CADTH Reimbursement Review

Cariprazine (Vraylar)

Sponsor: Allergan, an AbbVie company

Therapeutic area: Schizophrenia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Schizophrenia is a chronic mental illness that affects the way a person interacts with and understands the world. The condition, when active, is characterized by delusions, hallucinations, disorganized speech, disorganized behaviour, and impaired cognitive ability.¹ The symptoms associated with schizophrenia are categorized as either positive or negative in nature. Positive symptoms reflect a distortion or abundance of normal functions, while negative symptoms reflect a loss or restriction of normal functioning. The severity, duration, and frequency of these symptoms can cause social and occupational challenges. Antipsychotic medications, which target the characteristic symptoms of schizophrenia, form the cornerstone of treatment.^1-3

According to national data (2016 to 2017), 1 out of 100 Canadians aged 10 years or older is living with schizophrenia.⁴ Schizophrenia is associated with tremendous health, social, and economic burden, and people living with schizophrenia are at increased risk for other medical illnesses, suicide, substance abuse, homelessness, and unemployment.^5,6

Cariprazine is an atypical antipsychotic (AAP) drug that is approved by Health Canada for the treatment of schizophrenia in adults.⁷ 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.⁷ The suggested initial dosage is 1.5 mg daily, which may be increased in 1.5 mg increments to a maximum of 6 mg daily.⁷ 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 objective of this report is to perform a systematic review of the beneficial and harmful effects of cariprazine 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 who responded to CADTH’s call for input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received 2 responses to its call for patient input for this review: a submission from the Institute for Advancements in Mental Health (IAM) and a joint submission from the Schizophrenia Society of Canada (SSC) and the Canadian Mental Health Association (CMHA) Alberta Division. IAM, SSC, and CMHA are organizations that serve individuals living with mental illnesses, including schizophrenia, their families, and community members.

The patient input was based on 2 online surveys of members of IAM’s client network that were conducted in 2021 and 2018. Among the 19 respondents to the 2021 survey, 26% identified as living with symptoms of schizophrenia or psychosis, 37% were relatives of someone with lived experience, 5% were friends of someone with lived experience, and 32% were caregivers of someone with lived experience. Among the respondents to the 2018 survey, 12% self-described as having a diagnosis of schizophrenia or psychosis, 50% were caregivers, 63% were family members or friends of someone diagnosed, and 18% worked in social services. SSC drew information from its national online surveys, focus groups, and interviews, which were conducted mainly in Canada in 2021. Among the 239 survey respondents, 118 were patients with lived experience of early psychosis and schizophrenia and 121 were family members.

Patients indicated that symptoms of psychosis, including cognitive impairment, delusions, and hallucinations, have a significant impact on their day-to-day functioning. Negative symptoms, including social withdrawal and reduced motivation or apathy, diminish their quality of life and social engagement, resulting in challenges with reintegration. Patients also experience a lack of insight into their illness, which affects their ability to access treatment and support. This can cause significant strains in their relationships with their support network, ultimately leading to social isolation.

Respondents indicated that the advantage of taking antipsychotic medications is experiencing fewer episodes of mental illness, while the disadvantage is having to take the medication daily. The most common adverse effects of antipsychotic medications per respondents were drowsiness, restlessness, and weight gain. Two respondents with experience with cariprazine reported that the treatment could manage their negative symptoms and improve their relationships with peers.

Respondents stated that antipsychotic medications would be improved by having fewer adverse effects and a reduced cost because cost has been identified as a significant barrier to access. Additionally, respondents believe psychosocial therapy is most effective when provided together with pharmacological therapy. Treatment and recovery are a nonlinear, individual process. Finding the right medication that enables the highest level of functioning, while managing adverse effects, is often achieved through a trial-and-error process. To meet their unique needs, patients expect quick, simple, and affordable access to a wide range of therapeutic options to improve their treatment experience.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical expert indicated that current medications treat only the positive symptom domain in schizophrenia but not negative or cognitive symptoms, and that they do not reliably improve psychosocial function. Moreover, existing treatments have burdensome adverse effects which, in some cases, are life-threatening (diabetes, neuroleptic malignant syndrome) or irreversible (tardive dyskinesia).

According to the clinical expert, cariprazine could be suitable for most adult patients with schizophrenia, but the expert suggested it may be reserved as a second-line treatment. Cariprazine will be relatively expensive, and, for many patients, medications that have well-established efficacy and risk profiles will be appropriate for first-line treatment. Cariprazine may play a role when lack of tolerability or efficacy occur with existing and less expensive treatments. The expert indicated that cariprazine could be an option for patients in whom metabolic effects, weight gain, or sexual dysfunction are of great concern, and it may be selected for patients who have chronic negative symptoms, causing functional impairment.

In clinical practice, a routine mental status examination that thoroughly assesses hallucinations, delusions, and disorganized thought and behaviour and that shows documented improvement over an 8-week course of therapy would indicate a response to treatment, along with collateral input from caregivers, when available, indicating reduced behavioural signs of psychosis. The expert noted that evaluating negative symptoms is not as well-established in many clinical programs and may be under-reported, and because negative symptoms are not the primary target of antipsychotic drug therapy, they may go unnoticed until positive symptoms are controlled. Adherence to treatment and concurrent substance use must also be assessed, especially when treatment response is poor. Ongoing therapy for 2 or more years is often required, and a switch in therapies may be needed if patients experience significant adverse effects.

The expert stated that psychiatrists are most often involved in diagnosing schizophrenia and initiating therapy, which may occur in hospital settings. Once a patient is stable on a regular treatment regimen and has few or no psychiatric comorbidities, such as substance use or mood disorder, a family physician can manage the patient with some consultative support from a psychiatrist.

Clinician Group Input

Two clinician groups provided input to the submission: the Canadian Consortium for Early Intervention in Psychosis (CCEIP) group, and a national advisory board comprising Canadian psychiatrists with experience in the management of schizophrenia. Three clinicians with the CCEIP and 8 with the national advisory board contributed to these submissions. CCEIP noted the unmet need in young adults in the early phase of psychosis, in whom the current treatments may not optimize their long-term outcomes. Both groups agreed there is a need for treatments that improve negative symptoms and that can treat patients who do not respond to current drugs. Both groups advocated for cariprazine as a first-line antipsychotic drug for patients with schizophrenia, including those in the early phase of psychosis or those with negative symptoms.

Drug Program Input

The drug plans requested information on the place in therapy of cariprazine and whether coverage would be restricted to monotherapy. Considering the extended elimination half-life of cariprazine, the drug programs inquired whether the monitoring of treatment response or adverse effects will be different than that for other antipsychotic drugs.

According to the clinical expert, cariprazine may be reserved as second-line therapy. Considering the relative costs and the well-established efficacy and risk profiles for other less expensive antipsychotic drugs, existing drugs may remain as first-line agents for most patients. Additionally, the available evidence supports cariprazine as monotherapy. The expert indicated that the timing of follow-up may need to be adjusted because of the long half-life of the drug and its metabolites, but they did not expect cariprazine would require any additional monitoring, over and above what is required for other antipsychotic drugs.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Five double-blind randomized controlled trials (RCTs) met the inclusion criteria for the systematic review, including 3 short-term studies (RGH-MD-16, RGH-MD-04, RGH-MD-05), 1 randomized withdrawal study (RGH-MD-06), and 1 study in patients with predominant negative symptoms (RGH-188-005).

The 6-week double-blind studies RGH-MD-16, RGH-MD-04, and RGH-MD-05 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 dosage 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 to 732 patients, and the primary outcome in all trials was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item rating scale that assesses the presence and severity of psychopathology. It is scored from 30 to 210, with higher scores indicating more severe symptoms and psychopathology.

The mean age of patients enrolled in the acute schizophrenia trials ranged from 35.5 years (standard deviation [SD] = 9.3) to 39.3 years (SD = 10.8), 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 the majority of patients were categorized as markedly ill, based on the Clinical Global Impressions–Severity (CGI-S) score.

The objective of Study RGH-MD-06 was to evaluate the efficacy and safety of cariprazine relative to placebo to prevent 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 who could tolerate cariprazine and who met the treatment response criteria were randomized to receive double-blind cariprazine or placebo for 26 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 Study RGH-MD-06, the mean age of patients who entered the run-in stage was 38.4 years (SD = 10.4), and 71% were male. The mean PANSS total score was 91.3 points (SD = 10.1), and 54% of patients were markedly ill. Treatment responders who had completed the open-label cariprazine run-in and were randomized had a mean age of 37.7 years (SD = 10.1) and 39.2 years (SD = 10.9), 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), and most patients were mildly ill, based on the CGI-S score.

