David Hough

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

IMPORTANCEnTreatment 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.nnnOBJECTIVEnTo evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms.nnnDESIGN, SETTING, AND PARTICIPANTSnThis 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 (nu2009=u2009160) or placebo (nu2009=u2009145) in the DB phase.nnnINTERVENTIONSnPatients 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.nnnMAIN OUTCOMES AND MEASURESnTime from randomization to the first relapse event (time to relapse) in the DB phase.nnnRESULTSnIn the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratiou2009=u20093.45; 95% CI, 1.73-6.88; Pu2009<u2009.001); 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%).nnnCONCLUSIONS AND RELEVANCEnCompared 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.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier:NCT01529515.

Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study

Background: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18–70 years) with schizophrenia, previously stabilized on PP1M. Methods: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. Results: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. Conclusion: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.

A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia

BackgroundThere are no previous reports of paliperidone palmitates (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period.MethodsIn this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scales total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B.ResultsOf the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients psychoses remained stable.ConclusionsSafety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range.Trial registration noClinicalTrials.gov: NCT01150448

Risperidone Dosing in Children and Adolescents with Autistic Disorder: A Double-Blind, Placebo-Controlled Study

Efficacy and safety of 2 risperidone doses were evaluated in children and adolescents with autism. Patients (Nxa0=xa096; 5–17xa0years), received risperidone (low-dose: 0.125xa0mg/day [20 to <45xa0kg], 0.175xa0mg/day [>45xa0kg] or high-dose: 1.25xa0mg/day [20 to <45xa0kg], 1.75xa0mg/day [>45xa0kg]) or placebo. Mean baseline (range 27–29) to endpoint change in Aberrant Behavior Checklist-Irritability (primary endpoint) was significantly greater in the high-dose—(−12.4 [6.5]; pxa0<xa00.001), but not low-dose (−7.4 [8.1]; pxa0=xa00.164) group, versus placebo (−3.5 [10.7]). Clinical Global Impressions-Severity and Children’s Yale-Brown Obsessive Compulsive Scale scores improved significantly only in the high-dose group, consistent with ABC-I results. Somnolence, sedation and increased appetite occurred more frequently in high-versus low-dose groups. Overall, increased appetite occurred most frequently.

Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: A phase-1, single-dose, randomized, open-label study

This multicenter, randomized, open‐label, parallel‐group, phase‐1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3‐month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18–65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single‐dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75−525 mg eq) separated by a washout of 7–21 days. Overall, 245 of 308 (79.5%) PP3M‐dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half‐life was ∼2–4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose‐proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment‐emergent adverse events. Overall, safety and tolerability were similar to those of the 1‐month formulation. Results support a once‐every‐3‐months dosing interval in patients with schizophrenia or schizoaffective disorder.

A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia.

Paliperidone palmitate (PP) is a long‐acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries. To assess the options for i.m. injection sites, dose‐proportionality of PP was investigated after injection of a single dose (25–150u2009mgu2009eq.) of PP in either gluteal (nu2009=u2009106) or deltoid (nu2009=u200995) muscle of schizophrenic patients. Overall, mean (geometric) area under plasma concentration–time curve from time zero to infinity (AUC∞) of paliperidone increased proportionally with increasing PP doses, regardless of injection site. Mean maximum plasma concentration (Cmax) was slightly less than dose‐proportional for both injection sites at PP doses >50u2009mgu2009eq. Mean Cmax was higher after injection in the deltoid compared with the gluteal muscle, except for the 100u2009mgu2009eq. dose, while AUC∞ for both injection sites was comparable at all doses. Median time to reach Cmax (tmax) ranged from 13–14 days after deltoid and 13–17 days after gluteal injection across all doses. Single PP injections in deltoid and gluteal muscles in the dose range of 25–150u2009mgu2009eq. were generally tolerable both locally and systemically.

