Summary of Patient Input

Four patient groups, the Mood Disorders Society of Canada (MDSC), the Canadian Mental Health Association (CMHA-National), the Alberta Division of CMHA (CMHA-AB), and the Mood Disorders Association of Ontario (MDAO) provided patient input, in two submissions, for this summary. The groups gathered information from patients with MDD and their caregivers through social media, online discussions, phone interviews, a focus group discussion, and online surveys. The following is a summary of key input from the perspective of the patient groups:

• Depression negatively impacts a patient’s emotional, mental, and physical health; quality of life; and their ability to engage in day-to-day life. Some patients described experiencing stigma and social isolation as well as use of “negative coping” behaviours, including increased suicidal thoughts due to their depression. Relationships with family, friends, colleagues, and society were also reported to be negatively affected. The financial burden can be profound, as many patients are unable to work and must rely on disability payments or savings, may have limited access to government supports and resources, or have high out-of-pocket treatment costs.
• Although many treatments are available for depression, a substantial proportion of patients will not respond to multiple antidepressants, and treatment options for these patients are limited. Adverse effects can affect a patient’s overall quality of life and willingness and ability to seek new treatments.
• Patients with treatment-resistant depression are seeking new treatments that can quickly provide sustained control of their depression symptoms, leading to improvement in routine functioning and overall quality of life. Approval of esketamine in Canada will be welcomed by patients with treatment-resistant depression; however, it is recognized that challenges exist in the use of this drug due to the time required for the treatment (esketamine should be administered in a health care provider setting) and difficult access to the drug (limited availability of the drug as well as its high cost). Equitable and timely access to a full spectrum of psychological support is critical for individuals when medication alone does not resolve depression.

Clinical Trials

The systematic review included three four-week double-blind RCTs (TRD3001, TRD3002, and TRD3005) and one double-blind, randomized withdrawal study (TRD3003) in patients with moderate-to-severe MDD who had an inadequate response to at least two prior antidepressant therapies of adequate dose and duration for the current major depressive episode. The number of patients enrolled in the trials ranged from 138 patients in Study TRD3005 to 705 patients in TRD3003, with 59 to 115 patients per randomized treatment group.

In the four-week induction studies, patients received intranasal esketamine (28 mg to 84 mg, fixed or flexible dosing) or placebo twice weekly, plus a newly initiated oral selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant. Two trials enrolled adults 18 to 64 years old (TRD3001 and TRD3002) and one trial enrolled patients 65 years or older (TRD3005).

The longer-term relapse prevention study (TRD3003) included adults with moderate-to-severe treatment-resistant depression who underwent two treatment phases with intranasal esketamine plus a newly initiated SSRI or SNRI (four-week induction phase and 12-week optimization phase). Those who achieved stable remission with intranasal esketamine (56 mg or 84 mg weekly or every two weeks) were randomized to either continue esketamine plus antidepressant or switch to intranasal placebo plus antidepressant in the maintenance phase. Patients who achieved stable response underwent a separate randomization to esketamine or placebo.

Key limitations were the relatively short duration of the RCTs, differential losses to follow-up in the induction studies (which in some analyses may inflate the treatment effects of esketamine relative to placebo), and potential reporting bias related to unblinding due to the frequency of acute adverse effects (e.g., sedation, dissociation, nausea, and cardiovascular changes) that are known to be associated with esketamine. The patients enrolled reflect an enriched population; thus, the studies’ findings may overestimate the true benefits of esketamine in the real world. There is no direct evidence available comparing esketamine to other therapeutic options for patients with MDD who have not responded adequately to prior therapies.

Outcomes

Outcomes were defined a priori in CADTH’s systematic review protocol. Of these, the committee discussed depression symptom severity (based on the MADRS), disability (based on the Sheehan Disability Scale [SDS]), response, remission, and relapse. The primary outcome in three trials was the change from baseline in MADRS total score at four weeks. Time to relapse in the stable remission population was the primary outcome in Study TRD3003.

• The MADRS is a physician-rated measure of the severity of depression symptoms. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts. It is scored from zero to 60, with higher scores indicating more severe symptoms. There is evidence to support the validity of the MADRS, with a minimum clinically important difference (MCID) of 2 in patients with MDD.

