A Post-hoc Comparison of Paliperidone Palmitate to Oral Risperidone During Initiation of Long-acting Risperidone Injection in Patients with Acute Schizophrenia

| August 31, 2011 | 0 Comments

Srihari Gopal, MD; Gahan Pandina, PhD; Rosanne Lane, MAS; Isaac Nuamah, PhD; Bart Remmerie, Chem Eng; Danielle Coppola, MD; and David Hough, MD
Drs. Gopal, Pandina, Nuamah, Coppola, Hough, and Ms. Lane are from Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey; Mr. Remmerie is from Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica, N.V., Beerse, Belgium.

Innov Clin Neurosci. 2011;8(8):26–33.

Funding: Johnson & Johnson Pharmaceutical Research & Development, LLC, (Raritan, New Jersey) funded this study and was responsible for study design and data collection, analysis, and its interpretation. The sponsor also was responsible for deciding to publish the data.

Financial disclosures: Drs. Hough, Pandina, Nuamah, Coppola, and Gopal and Ms. Lane are employees of Johnson & Johnson Pharmaceutical Research & Development, LLC, in Raritan, New Jersey. Mr. Remmerie is an employee of Janssen Research & Development, a division of Janssen Pharmaceutica N.V., in Beerse, Belgium

Author participation: All authors met International Council of Medical Journal Editors criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, and made the final decision about where to publish these data, and approved the final draft submission to the journal. All authors contributed to study design, data interpretation, and literature analysis. Ms. Lane and Dr. Nuamah oversaw the statistical analyses and provided interpretation of the efficacy and safety data. Mr. Remmerie oversaw the pharmacokinetic analyses and provided interpretation of that data. Dr. Gopal provided an initial concept and draft manuscript that was further developed by Dr. Sandra Norris, with direction provided by all authors, and editorial assistance from Dr. Battisti.

ClinicalTrials.gov Registration: NCT00589914

Key words: Paliperidone palmitate, risperidone, acute schizophrenia, long-acting injection

Abstract:
Objective: First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone.

Design: Double-blind, randomized study.

Setting: Outpatient or inpatient.

Participants: Adults with established (?1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (1–6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, 100mg eq. on Day 8, and oral placebo supplementation for the first 28 days.

Measurements: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression–Severity score, and responder rate (percentage of patients with ?30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted.

Results: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression–Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period.

Conclusion: During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.

Background

The standard-of-care for treating acute exacerbations of schizophrenia currently involves oral antipsychotics,[1–3] whereas long-acting injectables are generally used for maintenance treatment of schizophrenia.[4,5] For patients being treated with long-acting injectable (LAI) risperidone, which is administered every two weeks, oral risperidone must also be used during the initial three weeks of treatment to ensure that adequate therapeutic plasma concentrations are maintained until the main release of risperidone from the microspheres at the injection site.[4] The long-acting injectable antipsychotic paliperidone palmitate is the palmitate ester of paliperidone (9-hydroxy-risperidone), the pharmacologically active ingredient. Paliperidone palmitate is formulated to provide sustained plasma concentrations of paliperidone, allowing once-monthly administration.6 The onset of exposure is rapid following the first initiation dose,[7] permitting its use for the treatment of acute schizophrenia without the need for oral supplementation.[6] Several randomized, controlled studies have demonstrated the superior efficacy of once-monthly paliperidone palmitate over placebo in short-term studies of acutely symptomatic schizophrenia patients.[8–10] Paliperidone palmitate is approved in the United States for the acute and maintenance treatment of schizophrenia in adults. However, there are limited data to compare the use of paliperidone palmitate with oral antipsychotics in acutely symptomatic patients.

In a recently published 13-week, double-blind, double-dummy, active-controlled study, Pandina et al[11] determined that paliperidone palmitate injection was noninferior to risperidone LAI for the treatment of schizophrenia. Patients randomized to risperidone LAI also received oral risperidone during the first 28 days (i.e., 1 week before and 3 weeks after the first injection of risperidone LAI). Due to the three-week lag period after the first dose of risperidone LAI on Day 8,12 the plasma exposure until Day 28 in this study was almost entirely due to the oral risperidone administration. Therefore, we conducted a post-hoc analysis of efficacy data at time points before and after the first 28 days of this study to compare the efficacy of paliperidone palmitate to oral risperidone for treatment of acute schizophrenia. Secondary objectives of the post-hoc analyses were to compare the plasma concentrations of paliperidone (active ingredient) in the paliperidone palmitate group to the active moiety (sum of risperidone and 9-OH risperidone) in the risperidone LAI group, as well as the incidence and types of treatment-emergent adverse events in the paliperidone palmitate and risperidone LAI groups, during the period of oral risperidone supplementation.

