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| Drug | Cladribine (Mavenclad) |
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| Indication | As monotherapy for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and delay the progression of disability. Cladribine is generally recommended in RRMS patients who have had an inadequate response to, or are unable to tolerate, one or more therapies for RRMS. |
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| Reimbursement Request | As per indication |
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| Dosage Form(s) | 10 mg tablet |
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| NOC Date | November 29, 2017 |
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| Manufacturer | EMD Serono Inc. |
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Introduction
Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disorder of the central nervous system.1 It causes disabling motor and sensory symptoms, including mobility problems, vision, issues with coordination, cognitive dysfunction, fatigue, and pain. The condition significantly impairs quality of life, limiting employment and social functioning, and it is a major cause of disability in young adults, with an onset as early as the teenage years.1 The disease is divided into four subtypes: relapsing-remitting MS (RRMS), primary-progressive MS, secondary-progressive MS, and progressive-relapsing MS. The most common form is RRMS, accounting for up to 90% of cases at first presentation.2 RRMS is characterized by clearly defined relapses with full recovery or with residual deficit upon recovery, with lack of progression of disability during the periods between relapses. Given the relatively young onset and severity of disability, the disease carries a significant burden on patients, caregivers, and the health care system, and the Multiple Sclerosis Society of Canada estimates that there are currently 100,000 patients with MS in Canada.1
There are multiple disease-modifying therapies (DMTs) available for MS, including oral (fingolimod, dimethyl fumarate, and teriflunomide), injectable (interferon beta-1a and 1b, pegylated interferon 1a, glatiramer acetate), and infusion (natalizumab, alemtuzumab, ocrelizumab) formulations, and they tend to be divided into first-line and second-line therapies, with the second-line agents being considered more efficacious but also more toxic (fingolimod, alemtuzumab, natalizumab), and reserved for patients with more active disease. Selection of therapy is guided by various factors: disease activity, disability progression, and findings on MRI, and is highly individualized. Switching between first-line therapies typically occurs to address a tolerability issue, while switching to a second-line drug occurs when there is suboptimal response to a first-line drug.3 Until recently, daclizumab (previously reviewed by CADTH) was indicated as a second-line therapy for patients with RRMS. However, during writing of this review, it was voluntarily withdrawn from markets worldwide by the manufacturer because of reports of serious inflammatory brain disorders, including immune-mediated encephalitis and meningoencephalitis.4
The mechanism of action of cladribine in treating MS is not fully understood. Cladribine inhibits DNA synthesis and has antiproliferative effects on lymphocytes, which likely mediate the destruction of myelin. It is the loss of myelin that characterizes MS. Cladribine is indicated as monotherapy for the treatment of adult patients with RRMS to reduce the frequency of clinical exacerbations and delay the progression of disability. It is administered orally, and is available as 10 mg tablets. The efficacy and safety of cladribine beyond two years has not been established, thus the recommended cumulative dose is 3.5 mg/kg over the course of two years, with one treatment course of 1.75 mg/kg per year followed by observation for another two years. The treatment course is spread over two weeks each year, one week at the beginning of the first month of that year and the other at the beginning of the second month. During each week, patients receive 10 mg or 20 mg daily (one or two tablets), based on body weight, over the course of four to five days. The following clinical assessments are recommended prior to starting and continuing therapy with cladribine: lymphocyte counts must be normal before initiating cladribine in year 1, and at least 800 cells/mm3 (i.e., grade 0 or 1) before initiating cladribine in year 2. The product monograph for cladribine notes that in year 2 therapy can be delayed for up to six months to allow for recovery of lymphocytes to at least 800 cells/mm3, but if recovery takes more than six months, the patient should discontinue cladribine.5
The objective of this report is to perform a systematic review of the beneficial and harmful effects of cladribine for the treatment of RRMS.