The objective of Study RGH-188-005 was to evaluate the safety, efficacy, and tolerability of cariprazine versus risperidone in patients with predominant negative symptoms of schizophrenia for at least 6 months (i.e., PANSS factor score for negative symptoms ≥ 24 and rating of ≥ 4, or 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 factor score for negative symptoms.

The mean age of patients enrolled in Study RGH-188-005 was 40.4 years (SD = 10.8), 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 (LS) mean 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 RGH-MD-05, to –10.4 (95% CI, –14.6 to –6.2; P < 0.0001) for the cariprazine 4.5 mg group in RGH-MD-16 (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 LS mean 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 achieved treatment response (≥ 30% improvement in the PANSS total score) favoured 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 Study RGH-MD-16 (all P < 0.05). In Study RGH-MD-04, the proportion of responders was higher for cariprazine 6 mg (31.8%; P = 0.013) than placebo (19.5%), but no difference was found between the cariprazine 3 mg group (24.5%; P = 0.28) and placebo group. No difference in the proportion of responders was detected between the cariprazine 3 mg to 6 mg (28.6%) or the 6 mg to 9 mg (34.7%) groups compared with the placebo group (24.8%) in Study RGH-MD-05 (both P > 0.05). There was no control of the type I error rate for the responder analyses; thus, any results showing a P less than 0.05 should be interpreted as supportive evidence only.

Two studies reported data on health-related quality of life measured using the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4) instrument. The between-group differences favoured cariprazine 3 mg to 6 mg groups versus placebo in Studies RGH-MD-04 and RGH-MD-05, but no differences were detected between the cariprazine 6 mg to 9 mg daily dosage group and placebo in Study RGH-MD-05. 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 Study RGH-MD-06. 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., ≥ 30% increase in PANSS total score; ≥ 2-point increase in CGI-S, or 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). The 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).

Predominant Negative Symptom Study

In Study RGH-188-005, the primary outcome was the change from baseline to week 26 in the PANSS factor score for negative symptoms (scored from 7 to 49, with a lower score indicating fewer symptoms). Both the treatment groups showed an improvement over time, with LS mean change score of –8.9 (standard error [SE] = 0.3) for cariprazine and –7.4 (SE = 0.4) for risperidone. The LS mean difference was –1.5 (95% CI, –2.4 to –0.5) favouring cariprazine versus risperidone (P = 0.002) (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 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 Study RGH-188-005. The clinician-rated PSP is scored from 0 to 100, with higher scores indicating better psychosocial function. In Study RGH-188-005, 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) and 9.7 points (SE = 0.8), respectively. The LS mean difference was 4.6 points (95% CI, 2.7 to 6.6), favouring cariprazine versus risperidone (P < 0.001). The between-group differences did not exceed the MID of 7 to 10 points reported in the literature.

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 events (AEs), 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 RGH-MD-06, respectively, and in 3% per group in Study RGH-188-005. 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 Study RGH-MD-04 (suicide, ischemic stroke and myocardial infarction), and 1 patient died in the risperidone group of Study RGH-188-005 (of carcinoma). No deaths were reported in the other treatment groups.

In the 6-week studies, treatment-emergent extrapyramidal symptoms were reported by ||| || ||| of patients in the placebo groups, ||| || ||| of patients in the cariprazine groups, and ||| ||| ||| of patients in the aripiprazole and risperidone groups, respectively (Table 5). The frequency of extrapyramidal symptoms was similar in the cariprazine and risperidone groups of Study RGH-188-005 (14% versus 13%). In Study RGH-MD-06, extrapyramidal symptoms were reported in ||| | of patients receiving open-label cariprazine, in ||| | of patients who remained on cariprazine and | ||| who switched to placebo during the double-blind phase. The frequency of discontinuation due to extrapyramidal symptoms 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% reported suicidal behaviour across treatment groups. One completed suicide ||| | ||||||| ||||||| was reported among patients receiving cariprazine, as well as | ||||||| ||||||| || | ||||||| || |||||||||||.

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% in the placebo group, 6% in the aripiprazole group, and 17% in the risperidone group. In Study RGH-MD-06, 11% of patients reported an increase in body weight of 7% or more during the open-label cariprazine phase, and 27% to 32% of patients in the cariprazine and placebo groups reported such an increase during the double-blind phase. In Study RGH-188-005, || and ||| in the cariprazine and risperidone groups, respectively, reported at least a 7% increase in weight.

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

ARIP = aripiprazole; CAR = cariprazine; CI = confidence interval; LS = least squares; PANSS = Positive and Negative Syndrome Scale; RIS = risperidone; SE = standard error.

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

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

^cAnalysis of covariance (ANCOVA) model with covariates for pooled study centre and baseline value, and last observation carried forward (LOCF) for missing data (modified intention-to-treat [mITT] population).

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

^eP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

^fMixed-effects model for repeated measures (MMRM) with pooled study centre, visit, treatment-by-visit interaction, baseline value, and baseline value-by-visit interaction (mITT population).

Source: Clinical Study Reports for RGH-MD-16,⁸ RGH-MD-05⁹ and RGH-MD-04.¹⁰

Table 3: Primary Efficacy Outcome in the Withdrawal Design Study (RGH-MD-06) — Time to Relapse

CAR = cariprazine; CI = confidence interval; HR = hazard ratio; NE = not estimable; PANSS = Positive and Negative Syndrome Scale.

^aRelapse was defined as 1 of the following: psychiatric hospitalization; increase in 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; score of greater than 4 on 1 or more of the following PANSS items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behaviour), P6 (suspiciousness and persecution), P7 (hostility), G8 (uncooperativeness) or G14 (poor impulse control).

^bHR based on Cox proportional hazards model (unadjusted), and P value based on log-rank test. Percentiles and 95% CI based on Kaplan-Meier estimates (double-blind mITT population).

Source: Clinical Study Report for RGH-MD-06.¹¹

Critical Appraisal

The design of the trials was consistent with European Medicines Agency (EMA) guidance for the investigation of drugs for schizophrenia.¹³ All studies were double-blind, and the methods used to randomize patients and conceal allocation appear to be 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), with some withdrawal imbalances between treatment groups within trials. 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 were conducted that explored different missing data assumptions, and these analyses supported the primary findings of the studies. Interpretation of the change in PANSS scores and health-related quality of life (HRQoL) data were limited by the lack of an MID. In addition, the type I error rate was not controlled for several outcomes of interest, such as the responder analyses and change in HRQoL scores.

In the study that enrolled patients with predominant negative symptoms, the use of risperidone as a comparator is 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 could 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. Thus, the treatment effects observed may be inflated, and the frequency of adverse effects under-reported relative to the broader population of patients with an acute exacerbation of schizophrenia.

The available evidence consisted of 4 placebo-controlled studies and 1 active controlled trial in a select patient population (predominant 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 predominant negative symptom study assessed functional outcomes. Thus, the treatment effects of cariprazine on these outcomes of importance to patients are unclear. The sample size and duration of the RCTs may have been insufficient to detect infrequent AEs.

Indirect Comparisons

Description of Studies

One unpublished indirect treatment comparison (ITC)¹⁴ that was used to inform the pharmacoeconomic analysis, and 2 published ITCs^15,16 submitted by the sponsor, were included in this report.

The unpublished ITC evaluated the efficacy and safety of cariprazine versus other oral AAPs used in Canada for the treatment of acute schizophrenia and the prevention of relapse. |||| |||| || |||| ||| ||||| ||||||||||||| ||| || |||| || ||||||| |||||||||| |||| |||| || |||||| ||| ||||| || |||||| ||||||| |||||||| ||||||| ||||||||||||| |||||| ||| ||||||| ||||||| ||| ||| ||||| ||||| ||| ||| |||||||||| || |||||||| ||| |||||||| || ||||| | ||| ||||||||||| || ||||| ||||| |||||| ||| ||||| |||||||| ||||||||| || |||| | || || ||| ||| ||||||||||| ||||||| |||||| ||| ||||||| ||||||| ||| ||| |||||||||| ||| |||||||| || |||| || || |||

The published ITCs focused on short-term efficacy and safety (Huhn et al. [2019]¹⁶) or metabolic effects (Pillinger et al. [2020]¹⁵) of antipsychotic drugs in patients with acute schizophrenia.