  • Response was defined as a 50% or greater decrease in MADRS total score and remission was defined as a MADRS total score 12 or lower.
  • Relapse was defined as a MADRS total score 22 points or more for two consecutive assessments; or hospitalization for worsening depression; or any other clinically relevant event that was suggestive of a relapse of depressive illness as per clinical judgment (for example, suicide attempt, completed suicide, or hospitalization for prevention of suicide).
• The SDS is a three-item scale on which patients rate the extent to which their work, social life or leisure activities, and home life or family responsibilities are impaired by their symptoms (zero indicates no disability; 10 indicates extreme disability). Total scores range from zero to 30, with higher scores indicating more severe disability. The MCID is not known.
• Although health-related quality of life and suicidality were identified as key efficacy outcomes of interest to patients, none of the included studies were designed or powered to evaluate these outcomes.

Efficacy

One of the three four-week induction studies (Study TRD3002) reported statistically significant differences favouring esketamine over placebo for the change from baseline in MADRS total scores, with a least squares mean difference (LSMD) of –4.0 points (95% confidence interval [CI], –7.3 to –0.6; one-sided P = 0.010). The mean difference exceeded the MCID for the MADRS and was interpreted as clinically relevant by the experts consulted for this review. The two other induction studies reported changes from baseline in MADRS total scores that were similar in magnitude and direction, but with a 95% CI that included the null. The LSMD in Study TRD3001 was –3.2 points (95% CI, –6.9 to 0.5; one-sided P = 0.044; not significant) between esketamine 84 mg and placebo, and 4.1 points (95% CI, –7.7 to –0.5; significance not tested) for esketamine 56 mg versus placebo. In Study TRD3005, which enrolled patients 65 years or older, the LSMD between esketamine and placebo for the change from baseline in MADRS score was – 3.6 points (95% CI, –7.2 to 0.07), which was not statistically significant with the one-sided P value of 0.029.

The study results for measures of disability, based on the change from baseline in SDS, were limited by the extent of missing data (20% to 25%), and uncertainty in the validity of and MCID for the SDS. For Study TRD3001, no statistically significant differences were found between esketamine and placebo; for Study TRD3003, statistical significance was not tested for the change in SDS due to failure of a prior outcome in the statistical testing hierarchy.

In the induction studies, the proportion of patients in the esketamine groups who met the criteria for response or remission was nominally higher than in the placebo groups, but no between-group comparisons were conducted. To evaluate the potential for rapid treatment response, two induction trials reported on the onset of clinical response by day 2 that was maintained to day 28. For study TRD3002, 8% and 5% in the esketamine and placebo groups, respectively, had onset of response by day 2, with no statistically significant differences between groups. In Study TRD3001, 10% and 9% in the esketamine groups versus 2% in the placebo group met the criteria for onset of clinical response by day 2. The analysis of between-group differences showed wide 95% CIs, which were inconclusive due to failure of a prior outcome in the statistical hierarchy.

Among patients who achieved stable remission at the end of the optimization period of Study TRD3003, 39 patients (45%) relapsed after being switched to placebo compared with 24 patients (27%) who remained on esketamine. Relapse was delayed in the esketamine group relative to placebo with a hazard ratio of 0.49 (95% CI, 0.29 to 0.84; P = 0.003). Among patients in the stable responder population, relapse was delayed for those who remained on esketamine compared to those who switched to placebo, with a hazard ratio of 0.30 (95% CI, 0.16 to 0.55; P < 0.001).

Harms (Safety)

In all of the reviewed studies, the proportion of patients who reported adverse events was higher for those who received esketamine (71% to 89%) than for those who received placebo (46% to 68%). The most commonly reported adverse events in the esketamine groups were dissociation, dizziness, vertigo, nausea, dysgeusia, somnolence, and increased blood pressure.

