Reimbursement Review

Cariprazine (Vraylar)

Sponsor: AbbVie Corporation

Therapeutic area: Schizophrenia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on Application Submitted for Review

NOC = Notice of Compliance.

Basis of Resubmission

Cariprazine was previously reviewed by CADTH for the treatment of schizophrenia in adults.¹ The evidence provided for the original review of cariprazine included 5 double-blind randomized controlled trials (RCTs), including 3 short-term placebo-controlled studies (the RGH-MD-16, RGH-MD-04, and RGH-MD-05 studies, referred to hereafter as the MD-16, MD-04, and MD-05 studies), 1 placebo withdrawal study (the RGH-MD-06 study, referred to hereafter as the MD-06 study),² and 1 active-controlled study in patients with predominantly negative symptoms (the RGH-188-05 study, referred to hereafter as the188-05 study), 2 open-label extension studies (RGH-MD-17 and RGH-MD-11, referred to hereafter as the MD-17 and MD-11 studies), and 3 indirect treatment comparisons (ITCs) — 2 published ITCs and 1 unpublished ITC versus other atypical antipsychotic (AAP) drugs available in Canada. The submission was initially discussed at the March 2022 Canadian Drug Expert Committee (CDEC) meeting and was issued a “do not reimburse” recommendation by the committee. A request for major reconsideration was submitted by the sponsor, which was discussed at the July 2022 CDEC meeting, and the original do not reimburse recommendation was upheld.

In response to the initial draft recommendation, Canada’s Drug Agency (CDA-AMC) received written feedback from 3 clinician groups, 2 individual clinicians, and 3 patient groups. This information was discussed as part of the deliberation on the major reconsideration of the recommendation. The feedback received was consistent across stakeholder groups, which spoke to the significant impact of mental health on the lives of patients and caregivers (particularly those living with schizophrenia), the heterogeneity of the condition and response to treatment, the challenges with conducting clinical trials in this population, and correspondingly, the need for additional treatment options.

The gaps identified by CDA-AMC within the original submission included uncertainty in the clinical relevance of the results of the submitted RCTs, uncertainty in the reported magnitude of effect in treating symptoms for patients presenting with predominantly negative symptoms, limited evidence of the long-term effects of continued cariprazine use, uncertainty in the comparative effectiveness of cariprazine compared to relevant comparators, and uncertainty in the generalizability of the 188-05 study due to its extensive screening and exclusion criteria.

The sponsor filed this resubmission based on new evidence that is intended to address the gaps identified by CDA-AMC and considered by CDEC in the recommendation for the original submission. The evidence provided in the resubmission included:

• 2 real-world evidence (RWE) studies of cariprazine; the first study included patients with schizophrenia and predominantly negative symptoms, and the second study included patients who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia and cannabis use disorder^3,4

• a responder analysis for the primary end point of the acute schizophrenia trials (the MD-16, MD-04, and MD-05 studies), as defined by a 20% change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score⁵

• a meta-regression reanalysis of the originally submitted network meta-analysis (NMA).⁶

The objective of this report is to review and critically appraise the totality of evidence submitted by the sponsor on the beneficial and harmful effects of cariprazine (Vraylar), 1.5 mg to 6 mg oral capsules, in the treatment of adult patients with schizophrenia. The emphasis of the clinical review of the resubmission is to appraise whether the additional evidence submitted addresses the gaps identified in the previous review, and to consider the new information alongside the evidence that was reviewed and appraised in the original submission.¹

As such, within the present Clinical Review Report, a summary of clinical evidence from the original Clinical Review report⁷ has been included (refer to the section titled Clinical Evidence From the Original Vraylar Review). This is followed by a summary of the new clinical evidence that was reviewed and appraised as part of the resubmission (refer to the section titled Clinical Evidence From the Vraylar Resubmission).

Introduction

Schizophrenia is a chronic mental illness that affects the way a person interacts with and understands the world. The condition is characterized by delusions, hallucinations, disorganized speech, disorganized behaviour, negative symptoms, and impaired cognitive ability.⁸ The symptoms associated with schizophrenia are categorized as either positive or negative in nature. Positive symptoms reflect a distortion of reality or an abundance of perceptual normal functions (e.g., delusions, conceptual disorganization, hallucinatory behaviour, excitement, hostility), while negative symptoms reflect a loss or restriction of normal functioning (e.g., blunted affect, emotional withdrawal, poor rapport, passive or apathetic social withdrawal, lack of spontaneity and flow of conversation, disturbance of volition). Other general and cognitive psychopathological manifestations include motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, poor impulse control, preoccupation, and active social avoidance. The severity, duration, and frequency of these symptoms can cause social and occupational challenges.

Despite its relatively low prevalence, schizophrenia is associated with tremendous health, social, and economic burden.⁹ People living with schizophrenia are at increased risk for other medical illnesses, suicide, substance abuse, homelessness, and unemployment.¹⁰ Moreover, the burden associated with schizophrenia extends beyond the individual living with the disease to families, caregivers, and the wider community. According to national data (2016 to 2017), 1 of 100 people residing in Canada aged 10 years or older is living with a diagnosis of schizophrenia; 56% of these individuals are men and 44% are women.¹¹ The incidence of schizophrenia in Canada was estimated to be approximately 49 per 100,000 in 2016, with an incidence of 58 per 100,000 in males and 41 per 100,000 in females.¹² In Canada, the all-cause mortality rate in people diagnosed with schizophrenia is 2.8 times higher than in those without, and 374 people died due to schizophrenia in 2004.^11,13

Schizophrenia is diagnosed by specific signs and symptoms that prevent reality-based judgment,⁸ as well as by a physical examination and the conduct of a thorough review of an individual’s medical, psychiatric, and family history. The most recent updated diagnostic criteria for schizophrenia are defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR).¹⁴ To receive an official diagnosis of schizophrenia, an individual must exhibit at least 2 symptoms consisting of delusions, hallucinations, disorganized speech, disorganized behaviour, and negative symptoms for at least a 1-month period, with some level of disturbance being present for 6 months.

Currently, there is no cure for schizophrenia. Treatment focuses on managing symptoms in the community and at work and includes medication and psychosocial interventions. Existing antipsychotic drug therapies fall into 1 of 2 classes: typical antipsychotic drugs and AAPs drugs. Per the clinical experts consulted by CDA-AMC for the purpose of this review, both typical antipsychotic and AAP drug classes are considered to be equally effective in the treatment of positive symptoms. Currently, there are no approved medications to specifically treat the negative and cognitive symptoms, which are the symptoms most impairing for long-term function. Canadian guidelines recommend that, following an acute episode of schizophrenia, patients should be offered maintenance treatment with antipsychotic medications. Canadian guidelines also recommend the prescription of clozapine for patients with treatment-resistant schizophrenia.

Cariprazine is an AAP drug that is approved by Health Canada for the treatment of schizophrenia in adults. Cariprazine is available as 1.5 mg, 3 mg, 4.5 mg and 6 mg oral capsules and the recommended dosage is 1.5 mg to 6 mg once daily. The suggested initial dose is 1.5 mg, which may be increased in 1.5 mg increments to a maximum of 6 mg daily. Cariprazine and its active metabolites have a long half-life; thus, the full dose-related treatment response and the occurrence of adverse effects may be delayed.

The reimbursement request for cariprazine is in line with the Health Canada indication for the treatment of schizophrenia in adults.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CDA-AMC’s call for input and from clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

CDA-AMC received 1 joint input for this review from the Schizophrenia Society of Canada (SSC) in collaboration with the Institute for Advancements in Mental Health (IAM), the Schizophrenia Society of Alberta (SSA), the Canadian Mental Health Association (CMHA) Alberta Division, and the Mood Disorders Society of Canada (MDSC). A series of interviews, focus groups, and surveys was conducted between 2021 and 2023. This included a 2-part national survey for persons with lived experience of early psychosis and schizophrenia (N = 118 responders) and 1 survey for family members of people with early psychosis and schizophrenia (N = 121 responders) conducted between 2021 and 2023, as well as a smaller survey for those with personal experience with cariprazine were conducted between November and December 2023.

Among the patient respondents, 76% reported 1 or more positive symptom, primarily delusions. One or more negative symptom was reported by 94% of patients, mainly consisting of social withdrawal and reduced motivation. Cognitive symptoms were reported by 97% of patients and included difficulty with attention and memory. According to the patient group input, more than 1 antipsychotic drug may be needed to address both positive and negative symptoms of schizophrenia, along with a holistic treatment plan that includes psychosocial rehabilitation, family education, recovery-oriented mental health services, psychological support services, substance use issues care, and trauma-informed care. The majority of patient responders (94%) was taking medications for early psychosis or schizophrenia, with drowsiness, restlessness, nausea, and weight gain being the most commonly experienced side effects. As the negative symptoms have a major impact on social engagement and integration, patients cite the need for a medication that can address the negative symptoms of schizophrenia. This is also because none of the typical antipsychotic drugs or AAP drugs are able to target negative symptoms. Patients also expressed a need for treatment options that have fewer side effects. Four patients had experience with cariprazine, accessed through private health plans. Most respondents indicated that cariprazine improved the positive, negative, and cognitive symptoms associated with their disease and positively impacted their quality of life (QoL) with tolerable side effects.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

Schizophrenia is a lifelong condition. Many individuals with schizophrenia do not respond to currently available treatment options and of those who do, many become refractory to treatment. Existing treatments have burdensome adverse effects that impact QoL, compliance, and tolerability. The clinical experts emphasized that current available treatment options have minimal to no impact on negative and cognitive symptoms of schizophrenia and there is no approved treatment for negative (and cognitive) symptom domains, which are among the major predictors of functional outcomes.

Antipsychotic medications are the mainstay of schizophrenia treatment; however, treatment with antipsychotic medications is mostly effective on positive symptoms. The clinical experts indicated that the primary goal of treatment with antipsychotic medications is to treat psychosis (i.e., positive symptoms of schizophrenia), which may improve QoL, burden of illness, and safety (i.e., the reduction of suicide and violence), as well as prevent relapse and progression of the disease. In most cases, antipsychotic medications have equal efficacy in treating the first episode of psychosis. Therefore, the clinical experts highlighted that in clinical practice, treatment usually begins with newer antipsychotic medications (i.e., partial agonists), which have a more benign and manageable side effect profile (e.g., aripiprazole). Treatment guidelines suggest 2 separate trials of antipsychotic medications of adequate dose and duration, followed by clozapine if response was poor (i.e., treatment-resistant schizophrenia). There are no guidelines for the management of schizophrenia after the failure of clozapine. Options generally include the addition of a second antipsychotic medication, a mood stabilizer, or electroconvulsive therapy (ECT). According to the clinical experts, the full remission of psychotic symptoms is ideal; however, many patients will not attain full remission. For inpatients, the main goal of treatment is to attain a degree of symptom control that is compatible with living in the community. For outpatients, symptom control as well as working on recovery goals (i.e., vocational, leisure, or self-care goals) become the target of treatment.

The clinical experts described the manifestation of schizophrenia as remarkably heterogenous and thus, treatment goals for each patient could be very different. The experts noted that efficacy is not necessarily predictable, and most often comes down to trial and error. The clinical experts indicated that cariprazine could be used similarly to other AAP medications as monotherapy, though it could be useful as a first-line therapy in the first episode of psychosis. Additionally, the clinical experts highlighted its potential for use as an add-on therapy to other drugs when needed and that it may have unique benefits for patients with prominent negative symptoms. Considering there are no other options available to treat negative symptoms, the experts stated that cariprazine is a good option to try and it is expected that some patients will benefit from it. Overall, the clinical experts stated that cariprazine would be another treatment option within their armamentarium. The experts stated that based on their experience, cariprazine is well tolerated overall and has a better side effect profile than many other antipsychotic drugs; however, for patients sensitive to akathisia, cariprazine may not be most appropriate. The experts stated that psychiatrists are most often involved in diagnosing schizophrenia and initiating therapy, to monitor potential adverse effects. However, the clinical experts also noted that general practitioners currently prescribe and monitor many antipsychotic drugs; thus, they should be able to prescribe cariprazine following proper education. Additionally, the clinical experts noted that no specialized setting would be required to prescribe and monitor treatment.

Clinician Group Input

Three clinician groups provided input for the submission: the Canadian Consortium for Early Intervention in Psychosis (CCEIP) group (3 clinicians contributed to the input), the National Advisory Board (20 clinicians contributed to the input), and a group of Quebec psychiatrists (7 clinicians contributed to the input).

Clinicians highlighted that early intervention with pharmacologic and nonpharmacologic approaches can help address important treatment goals such as improving the course of psychosis to lead to a period of stability, returning to preillness social and occupational levels of functioning, and decreasing the risk of suicide. The clinician groups agreed with the clinical experts consulted by CDA-AMC on the place in therapy of cariprazine as a first-line antipsychotic drug. They agreed that it is particularly relevant for patients with adherence concerns and reluctance to use long-acting injectable antipsychotic drugs, and those who have encountered tolerability issues, given the longer half-life and more favourable metabolic tolerability profile of cariprazine. However, the clinician groups highlighted that patients with treatment-refractory schizophrenia or with comorbidities would be least likely to benefit from treatment with cariprazine. They also highlighted that it is necessary to offer patients treatment options for both positive and negative symptoms, and in multiple formulations to reduce symptom burden and maximize health-related quality of life (HRQoL).

In alignment with the clinical experts consulted by CDA-AMC, the clinician groups noted that response is assessed through multidisciplinary clinical observation to establish a reduction in positive and negative symptoms, and improvement in QoL and the ability to function more independently. However, key evaluative scales for response in trials (e.g., PANSS) are not routinely conducted in clinical practice. The clinician groups stated that the discontinuation of therapy should be considered based on the lack of or suboptimal response, tolerability issues (generally including excessive drowsiness, cognitive disturbance, sexual dysfunction, metabolic effects, and hormonal and weight-related changes), as well as nonadherence, of which they state that tolerability and adherence issues are less a concern with cariprazine.

As noted by the clinical experts consulted by CDA-AMC, the clinician groups highlighted that the treatment of patients with schizophrenia is provided in both inpatient and outpatient settings as well as in the emergency department, often under the care of a multidisciplinary team, with medication decisions and choices usually determined by the psychiatrist.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for the initiation of therapy, considerations for the continuation or renewal of therapy, considerations for the prescribing of therapy, and system and economic issues. Refer to Table 7 for more details.

Clinical Evidence From the Original Vraylar Review

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Five double-blind RCTs met the inclusion criteria for the systematic review, including 3 short-term studies (the MD-16, MD-04, and MD-05 studies), 1 randomized withdrawal study (the MD-06 study), and 1 study in patients with predominantly negative symptoms (the 188-05 study).

The 6-week, double-blind MD-16, MD-04, and MD-05 studies evaluated the efficacy, safety, and tolerability of cariprazine compared with placebo in adults with an acute exacerbation of schizophrenia. Patients were randomized to receive placebo or either a fixed or flexible dosing of cariprazine (1.5 mg to 9 mg daily). Two studies also included an active control group for assay sensitivity (risperidone 4 mg daily or aripiprazole 10 mg daily). The sample size ranged from 446 patients to 732 patients and the primary outcome in all trials was the change from baseline to week 6 in the PANSS total score. The mean age of patients enrolled in the acute schizophrenia trials ranged from 35.5 years (standard deviation [SD] = 9.3 years) to 39.3 years (SD = 10.8 years), and the proportion of males ranged from 62% to 78% per treatment group. The mean baseline PANSS total score was approximately 96 points across studies, and most patients were categorized as markedly ill based on the Clinical Global Impression–Severity of Illness (CGI-S) score.

The objective of the MD-06 study was to evaluate the efficacy and safety of cariprazine relative to placebo in preventing the relapse of symptoms. Adults with acute schizophrenia were enrolled and received open-label cariprazine (3 mg to 9 mg daily) for up to 20 weeks. Those able to tolerate cariprazine and who met the treatment response criteria were randomized to receive double-blind cariprazine or placebo for 26 weeks to 72 weeks (N = 200). The study was stopped once the last patient randomized had completed 26 weeks in the double-blind period. Time to relapse was the primary outcome of this study. In the MD-06 study, the mean age of patients who entered the run-in stage was 38.4 years (SD = 10.4 years) and 71% were male. The mean PANSS total score was 91.3 points (SD = 10.1 points) and 54% of patients were markedly ill. Treatment responders who had completed the open-label cariprazine run-in stage and were randomized had a mean age of 37.7 years (SD = 10.1 years) and 39.2 years (SD = 10.9 years), and 71% and 61% of patients were male in the placebo and cariprazine groups, respectively. At randomization, the PANSS total score was 50.9 points (SD = 6.7 points), and most patients were mildly ill based on the CGI-S score.

The objective of the 188-05 study was to evaluate the safety, efficacy, and tolerability of cariprazine versus risperidone in patients with predominantly negative symptoms of schizophrenia for at least 6 months (i.e., a PANSS factor score for negative symptoms [FSNS] ≥ 24 and a rating of ≥ 4 [moderate] for 2 of 3 PANSS items for flat affect, avolition, and poverty of speech). A total of 461 adults were randomized to receive 26 weeks of double-blind cariprazine (3 mg to 6 mg daily) or risperidone (3 mg to 6 mg daily). The primary outcome was change from baseline to week 26 in the PANSS FSNS. The mean age of patients enrolled in the 188-05 study was 40.4 years (SD = 10.8 years), and 57% were male. The mean baseline PANSS score was approximately 76 points, with ███ of patients classified as moderately ill and ███ classified as markedly ill, according to the CGI-S score.

Efficacy Results

Acute Schizophrenia Trials

The primary efficacy objective was met in all 3 acute schizophrenia studies, with all cariprazine dosage groups (1.5 mg to 9 mg daily) showing statistically significant mean differences versus placebo in the change from baseline to week 6 in the PANSS total score. The least squares mean (LSM) differences versus placebo ranged from –6.8 (95% confidence interval [CI], –11.3 to –2.4; P = 0.003) for the cariprazine 3 mg to 6 mg group in the MD-05 study, to –10.4 (95% CI, –14.6 to –6.2; P < 0.0001) for the cariprazine 4.5 mg group in the MD-16 study (Table 2). No statistical testing was performed comparing cariprazine to risperidone or aripiprazole.