Results and Interpretation
Included Studies
One manufacturer-sponsored double-blind randomized controlled trial (RCT) was included in this systematic review. CLARITY was a multinational trial that randomized patients with RRMS (2005 McDonald criteria) and at least one relapse within 12 months of study entry 1:1:1 to cladribine 3.5 mg/kg (N = 433), cladribine 5.25 mg/kg, or placebo (N = 437), over a treatment course of 96 weeks. The dose of 3.5 mg/kg was the total cumulative dose over the course of the 96-week study, and is the recommended dose in the product monograph. Because it is not the approved dose for cladribine, the 5.25 mg/kg dose was not of interest for this review. The primary outcome was the annualized relapse rate at 96 weeks. Key secondary outcomes included a variety of MRI outcomes (T1- and T2-weighted and combined unique lesions). Other outcomes that were assessed but were not controlled for multiple comparisons included disability progression and health-related quality of life.
Key critical appraisal issues included the lack of an active comparator, as CLARITY was a placebo-controlled study. Only relapse and MRI outcomes were adjusted for multiple comparisons, while key efficacy outcomes such as disability progression and health-related quality of life were not. Additionally there was a significant amount of missing data for the health-related quality of life outcomes, particularly the Multiple Sclerosis Quality of Life–54 (MSQOL-54). All the subgroup analyses of interest to the review, including treatment history with DMTs (naive and frequency of relapses) in the past year were carried out post hoc, and thus should be considered hypothesis-generating. There is a lack of comparative long-term safety data for oral cladribine, and this is an important gap in knowledge, considering the potential risk for malignancies.
Efficacy
There was a lower annualized relapse rate with cladribine (0.14; 95% confidence interval [CI], 0.12 to 0.17) versus placebo (0.33; 95% CI, 0.29 to 0.38) and a statistically significant difference between groups in the rate of relapse over the course of 96 weeks (rate ratio of 0.43; 95% CI, 0.34 to 0.54; P < 0.001). This amounts to 19 fewer relapses per 100 patients per year of treatment with cladribine. The proportion of patients who were relapse-free over 96 weeks was higher with cladribine (80%) than with placebo (61%) (odds ratio of 2.53; 95% CI, 1.87 to 3.43; P < 0.001). There were fewer events of a three-month sustained progression in Expanded Disability Status Scale (EDSS) scores with cladribine (79%) versus placebo (86%), and the time to sustained progression in EDSS scores was statistically significantly different between groups in favour of cladribine (hazard ratio of 0.67; 95% CI, 0.48 to 0.93; P = 0.018). However, this outcome was not adjusted for multiple statistical comparisons and thus should be considered hypothesis-generating. The effect of cladribine on disability appears to be relatively modest compared with its effects on relapses.
Health-related quality of life was assessed using the disease-specific MSQOL-54, the EuroQoL 5-Dimensions questionnaire (EQ-5D), and the Short Form (36) Health Survey (SF-36), although there was a significant amount of missing data for the MSQOL-54 and, to a lesser extent, the EQ-5D, and no baseline data for the SF-36. Due to the lack of baseline data, SF-36 results were not reported in this review. This large amount of missing data is an important gap in knowledge about cladribine, given the importance of health-related quality of life to patients with MS. Only approximately 10% of the randomized population had a baseline and 96-week MSQOL-54 score, and the difference in score between groups at 96 weeks was not statistically significant. EQ-5D scores at baseline and 96 weeks were only available for approximately 80% of the randomized population. EQ-5D index score (difference from placebo of 0.058, P < 0.001) and visual analogue score (VAS) (difference from placebo of 4.55, P = 0.001) were improved for cladribine versus placebo and this difference was statistically significant, although again not adjusted for multiple comparisons. The difference between cladribine and placebo for EQ-5D index scores appeared to be clinically significant.
MRI results were improved for cladribine versus placebo and these differences were statistically significant for T1-weighted (treatment difference of −0.78; 95% CI, −0.92 to −0.65; P < 0.001), T2-weighted (treatment difference of −1.05; 95% CI, −1.22 to −0.87; P < 0.001), and combined unique lesions (treatment difference of −1.28; 95% CI, −1.49 to −1.0; P < 0.001). A larger proportion of cladribine versus placebo patients had no active T1-weighted or T2-weighted lesions compared with placebo. Cladribine was also superior to placebo for brain atrophy. However, this analysis was post hoc, was not adjusted for multiple comparisons, was missing approximately 20% of the randomized population, and only assessed changes between six and 24 months, not from baseline. The clinical expert consulted for this review considers these to be relatively minor improvements in brain atrophy over placebo. Other efficacy outcomes were not adjusted for multiple comparisons and for these there was a decrease in the proportion of patients using rescue medications with cladribine versus placebo, and an improvement in absenteeism for cladribine versus placebo.