Results

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The results of the 2 published ITCs |||| ||||||||| |||||||||| |||| ||| ||||||||||| ||| ||| 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, publication year of study, 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 network meta-analysis.

The relapse prevention network had several limitations, which 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 or 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 (RGH-MD-17¹⁷ and RGH-MD-11¹⁸) 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 (CGI-S ≤ 3). New patients who met the inclusion criteria were also eligible for Study RGH-MD-11.

In Study RGH-MD-17, 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 Study RGH-MD-11, 39% completed 48 weeks.

Efficacy Results

The mean PANSS total score decreased from baseline by –5.0 points (SD = 14.0) in Study RGH-MD-11, and –6.8 points (SE 1.3) in Study RGH-MD-17 (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 RGH-MD-17 and RGH-MD-11. AEs were reported by 81% to 83% of patients, including akathisia (14% to 16%), extrapyramidal disorder (7%), and headache or insomnia (9% to 14%). An increase in body weight of at least 7% was reported by 26% and 33% of patients in Study RGH-MD-11 and RGH-MD-17, respectively. In both studies, 10% to 13% of patients discontinued due to AEs or experienced an SAE, respectively. One completed suicide was reported in the extension studies.

Critical Appraisal

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

Conclusions

In adults experiencing an acute exacerbation of schizophrenia, cariprazine was associated with statistically significant but clinically modest improvements, relative to placebo, in schizophrenia symptoms and overall severity at 6 weeks, measured using the change in the PANSS total score and CGI-S.

Based on a withdrawal design study that randomized patients with acute schizophrenia who demonstrated a response to cariprazine, patients who continued with cariprazine were less likely to relapse than those who were switched to placebo.

In adults with schizophrenia and predominant negative symptoms, statistically significant differences were detected favouring cariprazine versus risperidone in the change in PANSS factor score for negative symptoms and functional status (based on the PSP score). However, the clinical relevance of the differences in these outcomes are unclear, as either the difference did not exceed the MID or the MID in negative symptoms trials was unclear.

No conclusions can be drawn on the impact of cariprazine on HRQoL, functional status, hospitalization, or persistence with therapy, due to study limitations or lack of data.

Extrapyramidal symptoms, headache, and insomnia were the most common AEs among those who received cariprazine, with some patients reporting clinically significant increased body weight. The safety data were limited by study duration (3 studies lasted 6 weeks), and patient selection issues (enriched population, specific subpopulation of patients with negative symptoms), or the lack of control group or blinding (extension studies).

The results of the 3 ITCs in acute schizophrenia were generally consistent and showed no difference in short-term symptom severity, as well as possible differences in some adverse effects, for cariprazine versus other antipsychotic drugs. Due to heterogeneity in the study design, patient populations, timing, and definition of relapse, no conclusions can be drawn from the unpublished ITC that assessed the prevention of relapse.

Introduction

Disease Background

Schizophrenia is a chronic mental illness that affects the way a person interacts with and understands the world. The condition, when active, is characterized by delusions, hallucinations, disorganized speech, disorganized behaviour, and impaired cognitive ability.¹ The symptoms associated with schizophrenia are categorized as either positive or negative in nature. Positive symptoms reflect a distortion or abundance of normal functions, while negative symptoms reflect a loss or restriction of normal functioning (Table 6). 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.²⁰ According to national data (2016–2017), 1 out of 100 Canadians aged 10 years or older is living with a diagnosis of schizophrenia of whom 56% are men and 44% are women.⁴ The incidence of schizophrenia in Canada has been 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.²¹ 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.⁴

Despite its relatively low prevalence, schizophrenia is associated with tremendous health, social, and economic burden.⁵ People living with schizophrenia are at increased for other medical illnesses, suicide, substance abuse, homelessness, and unemployment.⁶ Indeed, schizophrenia contributes 13.4 (95% uncertainty interval, 9.9 to 16.7) million years of life lived with disability to disease burden globally.²⁰ Furthermore, the life expectancy of those living with schizophrenia is approximately 20 years less than that of the general population.²² Most excess deaths among those with schizophrenia are due to underlying physical illness, especially chronic disease such as coronary heart disease, stroke, type II diabetes, respiratory disease and some cancer²²; suicide accounts for less than 15% of excess deaths.²³ In Canada, the all-cause mortality rate in people diagnosed with schizophrenia is 2.8 times higher than in those without.⁴ Moreover, the burden associated with schizophrenia extends beyond the individual living with the disease, to families, caregivers, and the wider community.^5,24 In terms of resource utilization in people aged 1 and older, more than 147,500 Canadians require health services for schizophrenia.⁴

The causes of schizophrenia are not fully understood.⁴ Structural changes in the brain and genetics, combined with lifestyle and environmental factors, may play a role in its etiology.⁴

Schizophrenia is diagnosed by specific signs and symptoms that prevent reality-based judgment.¹ 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 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).² Briefly, to receive an official diagnosis of schizophrenia, an individual must exhibit at least 2 the following symptoms most of the time during a 1-month period, with some level of disturbance being present for 6 months (note: at least 1 of the symptoms must be delusions, hallucinations, or disorganized speech):

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

• hallucinations

• disorganized speech and behaviour

• catatonic or coma-like daze

• bizarre or hyperactive behaviour

• reduced ability to function.

In determining a diagnosis, the diagnosing clinicians 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

Currently, there is no cure for schizophrenia. Treatment focuses on managing symptoms in the community and at work and includes medication and psychosocial interventions. Based on the input from the clinical expert consulted by CADTH for purpose of this review, in more severe or refractory cases, electroconvulsive therapy may be selectively used.

The clinical expert listed the following psychosocial interventions with evidence of effectiveness: cognitive behavioural therapy for psychosis; social skills training; cognitive remediation; and supported employment programs. However, these interventions are not offered consistently across the country, as they require access to professionals with special training and skills.

Antipsychotic medications, which target the characteristic symptoms of schizophrenia, form the cornerstone of treatment.^1-3 The underlying principles for pharmacotherapy include:

• individualization of medication (including patient preferences)

• simple medication regimens

• appropriate dosage

• attention to adverse effect profiles

• regular evaluation of response, including adverse effects

• short- and long-term clinical efficacy, safety, and tolerability.²⁵

The choice of antipsychotic medication should be a joint decision by the patient and clinician, considering the views of a caregiver, where appropriate.²⁶

According to the clinical expert consulted by CADTH, 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 most impairing for long-term function.

Existing antipsychotic drug therapies fall into 1 of 2 classes. Typical antipsychotic drugs — also known as conventional antipsychotic drug or neuroleptics — are the first-generation antipsychotic class. These drugs have antagonistic activity at dopamine D₂ receptors²⁷ and are associated with an increased incidence of extrapyramidal symptom adverse effects.²⁵ The second-generation or AAP drugs have antagonistic activity at D₂ receptors, histamine 1 (H₁) receptors, alpha-receptors, and serotonin (5-HT_2a) receptors. Table 7 provides a summary of the commonly prescribed oral antipsychotic drugs that are currently marketed in Canada. The risk of incidence of extrapyramidal symptoms appears to be reduced with AAP drugs; however, differences between typical and AAP drugs can be variable in this respect.²⁸ Both typical and atypical antipsychotic drugs classes are considered to be equally effective in the treatment of positive symptoms. AAPs appear to be more effective in the treatment of negative symptoms²⁵; however, AAPs are associated with an increased risk of weight gain and metabolic adverse effects.⁶

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.^6,29 Oral medications represent first-line treatment, although the formulations administered may differ under certain circumstances (e.g., in the case of nonadherence, or the need for rapid control of symptoms). Examples of alternative formulations that may be used in these situations include intramuscular, short-acting injectable treatments. Non-emergent 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.^30-32 Patients who experience multiple episodes are, as a rule, are offered a trial of another antipsychotic drug.^6,29,33 AAPs are, again, the treatment of choice, unless the patient prefers a typical antipsychotic or has had a prior good response to a typical antipsychotic drug.

Canadian guidelines recommend that, following an acute episode of schizophrenia, individuals 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 and possibly up to 5 years or longer.²⁶

Based on the input from the clinical expert, in patients who do not have a response rate of at least a 20% reduction in positive symptoms to 2 medication trials of different antipsychotic drugs, clozapine should be offered. 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.^34,35 Among this population, RCTs have reported a response rate with clozapine in the range of 30% to 60%,³⁶ and clozapine is the only recommended treatment in treatment-resistant schizophrenia.³⁷ The clinical expert 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 under-used.