The change from baseline to week 6 in the CGI-S score was the secondary outcome in the acute schizophrenia trials. The CGI-S assesses the overall severity of mental disorders on a 7-point scale ranging from 1 (normal) to 7 (extremely ill). The LSM differences favoured all dosage groups of cariprazine versus placebo, with treatment effects that ranged from –0.3 (95% CI, –0.6 to –0.1; P = 0.0115) to –0.6 (95% CI, –0.9 to –0.4; P < 0.0001) (Table 2).

The proportion of patients who attained treatment response (≥ 30% improvement in the PANSS total score) favoured the cariprazine 1.5 mg, 3 mg, and 4.5 mg groups (31.4%, 35.7% and 35.9%, respectively) and the risperidone group (43.5%) compared with the placebo group (18.9%) in the MD-16 study (all P < 0.05). In the MD-04 study, the proportion of responders was higher for cariprazine 6 mg (31.8%; P = 0.013) than placebo (19.5%), but with no difference detected for the cariprazine 3 mg group (24.5%; P = 0.28) versus placebo (19.5%). No difference in the proportion of responders was detected between the cariprazine 3 mg to 6 mg groups (28.6%) or the 6 mg to 9 mg groups (34.7%) compared with the placebo group (24.8%) in the MD-05 study (both P > 0.05). There was no control of the type I error rate for the responder analyses; thus, any results showing a P value of less than 0.05 should be interpreted as supportive evidence only.

Table 2: Key Efficacy Outcomes in Acute Schizophrenia Studies (MD-16, MD-04, and MD-05 Trials)

ANCOVA = analysis of covariance; ARIP = aripiprazole; CAR = cariprazine; CGI-S = Clinical Global Impression–Severity; CI = confidence interval; LOCF = last observation carried forward; LSM = least squares mean; mITT = modified intention to treat; MMRM = mixed model of repeated measures; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SE = standard error; vs. = versus.

^aThe PANSS total score is scored from 30 to 210 with higher scores indicating more severe symptoms and psychopathology.

^bThe CGI-S tool assessed the overall severity of mental disorders on a 7-point scale from 1 = normal to 7 = extremely ill.

^cAn ANCOVA model was used with pooled study centre and baseline value as covariates, and LOCF for missing data (mITT population).

^dThe P value was < 0.0001 for the comparison of the average effect of the cariprazine 3 mg and 4.5 mg groups vs. placebo.

^eThe P value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

^fAn MMRM was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction (mITT population).

Sources: Clinical Study Report for MD-16,⁵³ Clinical Study Report for MD-04,⁵⁵ and Clinical Study Report for MD-05.⁵⁴

Two studies reported data on HRQoL measured using the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4) instrument. The between-group differences favoured the cariprazine 3 mg to 6 mg groups versus placebo in the MD-04 and MD-05 studies, but no differences were detected between the cariprazine 6 mg to 9 mg dosage group and placebo in the MD-05 study. The type I error rate was not controlled for this outcome, and the clinical relevance of the differences is unclear as the minimal important difference (MID) is not known.

Withdrawal Design Trial

Time to relapse was the primary outcome in the MD-06 study. Relapse was defined as a composite end point that included clinical outcomes (hospitalization, self-harm or violent behaviour, suicidal or homicidal ideation) as well as criteria based on standardized symptom and disease severity rating scales (e.g., a ≥ 30% increase in the PANSS total score, a ≥ 2-point increase in CGI-S, and a score > 4 on 1 of 7 specific PANSS items).

Among patients who had demonstrated treatment response to cariprazine during the 20-week open-label phase, 47.5% of patients experienced a relapse after being switched to placebo compared with 24.8% of patients who remained on cariprazine therapy (Table 3). Between-group differences favoured cariprazine versus placebo with a hazard ratio (HR) of 0.45 (95% CI, 0.28 to 0.73; P = 0.001).

Predominantly Negative Symptoms Study

In the 188-05 study, the primary outcome was the change from baseline to week 26 in the PANSS FSNS (scored from 7 to 49 with a lower score indicating fewer symptoms). Both treatment groups showed an improvement over time with an LSM change score of –8.9 (standard error [SE] = 0.3) for cariprazine and –7.4 (SE = 0.4) for risperidone. The LSM difference was –1.5 (95% CI, –2.4 to –0.5; P = 0.002) favouring cariprazine versus risperidone (Table 4). The MID for the mean difference is unclear. The proportion of patients with at least a 20% reduction in the PANSS factors score for negative symptoms at week 26 was 69.2% and 58.1% in the cariprazine and risperidone groups, respectively, with an odds ratio (OR) of 2.1 (███ ███ ███ ██ █████████). There was no control of the type I error rate for the responder analysis; thus, these data should be interpreted as supportive evidence only.

The change from baseline to week 26 in the Personal and Social Performance Scale (PSP) was the secondary outcome in the 188-05 study. The clinician-rated PSP is scored from 0 to 100, with higher scores indicating better psychosocial function. In the 188-05 study, the cariprazine and risperidone groups both reported an improvement in the mean PSP scores at week 26 with increases of 14.3 points (SE = 0.6 points) and 9.7 points (SE = 0.8 points), respectively. The LSM difference was 4.6 points (95% CI, 2.7 to 6.6 points; P < 0.001), favouring cariprazine versus risperidone. The between-group differences did not exceed the MID of 7 points to 10 points reported in the literature.

Table 3: Primary Efficacy Outcome in the Withdrawal Design Study (MD-06 Study)

CAR = cariprazine; CGI-S = Clinical Global Impression–Severity of Illness; CI = confidence interval; DB = double-blind; HR = hazard ratio; mITT = modified intention to treat; NE = not estimable; PANSS = Positive and Negative Syndrome Scale.

^aThe HR was based on a Cox proportional hazards model (unadjusted), and the P value was based on a log-rank test. Percentiles and 95% CI were based on Kaplan-Meier estimates (DB mITT population).

^bRelapse was defined as 1 of the following: psychiatric hospitalization; an increase in the PANSS total score by ≥ 30% for patients who scored 50 or higher at randomization or a 10-point or more increase for patients who scored less than 50 at randomization; CGI-S score increased by 2 or more points; deliberate self-injury or aggressive or violent behaviour; suicidal or homicidal ideation that was clinically significant as judged by the investigator; and a score of greater than 4 on 1 or more of the following PANSS items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behaviour), P6 (suspiciousness/persecution), P7 (hostility), G8 (uncooperativeness), or G14 (poor impulse control).

Source: Clinical Study Report for MD-06.²

Table 4: Primary Efficacy Outcome in the Predominantly Negative Symptoms Study (188-05 Trial)

CAR = cariprazine; CI = confidence interval; LSM = least squares mean; mITT = modified intention to treat; MMRM = mixed model of repeated measures; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SD = standard deviation; SE = standard error; vs. = versus.

^aAn MMRM was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction (mITT population). The 7-item PANSS factor score for negative symptoms was scored from 7 to 49, with higher scores indicating more severe negative symptoms.

^bThe P value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

Source: Clinical Study Report for 188-05.¹⁵

Harms Results

Most patients in the short term studies (61% to 78%) and the longer-term studies (54% to 80%) reported 1 or more adverse event (AE), with a frequency that was generally similar between groups within trials (Table 5). Insomnia, akathisia, and headache were the most commonly reported AEs in the cariprazine groups.

The frequency of serious adverse events (SAEs) ranged from 1% to 9% of patients in the placebo groups, 3% to 6% of those in the cariprazine groups, and 3% to 4% of patients in the active control groups of the acute schizophrenia trials. In the longer-term studies, SAEs were reported in 7% and 14% of patients in the open-label and double-blind phases of the MD-06 study and in 3% of patients per group in the 188-05 study. Across all studies, the proportion of patients who withdrew due to AEs ranged from 9% to 15% in the placebo groups, 6% to 14% in the cariprazine groups, and 9% to 12% in the active control groups. Schizophrenia and psychotic disorders were the most frequently reported SAEs or AEs leading to withdrawal.

Two patients died in the 6 mg cariprazine dosage group of the MD-04 study (suicide; ischemic stroke and myocardial infarction), and 1 patient died in the risperidone group of the 188-05 study (carcinoma). No deaths were reported in the other treatment groups.

In the 6-week studies, treatment-emergent extrapyramidal symptoms (EPSs) were reported by 12% to 16% of patients in the placebo groups, 17% to 41% of patients in the cariprazine groups, and 16% and 29% of patients in the aripiprazole and risperidone groups, respectively (Table 5). The frequency of EPSs was similar in the cariprazine and risperidone groups of the 188-05 study (14% versus 13%). In the MD-06 study, EPSs were reported in 40% of patients receiving open-label cariprazine, in 21% of patients who remained on cariprazine, and 7% of patients who switched to placebo during the double-blind phase. The frequency of discontinuation due to EPS AEs was low, ranging from 0% to 2% per treatment group across the short-term and longer-term studies.

Suicidal ideation or behaviour was infrequently reported in the acute and longer-term studies. Based on the Columbia-Suicide Severity Rating Scale (C-SSRS), 1% to 5% of patients reported suicidal ideation and 0% to 0.4% of patients reported suicidal behaviour across treatment groups. One patient died by suicide and 1 suicide attempt was reported among patients receiving cariprazine, as well as 1 suicide attempt in a patient on risperidone.

Table 5: Summary of Harms From Pivotal and Protocol-Selected Studies

ARIP = aripiprazole; CAR = cariprazine; DB = double-blind; EPS = extrapyramidal symptom; OL = open-label; RIS = risperidone; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

^aSafety population.

^bSAEs reported include the double-blind and safety follow-up periods.

^cIn the MD-06 study, another 6 (0.8%) patients experienced an SAE during the safety follow-up period following the OL phase; following the DB phase, no cariprazine-treated patients and 2 (2%) patients in the placebo group reported an SAE. In the 188-05 study, no patients in the risperidone group and 2 patients in the cariprazine group experienced an SAE during the safety follow-up period.

Sources: Clinical Study Report for MD-16,⁵³ Clinical Study Report for MD-04,⁵⁵ Clinical Study Report for MD-05,⁵⁴ Clinical Study Report for MD-06,¹ and Clinical Study Report for 188-05.⁵⁸

In the 6-week studies, 5% to 11% of patients who received cariprazine reported a clinically important increase in body weight (defined as ≥ 7%) versus 2% to 4% of patients in the placebo group, 6% of patients in the aripiprazole group, and 17% of patients in the risperidone group. In the MD-06 study, 11% of patients reported a 7% or greater increase in body weight during the open-label cariprazine phase, and 27% to 32% of those in the cariprazine and placebo groups reported the same in the double-blind phase. In the 188-05 study, ██ ███ ██ in the cariprazine and risperidone groups, respectively, reported at least a 7% increase in weight.

Critical Appraisal

The design of the trials was consistent with European Medicines Agency (EMA) guidance for the investigation of drugs for schizophrenia. All studies were double-blinded, and the methods used to randomize patients and conceal allocation appear to have been appropriate. The baseline patient characteristics were similar between groups within studies, but all the trials reported a high proportion of early withdrawals (23% to 57% per treatment group) and with some withdrawal imbalances between treatment groups within trials. It is possible that the high proportion of discontinuations may have compromised randomization, and both the measured and unmeasured characteristics of the treatment groups may not have remained similar over time. Furthermore, many of the end point measurements reported in these trials had to be estimated by imputation, which may introduce bias. However, a number of sensitivity analyses was conducted that explored different missing data assumptions, and these analyses supported the primary findings of the studies. Interpretation of the change in the PANSS scores and HRQoL data were limited by the lack of MID. In addition, the type I error rate was not controlled for several outcomes of interest, such as the 30% or more responder analyses and change in HRQoL scores.

In the study that enrolled patients with predominantly negative symptoms, the use of risperidone as a comparator was a potential limitation, given its lack of demonstrated efficacy on negative symptoms. The clinical importance and relevance of the observed differences in outcomes in this trial are uncertain due to the lack of evidence for what is considered a significant difference in negative symptoms trials.

With respect to external validity, all trials excluded patients with psychiatric and medical comorbidities, including those with substance use disorders or those who were at risk of harming themselves or others. According to the clinical expert consulted, the numerous exclusion criteria have the potential to affect the external validity, as most patients seeking psychiatric care in Canada have complex medical and psychiatric conditions. Older adults (> 60 years) and those with schizoaffective disorders or treatment-resistant schizophrenia were also excluded; thus, the efficacy and safety in these populations is unknown. By design, the withdrawal study randomized an enriched population with a demonstrated response to treatment; as a result, the treatment effects observed may be inflated while the frequency of adverse effects may be under-reported relative to the broader population of patients with an acute schizophrenia exacerbation.

The available evidence consisted of 4 placebo-controlled studies and 1 active-controlled trial in a select patient population (predominantly negative symptoms). While 2 of the 6-week studies included an active control group, there was no a priori hypothesis evaluating risperidone or aripiprazole versus cariprazine; thus, head-to-head data on the comparative efficacy and safety in acute schizophrenia are lacking. None of the studies were designed to test for differences in hospitalization or treatment persistence. The impact of treatment on HRQoL was assessed in 2 studies but the type I error rate was not controlled for these analyses. Only the predominantly negative symptoms study assessed functional outcomes. Thus, the treatment effects of cariprazine on these outcomes of importance to patients is unclear. The sample size and duration of the RCTs may have been insufficient to detect infrequent AEs.

Indirect Comparisons

Description of Studies

One unpublished ITC that was used to inform the pharmacoeconomic analysis and 2 published ITCs submitted by the sponsor were included in this report.

The unpublished ITC evaluated the efficacy and safety of cariprazine versus other oral AAP drugs used in Canada for the treatment of acute schizophrenia and the prevention of relapse. Data from 70 RCTs on acute schizophrenia and 12 RCTs on relapse prevention were used to inform the fixed-effects or random-effects Bayesian NMA. The primary outcome for the acute model was the proportion of patients who attained at least a 30% improvement in the PANSS total scores (or other response criteria) at week 4 to week 8. For the maintenance therapy model, the primary outcome was the proportion of patients who relapsed at week 26 to week 72.

The published ITCs focused on short-term efficacy and safety (Huhn et al. [2019]¹⁶) or the metabolic effects (Pillinger et al. [2020]¹⁷) of antipsychotic drugs in patients with acute schizophrenia.

Results

For the acute treatment of schizophrenia, the results of the unpublished NMA ███████ ████ for the proportion of responders, but ████ ██ ███████████ ████████ ███████. The indirect evidence suggests that ███████████ ███ ████ █ ██████ ████ ██ █████████ ███████████████ ███ █████ ████ ██ ████████ ██ ██████████ ██████ █████ ███ ██.

The results of the 2 published ITCs ████ █████████ █████ and showed no difference in short-term symptom severity, and possible differences in some adverse effects for cariprazine versus other antipsychotic drugs. The authors of both ITCs rated confidence in the evidence for cariprazine as low or very low.

Critical Appraisal

Several sources of heterogeneity were noted across trials in the unpublished ITC, including differences in the baseline PANSS score, disease duration, the publication year of the study, the timing of the outcome assessment, outcome definitions, and placebo response rate. The statistical methods could not fully account for the heterogeneity; thus, the potential for bias is high and should be considered when interpreting the findings of the acute schizophrenia NMA.

The relapse prevention network had several limitations that affected the ability to draw conclusions from these analyses. Due to differences in study design across trials, there were important differences in the patients included, as well as heterogeneity in the timing of the outcomes and the definition of relapse. Moreover, the network was sparse, with many comparisons showing wide credible intervals (CrIs) and high uncertainty. Considering these limitations, the results of this ITC may not be representative of the true effect of cariprazine relative to placebo or comparators.

Comparative evidence for HRQoL and functional status, which were identified as important end points by patients, is lacking as the ITC did not analyze these outcomes.

Other Relevant Evidence

Description of Studies

Two open-label extension studies (the MD-17 and MD-11 studies) provided longer-term safety and tolerability data for patients with schizophrenia who completed 1 of the 6-week pivotal studies and had responded to treatment (with a CGI-S ≤ 3). New patients who met the inclusion criteria were also eligible for the MD-11 study.

In the MD-17 study, 93 patients received cariprazine (1.5 mg to 4.5 mg daily), and 49% of the patients completed 48 weeks of therapy. Of the 568 patients who received cariprazine (3 mg to 9 mg daily) in the MD-11 study, 39% of the patients completed 48 weeks of therapy.

Efficacy Results

The mean PANSS total score decreased from baseline by –5.0 points (SD = 14.0 points) in the MD-11 study and –6.8 points (SE = 1.3 points) in the MD-17 study (last observation carried forward [LOCF] for missing data). Minimal changes in the CGI-S scores were reported in both studies.

Harms Results

No new safety signals were reported based on the 48-week safety data in the MD-17 and MD-11 studies. AEs were reported by 81% to 83% of patients, including akathisia (14% to 16%), extrapyramidal disorder (7%), and headache or insomnia (9% to 14%). A 7% or greater increase in body weight was reported by 26% and 33% of patients in the MD-11 study and the MD-17 study, respectively. In both studies, 10% to 13% of patients discontinued due to AEs or experienced an SAE. One died by suicide was reported in the extension studies.

Critical Appraisal

Limitations of the extension studies include selection bias, the lack of a control group, and the lack of blinding. Reporting of harms and subjective measures (such as symptoms) may have been biased by knowledge of the treatment received. As only descriptive statistics were published, and without comparator groups, the interpretation of the results is limited. Moreover, there is potential for selection bias as patients who discontinued the parent RCTs due to AEs, lack of efficacy, or other reasons were excluded. In addition, some patients in the MD-11 study received a higher daily dose of cariprazine than is recommended by Health Canada.