Efficacy and Safety of Paliperidone Extended Release in Adolescents With Schizophrenia: A Randomized, Double-Blind Study

OBJECTIVEnTo evaluate the efficacy, safety, and tolerability of paliperidone extended release (ER) relative to aripiprazole in adolescent schizophrenia.nnnMETHODnIn this multicenter, double-blind, phase 3 study (screening [≤3 weeks], with an acute treatment period [8 weeks] and a maintenance period [18 weeks]), adolescents (12-17 years old) with schizophrenia (DSM-IV diagnosis; Positive and Negative Symptom Score [PANSS] total score 60-120) were randomized (1:1) to once-daily paliperidone ER (6 mg per day [days 1-7], flexibly dosed 3, 6, or 9 mg per day from week 2 to end of study [EOS]), or to aripiprazole (2 mg per day [days 1 and 2], 5 mg per day [days 3 and 4], 10 mg per day [days 5-7], flexibly dosed 5, 10, or 15 mg per day [week 2 to EOS]).nnnRESULTSnOverall, 76% of enrolled patients (174/228) completed the study (paliperidone ER, 75% [85/113]; aripiprazole, 77% [89/115]). There was no significant difference in change in PANSS total scores from baseline to day 56 (primary endpoint) (paliperidone ER versus aripiprazole, -19.3 [13.80] versus -19.8 [14.56], p = .935); responders, 67.9% versus 76.3%, p = .119) and day 182 (-25.6 [16.88] versus -26.8 [18.82], p = .877; responders, 76.8% versus 81.6%, p = .444). All secondary endpoints (maintenance of clinical stability, change in PANSS-negative symptoms, Clinical Global Impression-Severity, and Personal and Social Performance scores) were similar in both treatment groups. The most common (>10% patients) treatment-emergent adverse events for paliperidone ER were akathisia, headache, somnolence, tremor, and weight gain, and for aripiprazole were worsening of schizophrenia and somnolence. Extrapyramidal symptoms including dystonia and hyperkinesia occurred in >2% in paliperidone ER-treated versus aripiprazole-treated patients.nnnCONCLUSIONnPaliperidone ER did not demonstrate superior efficacy to aripiprazole in treating adolescent schizophrenia. Both drugs showed clinically meaningful improvements in symptom and functional measurements and were generally tolerable. Clinical Trial Registration Information-An Efficacy and Safety Study of Extended-Release (ER) Paliperidone in Adolescent Participants With Schizophrenia; http://clinicaltrials.gov; NCT01009047.

Incidence of tardive dyskinesia: a comparison of long-acting injectable and oral paliperidone clinical trial databases.

To assess the tardive dyskinesia (TD) rate in studies of once‐monthly long‐acting injectable (LAI) paliperidone palmitate (PP) and once‐daily oral paliperidone extended release (Pali ER).

Practical guidance for dosing and switching from paliperidone palmitate 1 monthly to 3 monthly formulation in schizophrenia

Abstract Objective: This commentary summarizes recommended dosing strategies for a recently developed 3 monthly long-acting injectable1 (LAI) formulation of paliperidone palmitate (PP3M) for the treatment of schizophrenia in adults. Methods: Recommendations for different dosing scenarios are based on the pharmacokinetic, efficacy and safety outcomes from phase 1 and phase 3 studies, population pharmacokinetic models, and model based simulations. Results: Switching to PP3M treatment is recommended only in patients previously treated with once monthly paliperidone palmitate LAI (PP1M) for at least 4 months. The first injection of PP3M (175 to 525u2009mg equivalent [eq.]) should be given at the time of next scheduled injection of PP1M as a 3.5-fold multiple of the last PP1M dose (50–150u2009mg eq.), with a dosing window of ±1 week. Following that first injection of PP3M, once-every-three-months maintenance injections with PP3M are recommended, with a dosing window of ±2 weeks. The doses of PP3M can be administered in either deltoid (≥90u2009kg: 1.5u2009inchu200922u2009G needle; <90u2009kg: 1.0u2009inchu200922u2009G needle) or gluteal muscles (1.5u2009inchu200922u2009G needle regardless of weight). In patients with mild renal impairment (creatinine clearance: 50–80u2009mL/min), a 25% dose reduction in PP1M and subsequent switching to a corresponding 3.5-dose multiple of PP3M (but not exceeding 350u2009mg eq.) is recommended. Appropriate dosing is recommended in elderly patients with diminished renal function not exceeding mild renal impairment. Similarly to PP1M, PP3M is not recommended in patients with moderate/severe renal impairment. Like PP1M, no dosage adjustment is required in patients with mild or moderate hepatic impairment or elderly patients with normal renal function. Conclusions: These data provide clinical guidelines for the optimum use of PP3M in patients with schizophrenia previously treated with PP1M for at least 4 months. Registration: ClinicalTrials.gov identifier: NCT01559272 and NCT01529515.

An Analysis of Potentially Prolactin-Related Adverse Events and Abnormal Prolactin Values in Randomized Clinical Trials with Paliperidone Palmitate

Background: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinomia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). Objective: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. Methods: Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs wore obtained from the sponsors clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. Results: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90, 3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, them was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. Conclusions: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.