The percentage of patients who stopped intranasal study drug treatment due to adverse events ranged from 1% to 7% of patients who received esketamine and 1% to 3% who received placebo. Serious adverse events were reported by 0% to 4% of patients in the esketamine groups, and 0% to 3% of patients in the placebo groups during the four trials. Worsening depression, anxiety, suicide ideation, increased blood pressure, hypertensive crisis, cerebral hemorrhage, dizziness, vertigo, and sedation were among the serious adverse events noted.

The sponsor reported three completed suicides among patients with treatment-resistant depression who were treated with esketamine during the phase II and phase III trials (2.9 events per 1,000 person-years). No suicides were reported among those who received placebo (100 person-years).

Longer-term comparative safety data for esketamine is limited.

Due to the hemodynamic and cognitive adverse effects, and the abuse potential of esketamine, the drug will be available through a controlled distribution program, and administration of the drug must be supervised by a health care provider who is experienced and equipped to manage adverse events such as respiratory depression or cardiovascular events.

Indirect Treatment Comparisons

No indirect treatment comparisons of adequate methodological quality were identified in the literature or were provided by the sponsor.

Cost and Cost-Effectiveness

Esketamine is available as a 28 mg intranasal solution at a submitted price of $273 per dose. The recommended initial dose of esketamine for adults in combination with oral antidepressants is 56 mg (two 28 mg devices) followed by subsequent doses of 56 mg or 84 mg twice weekly for the first four weeks, then weekly for weeks five to eight. From weeks nine onwards, the recommended dose is 56 mg or 84 mg weekly or every two weeks, based on the lowest frequency needed to maintain response or remission. At the recommended dose, the annual cost of esketamine is between $18,546 and $45,591 in year 1 and $14,196 and $42,588 in subsequent years.

The sponsor submitted a cost-utility analysis comparing esketamine plus oral antidepressant with oral antidepressant alone. The sponsor’s base case was conducted from the perspective of a Canadian publicly funded health care payer over a five-year time horizon. Patients started in the model in the resistant depression stage, which consisted of the acute phase (weeks 1 to 4), early maintenance (weeks 5 to 8), late maintenance (weeks 9 to 40), and recovery (weeks 41 and onwards). After this, patients could transition to the following health states: fail treatment and remain in the current depressive episode but initiate subsequent treatment; achieve a response or enter remission based on MADRS score; discontinue treatment; or, death. Patients could further improve or regress in terms of their MADRS score and subsequently transition to improved health states (i.e., remission or recovery) or deteriorated health states (i.e., loss of response, relapse, or recurrence). Treatment effects were informed using the TRANSFORM-2 and SUSTAIN-1 clinical trials.

CADTH identified the following key limitations of the sponsor’s submitted economic analyses:

• Response and remission rates for oral antidepressants alone were inappropriately adjusted based on the assumption that additional health care visits would result in an elevated placebo effect.
• The assumption that patients achieving and maintaining recovery would discontinue esketamine due to improved outcomes is currently uncertain in clinical practice.
• Inclusion of suicide-related mortality was associated with uncertainty based on the clinical findings, and inclusion of both suicide-related and all-cause population mortality potentially overestimate mortality in the model.
• Long-term maintenance of the treatment effect for esketamine plus oral antidepressant was uncertain as current clinical information is available up to a maximum of 91 weeks.

The CADTH base case reflected changes to the following parameters: applying unadjusted response and remission rates for the comparator (oral antidepressant); removing discontinuation rates for recovery for esketamine plus oral antidepressant treatment; and removing all-cause population mortality. Multiple structural limitations that were identified could not be addressed by CADTH (e.g., treatment effect waning and the impact of partial responders). Due to a lack of clinical information, CADTH was unable to include relevant comparators such as IV ketamine or adjunctive treatments.

In CADTH’s base case, esketamine plus oral antidepressant was associated with an incremental cost-effectiveness ratio of $125,376 per quality-adjusted life-year compared with oral antidepressant alone. At a willingness-to-pay threshold of $50,000 per quality-adjusted life-year gained, a price reduction of approximately 60% is required for esketamine plus oral antidepressant to be considered cost-effective. None of the scenario analysis reflecting different discontinuation rates for recovery or remission resulted in an ICER below $50,000 per quality-adjusted life-year gained.