Clinical Evidence From the Vraylar Resubmission Report

Systematic Review

Description of Studies

As part of the resubmission to CDA-AMC, a post hoc responder analysis for the primary end point of the acute schizophrenia trials (the MD-16, MD-04, and MD-05 studies) was submitted; it used a 20% within-group threshold for change from baseline in the PANSS total score. Pivotal studies in the acute population have previously been described.

Efficacy Results

In the MD-16 study, the proportion of patients with a 20% or greater improvement in the PANSS total score at week 6 among the cariprazine 1.5 mg, 3 mg, and 4.5 mg groups was ██████ █████ █ respectively, █████ of patients in the risperidone group and █████ in the placebo group. For the comparison of cariprazine to placebo, the OR was █████ ████ ███ ██ for the 1.5 mg group; █████ ████ ███ for the 3 mg group; and █████ ████ ███ █ for the 4.5 mg group. The comparison of risperidone 4 mg to placebo corresponded to an OR of █████ ██ ██████.

In the MD-04 study, the proportion of 20% responders at week 6 for cariprazine 3 mg and 6 mg was █████ ███ ██████ The proportion of responders at week 6 for aripiprazole was █████ and for placebo was █████ For the comparison of cariprazine to placebo, the OR for the 3 mg group was █████ ████ ██, and the OR for the 6 mg group was █████ ████. The comparison of aripiprazole to placebo corresponded to an OR of █████ ████ ███.

In the MD-05 study, the proportion of patients with a 20% or greater improvement in the PANSS total score at week 6 for the cariprazine 3 mg to 6 mg group, the cariprazine 6 mg to 9 mg group, and the placebo group was ██████ ████ respectively. For the comparison of the cariprazine groups to placebo, the OR for the 3 mg to 6 mg group was █████ ████, and the OR for the 6 mg to 9 mg group was █████ ████ ███

Harms Results

No additional harms analyses were included as part of the resubmission.

Critical Appraisal

The pivotal trials submitted are the same as those in the previous submission and the appraisal points raised by CDA-AMC related to the MD-16, MD-04, and MD-05 trials still apply. Results of the 3 post hoc analyses were in favour of cariprazine, demonstrating that 49% to 58% of patients treated with cariprazine experienced a 20% or greater improvement in the PANSS total score compared to placebo across trials (range of scores, 32% to 36%). As the included data were derived from a post hoc analysis, and the outcome was not part of any multiple testing procedure that controlled for type I error, any results showing a P value less than 0.05 was considered supportive. Because the threshold of clinical relevance was not defined, there is an uncertainty in our conclusions about the true magnitude of the effect of cariprazine compared to placebo in reducing PANSS scores by 20%.

Long-Term Extension Studies

Beyond the MD-17 and MD-11 studies, which were included in the original review of cariprazine, no additional long-term extension studies were included as part of this resubmission. Of note, the MD-17 and MD-11 studies are summarized in the Other Relevant Evidence subsection of the Clinical Evidence From the Original Vraylar Review section.

Indirect Comparisons

Description of Studies

In response to the identified gaps and concerns raised by CDA-AMC in the original submission, the sponsor submitted an updated NMA that included novel analyses of the change from baseline in the PANSS score, a 30% response rate, and the relapse rate. The NMA was submitted to address the high levels of heterogeneity in the patient and study characteristics that could not be fully accounted for by the statistical methods, and uncertainty about the comparative efficacy and safety of cariprazine in both the acute schizophrenia population and the population presenting with predominantly negative symptoms.

Analyses for other outcomes, including discontinuation due to adverse events (DAEs), discontinuation due to other reasons (DORs), weight gain, EPSs, and sedation and somnolence, were rerun using the same data inputs as those used in the original NMA. As such, the authors noted that there was no difference between analyses.⁶ Inputs from these new NMAs were used in the pharmacoeconomic model for cariprazine, which was also included in the resubmission to CDA-AMC.

Efficacy Results

Change From Baseline in PANSS and 30% Response Rate

Comparisons of cariprazine to the other active treatments included in the NMA ███ ███ ███████████ █ █████████████ ███████████ based on the change from baseline in the PANSS score in the random-effects NMA adjusted for placebo effect, the year of publication, and treatment duration. ██████████ ███ ███ ████ ████ ████ ███ ████████ ████ ██████████.

Comparisons of cariprazine to other active treatments ███ ███ ███████████ █ in the response to treatment based on the 30% response rate in the random-effects NMA adjusted for placebo effect. ███████████ ████████████ ███ ███ ████ ████ ████ ███ ████████ ██.

Results of sensitivity and subgroup analyses that aimed to address the sources of heterogeneity and methodological concerns were generally consistent with the primary analyses, ██████ ████ ██████████ ██████████ ███████████ ██████

Relapse Rate

█████ ███ ██ ███████████ ██████████ ████████ ███████ ███████████ ███ ████ ██ ███ ██████ ███████████ ███ ███████████ ██ ███████ ████ ██ ███ ███████ ███████████ ████████.

Results of the sensitivity and subgroup analyses in the relapse network were in line with the primary analysis, though results were associated with extremely wide 95% CrIs.

Harms Results

The models for other outcomes presented in the original submission — namely, DAEs, weight gain, EPS, and sedation and somnolence — were not rerun as the data inputs remained unchanged. Following a request for clarification by CDA-AMC, the authors highlighted several corrections that were applied to 3 studies included in the acute network dataset. Results for these outcomes were consistent with the original NMA.

For the relapse network, results for the outcomes of DAEs, DORs, weight gain, and EPSs remained unchanged from the original NMA.

Critical Appraisal

Given the similarities in conduct and statistical analysis between the original NMA and the updated NMA included in this resubmission, the key criticisms from the original NMA still apply (refer to the Indirect Evidence subsection of the Clinical Evidence From the Original Vraylar Review section). These criticisms included the potential for bias due to heterogeneity in the study characteristics that could not be fully accounted for, and the resulting uncertainty of the magnitude of the comparative efficacy and safety of cariprazine. To address the heterogeneity concerns outlined in the previous review, meta-regression was conducted to adjust for the heterogeneity of the study-reported treatment effect caused by potential effect modifiers, as well as supplementary analyses to remove or modify the heterogeneity introduced by the effect modifiers.

The studies included in the updated NMA were identical to those included in the original NMA summarized in the original Vraylar review and therefore subject to most of the same limitations that were previously described. However, the authors applied various outcome-specific exclusions to further reduce the number of studies in each analysis. Despite this, given the heterogeneity across the included studies’ patient populations, it was unclear if the transitivity assumption was met. There was notable variation across trials with regard to the baseline PANSS, the duration of time since diagnosis, the study publication year, and some patient demographics. Other potential sources of heterogeneity included the definition of relapse, which was based on the study-specific criteria. Data were missing on the patient subtype (first episode, not first episode, or mixed population) for up to 40% of studies, and it was unclear if patient subtypes were comparable across studies. Due to the heterogeneity in the time points of assessment for the outcomes included in the studies of the NMA, a 24-week time of assessment was selected as it was common across studies of the relapse network, as opposed to the longest evaluable time point for each study, which ranged from 26 weeks to 72 weeks.

Novel analyses were conducted for the change from baseline in the PANSS score, and a 30% response in the PANSS score in the acute network, and for the outcome of the relapse rate in the relapse population network. Per the authors, metabolically neutral AAP drugs — aripiprazole, brexpiprazole, lurasidone, and ziprasidone — were considered the most relevant comparators as these were identified as the treatments that cariprazine would most likely replace based on the original CDA-AMC review of cariprazine, other published NMAs, and the Institut national d’excellence en santé et en services sociaux (INESSS) recommendation for cariprazine.¹⁸ This assumption was not considered invalid by the clinical experts, though they also noted that comparisons to other antipsychotic drugs (i.e., asenapine, clozapine, olanzapine, paliperidone, quetiapine, and risperidone) are also relevant. Throughout the base-case and all supplementary analyses, █████ ███ █████████ ██ ███████████ █████ for outcomes of change from baseline in the PANSS score, a 30% response in the PANSS score, and the relapse rate. Other antipsychotic drugs (asenapine, olanzapine, paliperidone, and quetiapine) ████ █████████ ████████ ███. However, results for all comparisons were uncertain due to the wide 95% CrIs, with many estimates crossing the 0 or 1 threshold, suggesting notable imprecision and precluding conclusions on which treatment is favoured for these outcomes. Thus, the results may not be representative of the true comparative effect of cariprazine.

Studies Addressing Gaps in the Evidence From the Systematic Review

During the original review of cariprazine, CDA-AMC noted the following gaps in the submitted evidence: uncertainty in the generalizability of the results to the population of patients with schizophrenia in Canada, uncertainty in the comparative efficacy of cariprazine in treating negative symptoms, and limited evidence of long-term effects after continued cariprazine use.

To strengthen the totality of evidence for cariprazine and to address the concerns with the included evidence identified during the original review of cariprazine, the sponsor submitted 2 real-world observational studies: Rancans et al. (2021)³ and Szerman et al. (unpublished data).^3,4

Rancans et al. (2021)

Description of Study

The study by Rancans et al. (2021) was a prospective, observational, open-label, single-arm 16-week study of cariprazine conducted in 9 psychiatric clinics in Latvia (N = 116). Patients with insufficient symptom control with their previous antipsychotic treatment were included. The primary outcome of the study was the change from baseline in the Short Assessment of Negative Domains (SAND). Additional outcomes included the Clinical Global Impression–Improvement (CGI-I) and CGI-S scales, and safety.⁴

At baseline, the mean age was 37.4 years (SD = 11.3 years), and most patients were diagnosed with paranoid schizophrenia (82; 70.7%). Inadequate control of negative symptoms occurred in 103 (88.8%) patients, and the most frequent antipsychotic therapies were quetiapine (38; 32.8%), olanzapine (24; 20.7%), haloperidol (23; 19.8%), and aripiprazole (22; 19.0%).⁴

Results

The mean change from baseline in SAND total score at week 16 was −7.3 points (95% CI, −8.3 to −6.2 points), with greater changes occurring in negative symptom domains, where the change was −6.3 points (95% CI, −7.3 to −5.4 points) than in positive domains, where the change was −0.9 points (95% CI, −1.2 to −0.6 points). Results for the CGI-I and CGI-S suggested mean improvements of 2.6 points (95% CI, 2.4 to 2.8 points) and −0.9 points (95% CI, −1.0 to −0.7 points), respectively.⁴

A total of 46 (39.7%) patients experienced treatment-emergent adverse events (TEAEs), including but not limited to akathisia (15; 12.9%) and anxiety (12; 10.3%).⁴

Critical Appraisal

General principles of appraisal of prospective observational studies were applied to the study by Rancans et al. (2021); however, the study was noncomparative. In the absence of a frame of reference for comparison, it is not possible to determine whether the observed treatment effects of cariprazine on the outcomes were solely due to the drug, a placebo effect, or the natural history of the disease. Additionally, the outcome assessment was at a greater risk of measurement or reporting bias due to the lack of blinding and awareness of treatment assignment.

The primary outcome of this study was the change from baseline in SAND. It was not possible to assess the clinical importance of the change in SAND as it has not yet been validated as a measure of antipsychotic treatment efficacy. A total of 17% of patients did not complete the study and the amount of missing data was not reported, which may introduce selection bias into the reported estimates.

Overall, the transportability of the reported results to patients with schizophrenia in Canada is uncertain. The difference between populations in Latvia and Canada in their access to care, social support, patient characteristics, and the prognosis of patients with schizophrenia remains unknown.

Szerman et al. (Unpublished Data)

Description of Study

Szerman et al. (unpublished data) was a retrospective, cross-sectional, observational review of adult patients who met the DSM-5 criteria for schizophrenia and cannabis use disorder and were treated with cariprazine maintenance therapy for at least 6 months. A total of ██ ███ patients were enrolled at ██ ███ centres in Spain. The primary objective was to describe the change in PANSS, Clinical Global Impression–Schizophrenia (CGI-SCH), CGI-S, and CGI-I scores from the start of treatment to 6 months later among patients who completed at least 6 months of treatment with cariprazine.³

In the ██ patients included, the mean age at baseline was ████ ████. Most patients (██ ██) had multiple previous episodes of schizophrenia while ██ ██ patients had a first episode of schizophrenia. Patients included in the study were receiving treatment with cariprazine for 6 months, with the most frequently administered doses being 4.5 mg (██) and 3 mg (██). Most patients were also receiving other treatment, including ███████████████ ████████ ██████████████ ██.³

Results

At baseline, the mean score of the PANSS positive and negative subscales was ████ ███ █ ████ █, respectively. At the 6-month follow-up, the mean PANSS positive and negative subscale scores were ████ ███ █ ████ ██, respectively.³

From baseline to the 6-month mark, the CGI-SCH positive symptom scores decreased from ███ ███ █ ███, and the negative symptom scores decreased from ███ ███ █ ████. For the CGI-I, scores decreased from ███ ██ at baseline to ███ ██ 6 months later, and for the CGI-S, scores decreased from ███ ███ at baseline to ███ ██ at 6 months.³

No harms were evaluated in the study.

Critical Appraisal

General principles of appraisal of observational studies were applied to the study by Szerman et al. (unpublished data). The study was noncomparative, which limits the ability to interpret the observed changes from baseline as it is not possible to distinguish between the effect of cariprazine, a placebo effect, or the natural history of the disease in the absence of a frame of reference for comparison. The population was selected retrospectively based on 6 months of continuous treatment with cariprazine, which introduces selection bias in the study. Any patients with poor adherence, negative response, or early important AEs were not represented by the study and the reported results are not generalizable to the entire population of adults with schizophrenia and cannabis use disorder.

Overall, the transportability of the reported results to patients with schizophrenia in Canada is uncertain. The difference between populations in Spain and Canada in their access to care, social support, patient characteristics, and the prognosis of patients with schizophrenia remains unknown.

Conclusions

Schizophrenia is a severe and debilitating chronic disorder with a heterogenous presentation of positive, negative, and cognitive symptoms. Though there are multiple antipsychotic treatments available, there is a lack of treatments that effectively manage living with schizophrenia. As such, patients and clinicians have expressed a significant need for additional treatment options, particularly to manage the negative symptoms of schizophrenia.

Five RCTs (the MD-16, MD-04, MD-05, 188-05, and MD-06 trials), 2 open-label extension studies, and multiple NMAs were reviewed in the original submission and used as the basis of the original CDEC recommendation for cariprazine. As highlighted in the original review, this evidence demonstrated that cariprazine was associated with statistically significant improvements in schizophrenia symptoms and overall severity compared with placebo; however, the generalizability of results to patients with predominantly negative symptoms and the comparative effectiveness of cariprazine versus other antipsychotic drugs was uncertain.

In addition to the previously mentioned evidence, the sponsor included in this resubmission 1 post hoc analysis of 3 pivotal trials (the MD-16, MD-04, and MD-05 studies), an updated NMA to address heterogeneity concerns, and 2 RWE studies in an effort to address the uncertainty in the original review and corroborate the totality of evidence for cariprazine.

In general, the evidence provided for this resubmission was supportive of the findings in the original review; however, the uncertainties raised in the previous submission, and limitations in the quality of the evidence provided for this resubmission, remained a concern. Estimates of efficacy from the post hoc analysis of trial data were interpreted as nonconfirmatory, though they generally aligned with the results of the primary outcomes of the trials submitted during the original review. More specifically, while the results of the 30% responder analysis conducted during the original review were inconsistent, the results of the post hoc 20% responder analysis provided for this resubmission consistently favoured cariprazine over placebo. No definitive conclusions could be drawn on the effectiveness of cariprazine compared to other active treatments for adults with schizophrenia. The results of the updated NMA remained uncertain and imprecise due to the considerable heterogeneity across studies and wide CrIs. Additional supportive evidence in the form of the RWE studies was provided to validate the efficacy for patients presenting with predominantly negative symptoms, although these studies were subject to limitations. Though the results were generally consistent with the pivotal trial results, they could not be attributed to treatment with cariprazine due to the lack of a control group.

Overall, despite the limitations with the evidence included in the resubmission, the collective evidence included across the reviews generally suggested a consistent positive effect of cariprazine compared to placebo on outcomes related to positive and negative symptoms in patients with schizophrenia. Though cariprazine represents another potential treatment option for patients with schizophrenia, it remains unclear whether cariprazine is better or worse than other antipsychotic treatments available.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of cariprazine 1.5 mg, 3 mg, 4.5 mg, and 6 mg oral capsules in the treatment of schizophrenia in adults.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

Schizophrenia is a chronic mental illness that affects the way a person interacts with and understands the world. The condition is characterized by delusions, hallucinations, disorganized speech, disorganized behaviour, negative symptoms, and impaired cognitive ability.⁸ The symptoms associated with schizophrenia are categorized as either positive or negative in nature. Positive symptoms reflect a distortion of reality or an abundance of perceptual normal functions (e.g., delusions, conceptual disorganization, hallucinatory behaviour, excitement, hostility), while negative symptoms reflect a loss or restriction of normal functioning (e.g., blunted affect, emotional withdrawal, poor rapport, passive or apathetic social withdrawal, lack of spontaneity and flow of conversation, disturbance of volition). Other general and cognitive psychopathological manifestations include motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, poor impulse control, preoccupation, and active social avoidance. The severity, duration, and frequency of these symptoms can cause social and occupational challenges.