Methods

The methods of the study are described fully in detail elsewhere,[11] but are briefly reviewed as follows:

Patients. Adults (?18 years) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia for at least one year before screening, had a Positive and Negative Syndrome Scale (PANSS) total score of between 60 to 120, inclusive, at the screening visit, and body mass index (BMI) of 17.0 to 39.9kg/m2 were eligible for enrollment. No other criteria apart from PANSS were used to define the acute episode. The main exclusion criteria were a decrease of 25% or more in PANSS total score from screening to baseline (visits performed within 7 days of one another), significant risk of suicidal or violent behavior, and relevant history or current presence of any significant or unstable systemic disease.

An institutional review board or ethics committee at each study center approved the study protocol and its amendments. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and in accordance with International Conference on Harmonisation’s Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the respective protocols. All patients provided written informed consent prior to study participation.

Study drug. Eligible patients were randomly assigned in a 1:1 ratio to receive either paliperidone palmitate (Invega® Sustenna®, Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.) injected intramuscularly (IM) without oral antipsychotic supplementation or risperidone LAI (Risperdal® Consta®; Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.) injected IM with oral risperidone supplementation (per recommendation in current prescribing information).[4] Over the first 28 days of the study, patients in the paliperidone palmitate group received 150mg eq. of paliperidone (equates to 234mg of paliperidone palmitate) on Day 1, 100mg eq. (equates to 156mg of paliperidone palmitate) on Day 8, and a placebo injection (matched to risperidone LAI) on Days 8 and 22. In addition, these patients received oral placebo matched to oral risperidone for the first 28 days of the study. Patients randomized to risperidone LAI received a 25mg injection on Days 8 and 22 and placebo injections (matched to paliperidone palmitate) on Days 1 and 8. Risperidone LAI was initiated on Day 8 (7 days after the initiation of paliperidone palmitate) so that injection of study drugs would occur at the same visits, thereby preserving the study blind. For the first 28 days of the study (1 week before and 3 weeks after first injection of risperidone LAI), patients randomized to risperidone LAI also received 1 to 6mg daily of oral risperidone, with adherence assessed by returned tablet count. Thus, hereafter, the latter group is referred to as the “oral risperidone group” based on what is the pharmacologically active agent during the limited time period of these analyses. On Day 8 (when there were dual injections), the injections were not to be administered into the same muscle. The side or muscle site was alternated for each injection.

Patients without known exposure to oral or injectable risperidone or paliperidone before the double-blind period received paliperidone extended release (ER) (6mg per day) for 4 to 6 days during screening to test for tolerability and allergic or hypersensitivity reactions. This oral tolerability test occurred between Day -6 and Day -1 before the first injection of study drug.

Study design and outcome measures. The study was a randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter, noninferiority comparative study, which was conducted between March 2007 and July 2009 at 89 centers in 14 countries. The study consisted of a seven-day screening period for washout of disallowed psychotropic medications (mood stabilizers, including lithium and all anticonvulsants) followed by a 13-week double-blind treatment period (the first 5 weeks are relevant to the analyses reported here). A double-dummy approach was used to preserve the blind, given the differences between the two injectable study drugs based on appearance (i.e., 1 inch [23 gauge] to 1.5 inch [22 gauge] needle was used, based on body weight, to administer paliperidone palmitate into the deltoid muscle and 2-inch [23 gauge] needle used to administer risperidone LAI into the gluteal muscle), method of preparation (risperidone LAI requires reconstitution for use and paliperidone palmitate does not), site of administration (the first 2 doses of paliperidone palmitate were injected into the deltoid muscle and risperidone LAI was injected into the gluteus muscle), and administration schedules. Limited supplementation with benzodiazepines (i.e., up to 6mg/day lorazepam or equivalent dosage of another agent) was permitted, as the standard of care, for the management of agitation, anxiety, or sleep difficulties that often accompany the characteristic symptoms of schizophrenia, particularly during early treatment.

Efficacy measures included the PANSS (comprised of 30 items rated on a scale from 1=absent to 7=extreme) and Clinical Global Impression-Severity (CGI-S) (7-point global assessment with scores ranging from 1=not ill to 7=extremely severe), which were performed (as prespecified in the protocol) on Days 1, 4, 15, 22, and 36, and Personal and Social Performance Scale (PSP),[13] which was performed on Days 1, 15, and 36. A qualified clinical rater, and the same rater if possible, administered the scales at all visits. Spontaneously reported adverse events were monitored throughout the study.