One major obstacle to the effective treatment of schizophrenia is nonadherence to medications, resulting in cycles of relapse.^38,39

The clinical expert consulted for this review indicated that the ideal medication for schizophrenia would have the following properties:

• reduce the positive and negative symptoms of schizophrenia

• have a rapid onset of action

• have minimal adverse effects

• be given once daily orally, or once monthly (or less often) as an injectable treatment

• be associated with improved daily function, such as improved social and occupational activities, and quality of life.

According to the expert, currently no such medication exists.

Table 7: Characteristics of Orally Administered Antipsychotic Drugs in Canada

SL = sublingual.

^aTypical antipsychotic drugs listed in the systematic review protocol.

Drug

Cariprazine is an AAP that is approved by Health Canada for the treatment of schizophrenia in adults.⁷ The mechanism of action for cariprazine is unknown; however, it may be mediated through partial agonist activity at central dopamine D₃ and D₂ receptors, and serotonin 5-HT_1A receptors. Cariprazine also has antagonist activity at serotonin 5-HT_2A receptors.⁷ 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 to 4 days for cariprazine, 1 to 2 days for desmethyl cariprazine, and 1 to 3 weeks for didesmethyl cariprazine.⁷

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.⁷ The monograph states that patients should be maintained on the lowest effective dosage that provides optimal clinical response and tolerability.⁷ The suggested initial dose is 1.5 mg, which may be increased in 1.5 mg increments to a maximum of 6 mg daily.⁷ 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. Thus, 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.⁷

The sponsor has requested reimbursement as per the indication.⁵³ Cariprazine has not previously been reviewed by CADTH.

Cariprazine was approved by the FDA in 2015 and by the EMA in 2017 for the treatment of schizophrenia in adults.^54,55

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.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

CADTH received 2 responses to its call for patient input for this review: a submission from the Institute for Advancements in Mental Health (IAM) and a joint submission from the Schizophrenia Society of Canada (SSC) and the Canadian Mental Health Association (CMHA) Alberta Division. IAM, SSC, and CMHA are organizations that serve individuals living with mental illnesses, including schizophrenia, their families, and community members.

The patient input was based on 2 online surveys of members of IAM’s client network, conducted in 2021 and 2018. Among the 19 respondents of the 2021 survey, 26% identified as living with symptoms of schizophrenia or psychosis, 37% were relatives of someone with lived experience, 5% were friends of someone with lived experience, and 32% were caregivers of someone with lived experience. Among the respondents to the 2018 survey, 12% self-described as having a diagnosis of schizophrenia or psychosis, 50% were caregivers, 63% were family members or friends of someone diagnosed, and 18% worked in social services. SSC drew information from its national online surveys, focus groups, and interviews, which were conducted mainly in Canada in 2021. Among the 239 survey respondents, 118 were patients with lived experience of early psychosis and schizophrenia and 121 were family members.

Patients indicated that symptoms of psychosis, including cognitive impairment, delusions, and hallucinations, have a significant impact on their day-to-day functioning. Negative symptoms, including social withdrawal and reduced motivation or apathy, diminish their quality of life and social engagement, resulting in challenges with reintegration. Patients also experience a lack of insight into their illness, which affects their ability to access treatment and support. This can cause significant strains in their relationships with their support network, ultimately leading to social isolation.

Respondents indicated that the advantage of taking antipsychotic medications is experiencing fewer episodes of mental illness, while the disadvantage is having to take the medication daily. The most common adverse effects of antipsychotic medications per respondents were drowsiness, restlessness, and weight gain. Two respondents with experience with cariprazine reported that the treatment could manage their negative symptoms and improve their relationships with peers.

Respondents stated that antipsychotic medications would be improved by having fewer adverse effects and a reduced cost, as cost has been identified as a significant barrier to access. Additionally, respondents believe psychosocial therapy is most effective when provided together with pharmacological therapy. Treatment and recovery are a nonlinear, individual process. Finding the right medication that enables the highest level of functioning, while managing adverse effects, is often achieved through a trial-and-error process. To meet their unique needs, patients expect quick, simple, and affordable access to a wide range of therapeutic options to improve their treatment experience.

The patient input from IAM, SSC, and CMHA, Alberta division is presented in the Stakeholder Input section of the report.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of schizophrenia.

Unmet Needs

There are no treatments available that target the fundamental disease pathology of schizophrenia. The pathology of schizophrenia and related disorders is not fully understood.

The clinical expert indicated that the current medications treat only 1 of 3 symptom domains in schizophrenia. Antipsychotic drugs, in most cases, do not treat negative or cognitive symptoms, and do not reliably improve psychosocial function. Moreover, existing treatments have burdensome adverse effects which, in some cases, are life-threatening (diabetes, neuroleptic malignant syndrome) or irreversible (tardive dyskinesia).

Treatments for refractory disorders are few and have severe adverse effects or inconvenience, as exemplified by the risk of agranulocytosis with clozapine and attendant requirement for regular blood tests, and the invasiveness of electroconvulsive therapy.

Place in Therapy

The clinical expert indicated that cariprazine may be reserved as a second-line treatment. Cariprazine will be relatively expensive, and, for many patients, medications that have well-established efficacy and risk profiles will be appropriate for first-line treatment. When lack of tolerability or efficacy occur with existing and less expensive treatments, cariprazine may play a role.

Similar to aripiprazole and brexpiprazole, cariprazine has partial agonist effect at dopamine type 2 (D₂) receptors, which may differentiate these drugs from other antipsychotic drugs. The expert indicated that cariprazine could be an option for patients in whom metabolic effects, weight gain, or sexual dysfunction are of great concern. According to the expert, it may be selected for patients who have chronic negative symptoms causing functional impairment.

Patient Population

The expert indicated that cariprazine could be suitable for most adult patients with schizophrenia, and it may have unique benefits for patients with prominent negative symptoms. It may also be helpful for patients with a risk of weight gain and metabolic adverse effects. Whether it will be useful for patients at elevated risk for nonadherence is of clinical interest, but further data and experience are needed. Such patients in Canada are usually treated with long-acting injection antipsychotic drugs, and a different third-generation antipsychotic drug, aripiprazole, is available in such a formulation.

Schizophrenia is diagnosed in Canada using the criteria of DSM-5, with which psychiatrists and family physicians are familiar. A recommended assessment instrument for patients undergoing an antipsychotic drug treatment trial is the PANSS, a validated rating instrument that documents the burden of positive and negative symptoms. Patients with a high score on the negative scale might be considered candidates for cariprazine. However, the expert indicated that most clinicians do not use such rating scales in daily practice; hence, negative symptoms are often under-assessed.

There is no reliable a priori method to identify patients with schizophrenia who will respond to a given antipsychotic drug, especially among those who are naive to such treatment. However, in the expert’s opinion, patients whose disorder has not responded to 2 adequate antipsychotic drug treatment trials would have a low likelihood of benefiting from cariprazine and should be offered clozapine. Those with a high burden of negative symptoms could be considered candidates for cariprazine above other antipsychotic medications.

The expert indicated that cariprazine may be prescribed off-label for schizoaffective disorder, a related condition that is associated with mania and depression.

Assessing Response to Treatment

According to the clinical expert, a 20% reduction in positive symptoms on a valid psychosis rating scale (e.g., PANSS or Brief Psychiatric Rating Scale) is the most reliable way to confirm response to antipsychotic medication. However, such scales are often not used in clinical practice. Therefore, the routine mental status examination, which thoroughly assesses hallucinations, delusions, and disorganized thought and behaviour, is appropriate. Documented improvement of such findings over an 8-week course of therapy would indicate a response to treatment, along with collateral input from caregivers, when available, indicating reduced behavioural signs of psychosis. Adherence to treatment and concurrent substance use must also be assessed, especially when treatment response is poor.

Assessing negative symptoms is not as well-established in many clinical programs. Using a rating scale is most reliable, but, in any event, caregiver input is crucial to fully understand a patient’s ability to engage in activities, remain motivated, and respond emotionally to others.

Clinically meaningful improvement would also involve improved function, as manifested by more appropriate social interactions, greater consistency in activities of daily living, and/or reduction in risk for self-harm or aggression. The definition depends in part on the patient’s baseline function and the treatment setting. If a patient is in hospital, readiness for transition to the community is an important milestone. If the patient is living in the community, readiness to engage in rehabilitation or even to return to work or school are relevant milestones.