Global Burden of Disease studies reported that the age-standardized point prevalence of schizophrenia was 0.28% in 2016, with little variation across countries or regions.¹⁹ According to national data (2016 to 2017), 1 in 100 people residing in Canada aged 10 years or older is living with a diagnosis of schizophrenia; 56% of these individuals are men and 44% are women.¹¹ The incidence of schizophrenia in Canada was estimated to be approximately 49 per 100,000 in 2016, with an incidence of 58 per 100,000 in males and 41 per 100,000 in females.¹² The onset of schizophrenia typically occurs during middle to late adolescence or early adulthood. In general, men experience an earlier onset of schizophrenia than women, with new cases diagnosed in men at a rate 2 times higher than in women.¹¹

Despite its relatively low prevalence, schizophrenia is associated with tremendous health, social, and economic burden.⁹ People living with schizophrenia are at increased risk for other medical illnesses, suicide, substance abuse, homelessness, and unemployment.¹⁰ Indeed, schizophrenia contributes 13.4 million (95% uncertainty interval, 9.9 million to 16.7 million) years of life lived with disability to disease burden globally.¹⁹ Furthermore, the life expectancy of those living with schizophrenia is approximately 20 years less than that of the general population.²⁰ Most excess deaths among those with schizophrenia are due to underlying physical illness, especially chronic disease such as coronary heart disease, stroke, type 2 diabetes, respiratory disease, and some cancer;²⁰ suicide accounts for less than 15% of excess deaths.²¹ In Canada, the all-cause mortality rate in people diagnosed with schizophrenia is 2.8 times higher than in those without.¹¹ Moreover, the burden associated with schizophrenia extends beyond the individual living with the disease, to families, caregivers, and the wider community. In terms of resource utilization in people aged 1 year and older, more than 147,500 Canadians require health services for schizophrenia.¹¹ In a 2004 analysis, the direct health care and non–health care costs of schizophrenia were estimated to be 2.02 billion in Canada.¹³ Another study estimated the costs of treatment-resistant schizophrenia to be up to 11 times higher than costs for non–treatment-resistant schizophrenia.²²

The causes of schizophrenia are not fully understood. Structural changes in the brain and genetics, combined with lifestyle and environmental factors, may play a role in its etiology.¹¹

Schizophrenia is diagnosed by specific signs and symptoms that prevent reality-based judgment.⁸ The first step in diagnosis involves ruling out other mental health disorders and determining that symptoms are not due to substance abuse, medication, or another medical condition. The most recent updated diagnostic criteria for schizophrenia are defined in the DSM-5-TR.¹⁴ Briefly, to receive an official diagnosis of schizophrenia, an individual must exhibit at least 2 of the following symptoms during at least a 1-month period, with some level of disturbance being present for 6 months (note that at least 1 of the symptoms must be delusions, hallucinations, or disorganized speech). The symptoms are:

• delusions, such as a belief that a person is being poisoned

• hallucinations

• disorganized speech

• disorganized or catatonic behaviour

• negative symptoms.

In determining a diagnosis, the diagnosing clinician will perform a physical examination and conduct a thorough review of an individual’s medical, psychiatric, and family history. Safety is also carefully assessed. The diagnosing clinician may also order additional tests, including MRI and blood tests.

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

Currently, there is no cure for schizophrenia. Treatment focuses on managing symptoms primarily through medication and psychosocial interventions. Based on the input from the clinical expert consulted by CDA-AMC for the purpose of this review, in more severe or refractory cases, ECT may be selectively used.

Antipsychotic medications, which target the characteristic symptoms of schizophrenia, form the cornerstone of treatment.^8,14,23 The underlying principles for pharmacotherapy include:

• the individualization of medication (including patient preferences)

• simple medication regimens

• appropriate dosage

• attention to adverse effect profiles

• regular evaluation of response, including adverse effects

• short-term and long-term clinical efficacy, safety, and tolerability.²⁴

The choice of antipsychotic medication should be a joint decision by the patient and clinician, considering the views of a caregiver, where appropriate.²⁵

According to the clinical experts consulted by CDA-AMC, medications are prescribed in oral and parenteral formulations, and treat the positive symptoms of psychosis. Currently, there are no approved medications to specifically treat the negative and cognitive symptoms, which are the major predictor of functional outcomes.

Existing antipsychotic drug therapies fall into 1 of 2 classes: typical antipsychotic drugs and AAP drugs. Typical antipsychotic drugs, also known as conventional antipsychotic drugs or neuroleptic drugs, are the first-generation antipsychotic class. These drugs have antagonistic activity at dopamine type 2 (D2) receptors²⁶ and are associated with an increased incidence of EPS adverse effects.²⁴ The second-generation or AAP drugs have antagonistic activity at D2 receptors, histamine₁ receptors, alpha receptors, and serotonin (5-HT_2A) receptors. Table 6 provides a summary of the commonly prescribed oral antipsychotic drugs that are currently marketed in Canada. The risk of the incidence of EPSs appears to be reduced with AAP drugs; however, differences between typical antipsychotic and AAP drugs can be variable in this respect.²⁷ Both typical antipsychotic and AAP drug classes are considered to be equally effective in the treatment of positive symptoms. AAP drugs appear to be more effective in the treatment of negative symptoms;²⁴ however, AAP drugs are associated with an increased risk of weight gain and metabolic adverse effects.¹⁰

The treatment of schizophrenia is typically divided into 3 phases: acute, stabilization, and maintenance. In the acute phase, the patient is routinely experiencing psychotic or positive symptoms, with pharmacotherapy being initiated or adjusted as soon as possible.^10,28 AAP drugs (oral or intramuscular injections) represent first-line treatment, although the formulations administered may differ under certain circumstances (e.g., in the case of nonadherence, in the case of needing rapid control of symptoms). Examples of alternative formulations that may be used in these situations include intramuscular, short-acting injectable treatments. Nonemergent acute presentations still have a degree of urgency as a delay in treatment may lead to patient distress and/or harm to self or others. Moreover, a longer time to treatment has been linked to a less favourable outcome.^29-31 Patients who experience multiple episodes are, as a rule, offered a trial of another antipsychotic drug.^10,28,32 AAP drugs are, again, the treatment of choice unless the patient prefers a typical antipsychotic drug or has had a prior good response to a typical antipsychotic drug.

Canadian guidelines recommend that, following an acute episode of schizophrenia, patients should be offered maintenance treatment with antipsychotic medications at low or moderate regular dosages of around 30 mg to 400 mg of chlorpromazine equivalents, or 4 mg to 6 mg of risperidone or other equivalents daily for 2 years and possibly up to 5 years or longer.²⁵

Based on the input from the clinical experts, patients who have a poor response rate in the treatment of positive symptoms to 2 trials of different antipsychotic drugs are considered treatment-resistant and should be offered clozapine. Canadian guidelines also recommend the prescription of clozapine for patients with treatment-resistant schizophrenia. Approximately 25% to 30% of individuals with schizophrenia meet the criteria for treatment-resistant schizophrenia.^33,34 Among this population, RCTs have reported a response rate with clozapine in the range of 30% to 60%, and clozapine is the only recommended treatment in treatment-resistant schizophrenia.³⁵ The clinical experts noted that clinicians may be reluctant to start clozapine because of the regular blood tests required to monitor for severe adverse effects, and patients may refuse treatment. Consequently, clozapine is underused.

One major obstacle to the effective treatment of schizophrenia is nonadherence to medications, resulting in cycles of relapse.^36,37

The clinical experts consulted for this review indicated that the ideal medication for schizophrenia would reduce the positive and negative symptoms of schizophrenia, have minimal adverse effects, be associated with improved daily function such as improved social and occupational activities and QoL, and improve compliance. According to the experts, currently no such medication exists.

Drug Under Review

Cariprazine is available as 1.5 mg, 3 mg, 4.5 mg, and 6 mg oral capsules. The starting dosage of cariprazine is 1.5 mg daily increased gradually in 1.5 mg increments to a maximum recommended dosage of 6 mg daily.

The mechanism of action for cariprazine is unknown; however, it may be mediated through partial agonist activity at central dopamine type 3 and D2 receptors, and serotonin 5-HT_1A receptors. Cariprazine also has antagonist activity at serotonin 5-HT_2A receptors. Cariprazine forms 2 major metabolites — desmethyl cariprazine and didesmethyl cariprazine — that have in vitro receptor binding profiles similar to the parent drug. The drug and its active metabolites have an extended half-life of 2 days to 4 days for cariprazine, 1 day to 2 days for desmethyl cariprazine, and 1 week to 3 weeks for didesmethyl cariprazine. Due to the long half-life of the drug and its metabolites, changes in dosage will not be fully reflected in the plasma for several weeks; thus, treatment response and the occurrence of adverse effects may be delayed. The product monograph recommends that prescribers monitor patients for adverse reactions and treatment response for several weeks after starting cariprazine and after each dosage change.³⁸

Cariprazine has previously been reviewed by CDA-AMC for the treatment of schizophrenia in adults; however, it received a do not reimburse recommendation from CDEC on March 23, 2022, and this recommendation was upheld upon reconsideration on July 27, 2022.

The reimbursement request for cariprazine is in line with the Health Canada indication for the treatment of schizophrenia in adults. Cariprazine is also approved by Health Canada for use as monotherapy for the acute management of manic or mixed episodes associated with bipolar I disorder in adults, and the acute management of depressive episodes associated with bipolar I disorder in adults.³⁸

Table 6: Characteristics of Orally Administered Antipsychotic Drugs in Canada

SL = sublingual.

^aTypical antipsychotic drugs listed in the systematic review protocol.

Submission History

Basis of Resubmission

Cariprazine was previously reviewed by CADTH for the treatment of schizophrenia in adults.¹ The evidence provided for the original review of cariprazine featured 5 double-blind RCTs, including 3 short-term placebo-controlled studies (the MD-16, MD-04, and MD-05 trials), 1 placebo withdrawal study (the MD-06 trial),² and 1 active-controlled study in patients with predominantly negative symptoms (the 188-05 study), 2 open-label extension studies (the MD-17 and MD-11 studies), and 3 ITCs — 2 published ITCs and 1 unpublished ITC versus other AAP drugs available in Canada. The submission was initially discussed at the March 2022 CDEC meeting and was issued a do not reimburse recommendation by the committee. A request for major reconsideration was submitted by the sponsor, which was discussed at the July 2022 CDEC meeting; the original do not reimburse recommendation was upheld.

In response to the initial draft recommendation, CDA-AMC received written feedback from 3 clinician groups, 2 individual clinicians, and 3 patient groups. This information was discussed as part of the deliberation on the major reconsideration of the recommendation. The feedback received was consistent across stakeholder groups, which spoke to the significant impact of mental health on the lives of patients and caregivers (particularly for those living with schizophrenia), the heterogeneity of the condition and response to treatment, the challenges with conducting clinical trials in this population, and correspondingly, the need for additional treatment options.

The gaps identified by CDA-AMC in the original submission included uncertainty in the clinical relevance of the results of the submitted RCTs, uncertainty in the reported magnitude of effect in treating symptoms for patients presenting with predominantly negative symptoms, limited evidence of the long-term effects of continued cariprazine use, uncertainty in the comparative effectiveness of cariprazine compared to relevant comparators, and uncertainty in the generalizability of the 188-05 study due to the extensive screening and exclusion criteria.

The sponsor filed this resubmission based on new evidence that is intended to address the gaps identified by CDA-AMC and considered by CDEC in the recommendation for the original submission. The evidence provided in the resubmission included:

• 2 RWE studies of cariprazine; the first study included patients with schizophrenia and predominantly negative symptoms, and the second study included patients who met DSM-5 criteria for schizophrenia and cannabis use disorder^10,11

• a responder analysis for the primary end point of the acute schizophrenia trials (the MD-16, MD-04, and MD-05 studies), as defined by a 20% change from baseline in the PANSS total score¹²

• a meta-regression reanalysis of the originally submitted NMA.¹³

The objective of this report is to review and critically appraise the totality of evidence submitted by the sponsor on the beneficial and harmful effects of cariprazine (Vraylar) 1.5 mg to 6 mg oral capsules in the treatment of adult patients with schizophrenia. The emphasis of the clinical review of the resubmission is to appraise whether the additional evidence submitted addresses the gaps identified in the previous review, and to consider the new information alongside the evidence that was reviewed and appraised in the original submission.¹

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups. The full original patient input received by CDA-AMC has been included in the Stakeholder section of this report.

As part of the resubmission, CDA-AMC received 1 joint input for this review from SSC in collaboration with IAM, SSA, CMHA Alberta Division, and MDSC. SSC, IAM, SSA, CMHA, and MDSC are organizations that serve individuals, caregivers, and families living with mental illnesses, including schizophrenia, by advocating for these patients in the community, addressing stigma and discrimination, improving the QoL of those affected by mental health, and informing policy and research.

In collaboration with the submitting organizations, SSC led a series of interviews, focus groups, and surveys, conducted between 2021 and 2023. This included a 2-part national survey for persons with lived experience of early psychosis and schizophrenia (N = 118 responders), and 1 survey for family members of people with early psychosis and schizophrenia (N = 121 responders), as well as a smaller survey for those with personal experience with cariprazine conducted between November and December 2023. The intent of the surveys was to gain an understanding of the impact that positive symptoms, negative symptoms, and cognitive symptoms have on patients and caregivers.

The joint input indicated that the negative symptoms of schizophrenia (i.e., reduced motivation or apathy, reduced emotional expression or feeling, loss of interest, reduced verbal communication, social withdrawal, change in daily functioning, and change in productivity) are those that most people, particularly the public, are fearful of and uncomfortable with. As such, the negative symptoms of schizophrenia greatly diminish social engagement and the integration of patients with schizophrenia.

Among the patients with lived experiences, 76% reported 1 or more positive symptom, primarily delusions. One or more negative symptoms were reported by 94% of patients, mainly consisting of social withdrawal and reduced motivation. Cognitive symptoms were reported by 97% of patients and included difficulty with attention and memory. According to the family member respondents, cognitive symptoms were reported to a higher degree than positive or negative symptoms — mainly, difficulty with daily thinking and/or organizing and difficulty with attention and memory. Positive symptoms reported by family members included hallucinations and disorganized thinking, while the most frequently reported negative symptoms included reduced motivation or apathy, and social withdrawal. The majority of patient responders (94%) were taking medications for early psychosis or schizophrenia, with drowsiness, restlessness, nausea, and weight gain being the most experienced side effects. Additionally, hypertension, diabetes, and cardiovascular problems were considered to affect QoL moderately to greatly. Patient respondents indicated that they seek treatment options that have fewer side effects.

According to the patient group input, more than 1 antipsychotic drug may be needed to address both positive and negative symptoms of schizophrenia, along with a holistic treatment plan that includes psychosocial rehabilitation, family education, recovery-oriented mental health services, psychological support services, substance use issues care, and trauma-informed care. As the negative symptoms have a major impact on social engagement and integration, patients cite the need for a medication that can address the negative symptoms of schizophrenia as none of the typical antipsychotic drugs or AAP drugs are able to target negative symptoms.

Four patients had experience with cariprazine, which had been accessed through private health plans. Most respondents indicated that cariprazine improved the positive, negative, and cognitive symptoms associated with their disease and positively impacted their QoL with tolerable side effects.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

All CDA-AMC 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 for the resubmission was provided by 2 clinical specialists with expertise in the diagnosis and management of schizophrenia.

Unmet Needs

There are no treatments available that target the fundamental disease pathology, which is not fully understood for schizophrenia and related disorders. As such, there are no treatments available that reverse the course of the disease. Furthermore, the clinical experts emphasized that current available treatment options have minimal to no impact on negative and cognitive symptoms of schizophrenia and there is no approved treatment for negative (and cognitive) symptom domains, which are among the major predictors of functional outcomes.

Schizophrenia is a lifelong condition, and many individuals with schizophrenia do not respond to currently available treatment options. Among patients who do respond to treatment, many become refractory to treatment. Moreover, existing treatments have burdensome adverse effects that impact QoL, compliance, and tolerability. The clinical experts indicated that clozapine is an effective treatment for the resistant population. However, 30% to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine monotherapy and require further additions to their treatment regimen. The clinical experts also highlighted that there are only a few long-acting injectables available when adherence and noncompliance are an issue; however, the clinical experts considered there to be a need for more convenient formulations to improve compliance.

Place in Therapy

Treatment with antipsychotic medications is the mainstay of schizophrenia treatment. However, treatment with antipsychotic medications is mostly effective on positive symptoms, and there is minimal to no benefit for negative or cognitive symptoms of schizophrenia, which are 2 major predictors of functioning. The primary goal of treatment with antipsychotic medications is to treat psychosis (i.e., positive symptoms of schizophrenia), which may improve QoL, burden of illness, and safety (i.e., the reduction of suicide and violence), as well as prevent relapse and progression of the disease. In most cases, antipsychotic medications have equal efficacy in treating the first episode of psychosis. Therefore, the clinical experts highlighted that in clinical practice, treatment usually begins with newer antipsychotic medications (i.e., partial agonists), which have a more benign and manageable side effect profile (e.g., aripiprazole). Treatment guidelines suggest 2 separate trials of antipsychotic medications of adequate dose and duration, followed by clozapine if response was poor (i.e., treatment-resistant schizophrenia). However, many patients with multiple relapses tend not to respond to the previous medications and/or dosage. The clinical experts noted that 30% to 70% of patients with schizophrenia have a suboptimal response to clozapine (ultraresistant schizophrenia); however, there is no guideline for the management of schizophrenia after the failure of clozapine. Options generally include the addition of a second antipsychotic medication, a mood stabilizer, or ECT. The clinical experts also highlighted that amisulpride may be accessed through special access programs.

The mechanism of action of cariprazine is different than that of other available antipsychotic drugs. Similar to aripiprazole and brexpiprazole, cariprazine is a partial agonist for D2 receptors, which may differentiate these drugs from other antipsychotic drugs. The clinical experts indicated that cariprazine could be used similarly to other AAP medications as monotherapy, though it could also be useful as a first-line therapy in the first episode of psychosis. Additionally, the clinical experts highlighted cariprazine’s potential for use as add-on therapy to other drugs when needed, due to the potential benefits in addressing negative symptoms. Considering there are no other options available to treat negative symptoms, the experts stated that cariprazine represents an additional treatment option and it is expected that some patients will benefit from it. Overall, the clinical experts stated that cariprazine would be another treatment option within their armamentarium, which would be ideal when all other options have been exhausted.