Blood samples were collected on Days 1, 4, 8, 15, 22, and 36 (predose, as applicable) for pharmacokinetic analysis. Plasma concentrations of paliperidone (paliperidone palmitate group) and active moiety (oral risperidone group) were determined by a validated liquid chromatography/tandem mass spectrometry method, with a lower limit of quantification of 0.1ng/mL.[14]

Statistical analyses. An intent-to-treat (ITT) analysis set, including patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment, was utilized for the post-hoc analyses reported here. Since no efficacy assessments were conducted on Day 28 (end of initial oral supplementation treatment), those conducted at the nearest time points (Days 22 and 36) were included.

Changes from baseline in the PANSS total score, PSP total score, and CGI-S score were analyzed using analysis of covariance (ANCOVA) models, with treatment and country as factors and baseline score as a covariate, using the last observation carried forward (LOCF) approach. Least-square (LS) mean differences between the two treatment groups and associated 95-percent confidence intervals (CI) were calculated. The proportion of patients who were PANSS responders (defined as improvement in PANSS total score of at least 30% from baseline) was calculated at each time point; the between-groups difference at each time point was determined using the Cochran-Mantel-Haenszel test stratified by country. Descriptive statistics were calculated for the plasma concentrations of paliperidone (paliperidone palmitate group) and active moiety (oral risperidone group). Incidences of treatment-emergent adverse events that occurred during the first 28 days of the study (initial oral supplementation treatment) were summarized by treatment group.

Results

A total of 913 patients were included in the ITT population for post-hoc analyses; 453 patients were randomized to paliperidone palmitate and 460 were randomized to risperidone. Of these, 443 (98%) and 419 (91%), respectively, received both intended injection doses of active study drug during the initial weeks of the study. Risperidone-treated patients received a mean mode oral dose of 3.3 mg (range, 1–6mg) for the first 28 days of the study.

The treatment groups were similar based on demographic and other baseline characteristics (Table 1). The majority of the ITT population was white (79%) and over half were men (58%); their mean (standard deviation [SD]) age was 38.9 (11.95 years). Mean (SD) age at diagnosis of schizophrenia was 27.4 (9.11) years. Before study enrollment, patients most commonly (70%) used atypical agents to treat their schizophrenia, with a similar proportion of patients in each treatment group (45% paliperidone palmitate, 44% oral risperidone) having used oral risperidone. Most enrolled patients (92%) required treatment for paranoid schizophrenia. Mean (SD) PANSS total score at baseline was 84.7 (11.85) for patients randomized to paliperidone palmitate and 84.4 (11.25) for patients randomized to oral risperidone. A similar proportion of patients required a dose(s) of benzodiazepine during the first 36 days of the study for the management of agitation, anxiety, and/or sleep difficulties (26% of paliperidone palmitate assigned patients and 20% of oral risperidone patients).

PANSS total score improved (decreased) to a similar extent in the paliperidone palmitate and oral risperidone groups during the first 36 days (-12.8 and -11.6 in the respective groups at Day 36) (Figure 1), as did CGI-S scores (Figure 2). At each evaluation time point from Day 4 to Day 36, a slightly greater proportion of paliperidone palmitate-treated patients were classified as PANSS responders, compared with patients treated with oral risperidone (Figure 3). The difference between treatment groups for PANSS response was not statistically significant at any time point. At Day 4, there was a statistically significant between-group difference favoring paliperidone palmitate based on the change from baseline PANSS total score (Table 2). Otherwise, there were no statistically significant between-group (paliperidone palmitate vs. oral risperidone) differences at any evaluation time points during the first 36 days of treatment based on the change in PANSS total score, CGI-S score, or PSP (i.e., 95% CI) for the difference in LS mean contains zero at all time points).

The median plasma concentration-time profiles of active moiety (i.e., 9-OH risperidone [paliperidone] for the paliperidone palmitate group and risperidone plus 9-OH risperidone for the oral risperidone group) were similar over the first 36 days (Figure 4). Oral tolerability testing conducted during the screening period likely contributed to the plasma concentration of active moiety observed on Days 1 and 4.

The incidence of individual treatment-emergent adverse events was generally similar between groups, with the exception of insomnia, anxiety, and injection site pain, which occurred at higher incidence (difference of ?2%) in the paliperidone palmitate group compared with the oral risperidone group.

