Pilar Lim

Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial.

BACKGROUND Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic developed for schizophrenia treatment. It utilizes OROS technology to provide a unique pharmacokinetic profile, eliminating the need for titration and potentially leading to improved tolerability. Furthermore, paliperidone undergoes limited hepatic metabolism. METHODS The efficacy and safety of once-daily paliperidone ER (6 mg, 9 mg and 12 mg) were assessed versus placebo in 628 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. RESULTS All doses of paliperidone ER demonstrated significant improvement in PANSS score, all PANSS Marder factor scores (p<0.001) and personal and social functioning versus placebo (p<0.001). The PANSS total score also improved significantly in the olanzapine treatment arm. Significantly higher percentages of paliperidone ER patients demonstrated a > or =30% reduction in PANSS total score versus placebo (p<0.001). The incidence of movement disorder-related AEs and rating scales measurements were similar to placebo for the paliperidone ER 6 mg group and higher in the 9 mg and 12 mg groups. In the paliperidone ER groups there were no reports of glucose-related AEs or clinically relevant changes in plasma lipid levels and changes in mean bodyweight<1 kg. CONCLUSION In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. Paliperidone ER offers a distinctive treatment profile and may provide a valuable new treatment option for patients with schizophrenia.

Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study.

BACKGROUND Paliperidone extended-release tablet (paliperidone ER) is an oral psychotropic agent developed for schizophrenia treatment. Paliperidone (9-OH-risperidone, metabolite of risperidone), when used with OROS technology has a unique pharmacokinetic profile undergoing limited hepatic metabolism. METHODS The efficacy and safety of once-daily paliperidone ER (3 mg, 9 mg and 15 mg) were compared with placebo in 618 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An assay sensitivity group with known efficacy was included to confirm trial validity (olanzapine 10 mg). RESULTS All doses of paliperidone ER demonstrated significant improvements in PANSS total and PANSS factors scores (p<0.05) and in personal and social functioning (p<0.001) compared with placebo. Symptom improvement has been observed at the first observation assessment (Day 4) (p<0.001) compared with placebo, suggesting a rapid onset of action for paliperidone ER. Paliperidone ER was associated with a low incidence of treatment-emergent adverse events. The incidence of movement disorder-related adverse events and rating scale scores were similar in the paliperidone ER 3 mg and placebo groups and increased with dose. Increases in prolactin plasma levels and dose-related increases in body weight (<2 kg) were observed; there were no significant changes in serum lipid or glucose levels. CONCLUSION In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. As such, paliperidone ER may provide a valuable new treatment option for patients with schizophrenia.

Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study.

BACKGROUND Paliperidone extended-release tablet (paliperidone ER; Invega, Janssen L.P., Titusville, New Jersey) is an oral psychotropic for schizophrenia treatment. METHODS Efficacy and safety of once-daily paliperidone ER (6 and 12 mg) were assessed versus placebo in 444 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An olanzapine (10 mg) treatment arm was included to confirm trial validity. RESULTS Both doses of paliperidone ER demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total score (p < or = .006) and certain PANSS Marder factor scores compared with placebo (p < or = .025); PANSS total score also improved in the olanzapine treatment arm. Paliperidone ER 6 mg (p < or = .008), but not 12 mg, was associated with significant improvements in personal and social performance. The incidence of treatment-emergent adverse events (AEs) for paliperidone ER 6 mg was comparable with placebo and slightly greater with paliperidone ER 12 mg. Changes in blood glucose and lipid levels with paliperidone ER were comparable with placebo. Two patients treated with paliperidone ER experienced glucose-related AEs. Body-weight increases of 1-2 kg were observed with paliperidone ER. Although there were increases in plasma prolactin levels with paliperidone ER treatment, the incidence of prolactin-related AEs was < or =1%. CONCLUSIONS In this study, paliperidone ER, particularly the 6-mg dose, was effective and well tolerated, and provides a valuable new treatment option for schizophrenia.

Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled study ☆

OBJECTIVE We assessed efficacy and tolerability of the injectable atypical antipsychotic paliperidone palmitate in delaying time-to-relapse in adults with schizophrenia. METHODS Eligible patients (Positive and Negative Syndrome Scale [PANSS] total score < 120) were transitioned from previous antipsychotics to paliperidone palmitate during a 9-week, open-label phase. Patients received the first 2 intramuscular injections of paliperidone palmitate (50mg eq) one-week apart, then subsequent injections (25, 50, or 100mg eq, flexibly-dosed), once-monthly. Stable patients (PANSS total score < or = 75) continued into the 24-week maintenance phase. At maintenance phase endpoint, stabilized patients were randomized (1:1 ratio) to either continue paliperidone palmitate (at stabilized dose) or begin placebo in the variable-duration, double-blind phase. RESULTS The preplanned interim analysis (conducted after 68 relapse events) included 312 patients: mean age = 40 years, 55% men, 66% white, and mean transition baseline PANSS total score (SD): placebo, 69.5 (16.89); paliperidone palmitate, 69.3 (17.39). Time-to-relapse (primary endpoint) favored paliperidone palmitate (p<0.0001, log-rank test) at interim and final analysis (n=408). The hazard ratio (placebo/paliperidone palmitate) at the final analysis was 3.60 (95% CI: 2.45, 5.28). Treatment-emergent adverse event rates (final analysis set) were: 67% for transition and maintenance phases, and 45% (placebo) and 44% (paliperidone palmitate) for the double-blind phase. Across phases, the incidence of glucose-related adverse events was low (< or = 4%), while mean weight increased by 1.9 kg for paliperidone palmitate and remained unchanged for placebo patients. Injection site tolerability was comparable between groups. CONCLUSION Paliperidone palmitate significantly delayed time-to-relapse compared with placebo and presented no new safety signals.

A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia.

This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or muscle on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P ≤ 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (≥2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with ≥1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.Abbreviations: BMI - body mass index, CGI-S - Clinical Global Impression-Severity, EPS - extrapyramidal symptoms, ER - extended release, ITT - intent-to-treat, LAI - long-acting injectable, PANSS - Positive and Negative Syndrome Scale, PK - pharmacokinetic, PSP - Personal and Social Performance Scale, TEAE - treatment-emergent adverse events, VAS - Visual Analogue Scale

Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study

We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [-5.2 (21.5)] and PP 100 mg eq. [-7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56-71%), mild (24-39%), moderate (2-12%), or severe (0-2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.

A Controlled, Evidence-Based Trial of Paliperidone Palmitate, A Long-Acting Injectable Antipsychotic, in Schizophrenia

Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p⩽0.006) and PANSS negative and positive symptom Marder factor scores (p⩽0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5–6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.

Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia

Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N=252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age=43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score=56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (>or=5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated, irrespective of injection site, and thus could offer the choice of administration into either the deltoid or gluteal muscle to meet patient and physician preference.

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

OBJECTIVE Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. METHOD In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. CONCLUSIONS Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies.

Long-term efficacy and safety of paliperidone extended-release tablets (3−12 mg/day) were evaluated in pooled data from 52-week open-label extension (OLE) phases of three 6-week, placebo-controlled, double-blind (DB) trials involving 1083 schizophrenia patients. Forty-seven percent of patients completed the OLE phase. Outcome measures included Positive and Negative Syndrome Scale and Personal and Social Performance scale scores. Improvements observed on both scales in active treatment groups during the DB phases were maintained during the OLE phase. Most commonly (≥10% patients) reported adverse events (AEs) were insomnia, headache, and akathisia. One or more serious AEs were reported by 16% of patients; two patients had a treatment-emergent AE that resulted in death (suicide). Extrapyramidal symptom-related AEs were reported by 25% of patients. Median maximum movement disorder rating scale scores indicated no severity change during the OLE. Mean (±SD) increase in body weight from OLE baseline to end point was 1.1±5.47 kg across treatment groups and there were no clinically meaningful changes for plasma glucose, insulin or lipid levels. This analysis shows that paliperidone extended-release can maintain improvements in symptoms and functioning and is generally well tolerated for up to 52 weeks in schizophrenia patients.