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Original Investigation |

Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia A Randomized Clinical Trial

Joris Berwaerts, MD1; Yanning Liu, MS2; Srihari Gopal, MD, MHS1; Isaac Nuamah, PhD1; Haiyan Xu, PhD1; Adam Savitz, MD, PhD1; Danielle Coppola, MD1; Alain Schotte, PhD3; Bart Remmerie, Chem Eng3; Nataliya Maruta, MD, PhD4; David W. Hough, MD1
[+] Author Affiliations
1Janssen Research & Development, LLC, Titusville, New Jersey
2Johnson & Johnson Medical (China) Ltd, Beijing, China
3Division of Janssen Pharmaceutica NV, Janssen Research & Development, Beerse, Belgium
4Institute of Neurology, Psychiatry, and Narcology, Academy of Medical Science of Ukraine, Kharkiv, Ukraine
JAMA Psychiatry. 2015;72(8):830-839. doi:10.1001/jamapsychiatry.2015.0241.
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Importance  Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients.

Objective  To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms.

Design, Setting, and Participants  This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase.

Interventions  Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase.

Main Outcomes and Measures  Time from randomization to the first relapse event (time to relapse) in the DB phase.

Results  In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%).

Conclusions and Relevance  Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations.

Trial Registration  clinicaltrials.gov Identifier:NCT01529515

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Figure 1.
CONSORT Flow Diagram of Study Design

aTwo patients failed to meet criteria to enter the maintenance phase but continued into the maintenance phase by mistake and received an injection of the 3-month formulation of paliperidone palmitate at visit 8. These 2 patients withdrew from the maintenance phase because they did not meet criteria to enter the maintenance phase.

bDuration of the double-blind phase was variable, with the patients continuing until they experienced a relapse event and completed all end-of-study assessments; met 1 or more of the study discontinuation or withdrawal criteria; or had remained relapse free during the double-blind phase until the study was terminated for efficacy at the interim analysis (occurrence of 42 relapse events) or because of 70 relapse events being recorded.

cThe duration of exposure to the 3-month formulation of paliperidone palmitate (maintenance and double-blind phases) ranged from 16 to 540 days; the median treatment duration in the double-blind phase was 169 days.

dThe median duration of receiving placebo in the double-blind phase was 146 days.

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Figure 2.
Kaplan-Meier Plot of Time to Relapse During the Double-Blind Phase

The median time to relapse indicates the time (in days) since randomization at which the cumulative survival function equals 0.5. Shaded areas indicate 95% confidence interval for the estimated proportion of patients who remained in the study without relapse at distinct times after randomization in the double-blind phase. A, Interim analysis. The median time to relapse was 274 days for placebo and was not estimable for the 3-month formulation of paliperidone palmitate. B, Final analysis. The median time to relapse was 395 days for placebo and was not estimable for 3-month paliperidone palmitate. Of the 160 patients randomized to 3-month paliperidone palmitate in the double-blind phase (175 mg eq: 6 patients [4%]; 263 mg eq: 15 patients [9%]; 350 mg eq: 78 patients [49%]; and 525 mg eq: 61 patients [38%]), a total of 25 patients (16%) continued at week 36. A greater proportion of patients receiving 525 mg eq of 3-month paliperidone palmitate (14 of 61 patients [23%]) continued in the study to double-blind phase week 36 vs other dose groups (175 mg eq: 0 of 6 patients; 350 mg eq: 8 of 78 patients [10%]; 263 mg eq: 3 of 15 patients [20%]).

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Figure 3.
Positive and Negative Syndrome Scale (PANSS) Total Scores Over Time

Error bars indicate standard error.

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