The expert stated that, for patients in the acute phase who are managed in community, treatment response should be assessed at least twice a week, which can be done through in-person or virtual visits and collateral input. If the patient is in hospital and at risk of aggression or suicide, daily assessment by physician or nurse is necessary. Once a patient is in the stabilization phase, in community, assessment once every 1 or 2 weeks is adequate. In the maintenance phase, once a month or even every 3 months can be adequate. Assessment of adverse effects must also be done regularly; this includes involuntary movement examinations, weight and waist circumference measurement, and fasting glucose and lipids measurement.

Discontinuing Treatment

According to the clinical expert, patients often ask to discontinue antipsychotic medication prematurely because of adverse effects or because they lack insight into ongoing symptoms and risk of relapse. If a patient has been symptom-free and had good functional recovery for 2 or more years, discontinuation can be considered. If multiple relapses have occurred or the acute episodes have led to substantial risk of suicide or aggression, a longer symptom-free interval is necessary before discontinuation. If psychiatric comorbidity or substance use disorder is present, the decision will have to take this into account. Adverse effects may require rethinking treatment; these effects include weight gain and metabolic syndrome, involuntary movements, and hyperprolactinemia, with sexual dysfunction or galactorrhea. A feasible alternative medication must be available in those cases; otherwise, efforts to manage and minimize adverse effects will be necessary. Finally, patients who develop a resistant disorder will require a switch to clozapine, the only medication indicated for treatment-resistant schizophrenia.

Prescribing Conditions

The expert stated that psychiatrists are most often involved in diagnosing schizophrenia and initiating therapy, which may occur in hospital settings. Once a patient is stable on a regular treatment regimen and if they have few or no psychiatric comorbidities, such as substance use or mood disorder, a family physician can manage the patient with some consultative support from a psychiatrist.

Cariprazine could be initiated in hospital, typically in an acute psychiatry unit, or a community or tertiary mental health program. Family physicians who are familiar with antipsychotic medication could also initiate the treatment for patients with mild exacerbations who have demonstrated tolerability to cariprazine or similar medications.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Two clinician groups provided input to the submission: the CCEIP group, and a national advisory board. The CCEIP is a national, bilingual, not-for-profit organization of clinicians and researchers with a mandate to enhance optimum care for Canadians in the early phase of psychosis through improved service models and the generation and translation of knowledge. The second group is a national advisory board comprising Canadian psychiatrists with experience in the management of schizophrenia.

Unmet Needs

The CCEIP advocates for young adults in the early phase of psychosis (within the first 5 years of illness), as 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 to 5 years following the first presentation. The risk of relapse is high within 2 years, and nearly three-quarters of patients experience a relapse within 5 years. Suicide risk is high during the early phase following a relapse.

Both groups stated that up to 60% of patients with schizophrenia have negative symptoms; however, current treatments typically focus on the positive symptoms. In addition, at least one-third of patients are refractory to currently available treatment options. Limitations of current treatments with respect to tolerability may lead to poor adherence and contribute to further physical comorbidities. It is necessary to offer patients treatment options for both positive and negative symptoms that are well tolerated, acceptable, and, when possible, available in a long-acting formulation.

Place in Therapy

Although the CCEIP acknowledges the evidence available to date in early phase psychosis and in young adults is limited, they endorse cariprazine as a first-line drug for anyone in early phase psychosis, with a possible priority in those with significant negative symptoms. Considering the drug’s mechanism of action as a partial dopamine agonist, and its safety profile, the CCEIP recommends cariprazine early in the treatment course and as a monotherapy, rather than as a last option or as part of a polypharmaceutical regimen.

The national advisory board also advocated for cariprazine as a first-line antipsychotic drug based on its mechanism of action, safety profile, and potential impact on negative symptoms. In addition, the group stated that patients who have not fully responded over time (but not treatment-resistant), would also be considered for treatment with cariprazine.

Patient Population

Both groups endorsed the use of cariprazine as first-line therapy in patients with schizophrenia, with a focus on those with significant symptoms.

Patients with treatment-refractory schizophrenia or with comorbidities (specifically, individuals with substance abuse and intellectual impairment), would least likely benefit from this treatment.

Assessing Response to Treatment

The input provided by clinician groups was consistent with the views expressed by the clinical expert consulted by CADTH. In clinical trials, response is often defined as reduction in key evaluative scales (e.g., PANSS). However, in clinical practice, reduction in symptoms, improvement in quality of life, and ability to function more independently are the most relevant goals. In addition, control of symptoms, stability of illness, or prevention of recurrence or relapse are measures of successful treatment. The magnitude of the response to treatment varies among patients but may be accrued over time. This is where issues of tolerability and persistence of treatment become important.

Ongoing and frequent evaluation of response and tolerability is required. The experts did not identify any additional monitoring (e.g., blood tests or other interventions) that may be required for cariprazine specifically.

Discontinuing Treatment

The most common factors for discontinuing or switching treatment are suboptimal response or nonresponse, or intolerability of adverse effects. In early phase psychosis, if adherence is an issue, switching to a long-acting injectable antipsychotic drug may be considered. Decisions should be considered in conjunction with caregivers and patients, with specific objectives of switching in mind.

Prescribing Conditions

The management of patients with schizophrenia takes place in both inpatient and outpatient settings, is often multi-disciplinary, with medication decisions and choices usually determined by the psychiatrist.

The clinician group input received is provided in the Stakeholder Input section of this report.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 8.

Clinical Evidence

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 CADTH 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 CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 9. Outcomes in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

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 tool.¹

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 multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised 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 (ICTRP) 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 the CADTH Canadian Drug Expert Committee (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.⁵⁶ 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 CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

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 10 and Table 11.

A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

Five RCTs met the inclusion criteria for the systematic review, including 3 short-term studies (Table 10), 1 randomized withdrawal study, and 1 study in patients with predominant negative symptoms (Table 11).

The objective of studies RGH-MD-16, RGH-MD-04, and RGH-MD-05 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 fixed or flexible dosage 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 Study RGH-MD-16, 732 patients were randomized 1:1:1:1:1 to placebo, cariprazine 1.5 mg, 3 mg, or 4.5 mg daily, or risperidone 4 mg daily. Study RGH-MD-04 randomized 617 patients to placebo, cariprazine 3 mg, cariprazine 6 mg, or aripiprazole 10 mg daily (1:1:1:1), and Study RGH-MD-05 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; the investigator assessed that the patient was ready for discharge; and 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 in PANSS total score from baseline to week 6.

The objective of Study RGH-MD-06 (thereafter referred to as RGH-MD-06) was to evaluate the efficacy and safety of cariprazine in the prevention of 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- 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 dosage of 3 mg, 6 mg, or 9 mg daily (flexible dosage during the first 6 weeks and fixed dosage 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 dosage 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 dosage) or placebo for a minimum of 26 weeks and maximum of 72 weeks, or until relapse or early termination. 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 Study RGH-MD-06, 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 Study RGH-188-005 was to evaluate the safety, efficacy, and tolerability of cariprazine versus risperidone in patients with schizophrenia and predominant negative symptoms. The trial consisted of a 4-week lead-in period, during which patients continued with current antipsychotic drugs and were evaluated for 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 in the PANSS factor score for negative symptoms from baseline to week 26.

The studies were conducted between 2008 and 2014 in Eastern and Western Europe, 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 Study RGH-MD-16 were eligible to enter the open-label extension Study RGH-MD-17, and those who completed RGH-MD-04 or RGH-MD-05 were eligible to enter the open-label extension Study RGH-MD-11.

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

Source: Clinical Study Report for RGH-MD-04.¹⁰

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

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

^a All patients were hospitalized during screening and for the first 2 weeks of the run-in phase. After 2 weeks of open-label treatment in the run-in phase, patients may have been discharged and followed as outpatients, or they may have remained hospitalized for an additional 2 weeks.

Source: Clinical Study Report for RGH-MD-06.¹¹

Figure 4: Study Design Schematic for Trial RGH-188-005

D = day, IMP = investigational medicinal product.

Source: Clinical Study Report for Study RGH-188-005.¹²

Populations

Inclusion and Exclusion Criteria

The acute schizophrenia studies enrolled adults aged 18 to 60 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia and had a schizophrenia diagnosis for at least 1 year (excluding patients in their first episode of psychosis, who were allowed to enter Study RGH-MD-16). In addition, the current psychotic episode was less than 2 weeks in duration, and patients had a structured clinical interview for the PANSS total score between 80 and 120 and CGI-S score of at least 4, which is rated as moderately ill (additional criteria listed in Table 10).