The manufacturer submitted an indirect comparison (IDC) that assessed the relative efficacy and harms of cladribine versus other DMTs for RRMS. This IDC is reviewed in detail in Appendix 7. The IDC included 44 RCTs, and both the “high-efficacy” drugs such as natalizumab, ocrelizumab, fingolimod, and alemtuzumab were included, as well as the interferons, glatiramer, dimethyl fumarate, and teriflunomide. The manufacturer concluded that cladribine had comparable efficacy and harms when compared with these drugs. However, there were several limitations of the IDC, both with transparency of reporting and with methodology, that limits confidence in these conclusions. Lack of comparative data for cladribine versus the many other DMTs for MS remains a limitation of this CADTH Common Drug Review report.
Harms
With respect to harms, there were numerically more adverse events with cladribine than with placebo (81% versus 73%). The most common adverse events were headache (24% cladribine versus 17% placebo) and lymphopenia (22% versus 2%). According to the manufacturer, transient mild-to-moderate lymphopenia is to be expected with cladribine, given its mode of action. Serious adverse events occurred in 8% of cladribine patients and 6% of placebo patients, and 1% of patients in each group withdrew due to an adverse event. Infections, hematological disorders, and neoplasia were notable harms in this review. Herpes zoster occurred in 2% of cladribine patients and none in placebo, while lymphopenia occurred in 22% of cladribine patients and 2% placebo. Neoplasms that were benign, malignant, or unspecified (including cysts and polyps) occurred in 4% of cladribine and 2% of placebo patients. Neoplasms were a safety concern with cladribine and resulted in an apparent delay in approval of the drug in various jurisdictions, including Canada. An analysis of pooled data from various MS trials, including those using parenteral formulations of cladribine and observational studies, found more cases of cancer with cladribine than with placebo. With respect to CLARITY, the manufacturer attributed the difference in risk of neoplasia between groups to an unusually low risk of neoplasia in the placebo group. The manufacturer also submitted a published meta-analysis, which reported no statistically significant difference between cladribine and other MS drugs or placebo with respect to the risk of developing cancer. Ultimately cladribine was approved by Health Canada, but the reviewers recommend it be used as a second-line therapy, due to these safety concerns. This recommendation is not inconsistent with other DMTs with safety issues. However, these higher-risk drugs are also considered to be more efficacious than the safer alternatives, such as the interferons and glatiramer.
Conclusions
One double-blind RCT met the inclusion criteria for this review. CLARITY was a multinational, manufacturer-sponsored trial that compared cladribine with placebo over a treatment course of 96 weeks. The primary outcome was the annualized relapse rate, and cladribine was superior to placebo at 96 weeks for this outcome. Health-related quality of life was only assessed using the disease-specific MSQOL-54 in a small fraction of the population, and the EQ-5D also had a significant amount of missing data. Disability progression was assessed using the EDSS, and the risk of three-month sustained disability progression was lower with cladribine than with placebo. However, this analysis was not adjusted for multiple comparisons. The lack of health-related quality of life and symptom data is an important limitation in a condition characterized by significant symptoms and quality of life issues. MRI outcomes such as the change in number of T1 gadolinium-enhanced lesions per patient, active T2 lesions, and combined unique lesions, were all superior to placebo. With respect to brain atrophy, cladribine was also superior to placebo, but this post hoc analysis was not adjusted for multiple comparisons. There was a higher proportion of cladribine patients who were free of disease activity, and this difference was statistically significant, although this was a post hoc analysis. A numerically higher proportion of cladribine patients reported an adverse event over the 96-week study, and there was no notable difference in patients with a serious adverse event between groups. Lymphopenia was a common adverse event, and occurred numerically more frequently with cladribine than with placebo. Two per cent of cladribine patients developed herpes zoster during the study, compared with none in the placebo group. These adverse events, in addition to other potential safety concerns, have made cladribine a second-line therapy in RRMS, based on the indication. There are no long-term comparative safety data for oral cladribine.