Patient Population

The manifestation of schizophrenia is remarkably heterogenous; as a result, treatment goals for each patient could be very different. While there are many factors considered when choosing specific antipsychotic drugs, the experts noted that efficacy is not necessarily predictable, and most often comes down to trial and error. It was highlighted that cariprazine would not be reserved for patients who are intolerant of other antipsychotic drugs. The experts stated that based on their experience, cariprazine is well tolerated overall and has a better side effect profile than many other antipsychotic drugs. However, for patients sensitive to akathisia, cariprazine may not be the most appropriate choice.

The clinical experts noted that there is no lab or diagnostic tests to predict who will respond to treatment with various antipsychotic drugs, and that the choice of antipsychotic drug is usually decided by the clinical judgment of the treating psychiatrist in collaboration with patients and families to treat psychotic symptoms. However, the experts did note that patients with a high burden of negative symptoms could be considered as candidates for cariprazine above other antipsychotic medications.

Assessing the Response Treatment

According to the clinical experts, full remission of psychotic symptoms is ideal; however, many patients will not attain full remission. For inpatients, the main goal of treatment is to attain a degree of symptom control that is compatible with living in the community. For outpatients, controlling symptoms as well as working on recovery goals (i.e., vocational, leisure, or self-care goals) become the target of treatment. The clinical experts highlighted that no measures of treatment response are applied in clinical practice; rather, response to treatment is based on the subjective experience of patients, as well as improvement in functional capability and overall clinical assessment. With regard to clinical trials, a 20% to 30% reduction in PANSS (or other psychosis rating scale) total score is used to confirm response to antipsychotic medication. However, as noted, such measures are not used in routine practice in Canada. The clinical experts highlighted that response to treatment is different depending on the stage of disease, and evaluating response depends on the treatment setting. For inpatient treatment, response is assessed daily as symptoms of psychosis are managed, while in the outpatient setting, response may be assessed weekly to every 4 weeks through a multidisciplinary case management team, depending on how patients are handling their daily lives. Per the clinical experts, the most important outcomes are the reduction in negative symptoms as there are no approved treatments available to address these. However, given the heterogeneity of the disease, treatments generally impact different domains of positive and negative symptoms, making an overall response assessment difficult, with interpretations relying heavily on clinical judgment.

Though it is impossible to predict which patients will respond to treatment, the clinical experts highlighted that most patients (approximately 85%) respond to antipsychotic medications following their first psychotic episode. Treatment-resistant schizophrenia tends to occur in approximately 30% of patients, and patients with resistant or relapsed disease tend to respond to fewer treatments. Treatment response and the determination of treatment resistance is generally guided by the determination of the adequate dose and adequate duration while confirming adherence. Based on their experience, the clinical experts noted that early signs of intolerable side effects will predict poor outcomes; however, it also generally results in distrust between patients and health care practitioners.

Discontinuing Treatment

According to the clinical experts, the primary reason for the discontinuation of treatment is a lack of clinical response despite adequate dosage and duration, or intolerable side effects, which are common among antipsychotic treatments. Key side effects include akathisia as well as metabolic side effects and weight gain, which are common with other antipsychotic drugs. The clinical experts also noted that cariprazine is associated with a longer half-life; thus, it can be stopped abruptly without withdrawal symptoms or concerns.

Prescribing Considerations

The experts stated that psychiatrists are most often involved in diagnosing schizophrenia and initiating therapy, to monitor potential adverse effects. However, the clinical experts also noted that general practitioners currently prescribe and monitor many antipsychotic drugs; thus, they should be able to prescribe cariprazine following proper education. Additionally, the experts noted that no specialized setting would be required to prescribe and monitor treatment.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups. The full original clinician group input received by CDA-AMC has been included in the Stakeholder section of this report.

Three clinician groups provided input for the resubmission: the CCEIP group (3 clinicians contributed to the input), the National Advisory Board (20 clinicians contributed to the input), and a group of Quebec psychiatrists (7 clinicians contributed to the input). The CCEIP is a national, not-for-profit organization of clinicians and researchers with a mandate to enhance optimum care for patients living in Canada in the early phase of psychosis. The National Advisory Board consists of Canadian psychiatrists with experience in the management of schizophrenia. The psychiatrists from Quebec represent a group of clinicians that practices in both urban and rural settings.

Clinicians highlighted that early intervention with pharmacologic and nonpharmacologic approaches can help address important treatment goals such as improving the course of psychosis to lead to a period of stability, returning to preillness social and occupational levels of functioning, and decreasing the risk of suicide. The CCEIP highlighted many obstacles to current treatments, including treatment delays, nonadherence to treatment, substance use, low and ephemeral remission rates, and a lack of response for negative symptoms. In line with the clinical experts, the clinician groups highlighted that current treatment regimens in Canada focus primarily on positive symptoms (e.g., delusions, hallucinations). The CCEIP and the National Advisory Board identified significant unmet needs in the management of schizophrenia, highlighting that that there are currently no medications available in Canada that target negative symptoms. Given that up to 60% of patients with schizophrenia has negative symptoms, they considered this important as negative symptoms are a major driver of short-term and long-term functional outcomes that are strongly correlated with cognitive dysfunction, poorer QoL, increased disease burden, and higher costs.

The CCEIP highlighted that for young adults in the early phase of psychosis (within the first 5 years of illness), current treatments may not optimize their long-term outcomes. According to the CCEIP, there is a rapid period of progression of psychosis before and in the 3 years to 5 years following the first presentation. Moreover, clinician groups stated that nearly 75% of patients relapse within 5 years of their first episode, and at least one-third of patients are refractory to currently available treatment options. The lack of long-acting formulations may contribute to poor adherence and further physical and psychological comorbidities. For this reason, clinician groups noted that it is necessary to offer patients treatment options for both positive and negative symptoms, and in multiple formulations to reduce symptom burden and maximize HRQoL. Clinician groups highlighted that ideal treatments would address the constellation of positive, negative, and cognitive symptoms, and should be associated with improved tolerability.

In line with the clinical experts consulted by CDA-AMC, the CCEIP and the National Advisory Board indicated that cariprazine could be used as a first-line antipsychotic drug, with a focus on those with early phase psychosis, as these patients are most likely to respond to treatment. Additionally, clinician groups considered cariprazine ideal for patients with negative symptoms, as well as those who have not fully responded over time. The CCEIP and Quebec psychiatrists stated that cariprazine is particularly relevant for patients with adherence concerns and reluctance to use long-acting injectable antipsychotic drugs, and those who have encountered tolerability issues, given the longer half-life and more favourable metabolic tolerability profile of cariprazine. Conversely, patients with treatment-refractory schizophrenia or with comorbidities (specifically, individuals with substance abuse and intellectual impairment) would least likely benefit from treatment with cariprazine.

The input provided by clinician groups highlighted that response is assessed through multidisciplinary clinical observation to establish a reduction in positive and negative symptoms, improvement in QoL, and the ability to function more independently. In addition, gaining stability of illness or preventing recurrence or relapse are measures of successful treatment. In clinical trials, response is often defined as reduction in key evaluative scale scores (e.g., PANSS); however, the clinician groups also stated that these assessments are not routinely conducted in clinical practice. The clinician groups indicated that the discontinuation of therapy should be considered based on the lack of or suboptimal response, tolerability issues, as well as nonadherence. The Quebec psychiatrists stated that the main AEs likely to cause discontinuation of treatment include excessive drowsiness, cognitive disturbance, sexual dysfunction, metabolic effects, and hormonal and weight-related changes, which they note are less of a concern with cariprazine. If adherence is an issue, switching to a long-acting injectable antipsychotic drug should be considered, though the National Advisory Board and Quebec psychiatrists also stated that the tolerability of cariprazine represents a significant added value, improving treatment adherence, compliance, and overall acceptability, which is imperative for the success of schizophrenia therapy.

According to the CCEIP and the National Advisory Board, the treatment of patients with schizophrenia is provided in both inpatient and outpatient settings, as well as in the emergency department, often under the care of a multidisciplinary team, with medication decisions and choices usually determined by the psychiatrist.

Drug Program Input

The drug programs provide input on each drug being reviewed through CDA-AMC’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 CDA-AMC for the resubmission are summarized in Table 7.

Table 7: Summary of Drug Plan Input and Clinical Expert Response

AAP = atypical antipsychotic; CDEC = Canadian Drug Expert Committee; D2 = dopamine type 2; NMA = network meta-analysis; RWE = real-world evidence.

Clinical Evidence From the Original Vraylar Review

The clinical evidence included in the review of cariprazine is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CDA-AMC and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted, long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of cariprazine for the treatment of schizophrenia in adults

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CDA-AMC and Health Canada, as well as those studies meeting the selection criteria presented in Table 8. Outcomes included in the CDA-AMC review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 8: Inclusion Criteria for the Systematic Review

AE = adverse event; HRQoL = health-related quality of life; RCT = randomized controlled trial; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

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.⁵²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid, Embase (1974‒) via Ovid, and APA PyscINFO (1806‒) 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 consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Vraylar (cariprazine). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, 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 26, 2021. Regular alerts updated the search until the meeting of CDEC on March 23, 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.⁵³ Included in this search were the websites of regulatory agencies (US FDA and EMA). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

Two CDA-AMC 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.

Findings From the Literature

A total of 5 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 9 and Table 10.

A list of excluded studies is presented in Appendix 2.

Table 9: Details of Studies Included in the Systematic Review

BMI = body mass index; CDR = Cognitive Drug Research; C-SSRS = Columbia-Suicide Severity Rating Scale; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; CNS = central nervous system; CTT = Color Trails Test; CV = cardiovascular; DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; ECG = electrocardiogram; ECT = electroconvulsive therapy; EPS = extrapyramidal symptom; NSA-16 = 16-item Negative Symptom Assessment; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; SIADH = syndrome of inappropriate antidiuretic hormone secretion; SQLS-R4 = Schizophrenia Quality of Life Scale Revision 4.

Note: Three additional reports were included (US FDA Medical and Statistical Reports, EPAR report).

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ and Clinical Study Report for MD-05.

Table 10: Details of MD-06 and 188-05 Included Studies

BMI = body mass index; CDSS = Calgary Depression Scale for Schizophrenia; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; CNS = central nervous system; CV = cardiovascular; DB = double-blind; DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; ECG = electrocardiogram; ECT = electroconvulsive therapy; EPS = extrapyramidal symptom; G8 = general psychopathology 8; G9 = general psychopathology 9; G14 = general psychopathology 14; NA = not applicable; NSA-16 = 16-item Negative Symptom Assessment; P1 = positive 1; P2 = positive 2; P3 = positive 3; P5 = positive 5; P6 = positive 6; P7 = positive 7; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; RCT = randomized controlled trial; SIADH = syndrome of inappropriate antidiuretic hormone secretion.

^aDuring the lead-in period, patients continued their current antipsychotic medications and were assessed for clinical status and the presence, severity, and stability of negative symptoms at week 2 and week 4.

^bThis included a 2-week treatment titration period followed by a 24-week treatment continuation period. During the titration period, patients’ current antipsychotic medications were down-titrated and the study drug was up-titrated to the target dose of either cariprazine 4.5 mg daily or risperidone 4 mg daily. The study drug was the only antipsychotic medication patients received during the stabilization period.

Sources: Clinical Study Report for MD-06² and Clinical Study Report for 188-05.¹⁵

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Five RCTs met the inclusion criteria for the systematic review in the original review of cariprazine, including 3 short-term studies (Table 9), 1 randomized withdrawal study, and 1 study in patients with predominantly negative symptoms (Table 10).

The objective of the MD-16, MD-04, and MD-05 studies was to assess the efficacy, safety, and tolerability of cariprazine compared with placebo in patients with an acute exacerbation of schizophrenia. These 6-week, double-blind RCTs randomized patients to receive placebo or either a fixed or flexible dosing of cariprazine. Two studies also included an active control group for assay sensitivity (i.e., to ensure the study was adequate to detect a drug effect if cariprazine did not separate from placebo). In the MD-16 study, 732 patients were randomized 1:1:1:1:1 to placebo, cariprazine 1.5 mg, cariprazine 3 mg, or cariprazine 4.5 mg daily, or risperidone 4 mg daily. The MD-04 study randomized 617 patients to placebo, cariprazine 3 mg, cariprazine 6 mg, or aripiprazole 10 mg daily (1:1:1:1), and the MD-05 study randomized 446 patients to either placebo, cariprazine 3 mg to 6 mg daily, or cariprazine 6 mg to 9 mg daily (1:1:1). All 3 studies used a similar study design, as shown in Figure 2. Patients were hospitalized before randomization during the medication washout period and for at least the first 4 weeks of the double-blind treatment period. After 4 weeks, patients could be discharged at the discretion of the investigator if the CGI-S score was 3 (mildly ill) or less, and if the investigator assessed that the patient was ready for discharge and that there was no significant risk of suicide or violent behaviour. Patients not meeting these criteria remained in hospital, and any discharged patient who experienced a clinical deterioration could be readmitted. To randomize patients to treatment, each study site was supplied with study drug products corresponding to a sequence of randomized numbers; as patients were enrolled, they were assigned the first (lowest) available number in the sequence. The primary outcome was change from baseline to week 6 in the PANSS total score.

The objective of the MD-06 study was to evaluate the efficacy and safety of cariprazine in the prevention of the relapse of symptoms in patients with schizophrenia, relative to placebo. The trial included a drug washout screening phase (up to 7 days), an 8-week run-in phase, a 12-week stabilization phase, a 26-week to 72-week double-blind phase, and a 4-week safety follow-up phase (Figure 3). During the run-in phase, all patients received open-label cariprazine at a dose of 3 mg, 6 mg, or 9 mg daily (flexibly dosed during the first 6 weeks with dosing fixed for the last 2 weeks). Patients who completed the run-in phase and met the treatment response and tolerability criteria (≥ 20% reduction in the PANSS total scores with a score ≤ 60 points, and a score ≤ 4 on specific PANSS items, a CGI-S score ≤ 4, and no significant tolerability issues.) entered the stabilization phase, and continued to receive open-label cariprazine at the same fixed dose as they received previously. Patients who completed the stabilization phase and met the week 20 response and tolerability criteria (N = 200) were randomized (1:1) using an interactive voice or web response system to receive double-blind cariprazine (same dose) or placebo for a minimum of 26 weeks and a maximum of 72 weeks, or until relapse or early termination occurred. The study was stopped once the last patient randomized had completed 26 weeks in the double-blind period. Time to relapse was the primary outcome of the study.

In the MD-06 study, all patients were hospitalized during the drug washout screening phase (while prior psychotropic medications were stopped) and for the first 2 weeks of the run-in phase. Patients could be discharged after 2 weeks in the run-in phase or could remain in hospital for another 2 weeks at the discretion of the investigator.

The objective of the 188-05 study was to evaluate the safety, efficacy, and tolerability of cariprazine versus risperidone in patients with schizophrenia and predominantly negative symptoms. The trial consisted of a 4-week lead-in period, where patients continued with current antipsychotic drugs and were evaluated for the stability of schizophrenia symptoms (Figure 4). After the lead-in phase, those who continued to meet the inclusion criteria (N = 461) were then randomized (1:1) via an interactive voice or web response system to receive double-blind cariprazine or risperidone for 26 weeks. In the first 2 weeks after randomization, prior antipsychotic drugs were down-titrated and discontinued, and the study drug was up-titrated to the target dose of cariprazine 4.5 mg daily (range, 3 mg to 6 mg) or risperidone 4 mg daily (range, 3 mg to 6 mg). The primary outcome was change from baseline to week 26 in the PANSS FSNS.

The studies were conducted between 2008 and 2014 in Eastern and Western Europe, the US, South Africa, India, Malaysia, and Colombia. There were no Canadian study sites in any of the included studies.

Patients who completed the 6-week MD-16 study were eligible to enter the open-label MD-17 extension study, and those who completed the MD-04 or MD-05 study were eligible to enter the open-label MD-11 extension study.

Figure 2: Study Design Schematic for MD-04 Trial on Acute Schizophrenia

Source: Clinical Study Report for MD-04.⁵⁸

Figure 3: Study Design Schematic for MD-06 Randomized Withdrawal Trial

DBP = double-blind phase; ET = early termination; IP = investigational product; RIP = run-in phase; SFU = safety follow-up; SP = stabilization phase.

^aAll patients were hospitalized during screening and for the first 2 weeks of the RIP. After 2 weeks of open-label treatment in the RIP, patients could be discharged and followed as outpatients, or they could remain hospitalized for an additional 2 weeks.

Source: Clinical Study Report for MD-06.²

Figure 4: Study Design Schematic for 188-05 Trial

D = day, IMP = investigational medicinal product.

Source: Clinical Study Report for 188-05.¹⁵

Populations

Inclusion and Exclusion Criteria

The acute schizophrenia studies enrolled adults aged 18 years to 60 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia, and who had had a schizophrenia diagnosis for at least 1 year (excluding patients in their first episode of psychosis who were allowed to enter the MD-16 study). In addition, the current psychotic episode was less than 2 weeks in duration and patients had a structured clinical interview for a PANSS total score of between 80 and 120 and a CGI-S score of at least 4, which is rated as moderately ill (additional criteria listed in Table 9).

The patients enrolled in the withdrawal design study (the MD-06 trial) were required to meet inclusion criteria at screening that was similar as those in the 6-week studies; however, at week 8 and week 20, additional criteria were applied. The patients had to show at least a 20% reduction in the PANSS total score with a score 60 points or less, and a score of 4 or less on specific PANSS items, a CGI-S score of 4 or less, and no significant cariprazine tolerability issues (refer to Table 10).