The patients enrolled in the withdrawal design study (MD-06) were required to meet similar inclusion criteria at screening as in the 6-week studies; however, at weeks 8 and 20, additional criteria were applied. The patients had to show at least a 20% reduction in the PANSS total scores, with a score of 60 points or lower, a score of 4 or lower on specific PANSS items, a CGI-S score of 4 or lower, and no significant cariprazine tolerability issues (Table 11).

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 (CNS) 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. Studies RGH-MD-04, RGH-MD-05, and RGH-MD-06 excluded patients experiencing a first episode of psychosis.

Study RGH-188-005 enrolled adults 18 to 65 years of age who DSM-IV-TR criteria for schizophrenia (for at least 2 years) and had predominant negative symptoms for at least 6 months (i.e., PANSS factor score for negative symptoms ≥ 24 and rating of ≥ 4 moderate for 2 of 3 PANSS items for flat affect, avolition, and poverty of speech). Before enrolment, patients could be receiving antipsychotic drugs if the total daily dosage was equivalent to 6 mg risperidone (if on 1 drug) or 8 mg (if on 2 drugs). Study RGH-188-005 excluded patients with other psychiatric, neurologic, or behavioural disorders; clinically unstable schizophrenia; significant positive schizophrenia symptoms; moderate to severe depressive symptoms; or those who had used an antidepressant in past 3 months. Other psychiatric, medical, or treatment-related exclusion criteria were similar to those for the acute trials (Table 11).

Baseline Characteristics

The mean age of patients enrolled in the acute schizophrenia trials ranged from 35.5 years (SD = 9.3) to 39.3 years (SD = 10.8), and the proportion of males ranged from 62% to 78% per treatment group (Table 12, Table 13). The race distribution varied across studies. In Studies RGH-MD-16 and RGH-MD-04, at least half of patients were White and approximately 23% of patients were Black. In Study RGH-MD-05, Black patients 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 Study RGH-MD-04 and 6.3 (SD = 8.1) for Study RGH-MD-16 but was lower for Study RGH-MD-05 (mean = 4.1; SD = 5.4). In general, the patient characteristics appeared to be balanced between groups within trials.

In the withdrawal design study (MD-06), the mean age of patients who entered the run-in stage was 38.4 years (SD = 10.4), 71% were men, 41% were Black, and 39% were White. The demographics of patients who were randomized was similar. In the placebo and cariprazine groups, respectively, the mean age was 37.7 (SD = 10.1) and 39.2 (SD = 10.9), and 71% and 61% were men. The overall proportion of patients who were Black was 31%, and 42% were White. At the start of the run-in phase, the mean PANSS total score was 91.3 points (SD = 10.1), and 54% of patients were markedly ill. At randomization, the PANSS total score was 50.9 points (SD = 6.7), 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 14).

The mean age of patients enrolled in Study RGH-188-005 was 40.4 years (SD = 10.8), 57% were male, and 95% were White (Table 15). Overall, 60% of patients had less than 5 prior exacerbations, and 30% had between 5 and 10 events. The mean baseline PANSS score was approximately 76 points (SD = approximately 8), with ||| classified as moderately ill and ||| classified as markedly ill, according to the CGI-S score.

Table 12: Summary of Baseline Characteristics for Acute Schizophrenia Study RGH-MD-16

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

^aBased on modified intention-to-treat (mITT) population.

Source: Clinical Study Report for RGH-MD-16.⁸

Table 13: Summary of Baseline Characteristics for Acute Schizophrenia Studies RGH-MD-04 and RGH-MD-05

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

^aBased on mITT population.

Source: Clinical Study Reports for RGH-MD-05⁹ and RGH-MD-04.¹⁰

Table 14: Summary of Baseline Characteristics for Withdrawal and Negative Symptom Studies RGH-MD-06 and RGH-188-005

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

^aFor Study RGH-188-005, the data reported are the number of psychiatric hospitalizations in the past 12 months.

^bBased on mITT population.

^cBased on mITT population for Study RGH-MD-06.

Source: Clinical Study Reports for RGH-MD-06¹¹ and RGH-188-005.¹²

Interventions

Study Medications

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

In Study RGH-MD-16, 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, 3 mg, or 4.5 mg, or risperidone 4 mg per day. The dosage of cariprazine and risperidone was increased over the first 1 to 2 days of therapy for patients in the risperidone and the cariprazine 3 mg and 4.5 mg groups, until the randomized daily dose was reached.

In Study RGH-MD-04, 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 dosage of cariprazine was increased over the first few days by 1.5 mg daily until the randomized dosage (i.e., 3 mg or 6 mg per day) was reached. There was no-dose titration period for patients assigned to aripiprazole.

In Study RGH-MD-05, 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 dosage regimen, with response assessed at week 2, after which the dosage of study drug was fixed. At the start of therapy, each patient received 1 capsule a day that provided either placebo or cariprazine 3 mg or 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 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-dosage group, the dosage was increased to 6 mg per day, and for those in the high-dosage group, it 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 dosage of study drug. The dosage of cariprazine remained fixed between weeks 3 and 6. At the start of therapy, and with the any-week 2 dosage increases, the dosage of cariprazine was titrated up in 1.5 mg increments over 1 to 4 days (depending on the target dosage).

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 for RGH-MD-16 states that blinding was maintained for all patients.

In Study RGH-MD-06, 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 at a flexible dosage of 3 mg, 6 mg, or 9 mg daily for the first 6 weeks, with dosage fixed for the last 2 weeks. During the run-in phase, tolerability and treatment response were assessed on day 4, and the dosage of cariprazine could be increased at the discretion of the investigator from 3 mg to 6 mg daily; starting on day 10, the dosage could be increased to 9 mg daily. The dosage could be decreased at any time during the first 6 weeks of the run-in phase if there were significant tolerability issues. No further dosage 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 (Table 11) continued to receive open-label cariprazine 3 mg, 6 mg, or 9 mg for 12 weeks, based on the same fixed dosage as the end of the run-in phase. No dosage increases were allowed, but a dosage 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 (Table 11) were randomized to receive double-blind placebo or cariprazine at the same fixed dosage as they received earlier (3 mg, 6 mg, or 9 mg daily) for a minimum of 26 weeks, maximum of 72 weeks, or until relapse.

In Study RGH-188-005, patients enrolled could have been untreated or were receiving treatment with 1 or 2 antipsychotic drugs at a maximum total daily dosage equivalent to 6 mg of risperidone (if on 1 drug) or 8 mg (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 dosage allowed. Patients were then randomized to receive double-blind cariprazine or risperidone, with the study drug up-titrated and the prior antipsychotic down-titrated during the first 2 weeks. The dosage of study drug was increased in 1.5 mg increments for cariprazine and 1 mg increments for risperidone, to the target dosage of cariprazine 4.5 mg daily and risperidone 4 mg daily by day 14. Dosages were fixed for 1 week, then, from day 21 onwards, the dosage of the double-blind study medication could be decreased at the investigator’s discretion to cariprazine 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. The investigator could return the dosage to the target dosage. Decreasing or increasing the dosage of the study drug from the target dosage 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 to avoid 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 three 6-week trials and Study RGH-MD-06, patients were prohibited from receiving other psychotropic medications, including the following: antipsychotic drugs or neuroleptics, 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). Psychotropic medications were tapered and discontinued before randomization, during the washout period (up to 7 days in duration). In Study RGH-188-005, patients continued prior antipsychotic medications during the lead-in phase, and then these medications were down-titrated and discontinued over the first 2 to 4 weeks after randomization. Other psychotropic medications from the list were discontinued during the lead-in period. Patients who received prohibited psychotropic medications were withdrawn from the studies.

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

During the trials, pre-specified doses of zolpidem, zaleplon, chloral hydrate, eszopiclone, or zopiclone (RGH-MD-06 and RGH-188-005 only) were allowed for the treatment of insomnia. In addition, diphenhydramine, benztropine (or trihexyphenidyl), and propranolol were allowed to manage extrapyramidal symptoms or akathisia that emerged or worsened during the studies. In Study RGH-188-005, no medications for extrapyramidal symptoms 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 pre-specified doses, was allowed. Lorazepam (or alternatives) was also allowed during the run-in phase of Study RGH-MD-06 and after randomization in Study RGH-188-005 during the titration phase, with a maximum dosage of 2 mg per day thereafter.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 15. These end points are further summarized in this section. A detailed discussion and critical appraisal of the outcome measures are 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 Study RGH-MD-06. In Study RGH-188-005, the primary outcome was the change from baseline to week 26 in the PANSS factor score for negative symptoms, and the secondary outcome was the change from baseline in the PSP score. According to the Clinical Study Reports, the outcome assessments were conducted by experienced raters who met the training requirements for each instrument.