Discussion

We conducted a post-hoc analysis of the initiation phase of a previously reported, double-blind, noninferiority study to compare efficacy and tolerability of paliperidone palmitate without oral supplementation and risperidone LAI treatment supplemented with oral risperidone for the first month.[11] In this analysis, paliperidone palmitate provided similar efficacy to that of oral risperidone in improving the acute symptoms associated with exacerbation of schizophrenia. Although efficacy scales were not administered at the Day 28 time point, analyses were conducted based on the nearest evaluation time points, both earlier and later (Days 22 and 36). At each evaluation time point during the first 36 days after initiation of treatment, a slightly greater, although not statistically significant, proportion of paliperidone palmitate-treated patients were classified as PANSS responders, compared with patients treated with oral risperidone at initiation of risperidone LAI administration. We do appreciate that at the later time point (Day 36), the release of risperidone from the microsphere formulation has most likely already started and may have been contributory to the effectiveness of the oral risperidone group. Early clinical response to treatment with IM paliperidone palmitate, comparable to that of oral risperidone, was also observed based on CGI-S (global symptoms) and PSP (functioning) results. The lack of statistical separation between the two treatment groups at the specified time points used in this analysis underscores that both paliperidone palmitate and oral risperidone are similarly efficacious in acutely symptomatic disease. In contrast to these findings, most LAI antipsychotics are not associated with rapid onset of symptom relief and generally take several weeks to months to achieve a therapeutic effect.[15]

The treatment-emergent adverse event profile was generally similar for paliperidone palmitate and oral risperidone at initiation of risperidone LAI administration (over the first 28 days), with the exception of insomnia, anxiety, and injection-site pain, the latter being entirely dependent on an injection having been administered. While a higher incidence of injection site pain was noted for the paliperidone palmitate group (4.6%) compared with the oral risperidone group (0.7%), the site of injection (deltoid muscle vs. gluteal muscle, respectively) is likely to have played a role in this comparison.[8] The type and frequency of treatment-emergent adverse events in the risperidone group were consistent with expectations based on product labeling.[4] In both treatment groups, the incidences of treatment-emergent adverse events were slightly lower during the first 28 days, as compared to the 13 weeks of the full study.[11]

An optimized dosing regimen for paliperidone palmitate, which is consistent with the current label recommendations, was used in this study to achieve early and effective plasma concentrations following IM administration without oral antipsychotic supplementation.16 Initiation of treatment with a 150mg eq. dose on Day 1, followed by a 100mg eq. dose on Day 8, resulted in mean paliperidone plasma concentrations that exceeded a previously established antipsychotic efficacy threshold of 7.5ng/mL17–19 from the first sampling point after dosing (Day 4) and thereafter (Figure 4). The deltoid injection site for treatment initiation phase was selected based on clinical trials and population pharmacokinetic modeling, which showed that rapid attainment of therapeutic concentrations are achieved when paliperidone palmitate is injected into the deltoid (vs. gluteal) muscle.[7] The similar median plasma concentrations of the respective active moieties in the treatment groups over the first 36 days likely explain the similar adverse event and efficacy profile observed during this study period.

These results are from a post-hoc analysis and should be confirmed in a prospectively designed study. Furthermore, the original double-blind study was designed and powered as a noninferiority efficacy comparison of paliperidone palmitate and risperidone LAI, based on change from baseline to endpoint in PANSS total score. Thus, any inferences regarding relative efficacy and safety for other variables, or at different time points, in the present analysis should be interpreted with caution. Oral tolerability testing (required for patients without exposure before the double-blind period) likely explains the active moiety plasma concentrations observed in some patients on Day 1, and may have partially contributed to the exposure data on Day 4.

The results from this analysis provide evidence that treatment with IM paliperidone palmitate is similarly efficacious and tolerable to that of oral risperidone (1–6mg/day) during initiation of risperidone LAI. This further suggests that paliperidone palmitate is clinically suitable for the management of acutely symptomatic patients with schizophrenia without the need for oral supplementation.

Acknowledgments

Sandra Norris, PharmD, provided writing assistance and Wendy P. Battisti, PhD (Johnson & Johnson Pharmaceutical Research & Development, LLC) provided additional editorial assistance. We also thank the patients, without whom this study could not have been accomplished, and the study investigators who contributed data to the original study.

References
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Category: Original Research, Past Articles, Psychiatry, Schizophrenia, Suicidality

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