Clinical Trials

Date: 2012-02-28

Type of information: Results

phase: 3

Announcement: results

Company: Forest Laboratories (USA) Gedeon Richter (Hungary)

Product: cariprazine

Action mechanism:

• dopamine D3 receptor partial agonist. Cariprazine has been discovered by researchers at Gedeon Richter. This orally active, potent dopamine D3-preferring D3/D2 receptor partial agonist is an atypical antipsychotic for the treatment of patients with schizophrenia and for patients with manic or mixed episodes associated with bipolar I disorder. The safety and efficacy of cariprazine was studied in a clinical trial program of more than 2700 patients. In addition, cariprazine is being investigated for the treatment of bipolar depression and adjunctive MDD in adults. Cariprazine was discovered and co-developed by Gedeon Richter Plc and is licensed to Actavis, now Allergan, in the U.S. and Canada.

Disease: schizophrenia

Therapeutic area: CNS diseases - Mental diseases

Country:

Trial details:

• The first Phase III, multinational, multicenter, double-blind, placebo controlled, parallel-group study evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia. Eligible patients were those that met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia and had a PANSS total score between 80 and 120 at screening and baseline. Following a washout period of no antipsychotic therapy for up to 7 days, a total of 617 patients between 18 and 60 years old were randomized to one of the following treatment arms: 3 mg/d cariprazine, 6 mg/d cariprazine, 10 mg/d aripiprazole or placebo given once daily for 6 weeks followed by an additional 2-week safety follow-up period, where no drug was administered. Patients were hospitalized during the washout period and for the first 4 weeks of the double-blind treatment. Thereafter, patients were followed either as inpatients or outpatients, as determined by the site investigator and based on patient status. The protocol-specified primary endpoint was the change from baseline to Week 6 in the PANSS total score for the individual cariprazine treatment groups compared to placebo treatment using a mixed-effects model for repeated measures (MMRM) analysis. Overall, 67% of patients completed the study. The premature discontinuation rates (all causes, including adverse-event related) were 33% for cariprazine 3 mg/day, 38% for cariprazine 6 mg/day, 25% for 10mg/day aripiprazole and 38% for placebo. Cariprazine was generally well tolerated; the most common adverse events (=10%) observed in any treatment group being akathisia, insomnia, and headache.
• The second Phase III, multinational, multicenter, double-blind, placebo controlled, parallel-group study evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia. Patients enrolled in the study met the DSM-IV-TR criteria for schizophrenia and had a PANSS total score between 80 and 120 at screening and baseline. Following a washout period of no antipsychotic therapy for up to 7 days, a total of 446 patients between 18 and 60 years old were randomized to one of the following treatment arms: 3-6 mg/d cariprazine, 6-9 mg/d cariprazine, or placebo given once daily for 6 weeks followed by an additional 2 week safety follow-up period where no drug was administered. Patients were hospitalized during the washout period and for the first 4 weeks of the double-blind treatment. Thereafter, patients were followed either as inpatients or outpatients, as determined by the site investigator and based on patient status. The protocol-specified primary endpoint was the change from baseline to week 6 in the PANSS total score for each cariprazine treatment group compared to placebo treatment using the MMRM analysis. Overall 61% of patients completed the study. The premature discontinuation rates (all causes, including adverse-event related) were 36% for cariprazine 3-6 mg/day, 42% for cariprazine 6-9 mg/day, and 40% for placebo. Cariprazine was generally well tolerated with the most common adverse events (=10%) observed in any treatment group being akathisia, headache, insomnia, restlessness, and extrapyramidal disorder.

Latest news:

• * On February 28, 2012, Forest Laboratories and Gedeon Richter have announced positive top-line results in 2 Phase III clinical trials of cariprazine (RGH-188) for the treatment of acute exacerbation of schizophrenia. For the primary endpoint in each study, the Positive And Negative Syndrome Scale (PANSS), the data showed that cariprazine-treated patients experienced significant symptom improvement compared to placebo-treated patients. All doses showed statistically significant separation from placebo starting at week 2 and at each subsequent time point with the higher dose showing separation as early as week 1 of treatment.
• First study: Statistically significant improvement in PANSS total score was observed in each of the cariprazine dose groups relative to the placebo treatment group (3 mg/day: -6.0, p=0.0044 and 6 mg/day: -8.8, p<0.0001) by MMRM analysis. The change from baseline in PANSS total score was statistically significant at every time point starting at week 1 for the cariprazine 6 mg/d group and week 3 onwards for the cariprazine 3 mg/d group. Statistically significant improvements were also seen in the aripiprazole group relative to placebo in the PANSS total score at each week. Second study: Statistically significant improvement in PANSS total score was observed in each of the cariprazine dose groups relative to the placebo treatment group (3-6 mg/day: -6.8, p=0.0029 and 6-9 mg/day: -9.9, p< 0.0001) by MMRM analysis. The change from baseline was statistically significant at every time point starting at week 1 for the cariprazine 6-9 mg/d group and week 2 onward for the cariprazine 3-6 mg/d group. Further analyses of the data in each study will be completed in the coming weeks. The results of these 2 studies were consistent with the results of the previously completed placebo-controlled Phase Iib fixed-dose study in this population. Cariprazine is also currently being investigated in clinical studies for patients with bipolar depression, and as an adjunct treatment for Major Depressive Disorder (MDD). Forest has now 3 positive schizophrenia trials and 3 positive bipolar mania trials and the company looks forward to filing the NDA for both indications in 2012.

   

Is general: Yes