Positive and Negative Syndrome Scale

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 factor score for negative symptoms 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 16 lists the items included in PANSS positive, negative, and factor score for negative symptoms 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 depend on the baseline severity. However, at least a 20% decrease in the factor score for negative symptoms or the total score, or at least a 15-point reduction in the total score, may be associated with clinical improvement.^65-70 According to the EMA, a responder threshold of 30% reduction on the total PANSS score from baseline is considered clinically relevant in short-term clinical trials.⁷¹

Clinical Global Impressions–Severity or Improvement

The CGI-S measures the overall severity of mental disorders at the time of the clinician’s assessment, and the Clinical Global Impressions–Improvement (CGI-I) measures the change from baseline in the overall severity of illness, each based on a 7-point scale (Table 17). 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 drug treatment in a number of clinical trials.^67-69

Time to Relapse

The primary efficacy parameter in Study RGH-MD-06 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

• increase in 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

• 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

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

Changes in the PANSS or CGI-S scores were 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.⁷² The PSP is scored from 1 to 100, with a higher score indicating higher personal and social functioning. A between-group difference of 7 to 10 points has been reported in the literature as representing an MID.^68,69

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 with higher scores indicating relatively worse quality of life. 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 and 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.⁷³

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 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 18.

In Study RGH-MD-16, the change from baseline to week 6 in the PANSS total score and other continuous outcomes were analyzed using an ANCOVA model that included study centre and the baseline value as covariates. LOCF was used to impute missing post-baseline 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 3.0 mg and 4.5 mg daily dosages 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 3.0 mg and 4.5 mg dosage groups were 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 enrolment of 135 patients in each of the treatment groups, Study RGH-MD-16 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.

Study RGH-MD-04 and RGH-MD-05 used similar methods to conduct the statistical analyses. The primary outcome of change from baseline in the PANSS total score was analyzed using an MMRM that included 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, based on the assumption that patient data are missing at random. Sensitivity analyses that used a pattern-mixture model or ANCOVA with LOCF were run to explore alternative assumptions for missing data. The pattern-mixture model assumes that the probability of dropout at a specific visit depends 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 model or ANCOVA (LOCF) models, and responder analyses were run using logistic regression models (Table 18). All statistical tests were 2-sided with an alpha level of 0.05.

Studies RGH-MD-04 and RGH-MD-05 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 PANSS total score. If at least 1 dosage group showed P < 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. Significance for a given dosage group could only be claimed for the CGI-S if the primary null hypothesis was rejected (i.e., PANSS total score was statistically significant for that dose group). There was no control of multiplicity for other comparisons (e.g., aripiprazole versus placebo) or outcomes.

Studies RGH-MD-04 and RGH-MD-05 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, 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 withdrawal design study, RGH-MD-06, the primary outcome was the time to relapse for cariprazine versus placebo among patients who demonstrated adequate response and tolerability to cariprazine during the run-in and stabilization periods. Between-group differences were tested based on a log-rank test with, the HR and 95% CI 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 Study RGH-MD-06 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 planned to be enrolled in the study, assuming 50% of patients would complete the run-in phase and 40% would complete the stabilization phase. No citations were listed to support the assumptions used in the power calculations.

The primary outcome of Study RGH-188-005 was the change from baseline to week 26 in the PANSS factor score for negative symptoms, which was analyzed using an MMRM model that included 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) to examine the impact of different assumptions for missing data. A similar model was used for the secondary outcome (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, Study RGH-188-005 had an estimated power of 90% to detect an effect size of 0.25 in the PANSS factor score for negative symptoms 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 10% attrition rate. Data sources for the assumptions used in the power calculations were not listed in the Clinical Study Report.

With regards to subgroups, Studies RGH-MD-16 and RGH-MD-06 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 studies RGH-MD-16, RGH-MD-04, and RGH-MD-05, and RGH-188-005, the safety population included all randomized patients who received at least 1 dose of study drug. The mITT population included all randomized patients who received at least 1 dose of study drug and had at least 1 post-baseline assessment of the primary efficacy outcome.

Study RGH-MD-06 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 post-baseline 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 double-blind study drug

• double-blind mITT population: all patients in the double-blind safety population who had at least 1 post-randomization 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 of withdrawals ranged from 38% to 48% in the placebo groups, 33% to 42% in the cariprazine groups, and 25% to 28% 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 Study RGH-MD-16, in which 48% in the placebo group withdrew versus 28% to 38% in the active treatment groups (risperidone or cariprazine), and Study RGH-MD-04, in which 25% withdrew from the aripiprazole group versus 33% to 38% in the cariprazine groups and 38% in the placebo group.

In Study RGH-MD-05, 1 centre in the US (N = 6) and 1 in India (N = 6) were excluded from the analyses due to violations of good clinical practice in study conduct. Of these patients, 8 patients completed the study and 4 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 (patient had received placebo for 7 days).

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% discontinued during the stabilization phase, and another 15% opted to not continue into the next phase of the trial. Thus, 200 patients (26%) of the 765 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 the randomization limits had been met (7%) and withdrawal of consent (5%). During the double-blind phase, 16% and 18% completed the study, 48% and 25% had a relapse, and 36% and 57% 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. The Clinical Study Report 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 predominant negative symptom Study RGH-188-005, 461 patients (87%) of the 533 screened were randomized. In both the cariprazine and risperidone groups, 23% of patients discontinued the study, primarily due to AEs (10% and 11%), or withdrawal of consent (7% and 7%).

Table 19: Patient Disposition for Acute Schizophrenia Study RGH-MD-16

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

^aOf the 279 patients who failed screening, the reasons for exclusion were: patient did not meet eligibility criteria (n = 221), withdrawal of consent (n = 47), discontinued due to adverse events (n = 6), other (n = 5).

Source: Clinical Study Report for RGH-MD-16.⁸

Table 20: Patient Disposition for Acute Schizophrenia Studies RGH-MD-04 and RGH-MD-05

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

^aOf the 217 patients who failed screening in Study RGH-MD-04, the reason for exclusion was: did not meet eligibility criteria (n = 185), withdrawal of consent (n = 22), discontinued due to adverse events (n = 2), protocol violation (n = 2), other (n = 6).

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

Source: Clinical Study Reports for RGH-MD-05⁹ and RGH-MD-04.¹⁰

Table 21: Patient Disposition for Withdrawal Design Study RGH-MD-06

mITT = modified intention-to-treat.

^aOf the 384 patients who were screened but not enrolled, the most common reason for exclusion was patient did not meet study criteria (n = 339), withdrawal of consent (n = 40), adverse event (n = 1), or other (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 RGH-MD-06.¹¹

Table 22: Patient Disposition for Predominant Negative Symptom Study RGH-188-005

mITT = modified intention-to-treat.

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

Source: Clinical Study Report for RGH-188-005.¹²

Exposure to Study Treatments

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) to 36.4 days (SD = 11.8) (Table 23).

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

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

For the withdrawal design study (RGH-MD-06), the mean duration of treatment was 75.7 days (SD = 54.2) in the open-label cariprazine phase, and 205.9 days (SD = 176.7) in the placebo group and 257 days (SD = 184.0) in the cariprazine group (Table 24) in the double-blind phase. The final daily dosage of cariprazine in the double-blind phase was 3 mg for 14% of patients, 6 mg for 37%, and 9 mg for 50% of patients.

In Study RGH-MD-06, 193 patients (25%) received lorazepam and 22 patients (2.9%) received another benzodiazepine as rescue medication during the open-label treatment period. In the double-blind period, 8 patients (8%) in the placebo group and 6 (6%) 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.

In the predominant negative symptom trial RGH-188-005, most patients (91%) were receiving a psycholeptic drug before enrolment, which was titrated down over a median 15 days (range 1 to 29). The mean study drug duration was similar between groups (cariprazine 155.0 days [SD = 53.6], risperidone 157.8 days [SD = 51.6]). Most patients received the target dose of cariprazine 4.5 mg daily (|||||) and risperidone 4 mg daily (|||||) (Table 25).

The Clinical Study Report for Study RGH-188-005 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.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in this section. Refer to Appendix 3 for supplementary efficacy data.

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 in this section for the acute and relapse studies. Refer to the Disposition section for a summary of premature study discontinuation and to the Harms section for study drug discontinuation due to AEs.

