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

Jane Oh, Mercer University College of Pharmacy 2015

According to the American Psychiatric Association, schizophrenic patients may experience relapse of symptoms due to poor adherence, which may be influenced by a lack of insight to their disease and of the importance of medication adherence. Long-acting injectable (LAI) antipsychotics circumvent this barrier by eliminating the need to take medication on a daily basis.1

The original formulation of paliperidone palmitate was to be used as a once-monthly antipsychotic LAI to treat schizophrenia and to reduce relapse risk.2 Recent development of a three-month formulation offers an even longer dosing interval to decrease nonadherence and the risk of relapse.3

Title: Efficacy and safety of the three-month formulation of paliperidone palmitate versus placebo for relapse prevention of schizophrenia
Design Randomized, double-blind, multicenter (eight countries), placebo-controlled clinical trial
Objective

(Primary)

To evaluate the efficacy and safety of the three-month formulation of paliperidone palmitate versus placebo in delaying time to relapse of schizophrenia symptoms
Study Groups Age 18-70 years, Diagnostic Statistical Manual of Mental Disorders (DSM)-IV- Text Revision diagnosis of schizophrenia for at least one year, Positive and Negative Syndrome Scale (PANSS) total score lower than 120, and a stable residence for the previous three months. Major exclusion criteria: primary, active DSM-IV diagnosis other than schizophrenia; significant suicide risk; substance dependence within six months before screening; history of: neuroleptic malignant syndrome, tardive dyskinesia, or any malignant neoplasm excluding basal cell carcinoma in the previous five years
Methods Transition phase: Once-monthly doses of the one-month formulation of paliperidone palmitate (50, 75, 100, or 150mg eq) intramuscularly
Maintenance phase: Single dose of the three-month formulation intramuscularly (three and one-half times the standard dose of once-monthly paliperidone palmitate)
DB phase: Three-month fixed dose of paliperidone palmitate (175, 263, 350, or 525mg eq; n= 160) versus placebo (Intralipid, 20%; n= 145) every three months intramuscularly
Duration April 26, 2012, through April 9, 2014
Primary outcome measure Time from randomization to the first relapse event (time to relapse) in the DB phase
Baseline Characteristics Mean age 37.8, male 75%, 64% white, mean weight 77.6 kg, mean BMI 26.2, mean age at schizophrenia diagnosis 26.9, use of depot antipsychotics prior to study start 17%, mean PANSS score at DB phase baseline 54.5
Results Time to first relapse in the DB phase interim analysis: paliperidone palmitate group versus placebo group (hazard ratio= 3.45; 95% CI, 1.73- 6.88; P< .001); median time to relapse: placebo= 274 days, 3-month paliperidone palmitate= not estimable due to early study termination due to efficacy
Adverse Events Common Adverse Effects: headache 9%, increased weight 9%, nasopharyngitis 6%, extrapyramidal symptoms 8% including akathisia 4%, anxiety 8%, insomnia 7%, upper respiratory tract infection 4%, cough 3%, urinary tract infection 3%, influenza 2%, schizophrenia 1%, weight decreased 1%, agitation 1%, decreased appetite 1%, irritability 1%, diabetes mellitus- and hyperglycemia- related treatment-emergent adverse events (TEAEs) 3% including increased blood glucose level 2%, injection site-related TEAEs 4%, and prolactin-related TEAEs 1% including amenorrhea 2%
Serious Adverse Events: 3%
Percentage that Discontinued due to Adverse Events: 0%
Study Author Conclusions Compared with placebo, the three-month formulation of paliperidone palmitate administered four times yearly significantly delayed time to relapse in patients with schizophrenia. The three-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations.

This study shows a potential new treatment option in schizophrenia through the use of higher doses of paliperidone palmitate using its extended elimination half-life to dose patients only four times a year. The 3.5-fold dose conversion ratio used in this study was generally tolerable in terms of safety, and also resulted in delayed relapse times in patients with schizophrenia.4 Currently, there is an ongoing noninferiority study comparing both LAI formulations of paliperidone palmitate in the one-month and three-month formulations in patients with schizophrenia.5

References:

  1. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia second edition. American Psychiatric Association. 2010. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf. Accessed April 2, 2015.
  2. About Invega® Sustenna® (paliperidone palmitate): A once-monthly schizophrenia medication. Janssen. http://www.invegasustenna.com/about-invega-sustenna. Accessed April 2, 2015.
  3. FDA grants priority review for three-month paliperidone palmitate for the treatment of schizophrenia. PR Newswire Association. http://www.prnewswire.com/news-releases/fda-grants-priority-review-for-three-month-paliperidone-palmitate-for-the-treatment-of-schizophrenia-300022224.html. Accessed April 2, 2015.
  4. Berwaerts J, Liu Y, Gopal S, et al. Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2015; doi: 10.1001/jamapsychiatry.2015.0241. Accessed April 1, 2015.
  5. Study of paliperidone palmitate 3 month and 1 month formulations for the treatment of patients with schizophrenia. U.S. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT01515423. Accessed April 2, 2015.
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