In the acute schizophrenia and withdrawal design studies, patients were excluded if they met DSM-IV-TR diagnostic criteria for other mental health disorders, including schizoaffective, bipolar, developmental, cognitive, or severe Axis II disorders. In addition, patients with alcohol or substance abuse or dependence, treatment-resistant schizophrenia, active suicidal or homicidal intent, or a history of prior attempt were excluded from the studies. Medical exclusions included patients with HIV, hepatitis B, or hepatitis C (unless stable), a history of seizures or related central nervous system disorders, tardive dyskinesia or neuroleptic malignant syndrome, or any clinically significant cardiovascular disease or uncontrolled medical condition. Patients who had used clozapine in the past 10 years were excluded (except for episodic use of clozapine for insomnia at ≤ 100 mg per day) or required concomitant treatment with a prohibited medication. The MD-04, MD-05, and MD-06 studies excluded patients experiencing a first episode of psychosis.

The 188-05 study enrolled adults aged 18 years to 65 years who met the criteria of the DSM-IV-TR for schizophrenia (for at least 2 years) and had predominantly negative symptoms for at least 6 months (i.e., PANSS FSNS ≥ 24 and a rating of ≥ 4 [moderate] for 2 of 3 PANSS items for flat affect, avolition, and poverty of speech). Prior to enrolment, patients could be receiving antipsychotic drugs if the total daily dose was equivalent to 6 mg risperidone (if on 1 drug) or 8 mg risperidone (if on 2 drugs). The 188-05 study excluded patients with other psychiatric, neurological, or behavioural disorders, clinically unstable schizophrenia, significant positive schizophrenia symptoms, moderate to severe depressive symptoms, or who had used an antidepressant in the past 3 months. Other psychiatric, medical, or treatment-related exclusion criteria were similar to those of the acute trials (refer to Table 10 for details).

Interventions

In the MD-16, MD-04, and MD-05 studies, the double-blind treatment period was 6 weeks in duration.

In the MD-16 study, the study drug was supplied as encapsulated cariprazine 1.5 mg or 3 mg tablets, encapsulated risperidone 2 mg tablets, or encapsulated placebo that were identical in appearance and packaging. Each patient received 2 capsules a day that provided either placebo, cariprazine 1.5 mg, cariprazine 3 mg, or cariprazine 4.5 mg, or risperidone 4 mg per day. The dose of cariprazine and risperidone was increased over the first 1 day to 2 days of therapy for patients in the risperidone group and the cariprazine 3 mg and 4.5 mg groups until the randomized daily dose was reached.

In the MD-04 study, patients received identical-looking capsules that contained cariprazine 1.5 mg, cariprazine 3 mg, placebo, or aripiprazole 5 mg. Each patient received 2 capsules a day that provided either placebo, cariprazine 3 mg or 6 mg, or aripiprazole 10 mg daily. The initial dose of cariprazine was increased over the first few days by 1.5 mg daily until the randomized dose (i.e., 3 mg or 6 mg per day) was reached. There was no dose titration period for patients assigned to aripiprazole.

In the MD-05 study, patients received identical-looking capsules that contained cariprazine 1.5 mg, cariprazine 3 mg, cariprazine 6 mg, or placebo. The study used an initial flexible dosing regimen with response assessed at week 2, after which the dose of the study drug was fixed. At the start of therapy, each patient received 1 capsule a day that provided either placebo, cariprazine 3 mg, or cariprazine 6 mg daily for the first 2 weeks of therapy. At the end of week 2, treatment response was assessed and patients with an inadequate response (< 20% improvement in the PANSS total score) and who did not have significant tolerability issues received a dose increase of 1 capsule per day. Thus, for patients in the cariprazine low-dose group, the dose was increased to 6 mg per day, and for those in the high-dose group, the dose was increased to 9 mg per day. At week 2, patients with tolerability issues or those showing an adequate response to therapy remained on the initial dose of the study drug. The dose of cariprazine remained fixed between week 3 and week 6. At the start of therapy, and with the any-week 2 dose increases, the dose of cariprazine was titrated up in 1.5 mg increments over 1 day to 4 days (depending on the target dose).

For the short-term studies, the study sites had access to a tear-off label that contained the treatment allocation for each package of study drug, which was to be opened only in case of an emergency. Patients were disqualified from continuing in the study if the randomization code was broken by the study site. The Clinical Study Report (CSR) for the MD-16 study states that blinding was maintained for all patients.

In the MD-06 study, the study drug was supplied as capsules that contained either placebo, cariprazine 1.5 mg, or cariprazine 3 mg that were identical in appearance and packaging. During the 8-week run-in phase, patients received open-label cariprazine that was flexibly dosed at 3 mg, 6 mg, or 9 mg daily for the first 6 weeks, with dosing fixed for the last 2 weeks. During the run-in phase, tolerability and treatment response were assessed on day 4, and the dose of cariprazine could be increased at the discretion of the investigator from 3 mg to 6 mg daily; starting on day 10, the dose could be increased to 9 mg daily. The dose could be decreased at any time during the first 6 weeks of the run-in phase if there were significant tolerability issues. No further dose adjustments, except for a temporary 3-day drug holiday for dose-limiting AEs, were allowed after the first 6 weeks of the run-in phase. Patients who met the treatment response and tolerability inclusion criteria for the stabilization phase (refer to Table 10) continued to receive open-label cariprazine 3 mg, 6 mg, or 9 mg for 12 weeks based on the same fixed dose as that of the end of the run-in phase. No dose increases were allowed, but a dose decrease, or temporary drug holiday of 3 days, was allowed if there were significant tolerability issues as judged by the investigator. Patients who could not tolerate cariprazine 3 mg daily were discontinued from the study. At week 20, patients who continued to meet the treatment response and tolerability inclusion criteria (refer to Table 10) were randomized to receive double-blind placebo or cariprazine at the same fixed dose as received earlier (3 mg, 6 mg, or 9 mg daily) for a minimum of 26 weeks, a maximum of 72 weeks, or until relapse occurred.

In the 188-05 study, patients enrolled could have been untreated or were receiving treatment with 1 or 2 antipsychotic drugs at a maximum total daily dose equivalent to 6 mg of risperidone (if on 1 drug) or 8 mg of risperidone (if on 2 drugs). Patients remained on the same antipsychotic drug regimen during the 28-day prospective lead-in period, with no change in drug or dose allowed. Patients were then randomized to receive double-blind cariprazine or risperidone, with the study drug up-titrated and the prior antipsychotic drug down-titrated during the first 2 weeks. The dose of study drug was increased in 1.5 mg increments for cariprazine and 1 mg increments for risperidone to the target dose of cariprazine 4.5 mg daily and risperidone 4 mg daily by day 14. Doses were fixed for 1 week, then from day 21 onward, the dose of the double-blind study medication could be decreased at the investigator’s discretion to cariprazine 3 mg or risperidone 3 mg per day, in case of poor tolerability, or increased to 6 mg per day of cariprazine or risperidone in the case of impending psychotic deterioration. Doses could return to the target dose as determined by the investigator. Decreasing or increasing the dose of the study drug from the target dose was allowed only once for each modification during the double-blind phase. In addition, short 3-day treatment interruptions were allowed, if needed. During the first 2 weeks following randomization, the dosage of the antipsychotic medication that the patient took during the prospective lead-in period was down-titrated. The investigator had the option to extend the withdrawal of prior antipsychotic drugs to 4 weeks if needed to decrease the severity of symptoms associated with the withdrawal effects or the occurrence of an impending deterioration. The study drug was supplied as encapsulated risperidone 1 mg, 2 mg, or 3 mg, or cariprazine 1.5 mg or 3 mg that were identical in appearance. The total duration of the double-blind treatment period was 26 weeks.

Concomitant and Prohibited Medications

In the 3-week to 6-week trials and the MD-06 study, patients were prohibited from receiving other psychotropic medications, including the following: antipsychotic drugs or neuroleptic drugs, antidepressants (including monoamine oxidase-B inhibitors), stimulants, anticonvulsants or mood stabilizers, sedatives, hypnotics, anxiolytics, dopamine-releasing drugs or dopamine agonists, and psychotropic drugs not otherwise specified (including herbal products). Tapering and the discontinuation of psychotropic medications occurred before randomization, during the washout period (up to 7 days in duration). In the 188-05 study, patients continued prior antipsychotic medications during the lead-in phase, and then these medications were down-titrated and discontinued over the first 2 weeks to 4 weeks after randomization. Other psychotropic medications from the previously mentioned list were to be discontinued during the lead-in period. Patients who received prohibited psychotropic medications were withdrawn from the studies.

ECT was not allowed during the MD-04, MD-05, and MD-06 studies. Patients were asked to abstain from alcohol during the studies. Strong inducers and inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 were to be avoided due to effects on cariprazine pharmacokinetics.

During the trials, prespecified doses of zolpidem, zaleplon, chloral hydrate, eszopiclone, or zopiclone (the MD-06 and 188-05 trials only) were allowed for the treatment of insomnia. In addition, diphenhydramine, benztropine (or trihexyphenidyl), and propranolol were allowed to manage EPSs or akathisia that emerged or worsened during the studies. In the 188-05 study, no medications for EPSs were allowed during the lead-in period, but rescue therapy was permitted during the double-blind phase.

Rescue therapy with lorazepam was allowed to control agitation, restlessness, irritability, hostility, and insomnia during the washout period and double-blind treatment period of the 6-week trials, with maximum dosage limits that decreased over time from 6 mg to 2 mg per day. For countries where lorazepam was not available, rescue therapy with oxazepam and diazepam, at prespecified doses, was allowed. Lorazepam (or alternatives) was also allowed during the run-in phase of the MD-06 study and after randomization in the 188-05 study during the titration phase, with a maximum dose of 2 mg per day thereafter.

Outcomes

A list of efficacy end points identified in the CDA-AMC review protocol that were assessed in the clinical trials included in this review is provided and further summarized in Table 11. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

The primary outcome in the 6-week trials was the change from baseline in the PANSS total score, with the change from baseline in the CGI-S as the secondary outcome. Time to relapse was the primary outcome in the MD-06 study. In the 188-05 study, the primary outcome was the change from baseline to week 26 in the PANSS FSNS and the secondary outcome was the change from baseline in the PSP score. The CSRs report that the outcome assessments were conducted by experienced raters who met the training requirements for each instrument.

Table 11: Summary of Outcomes of Interest Identified in the CDA-AMC Review

CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; NA = not applicable; NSA-16 = 16-item Negative Symptom Assessment; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale.

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ Clinical Study Report for MD-05,⁶¹ Clinical Study Report for MD-06,² and Clinical Study Report for 188-05.¹⁵

PANSS

The PANSS is a 30-item rating scale that assesses the presence and severity of psychopathology. It consists of 3 subscales (positive symptoms, negative symptoms, and general psychopathology), as well as a total score. The PANSS is based on a structured clinical interview, with each item scored on a 7-point scale (1 [absent] to 7 [extreme]). The positive and negative subscale scores range from 7 to 49, and the total score ranges from 30 to 210, with higher scores indicating more severe symptoms or psychopathology.

The 7-item PANSS FSNS includes 5 items from the negative subscale and 2 items from the general psychopathology subscale and is scored from 7 to 49, with higher scores representing more severe symptoms. Table 12 lists the items included in PANSS positive, negative, and FSNS subscales.

Appendix 4 outlines the available data on the validity and reliability of the PANSS total and subscale scores. No data were available on responsiveness. The MID is unclear and may be dependent on the baseline severity. However, at least a 20% decrease in the FSNS or the total score, or at least a 15-point reduction in the total score, may be associated with clinical improvement.^62-67 According to the EMA, a responder threshold of a 30% reduction on the total PANSS score from baseline is considered clinically relevant in short-term clinical trials.⁶⁸

Table 12: Items in the PANSS Positive, Negative, and FSNS

FSNS = factor score for negative symptoms; PANSS = Positive and Negative Syndrome Scale.

Source: Clinical Study Report for MD-16.⁵⁷

CGI-S or CGI-I

The CGI-S tool measures the overall severity of mental disorders at the time of the clinician’s assessment, and the CGI-I tool measures the change from baseline in the overall severity of illness, each based on a 7-point scale (Table 13). There is limited information on the validity and reliability of these measures in patients with schizophrenia. A 1-point change has been used as a predefined measure of clinical improvement or criteria for response to antipsychotic treatment in a number of clinical trials.^65-67

Table 13: Descriptions and Scoring for the CGI-S and CGI-I Tools

CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness.

Source: Clinical Study Report for MD-16.⁵⁷

Time to Relapse

The primary efficacy parameter in the MD-06 study was the time to first relapse during the double-blind period, defined as the number of days from the randomization date to the relapse date. Relapse was defined as meeting 1 or more of the following criteria:

• psychiatric hospitalization due to worsening of the patient’s underlying condition

• an increase in the PANSS total score by 30% or more for patients who scored 50 or higher at randomization or a 10-point or more increase for patients who scored less than 50 at randomization

• an increase from the end of the stabilization period in CGI-S score by 2 or more points

• deliberate self-injury or aggressive or violent behaviour

• suicidal or homicidal ideation that was clinically significant as judged by the investigator

• a score of greater than 4 on 1 or more of the following PANSS items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behaviour), P6 (suspiciousness/Persecution), P7 (hostility), G8 (uncooperativeness) or G14 (poor impulse control).

Changes in the PANSS or CGI-S scores were to be confirmed at a repeat visit within 7 days. Patients who did not meet the relapse criteria were censored at the time of study completion or discontinuation from the study.

Personal and Social Performance Scale

The PSP is a single-item, clinician-rated scale that assesses the presence and level of difficulties in personal and social functioning in patients with schizophrenia over the previous month in 4 main areas: socially useful activities, including work; personal and social relationships; self-care; and disturbing and aggressive behaviours.⁶⁹ The PSP is scored from 1 to 100, with a higher score indicating higher personal and social functioning. A between-group difference of 7 points to 10 points has been reported in the literature as representing an MID.^65,66

Schizophrenia Quality of Life Scale Revision 4

The SQLS-R4 is a 33-item scale with 2 domains (psychosocial; cognition and vitality) that measure HRQoL in individuals with schizophrenia. The items are scored on a 5-point scale (never to always), with scoring transformed to range from 0 to 100 for both the total and subscale scores, and higher scores indicating relatively worse QoL. No information on the MID was identified for the SQLS-R4.

16-Item Negative Symptom Assessment

The 16-item Negative Symptom Assessment (NSA-16) is a 16-item scale that examines the presence, severity, and range of negative symptoms associated with schizophrenia. It includes 5 domains: communication, emotion/affect, social involvement, motivation, and retardation. Each item is rated on a 6-point scale and the total score ranges from 16 to 96, with higher scores indicating more severe symptoms. There is evidence of construct validity in patients with schizophrenia, but the MID is unclear.⁷⁰

Harms

An AE was defined as any untoward medical occurrence that did not necessarily have a causal relationship with the study drug reported during treatment or up to 30 days after the last dose of the study drug. SAEs included any death, life-threatening adverse drug experience, inpatient hospitalization or prolongation of hospitalization, persistent or significant disability, congenital anomaly or birth defect, or any event that required medical intervention to prevent 1 of the outcomes listed in the definition.

Suicidal ideation or behaviour was documented using the C-SSRS.

Statistical Analysis

The statistical analyses conducted in the RCTs are summarized in Table 14.

In the MD-16 study, the change from baseline to week 6 in the PANSS total score and other continuous outcomes was analyzed using an analysis of covariance (ANCOVA) model that included a study centre and the baseline value as covariates. LOCF was used to impute missing postbaseline outcome values. A sequential multiple-comparison procedure was used to control the overall type I error for the 3 doses of cariprazine. In step 1, the average effect of the 3 mg and 4.5 mg doses was compared with that of placebo. If the global test was significant at the 2-sided significance level of 0.05, then step 2 was performed; otherwise, the analysis was stopped. For step 2, each of the 3 mg and 4.5 mg dosage groups was compared with placebo. If both tests were statistically significant, then step 3 was performed; otherwise, the analysis was stopped. In step 3, the cariprazine 1.5 mg dosage group was compared with placebo at the 2-sided significance level of 0.05. A similar 3-step closed testing procedure was used for the inferential testing of the secondary outcome (CGI-S) only if the results of the primary outcome for all 3 comparisons were significant at the 0.05 level. There was no control of type I error for the comparison between risperidone and placebo for the primary or secondary outcomes, or for other efficacy outcomes reported.

Based on the enrolment of 135 patients in each of the treatment groups, the MD-16 study was estimated to have 80% power to detect an effect size of 0.4 for cariprazine and placebo (adjusting for multiple comparisons of the 3 cariprazine doses) for the change from baseline in the PANSS total score. No citations were provided to support the assumed effect size used in the power calculations, and it is unclear if losses to follow-up were considered in the calculations.

The MD-04 and MD-05 studies used similar methods to conduct the statistical analyses. The primary outcome of change from baseline in the PANSS total score was analyzed using a mixed model of repeated measures (MMRM) that included pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction terms. MMRM models were run based on observed case data with no imputation for missing data, centred on the assumption that patient data are missing at random. Sensitivity analyses were run that used a pattern-mixture model or an ANCOVA model with LOCF to explore alternate assumptions for missing data. The pattern-mixture model assumes that the probability of dropout at a specific visit is dependent on the observed value and the possibly missing value up to that visit, but not future values beyond that visit. Secondary and other continuous outcomes were analyzed using the same MMRM or ANCOVA (LOCF) models, and responder analyses were run using logistic regression models as described in Table 14. All statistical tests were 2-sided with an alpha of 0.05.

The MD-04 and MD-05 studies used a matched parallel gatekeeping procedure to control the overall type I error rate. In the first step, each cariprazine dosage group was compared with placebo for the change from baseline in the PANSS total score. If at least 1 dosage group showed a P value less than 0.05, then testing of the secondary hypothesis proceeded, and each cariprazine dosage group was compared with placebo for the change from baseline in the CGI-S score. The significance for a given dosage group could only be claimed for the CGI-S if the primary null hypothesis was rejected (i.e., the PANSS total score was statistically significant for that dosage group). There was no control of multiplicity for other comparisons (e.g., aripiprazole versus placebo) or outcomes.

