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Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

ABSTRACT: Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ?1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12?mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatment-emergent adverse events versus placebo was similar for cariprazine 1.5-3?mg/day and higher for cariprazine 4.5-6 and 9-12?mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (?1to2?kg) versus placebo were observed. Within the Food and Drug Administration-approved dose range (1.5-6?mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.

SUBMITTER: Earley W

PROVIDER: S-EPMC5625952 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

Earley Willie W Durgam Suresh S Lu Kaifeng K Laszlovszky István I Debelle Marc M Kane John M JM

International clinical psychopharmacology 20171101 6

Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients wh ...[more]

PMID: 28692485

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Project description:Introduction In the early stage of schizophrenia (first 5 years), the most important clinical target besides symptom control is relapse prevention as each relapse significantly decreases the possibility of preferable long-term outcomes. Early discontinuation of antipsychotic medication due to intolerable side-effects is one of the most common causes of relapse. Objectives This poster aims to present cariprazine’s tolerability in the early stage of schizophrenia. Methods Data from 4 randomized, double-blind, placebo-controlled trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) with similar design (1 week of wash out period, 6 weeks of treatment and 2-4 weeks of follow-up) were pooled. For the post-hoc analysis, patients with early stage of schizophrenia (defined as having a disease duration of less than 5 years) were extracted from the whole safety population, and approved doses of cariprazine (1.5-6.0 mg/day) were combined. Treatment-emergent adverse events (TEAEs) and discontinuation rates were analysed versus placebo. Results Overall, 169 placebo- (PBO) and 322 cariprazine-treated (CAR) patients were identified as having schizophrenia for less than 5 years. 67.7% cariprazine- and 56.2% placebo-treated patients reported at least one TEAE; most frequently insomnia (10.9 % CAR; 12.4% PBO), akathisia (9.6% CAR; 2.4% PBO) and extrapyramidal symptoms (9.3% CAR; 1.8% PBO). Discontinuation due to adverse events was reported in only 8.4% of cariprazine- and 14.8% of placebo-treated patients. Relapse occurred in 3.1% of cariprazine- and 5.3% of placebo-treated patients. Conclusions Cariprazine was generally well-tolerated in the early stage of schizophrenia; given the limitations of this analysis, additional research is warranted. Conflict of interest Studies were funded by Gedeon Richter Plc. and Allergan Plc (prior to its acquisition by AbbVie). Dombi, Acsai, Dr. Barabássy, Dr. Sebe, Dr. Laszlovszky, Dr Vass, Dr. Szatmári and Dr. Németh are employees of Gedeon Richter Plc., Dr. Earley and Dr. Patel a

Project description:BackgroundLong-term treatment with antipsychotic agents is indicated for patients with schizophrenia, but treatment is associated with adverse events (AEs) that contribute to medication discontinuation and nonadherence. Understanding drug safety profiles is critical to avoid unwanted side effects. Cariprazine is a potent dopamine D3/D2 receptor partial agonist that is approved for the treatment of adults with schizophrenia (EU, US) and acute manic/mixed and depressive episodes associated with bipolar I disorder (US).MethodsPost hoc analyses were conducted to characterize the safety profile of cariprazine within the recommended 1.5-6 mg/d dose range for schizophrenia; data from 8 short- or long-term clinical trials were analyzed.ResultsIn the pooled cariprazine-treated safety population (n=2048), the rate of study completion was 52.8%, with withdrawal of consent, insufficient response, and AEs the most common reasons for premature discontinuation. The most commonly reported AEs (>10%) in the overall cariprazine-treatment group were akathisia (14.6%), insomnia (14.0%), and headache (12.1%); most AEs were considered mild (71.0%) or moderate (26.5%). Most akathisia was mild/moderate (97.5%) and >93% of patients remained on treatment; akathisia events were managed by rescue medications (56.3%) or dose reduction (18.3%). The metabolic profile of cariprazine was neutral in patients with short- and long-term exposure; mean weight gain was 1 kg for overall cariprazine, with an AE of weight increased reported for 5.1%. Other AEs of special interest that occurred at >3% for overall cariprazine were extrapyramidal disorder (7.0%), sedation (3.7%), and somnolence (3.1%); prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation occurred at ≤1%.ConclusionAkathisia, the most common cariprazine-related AE, was mild/moderate and resulted in few study discontinuations; symptoms were well managed and most patients remained on treatment. Results of this analysis indicated that cariprazine in the recommended dose range was safe and generally well tolerated in patients with schizophrenia.Trial registrationStudies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012-005485-36).

Project description:Abstract Background: Relapse is common in schizophrenia; identifying characteristics associated with relapse may help improve disease management. Cariprazine, a D3/D2 receptor partial agonist, is approved in the United States for the treatment of schizophrenia. Post hoc analyses of a long-term, randomized, double-blind (up to 72 weeks), relapse prevention trial (NCT01412060) were performed to identify characteristics associated with relapse in placebo- and cariprazine-treated patients. Methods: Baseline characteristics in cariprazine-treated (3, 6, or 9?mg/d) or placebo-treated patients were evaluated in relation to relapse status. Demographic variables included age, sex, race, weight, and BMI. Psychiatric history variables included mean age at illness onset, duration of schizophrenia, duration of current episode, number of lifetime psychotic episodes, previous hospitalizations, and acute exacerbations in the past year. Baseline rating scale severity scores (eg, Positive and Negative Syndrome Scale [PANSS] and Clinical Global Impressions-Severity [CGI-S]) were evaluated. Differences in demographic and psychiatric history variables were evaluated using the Student t test (categorical variables) or Fisher exact test (continuous variables); rating scale severity scores were evaluated with 2-way ANOVA with relapse and study center as factors. Results: Relapse occurred in nearly twice as many placebo-treated (47.5%) as cariprazine-treated patients (24.8%) (hazard ratio [95% CI] = 0.45 [0.28, 0.73]). For cariprazine-treated patients who relapsed vs those who did not, significant differences were seen in baseline age (mean, 43 vs 38 y), weight (85 vs 73?kg), BMI (29 vs 26?kg/m2), and race (all, P < .05); for placebo-treated patients, there were no significant differences in demographic variables based on relapse status. In both treatment groups, patients who relapsed vs patients who did not relapse had a greater mean number of previous hospitalizations (cariprazine = 8.4 vs 4.3 [P = .0199]; placebo = 4.9 vs 2.8 [P = .0183]). Cariprazine patients who relapsed vs those who did not had longer illness duration (18.1 y vs 9.9 [P = .0005]); the number of lifetime episodes also differed by relapse status (P = .0016), with a greater percentage of relapsed patients experiencing ?5 episodes. Baseline PANSS total score and CGI-S scores were not significantly different in relapsed vs nonrelapsed patients in either treatment group. Conclusion: While patients treated with cariprazine had a lower rate of relapse than placebo overall, the results suggest that patients who were older, heavier, or had a later stage of illness may be more prone to relapse during cariprazine treatment. In patients randomized to placebo, demographic characteristics and psychiatric history were not as meaningful in predicting relapse. Greater symptom severity at baseline did not appear to be associated with relapse.

Project description:BackgroundIntranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia.ObjectiveThe aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD).MethodsA total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance.ResultsOf 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings.ConclusionFindings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies.Clinical trial registrationTRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Dataset Information

Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

Publications

Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

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