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 LS mean differences versus placebo ranged from –6.8 (95% CI, –11.3 to –2.4; P = 0.003) for the cariprazine 3 to 6 mg group in RGH-MD-05, to –10.4 (95% CI, –14.6 to –6.2; P < 0.0001) for the cariprazine 4.5 mg group in RGH-MD-16 (Table 26).

The active control groups in Studies RGH-MD-16 and RGH-MD-04 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 Study RGH-MD-16 (all P < 0.05). In Study RGH-MD-04, 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 was 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 (28.6%) or the cariprazine 6 mg to 9 mg (34.7%) groups and the placebo group (24.8%) in Study RGH-MD-05 (both P > 0.05). There was no control of the type I error rate for the responder analyses; thus, any results showing a P < 0.05 should be interpreted as supportive evidence only (Appendix 3, Table 43).

The analyses of the change from baseline in the PANSS positive and negative subscale scores were consistent with analyses of primary outcomes, with all but 1 analysis showing results that favoured cariprazine versus placebo (Appendix 3, Table 44). These outcomes, however, were not controlled for 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 RGH-MD-16, and the ANCOVA (LOCF) and pattern-mixture model in RGH-MD-04 and RGH-MD-05. In Study RGH-MD-16, 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.”⁶²

The change from baseline to week 6 in the CGI-S score was the secondary outcome in the acute schizophrenia trials. The LS mean 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 27).

Table 27 also summarizes the CGI-I score at week 6 and the LS mean 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 are shown in Appendix 3, Table 45. Most comparisons favoured cariprazine versus placebo. However, interpretation of these data may be limited by the lack of MID for the NSA-16, and the potential for inflated type I error rate due to multiple testing.

Health-Related Quality of Life

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

In Study RGH-MD-04, the LS mean difference in the change from baseline in SQLS-R4 total scores was –6.8 points (95% CI, –11.2 to –2.4; P = 0.0027) for cariprazine 3 mg, and –8.3 points (95% CI, –12.7 to –4.0; P = 0.0002) for cariprazine 6 mg versus placebo (Table 28). In Study RGH-MD-05, the LS mean difference favoured the lower-dose cariprazine group (3 mg to 6 mg) versus placebo (–5.0 points, 95% CI, –9.8 to –0.1; P = 0.044) but not the cariprazine 6 mg to 9 mg group (–3.5 points, 95% CI, –8.5 to 1.4; P = 0.157). The type I error rate was not controlled for this outcome; thus, any data showing P < 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% were re-hospitalized between day 29 and day 42, across the 3 studies.

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

Withdrawal Design Trial

Relapse

Time to relapse was the primary outcome in Study RGH-MD-06. 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 RGH-MD-06, 47.5% experienced a relapse after being switched to placebo, compared with 24.8% of patients who remained on cariprazine therapy (Table 29). 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, respectively, was 30% or more increase in the PANSS total score (43.4% versus 20.8%), followed by an increase of 2 points or more in CGI-S score (28.3% and 4.0%), or a score greater than 4 on specific PANSS items (25.3% and 10.9%). The relapse study reported that 9 patients per treatment group (9%) were hospitalized due to worsening condition during the double-blind period. Four patients (4%) in the placebo group and no patients in the cariprazine group reported deliberate self-injury, or aggressive or violent behaviour.

The cumulative incidence of relapse during the double-blind phase of Study RGH-MD-06 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 that remained in the study was low at the later time points, with less than half the patients at risk at 6 months of follow-up.

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 PANSS total score, CGI-S, and PSP scores are shown in Appendix 3, Table 46. No between-group comparisons were reported for these outcomes.

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

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

Source: Clinical Study Report for RGH-MD-06.¹¹

Predominant Negative Symptom Study

Symptoms

In Study RGH-188-005, the primary outcome was the change from baseline to week 26 in the PANSS factor score for negative symptoms. The scores range from 7 to 49, with a lower score indicating fewer symptoms. Both the treatment groups showed an improvement over time, with LS mean change score of –8.9 for cariprazine and –7.4 for risperidone. The LS mean difference was –1.5 (95% CI, –2.4 to –0.5) favouring cariprazine versus risperidone (P = 0.002) (Table 30). Sensitivity analyses based on ANCOVA (LOCF) and pattern-mixture model showed results that were consistent with the primary MMRM analysis.

In the responder analysis, 157 patients who received cariprazine (69.2%) and 133 patients who received risperidone (58.1%) achieved at least a 20% reduction in the PANSS factor score for negative symptoms at week 26. The Clinical Study Report states that the planned logistic regression model had poor fit; 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 (study centre and baseline value as covariates, LOCF for missing data), which estimated the response odds ratio 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 30. Between-group differences favoured cariprazine versus risperidone for the LS mean change from baseline in the PANSS negative subscale (LS mean change = –1.5 points; 95% CI, –2.4 to –0.6; P < 0.001), the CGI-S score (LS mean change = –0.2, 95% CI, –0.4 to –0.1; P = 0.005), and CGI-I score (LS mean change = –0.4; 95% CI, –0.6 to –0.2; 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 less than 0.05 should be interpreted as supportive evidence only.

Functional Capacity

The change from baseline to week 26 in the PSP was the secondary outcome in Study RGH-188-005. The PSP is scored from 0 to 100, with higher scores indicating better psychosocial function. A between-group difference of 7 to 10 points has been reported in the literature as the MID.

In Study RGH-188-005, 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 LS mean difference was 4.6 points (95% CI, 2.7 to 6.6), favouring cariprazine versus risperidone (P < 0.001) (Table 31).

Harms

Only those harms identified in the review protocol are reported in this section. Refer to Table 32, Table 33, and Table 34 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 32, Table 33). 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 (RGH-MD-06), 80% of patients reported an AE during the 20-week open-label cariprazine treatment phase, compared with 74% and 65% who received cariprazine and placebo, respectively, during the 26- to 72-week double-blind phase. Akathisia was reported by 19% of patients during open-label treatment, but by only 3% to 5% of patients during the double-blind phase. The frequency of insomnia (14%) and headache (12%) were higher during open-label treatment than during the double-blind treatment phase (7% or 8% per group) (Table 34).

In the 26-week study in patients with predominant negative symptoms, 54% of patients in the cariprazine group and 57% in the risperidone group experienced 1 or more AEs (Table 34). Insomnia, akathisia, and headache were reported in 6% to 9% of patients in the cariprazine group and 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 of RGH-MD-06 and in 3% of patients in Study RGH-188-005. 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 Study RGH-MD-04 (suicide, ischemic stroke and myocardial infarction), and 1 patient died in the risperidone group of Study RGH-188-005 (of carcinoma). No deaths were reported in the other treatment groups.

Notable Harms

In the 6-week studies, treatment-emergent extrapyramidal symptoms were reported by ||| || ||| of patients in the placebo group, ||| || ||| of patients in the cariprazine groups, and ||| ||| ||| of patients in the aripiprazole and risperidone groups, respectively (Table 32, Table 33). In Study RGH-188-005, the frequency of extrapyramidal symptoms was similar in the cariprazine and risperidone groups (14% versus 13%). In Study RGH-MD-06, extrapyramidal symptoms were reported in ||| of patients receiving open-label cariprazine, in ||||| of patients who remained on cariprazine and |||| 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% reported suicidal behaviour across treatment groups. In the 6-week Study RGH-MD-16, | ||||||| of patients in the cariprazine 4.5 mg group discontinued due to suicidal ideation, and in Study RGH-MD-05, | ||||||| of patients in the placebo group discontinued due to a suicidal ideation SAE. One completed suicide was reported in the cariprazine 6 mg group of Study RGH-MD-04. During the open-label cariprazine phase of Study RGH-MD-06, | |||||||| |||||| discontinued due to suicidal ideation, | |||||||| |||||| had SAEs of suicidal ideation, and | ||||||| had a suicide attempt classified as an SAE. ||| ||||||| |||||| attempted suicide in the risperidone group of Study RGH-188-005 (SAE).

During the run-in phase of RGH-MD-06, 1 patient receiving cariprazine reported 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% in the placebo group, 6% in the aripiprazole group, and 17% in the risperidone group. In Study RGH-MD-06, 11% of patients reported a 7% or higher increase in body weight during the open-label cariprazine phase, and 27% to 32% of those in the cariprazine and placebo groups of the double-blind phase reported such an increase. In Study RGH-188-005, ||||| and || || in the cariprazine and risperidone groups, respectively, reported at least a 7% increase in weight. Treatment-emergent adverse events (TEAEs) related to metabolic effects are shown in Table 32, Table 33, and Table 34.