Table 14: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; DB = double-blind; LOCF = last observation carried forward; mITT = modified intention to treat; MMRM = mixed model of repeated measures; NR = not reported; NSA-16 = 16-item Negative Symptom Assessment; OC = observed case; OL = open-label; PANSS = Positive and Negative Syndrome Scale; PH = proportional hazards; PSP = Personal and Social Performance Scale; SQLS-R4 = Schizophrenia Quality of Life Revision 4; vs. = versus.

^aFor analysis of CGI-I, the baseline CGI-S value was included in the model.

^bThis outcome was planned to be analyzed using an MMRM model in the statistical plan, but data were reported based on an ANCOVA mixed-effects model using OC data (no imputation for missing data).

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ Clinical Study Report for MD-05,⁶¹ Clinical Study Report for MD-06,² and Clinical Study Report for 188-05.¹⁵

The MD-04 and MD-05 studies were estimated to have 88% power to detect a difference between cariprazine and placebo in the PANSS total score, based on 150 patients per group and adjusting for multiplicity for the 2 dosage groups and 2 efficacy parameters. These calculations were based on an estimated effect size of 0.42 for the primary outcome, a 2-sided significance level of 5%, a correlation coefficient of within-patient assessments of 0.7, and a 35% withdrawal rate. No citations were listed to support the assumptions used in the power calculations.

In the MD-06 withdrawal design study, the primary outcome was the time to relapse for cariprazine versus placebo among patients who demonstrated adequate response to and tolerability of cariprazine during the run-in and stabilization periods. Between-group differences were tested based on a log-rank test with the HRs and 95% CIs based on an unadjusted Cox proportional hazards model. Patients who did not experience a relapse were censored at their early withdrawal date or the study termination date. No secondary outcomes were defined in the study, and all other efficacy outcomes were reported descriptively, with no between-group comparisons estimated.

The sample size of the MD-06 study assumed a 46-week accrual period and a 26-week double-blind treatment period; thus, the maximum follow-up period was 72 weeks. An HR of 0.48 was assumed for the time to relapse, based on a 26-week cumulative relapse rate of 25% and 45% for the cariprazine and placebo groups, respectively, and an early termination rate (for reasons other than relapse) of 20%. With a total of 80 relapse events observed, the study would have 90% power to detect a difference between cariprazine and placebo using a 2-tailed log-rank test at a 5% significance level. Based on these calculations, 180 patients would need to be randomized in the double-blind phase. To achieve this sample size, an estimated 900 patients were to be enrolled in the study, assuming 50% of patients would complete the run-in phase and 40% of patients would complete the stabilization phase. No citations were listed to support the assumptions used in the power calculations.

The primary outcome of the 188-05 study was the change from baseline to week 26 in the PANSS FSNS, which was analyzed using an MMRM model that included pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction terms. Sensitivity analyses were run using a pattern-mixture model and ANCOVA (LOCF) model to examine the impact of different assumptions for missing data. A similar model was used for the secondary outcome (the change from baseline in the PSP score). The secondary outcome was formally tested only if the primary outcome was statistically significant. There was no control of multiplicity for any other outcomes reported.

With a planned sample size of 210 patients per treatment group, the 188-05 study had an estimated power of 90% to detect an effect size of 0.25 in the PANSS FSNS at a 2-sided significance level of 5%. The power calculations assumed a treatment difference of 2.25 points and a pooled SD of 9 points, a correlation coefficient of 0.2 between repeated measurements, and a 10% attrition rate. Data sources for the assumptions used in the power calculations were not listed in the CSR.

With regard to subgroups, the MD-16 and MD-06 studies did not analyze any subgroups, and the other 3 studies did not report data for any subgroups of interest that were listed in the protocol of this review.

Analysis Populations

In the MD-16, MD-04, MD-05, and 188-05 studies, the safety population included all randomized patients who received at least 1 dose of the study drug. The modified intention-to-treat (mITT) population included all randomized patients who received at least 1 dose of the study drug and had at least 1 postbaseline assessment of the primary efficacy outcome.

The MD-06 study included the following populations:

• run-in safety population (all patients who took at least 1 dose of open-label cariprazine during the run-in phase)

• stabilization safety population (all patients who took at least 1 dose of open-label cariprazine during the stabilization phase)

• open-label mITT population (all patients in the run-in safety population who had at least 1 postbaseline assessment of the PANSS during the open-label phase of the study)

• randomized population (all patients in the stabilization safety population who were randomized to a treatment group during the double-blind phase of the study)

• double-blind safety population (all patients in the randomized population who took at least 1 dose of the double-blind study drug)

• double-blind mITT population (all patients in the double-blind safety population who had at least 1 postrandomization assessment of PANSS or CGI-S during the double-blind phase of the study).

Results

Patient Disposition

Across the 6-week trials, 67% to 74% of patients screened were randomized to placebo or active treatment groups. The frequency with withdrawals ranged from 38% to 48% of patients in the placebo groups, 33% to 42% of patients in the cariprazine groups, and 25% to 28% of patients in the active control groups. AEs, insufficient therapeutic response, and withdrawal of consent were the most commonly reported reasons for withdrawal. The frequency of withdrawals was generally similar across groups within studies, except for the MD-16 trial where 48% of patients in the placebo group withdrew versus 28% to 38% of patients in the active treatment groups (risperidone or cariprazine), and in the MD-04 study, where 25% of patients withdrew from the aripiprazole group versus 33% to 38% of patients in the cariprazine groups and 38% of patients in the placebo group.

In the MD-05 study, 1 US centre (N = 6) and 1 centre in India (N = 6) were excluded from the analyses due to good clinical practice violations in study conduct. Of these patients, 8 patients completed the study and 4 patients withdrew early. Sensitivity analyses that included these patients showed results that were similar to the analysis that excluded these centres. One patient was enrolled in the study twice. The second enrolment was excluded from the analysis (the patient had received placebo for 7 days).

Table 15: Patient Disposition for MD-16 Study on Acute Schizophrenia

CAR = cariprazine; mITT = modified intention to treat; RIS = risperidone.

^aOf the 279 patients who did not advance past the screening stage, the reasons for exclusion were as follows: the patient did not meet eligibility criteria (n = 221), there was withdrawal of consent (n = 47), the patient discontinued due to an adverse event (n = 6), or other reason (n = 5).

Source: Clinical Study Report for MD-16.⁵⁷

Table 16: Patient Disposition for MD-04 and MD-05 Studies on Acute Schizophrenia

ARIP = aripiprazole; CAR = cariprazine; mITT = modified intention to treat.

^aOf the 217 patients who did not advance past the screening stage in the MD-04 study, the reasons for exclusion were as follows: the patient did not meet eligibility criteria (n = 185), there was withdrawal of consent (n = 22), the patient discontinued due to an adverse event (n = 2), there was a protocol violation (n = 2), or other reason (n = 6).

^bA total of 218 patients were screened but were not randomized in the MD-05 study because they did not meet the eligibility criteria (n = 171), withdrew consent (n = 35), there was an adverse event (n = 3), there was a protocol violation (n = 1), or other reason (n = 8).

Sources: Clinical Study Report for MD-04⁵⁸ and Clinical Study Report for MD-05.⁶¹

Table 17: Patient Disposition for MD-06 Withdrawal Design Study

mITT = modified intention to treat.

^aOf the 384 patients who were screened but not enrolled, the most common reasons for exclusion were that the patient did not meet study criteria (n = 339), there was withdrawal of consent (n = 40), there was an adverse event (n = 1), or other reason (n = 4).

^bThe Clinical Study Report states, “Nearly all ‘other reasons’ for discontinuation were because the last randomized patient had completed at least 26 weeks of double-blind treatment, thus, per protocol, double-blind treatment for all active patients was stopped.”

Source: Clinical Study Report for MD-06.²

Table 18: Patient Disposition for 188-05 Study on Predominantly Negative Symptoms

mITT = modified intention to treat.

^aThere were 72 patients screened but not randomized. The most common reasons for this were that the patient did not meet study criteria (n = 57), there was withdrawal of consent (n = 14), or the patient was lost to follow-up (n = 1).

Source: Clinical Study Report for 188-05.¹⁵

In the relapse prevention study, 67% of patients screened entered the run-in phase and started open-label cariprazine (N = 765). During the run-in phase, 45% of patients withdrew, 13% of patients discontinued during the stabilization phase, and another 15% of patients opted to not continue into the next phase of the trial. Thus, 200 (26%) patients of the 765 patients who started the trial were randomized. During the run-in phase, the most common reasons for discontinuation were withdrawal of consent (15%), AEs (12%), and insufficient therapeutic response (11%). In the stabilization phase, the most common reason for withdrawal was randomization limits having been met (7%) and withdrawal of consent (5%). During the double-blind phase, 16% and 18% of patients completed the study, 48% and 25% of patients had a relapse, and 36% and 57% of patients discontinued from the study in the placebo and cariprazine groups, respectively. Withdrawal of consent accounted for 10% and 15% of discontinuations, and other reasons were listed for 11% and 27% of placebo and cariprazine-treated patients, respectively. The CSR states the “nearly all” other reasons were because the last randomized patient had completed at least 26 weeks of treatment, and the study was stopped.

In the 188-05 study of predominantly negative symptoms, 461 (87%) patients of the 533 patients screened were randomized. In both the cariprazine and risperidone groups, 23% of patients discontinued the study primarily due to AEs (10% and 11% of patients, respectively) or withdrawal of consent (7% and 7% of patients, respectively).

Baseline Characteristics

The mean age of patients enrolled in the acute schizophrenia trials ranged from 35.5 years (SD = 9.3 years) to 39.3 years (SD = 10.8 years), and the proportion of males ranged from 62% to 78% per treatment group (Table 19 and Table 20). The race distribution varied across studies. In the MD-16 and MD-04 studies, at least half of patients were white, and approximately 23% of patients were Black. In the MD-05 study, Black and Asian patients each comprised approximately 37% of patients enrolled, and 19% of patients were white. The mean baseline PANSS total score was approximately 96 points across studies (range, 95.6 to 98.1), and the majority of patients were categorized as markedly ill based on the CGI-S score. The mean number of prior hospitalizations was 7.4 (SD = 8.2) for the MD-04 study and 6.3 (SD = 8.1) for the MD-16 study but was lower for the MD-05 study (mean = 4.1; SD = 5.4). In general, the patient characteristics appeared to be balanced between groups within trials.

Table 19: Summary of Baseline Characteristics for MD-16 Study on Acute Schizophrenia

BMI = body mass index; CAR = cariprazine; CGI-S = Clinical Global Impression–Severity of Illness; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SD = standard deviation.

^aBased on the modified intention-to-treat population.

Source: Clinical Study Report for MD-16.⁵⁷

In the MD-06 withdrawal design study, the mean age of patients who entered the run-in stage was 38.4 years (SD = 10.4 years), 71% was male, 41% was Black, and 39% was white. The demographics of patients who were randomized was similar. In the placebo and cariprazine groups, respectively, the mean age was 37.7 years (SD = 10.1 years) and 39.2 years (SD = 10.9 years), and 71% and 61% of patients were male. The overall proportion of patients who were Black was 31%, and 42% was white. At the start of the run-in phase, the mean PANSS total score was 91.3 (SD = 10.1) points and 54% of patients were markedly ill. At randomization, the PANSS total score was 50.9 points (SD = 6.7 points), and most patients were mildly ill based on the CGI-S score. There were differences between groups in the number of previous psychiatric hospitalizations; however, the impact of these differences is unclear (Table 21).

Table 20: Summary of Baseline Characteristics for MD-04 and MD-05 Studies on Acute Schizophrenia

ARIP = aripiprazole; BMI = body mass index; CAR = cariprazine; CGI-S = Clinical Global Impression–Severity of Illness; PANSS = Positive and Negative Syndrome Scale; SD = standard deviation.

^aBased on the modified intention-to-treat population.

Sources: Clinical Study Report for MD-04⁵⁸ and Clinical Study Report for MD-05.⁶¹

The mean age of patients enrolled in the 188-05 study was 40.4 years (SD = 10.8 years), 57% were male, and 95% were white (Table 21). Overall, 60% of patients had fewer than 5 prior exacerbations and 30% of patients had between 5 events and 10 events. The mean baseline PANSS score was approximately 76 points (SD = approximately 8 points), with ███ classified as moderately ill and ███ classified as markedly ill, according to the CGI-S score.

Exposure to Study Treatment

In the 6-week acute schizophrenia trials, the treatment duration for placebo and active treatment groups was generally similar between groups and ranged from 30.5 days (SD = 13.8 days) to 36.4 days (SD = 11.8 days) (details shown in Table 22).

In the MD-05 study, the overall modal daily dose for patients in the cariprazine 3 mg to 6 mg group was 3 mg for 57 (38%) patients and 6 mg for 93 (62%) patients (1 patient received 1.5 mg daily). For those in the cariprazine 6 mg to 9 mg group, the modal dose was 6 mg for 58 (39%) patients and 9 mg for 84 (57%) patients (6 [4%] patients received a dose of 1.5 mg or 3 mg per day).

Approximately half of patients in the MD-16 and MD-04 studies received rescue therapy with benzodiazepines whereas in the MD-05 study, at least 80% of patients required rescue therapy.

Table 21: Summary of Baseline Characteristics for MD-06 and 188-05 Studies on Withdrawal and Negative Symptoms

BMI = body mass index; CAR = cariprazine; CGI-S = Clinical Global Impression–Severity of Illness; NR = not reported; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SD = standard deviation.

^aFor the 188-05 study, the data reported are the number of psychiatric hospitalizations in the past 12 months.

^bBased on the modified intention-to-treat population.

^cThis was based on the mITT population for study MD-06.

Sources: Clinical Study Report for MD-06² and Clinical Study Report for 188-05.¹⁵

Table 22: Treatment Exposure for MD-16, MD-04, and MD-05 Studies on Acute Schizophrenia

ARIP = aripiprazole; CAR = cariprazine; RIS = risperidone; SD = standard deviation.

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ and Clinical Study Report for MD-05.⁶¹

For the withdrawal design study (the MD-06 trial), the mean duration of treatment was 75.7 days (SD = 54.2 days) in the open-label cariprazine phase, and for the double-blind phase, the mean treatment duration was 205.9 days (SD = 176.7 days) in the placebo group and 257 days (SD = 184.0 days) in the cariprazine group (Table 23). The final daily dose of cariprazine in the double-blind phase was 3 mg for 14% of patients, 6 mg for 37% of patients, and 9 mg for 50% of patients.

In the MD-06 study, 193 (25%) patients received lorazepam, and 22 (2.9%) patients received another benzodiazepine as rescue medication during the open-label treatment period. In the double-blind period, 8 (8%) patients in the placebo group and 6 (6%) patients in the cariprazine group received rescue treatment with a benzodiazepine. The proportion of patients who received rescue therapy for extrapyramidal adverse effects or insomnia was similar between treatment groups in the double-blind phase.

Table 23: Treatment Exposure for MD-06 Withdrawal Design Study

CAR = cariprazine; NA = not applicable; SD = standard deviation.

^aThe final dose in a total of 15 patients was either 1.5 mg, 4.5 mg, or 90 mg (an overdose in 1 patient).

Source: Clinical Study Report for MD-06.²

In the 188-05 predominantly negative symptoms trial, most patients (91%) were receiving a psycholeptic drug before enrolment, which was titrated down over a median 15 days (range, 1 to 29 days). The mean study drug duration was similar between groups (cariprazine: 155.0 days [SD = 53.6 days]; risperidone: 157.8 days [SD = 51.6 days]). Most patients received the target dose of cariprazine 4.5 mg daily (███) and risperidone 4 mg daily (███) (Table 24).

The CSR for the 188-05 trial states that the use of rescue therapy for insomnia, treatment-emergent extrapyramidal adverse effects, and agitation was generally low during the trial, with no notable differences between treatment groups.

Table 24: Treatment Exposure for 188-05 Study on Predominantly Negative Symptoms

CAR = cariprazine; RIS = risperidone; SD = standard deviation.

Source: Clinical Study Report for 188-05.¹⁵

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol of the original cariprazine review are reported as follows. Supplementary efficacy data are included in Appendix 3.

None of the included studies analyzed data on psychiatric hospitalization or persistence with therapy as an efficacy parameter. The limited information on hospitalizations has been summarized as follows for the acute and relapse studies. Please refer to the Disposition section for a summary of premature study discontinuation, and to the Harms section for study drug DAEs.

Acute Schizophrenia Studies

Symptoms

The primary outcome in the 3 acute schizophrenia trials was the change from baseline to week 6 in the PANSS total score for cariprazine versus placebo.

All the active and placebo treatment groups showed an improvement in the mean PANSS total score at week 6. The primary efficacy objective was met in all 3 studies, with all cariprazine dosage groups (1.5 mg to 9 mg daily) showing statistically significant mean differences versus placebo. The LSM differences versus placebo ranged from –6.8 (95% CI, –11.3 to –2.4; P = 0.003) for the cariprazine 3 mg to 6 mg group in the MD-05 study to –10.4 (95% CI, –14.6 to –6.2; P < 0.0001) for the cariprazine 4.5 mg group in the MD-16 trial (Table 25).

The active control groups in the MD-16 and MD-04 studies also showed differences that favoured risperidone and aripiprazole versus placebo in the change from baseline in the PANSS total score, but these analyses were not part of the fixed testing procedure to control the type I error. No statistical testing was performed comparing cariprazine to active control groups.

The proportion of patients with a 30% or greater improvement in the PANSS total score was higher for the cariprazine 1.5 mg, 3 mg, and 4.5 mg groups (31.4%, 35.7%, and 35.9%, respectively) and the risperidone group (43.5%) compared with the placebo group (18.9%) in the MD-16 study (all P < 0.05). In the MD-04 study, the proportion of responders was higher for cariprazine 6 mg (31.8%; P = 0.013) and aripiprazole (30.0%; P = 0.031) than placebo (19.5%), but with no difference detected between cariprazine 3 mg and placebo (24.5%, P = 0.28). No difference in the proportion of responders was detected between the cariprazine 3 mg to 6 mg group (28.6%) or the cariprazine 6 mg to 9 mg group (34.7%) and the placebo group (24.8%) in the MD-05 study (both P > 0.05). There was no control of the type I error rate for the responder analyses; thus, any results showing a P value of less than 0.05 should be interpreted as supportive evidence only (Appendix 3, Table 50).

