OR Crohn OR Crohns OR healthy)
International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.
Strategy, Advanced Search: (Intervention: Skyrizi* OR risankizumab* OR ABBV-066 OR ABBV066 OR BI-655066 OR BI655066 OR 655066 to 01 OR L04AC18 OR 90ZX3Q3FR7 OR 1612838 to 76 to 2) AND (Condition: Crohn OR Crohn OR Crohns OR healthy); Recruitment status: all.
Produced by Health Canada. Targeted search used to capture registered clinical trials.
Search terms: Drug = risankizumab, Filter = Crohn; plus Condition = Crohn, Filter = ABBV
European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.
Strategy: (Skyrizi OR risankizumab OR ABBV-066 OR ABBV066 OR BI-655066 OR BI655066 OR 655066 to 01 OR L04AC18 OR 90ZX3Q3FR7 OR 1612838 to 76 to 2) AND (Crohn OR Crohn OR Crohns)
New European Union clinical trials register launched January 31, 2022, produced by the European Union. Targeted search used to capture registered clinical trials.
Strategy: Viewed all trials in the database and searched for Crohn
Search dates: November 15 to 21, 2022.
Keywords: risankizumab, Skyrizi; Crohn disease, Crohn
Limits: no date limits.
Updated: Search updated before the completion of stakeholder feedback period
Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:
Note that this appendix has not been copy-edited.
To describe the following outcome measures and review their measurement properties (validity, reliability, responsiveness to change, and MID):
Summary of Outcome Measures and Their Measurement Properties.
Note that this appendix has not been copy-edited.
Network Meta-Analysis Estimates of Efficacy Outcomes in the Induction Phase (Reference — Placebo).
Network Meta-Analysis Estimates of Efficacy Outcomes in the Maintenance Phase (Reference — Placebo).
Network Meta-Analysis Estimates of Safety Outcomes in the Induction Phase (Reference — Placebo).
Network Meta-Analysis Estimates of Safety Outcomes in the Maintenance Phase (Reference — Placebo).
Note that this appendix has not been copy-edited.
MOTIVATE and ADVANCE Studies Graphical Multiple Testing Procedure for the US Protocol.
MOTIVATE and ADVANCE Graphical Multiple Testing Procedure for the OUS Protocol.
FORTIFY Graphical Multiple Testing Procedure for the US Protocol.
FORTIFY Graphical Multiple Testing Procedure for the OUS Protocol.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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