The results of the analyses of the change from baseline in the PANSS positive and negative subscale scores were consistent with the results of the analyses of primary outcomes, with all but 1 analysis showing results that favoured cariprazine versus placebo (Appendix 3, Table 51). These outcomes, however, were not controlled for the type I error rate and should be interpreted as supportive evidence only.

Sensitivity analyses generally showed results that were consistent with the primary analysis, including the MMRM analysis in the MD-16 trial, and the ANCOVA (LOCF) and pattern-mixture models in the MD-04 and MD-05 trials. In the MD-16 study, the ANCOVA analysis based on observed case data did not show statistically significant differences for cariprazine versus placebo. Additional conservative sensitivity analyses requested by the EMA for the PANSS (baseline observation carried forward) or responder analyses (nonresponder imputation) were reported to show “reasonably similar estimates of the treatment effects.”⁷¹

Table 25: Change From Baseline to Week 6 in PANSS Total Score (mITT Population)

ANCOVA = analysis of covariance; ARIP = aripiprazole; CAR = cariprazine; CI = confidence interval; LOCF = last observation carried forward; LSM = least squares mean; mITT = modified intention to treat; MMRM = mixed model of repeated measures; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SD = standard deviation; SE = standard error; vs. = versus.

^aAn ANCOVA model was used with pooled study centre and baseline value as covariates, and LOCF for missing data (mITT population).

^bP value was < 0.0001 for the comparison of the average effect of the cariprazine 3 mg and 4.5 mg groups vs. placebo.

^cP value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

^dAn MMRM was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction.

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ and Clinical Study Report for MD-05.⁶¹

The change from baseline to week 6 in the CGI-S score was the secondary outcome in the acute schizophrenia trials. The LSM differences favoured all cariprazine dosage groups versus placebo, with treatment effects that ranged from –0.3 (95% CI, –0.6 to –0.1; P = 0.0115) to –0.6 (95% CI, –0.9 to –0.4; P < 0.0001) (Table 26).

Table 26 also summarizes the CGI-I score at week 6 and the LSM differences versus placebo. The point estimates ranged from –0.5 to –0.9 for cariprazine groups versus placebo. There was no control for the type I error rate for this outcome; thus, these data should be interpreted as supportive evidence only.

Data for the NSA-16 is shown in Appendix 3, Table 52. Most comparisons favoured cariprazine versus placebo; however, the interpretation of these data may be limited by the lack of an MID for the NSA-16, and the potential for an inflated type I error rate due to multiple testing.

Table 26: Change From Baseline to Week 6 in CGI-S and CGI-I Scores (mITT Population)

ANCOVA = analysis of covariance; ARIP = aripiprazole; CAR = cariprazine; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; CI = confidence interval; LOCF = last observation carried forward; LSM = least squares mean; mITT = modified intention to treat; MMRM = mixed model of repeated measures; RIS = risperidone; SD = standard deviation; SE = standard error; vs. = versus.

^aAn ANCOVA model was used with pooled study centre and baseline CGI-S value as covariates, and LOCF for missing data (mITT population).

^bP value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

^cP value was < 0.0001 for the comparison of the average effect of the cariprazine 3 mg and 4.5 mg groups vs. placebo.

^dMMRM was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction.

Sources: Clinical Study Report for MD-16,⁵⁷ Clinical Study Report for MD-04,⁵⁸ and Clinical Study Report for MD-05.⁶¹

Health-Related Quality of Life

Two 6-week studies reported data on HRQoL using the SQLS-R4. The SQLS-R4 total score ranges from 0 to 100, with higher scores indicating worse QoL. The MID of this instrument is unclear.

In the MD-04 study, the LSM difference in the change from baseline in SQLS-R4 total scores was –6.8 points (95% CI, –11.2 points to –2.4 points; P = 0.0027) for the cariprazine 3 mg group and –8.3 points (95% CI, –12.7 points to –4.0 points; P = 0.0002) for the cariprazine 6 mg group versus the placebo group (Table 27). In the MD-05 study, the LSM difference favoured the lower-dose cariprazine group (3 mg to 6 mg) versus the placebo group by –5.0 points (95% CI, –9.8 points to –0.1 points; P = 0.044) but not the cariprazine 6 mg to 9 mg group (–3.5 points (95% CI, –8.5 points to 1.4 points; P = 0.157). The type I error rate was not controlled for this outcome; thus, any data showing a P value of less than 0.05 should be interpreted as supportive evidence only.

Hospitalization

All patients were hospitalized for at least 28 days in the acute schizophrenia studies. Overall, 18% to 29% of patients were discharged after day 28, and 1% to 2% of patients were rehospitalized between day 29 and day 42, across the 3 studies.

In the MD-16 study, the proportion of patients discharged was 17% for the placebo group, 25% to 40% for the cariprazine groups, and 36% for the risperidone group. In the MD-04 study, 12% of patients in the placebo group, 15% to 20% of patients in the cariprazine groups, and 22% of patients in the aripiprazole group were discharged. In the MD-05 study, 20% of patients in the placebo group and 23% to 28% of patients in the cariprazine groups were discharged. The frequency of rehospitalizations was low and generally similar between groups within studies.

Table 27: Change From Baseline to Week 6 in SQLS-R4 Total Score (mITT Population)

ANCOVA = analysis of covariance; ARIP = aripiprazole; CAR = cariprazine; CI = confidence interval; LOCF = last observation carried forward; LSM = least squares mean; mITT = modified intention to treat; SD = standard deviation; SE = standard error; SQLS-R4 = Schizophrenia Quality of Life Scale Revision 4; vs. = versus.

^aAn ANCOVA model was used with pooled study centre and baseline value as covariates, and LOCF for missing data (mITT population).

^bThe P value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

Sources: Clinical Study Report for MD-04⁵⁸ and Clinical Study Report for MD-05.⁶¹

Withdrawal Design Trial

Relapse

Time to relapse was the primary outcome in the MD-06 study. Relapse was defined as a composite end point that included clinical outcomes (e.g., hospitalization, self-harm) as well as criteria based on standardized symptom and disease severity rating scales.

Among patients who had demonstrated treatment response to cariprazine during the 20-week open-label phase of the MD-06 study, 47.5% of patients experienced a relapse after being switched to placebo compared with 24.8% of patients who remained on cariprazine therapy (Table 28). The between-group differences favoured cariprazine versus placebo with an HR of 0.45 (95% CI, 0.28 to 0.73; P = 0.001).

The most common relapse criteria reported in the placebo and cariprazine groups was a 30% or greater increase in the PANSS total score (43.4% versus 20.8%, respectively), followed by an increase of 2 points or more in CGI-S score (28.3% versus 4.0%, respectively), or a score greater than 4 on specific PANSS items (25.3% versus 10.9%, respectively). The relapse study reported that 9 (9%) patients per treatment group were hospitalized due to worsening conditions during the double-blind period. Four (4%) patients in the placebo group and no patients in the cariprazine group reported deliberate self-injury or aggressive or violent behaviour.

Table 28: Time to Relapse for MD-06 Study (DB mITT Population)

CAR = cariprazine; CGI-S = Clinical Global Impression–Severity of Illness; CI = confidence interval; DB = double-blind; HR = hazard ratio; mITT = modified intention to treat; NE = not estimable; PANSS = Positive and Negative Syndrome Scale.

^aThe HR was based on a Cox proportional hazards model (unadjusted) and the P value was based on a log-rank test. Percentiles and 95% CI were based on Kaplan-Meier estimates.

^bThese were P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behaviour), P6 (suspiciousness/persecution), P7 (hostility), G8 (uncooperativeness), or G14 (poor impulse control).

Source: Clinical Study Report for MD-06.²

The cumulative incidence of relapse during the double-blind phase of the MD-06 study is shown in Figure 5. The Kaplan-Meier curves begin to separate after 50 days, with the placebo group showing a higher incidence of relapse than the cariprazine group. However, it should be noted that the number of patients who remained in the study was low in the later time points, with less than half the patients at risk at 6 months of follow-up.

Figure 5: Kaplan-Meier Curves of Cumulative Rate of Relapse in MD-06 Study (DB mITT Population)

DB = double-blind; mITT = modified intention to treat.

Source: Clinical Study Report for MD-06.²

A post hoc sensitivity analysis was conducted to assess the robustness of the primary analysis results to the potential violation of the noninformative censoring assumption. In this reference-based controlled imputation, the statistical significance of cariprazine versus placebo for the time to relapse was retained over the range of the sensitivity parameters.

Descriptive data on the within-group change in the PANSS total, CGI-S, and PSP scores are shown in Appendix 3, Table 53. No between-group comparisons were reported for these outcomes.

Predominantly Negative Symptoms Study

Symptoms

In the 188-05 study, the primary outcome was the change from baseline to week 26 in the PANSS FSNS. The scores ranged from 7 to 49, with a lower score indicating fewer symptoms. Both treatment groups showed an improvement over time with an LSM change score of –8.9 for the cariprazine group and –7.4 for the risperidone group. The LSM difference was –1.5 (95% CI, –2.4 to –0.5; P = 0.002), favouring cariprazine versus risperidone (Table 29). Sensitivity analyses based on ANCOVA (LOCF) and pattern-mixture models showed results that were consistent with the primary MMRM analysis.

In the responder analysis, 157 (69.2%) patients who received cariprazine and 133 (58.1%) patients who received risperidone attained at least a 20% reduction in the PANSS FSNS at week 26. The CSR states that the planned logistic regression model had poor fit and thus, estimates had poor reliability. The between-group difference in the percentage of responders was reported based on a post hoc logistic regression model using Firth’s penalized likelihood approach (with the study centre and baseline value as covariates and LOCF for missing data); this estimated a response OR of 2.1 (95% CI, 1.3 to 3.3; P = 0.002) for cariprazine versus risperidone. Of note, this outcome should be interpreted as supportive evidence only as there was no control of the type I error rate.

Additional results are shown in Table 29. Between-group differences favoured cariprazine versus risperidone for the LSM change from baseline in the PANSS negative subscale at –1.5 points (95% CI, –2.4 points to –0.6 points; P < 0.001), the CGI-S score at –0.2 points (95% CI, –0.4 points to –0.1 points; P = 0.005), and the CGI-I score at –0.4 points (95% CI, –0.6 points to –0.2 points; P < 0.001). No differences were detected between groups for the PANSS total score or positive subscale score. There was no control of type I error rate; thus, any outcomes showing P values of less than 0.05 should be interpreted as supportive evidence only.

Table 29: Symptom Severity Outcomes in 188-05 Study (mITT Population)

CAR = cariprazine; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity of Illness; CI = confidence interval; LSM = least squares mean; mITT = modified intention to treat; MMRM = mixed model of repeated measures; NA = not applicable; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SD = standard deviation; SE = standard error; vs. = versus.

^aMMRM was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline value-by-visit interaction.

^bP value was not adjusted for multiple testing (i.e., the type I error rate was not controlled).

Source: Clinical Study Report for 188-05.¹⁵

Functional Capacity

The change from baseline to week 26 in the PSP was the secondary outcome in the 188-05 study. The PSP is scored from 0 to 100, with higher scores indicating better psychosocial function. A between-group difference of 7 points to 10 points has been reported in the literature as the MID.

In the 188-05 study, the cariprazine and risperidone groups both reported an improvement in the mean PSP scores at week 26 with increases of 14.3 points and 9.7 points, respectively. The LSM difference was 4.6 points (95% CI, 2.7 points to 6.6 points; P < 0.001), favouring cariprazine versus risperidone (Table 30).

Table 30: Change From Baseline to Week 26 in PSP Scores — 188-05 Study on Predominantly Negative Symptoms (mITT Population)

ANCOVA = analysis of covariance; CAR = cariprazine; CI = confidence interval; LSM = least squares mean; mITT = modified intention to treat; PSP = Personal and Social Performance Scale; RIS = risperidone; SD = standard deviation; SE = standard error; vs. = versus.

^aANCOVA mixed-effects model was used with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline-value-by-visit interaction as covariates.

Source: Clinical Study Report for 188-05.¹⁵

Harms

Only those harms identified in the review protocol are reported as follows. Refer to Table 31, Table 32, and Table 33 for detailed harms data.

Adverse Events

Among the 6-week studies, the frequency of AEs ranged from 66% to 67% in the placebo groups, 61% to 78% in the cariprazine groups, and 66% to 68% in the active control groups (Table 31 and Table 32). The most frequently reported AEs in the cariprazine groups were insomnia, akathisia, and headache (each reported in 7% to 17% of patients).

In the withdrawal design study (the MD-06 trial), 80% of patients reported an AE during the 20-week, open-label cariprazine treatment phase, compared with 74% and 65% of patients who received cariprazine and placebo, respectively, during the 26-week to 72-week double-blind phase. Akathisia was reported by 19% of patients during open-label treatment, but only 3% to 5% of patients during the double-blind phase. The frequency of insomnia (14%) and headache (12%) was higher during the open-label treatment phase than during the double-blind treatment phase (7% or 8% per group) (Table 33).

In the 26-week study in patients with predominantly negative symptoms (the 188-05 study), 54% of patients in the cariprazine group and 57% of patients in the risperidone group experienced 1 or more AE (Table 33). Insomnia, akathisia, and headache were reported in 6% to 9% of patients in the cariprazine group and in 5% to 10% of those in the risperidone group.

Serious Adverse Events

The frequency of SAEs ranged from 1% to 9% of patients in the placebo groups, 3% to 6% of those in the cariprazine groups, and 3% to 4% of patients in the active control groups of the acute schizophrenia trials. SAEs were reported in 7% and 14% of patients in the open-label and double-blind phases, respectively, of the MD-06 trial and in 3% of patients per group in the 188-05 study. Schizophrenia and psychotic disorder were the most frequently reported SAEs.

Withdrawals Due to Adverse Events

The proportion of patients who withdrew from the studies due to AEs ranged from 9% to 15% in the placebo groups, 6% to 14% in the cariprazine groups, and 9% to 12% in the active control groups. Schizophrenia and psychotic disorder were the most common AEs leading to study withdrawal.

Mortality

Two patients died in the 6 mg cariprazine dosage group of the MD-04 study (suicide; ischemic stroke and myocardial infarction), and 1 patient died in the risperidone group of the 188-05 study (carcinoma). No deaths were reported in the other treatment groups.

Notable Harms

In the 6-week studies, treatment-emergent EPSs were reported by 12% to 16% of patients in the placebo group, 17% to 41% of patients in the cariprazine groups, and 16% and 29% of patients in the aripiprazole and risperidone groups, respectively (Table 31 and Table 32). The frequency of EPSs was similar in the cariprazine and risperidone groups of the 188-05 study (14% versus 13% of patients), and in the MD-06 study, EPSs were reported in 40% of patients receiving open-label cariprazine, in 21% of patients who remained on cariprazine, and in 7% of patients who switched to placebo during the double-blind phase. The frequency of discontinuation due to extrapyramidal AEs was low, ranging from 0% to 2% per treatment group across the short-term and longer-term studies.

Suicidal ideation or behaviour was infrequently reported in the acute and longer-term studies. Based on the C-SSRS, 1% to 5% of patients reported suicidal ideation and 0% to 0.4% of patients reported suicidal behaviour across treatment groups. In the 6-week MD-16 study, 1 patient in the cariprazine 4.5 mg group discontinued due to suicidal ideation, and in the MD-05 study, 1 patient in the placebo group discontinued due to a suicidal ideation SAE. One died by suicide was reported in the cariprazine 6 mg group of the MD-04 study. During the open-label cariprazine phase of the MD-06 study, 7 (0.9%) patients discontinued due to suicidal ideation, 5 (0.7%) patients had SAEs of suicidal ideation, and 1 patient had a suicide attempt classified as an SAE. ███ ███████ ██████ attempted suicide in the risperidone group of the 188-05 study (an SAE).

During the run-in phase of the MD-06 study, 1 patient receiving cariprazine reported a treatment-emergent gambling behaviour described as an impulse control disorder. No other AEs related to compulsive behaviour were reported in the other 4 studies.

The frequency of sedation or somnolence ranged from 0% to 8% across the cariprazine groups compared with 0% to 3% in the placebo groups and 0% to 11% in the active control groups.

In the 6-week studies, 5% to 11% of patients who received cariprazine reported a clinically important increase in body weight (defined as ≥ 7%) versus 2% to 4% of patients in the placebo group, 6% of patients in the aripiprazole group, and 17% of patients in the risperidone group. In the MD-06 study, a 7% or greater increase in body weight was reported in 11% of patients during the open-label cariprazine phase, and in 27% to 32% of those in the cariprazine and placebo groups of the double-blind phase. In the 188-05 study, ██ and ██ in the cariprazine and risperidone groups, respectively, reported at least a 7% increase in weight. TEAEs related to metabolic effects are shown in Table 31, Table 32, and Table 33.

Table 31: Summary of Harms in MD-16 Study (DB Phase, Safety Population)

CAR = cariprazine; C-SSRS = Columbia-Suicide Severity Rating Scale; DB = double-blind; EPS = extrapyramidal symptom; NR = not reported; RIS = risperidone; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aFrequency > 10%.

^bSAEs were reported during the double-blind and safety follow-up periods.

^cReported in 2 or more patients in 1 treatment group.

^dFrequency > 3%.

^eOne patient in the risperidone group died of cardiorespiratory arrest, 1 day after randomization before receiving a dose of risperidone. No deaths were reported during the safety follow-up period.

Source: Clinical Study Report for MD-16.⁵⁷

Table 32: Summary of Harms in MD-04 and MD-05 Studies (Safety Population)