To study the safety and efficacy of the long-acting methylphenidate formulation PRC-063 in adolescents with attention-deficit/hyperactivity disorder (ADHD).
Adolescents 12 to ≤17 years who met
...(DSM)-5 criteria for ADHD and had a baseline ADHD Rating Scale DSM-5 (ADHD-5-RS) score ≥24 participated in a randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study. Participants were randomized 1:1:1:1:1 to receive placebo or one of four doses of PRC-063 once daily for 4 weeks. The primary endpoint was change from baseline in least-squares mean clinician-rated ADHD-5-RS total score for PRC-063 (all doses combined) versus placebo. Other efficacy assessments included Conners third Edition: Self-Report (C3SR) and Clinical Global Impression-Improvement (CGI-I). A subset of double-blind study participants entered a subsequent open-label, dose-optimized study. Safety outcomes in both studies included treatment-emergent adverse events (TEAEs).
Three hundred fifty-four participants were included in the primary analysis. The least-squares mean change from baseline in ADHD-5-RS total score was -15.17 for PRC-063 versus -10.98 for placebo (least-squares mean difference -4.2,
= 0.0067). For individual PRC-063 doses, improvements in ADHD-5-RS total score versus placebo were significant for 45 mg (
= 0.0155) and 70 mg (
= 0.0401), but not for 25 or 85 mg. A significant improvement for PRC-063 versus placebo was recorded for C3SR Inattention (
= 0.0168), but not for the other C3SR subscales. About 52.7% of participants randomized to PRC-063 were responders based on CGI-I versus 32.4% of those randomized to placebo (
= 0.0004). Further improvements in ADHD symptoms based on ADHD-5-RS were observed from 1 month through 6 months of open-label treatment (
< 0.0001). There were two serious adverse events (both during the open-label study), one of which (aggressive behavior) was assessed as related to study drug. The only TEAEs that occurred in >10% of participants during double-blind treatment were decreased appetite (20.1%) and headache (15.0%). Most TEAEs were of mild or moderate severity.
PRC-063 significantly improved ADHD symptomatology in adolescents. It was generally well tolerated, with an AE profile consistent with other long-acting stimulants. NCT02139111 and NCT02168127.
Objective:
To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit hyperactivity disorder ...(ADHD) in a randomized, double-blind, crossover study.
Method:
Following up to 21 days of each treatment in each treatment course (PRC-063/LDX or LDX/PRC-063), subjects completed a 15-hour driving simulator laboratory assessment. The primary outcome measure was the Tactical Driving Quotient (TDQ) and the Clinical Global Impressions-Improvement (CGI-I) scale was a secondary outcome measure.
Results:
Forty-four subjects completed the study. PRC-063 and LDX had equivalent effects on driving performance through a 15-hour time period (least square mean difference −0.3 standard error 1.08, 95% confidence interval −2.4, 1.8, p = .793). Consistent improvement in CGI-I was observed. The incidence of treatment-emergent adverse events was similar for each treatment sequence.
Conclusions:
PRC-063 and LDX had comparable effects on driving performance, from 1 through 15 hours, the last time point measured.
Objective: To evaluate the efficacy and safety of a 16-hr multilayer-release methylphenidate (PRC-063) in a community-based adult ADHD population. Method: In a double-blind study, 375 participants ...were randomized to one of four fixed doses of PRC-063 or placebo. The primary outcome was the ADHD-Rating Scale-5 (RS). The first 50% of double-blind completers were invited to participate in a 6-month dose-optimized open-label study to assess response and safety. Results: In total, 333 participants completed the double-blind trial; 184 entered the open-label study. PRC-063 produced greater symptom reduction in ADHD-RS-5 total score from baseline compared with placebo in the double-blind study (least-square LS mean = −4.7 −7.7, −1.6, p = .003). The most frequent adverse events were headache, insomnia, and decreased appetite. No significant sleep quality impact was observed (p = .123). Significant improvements in ADHD-RS-5 scores from baseline continued through the open-label study (p < .0001), coincident with dose optimization. Conclusion: PRC-063 was well tolerated and significantly improved ADHD symptomatology in adults.
Objective: The aim of this study is to assess the onset and duration of efficacy of multilayer-release methylphenidate (PRC-063) over 16 hr compared with placebo in adults with ADHD using the ...simulated adult workplace environment. Method: After dose-optimization with PRC-063, participants entered a double-blind, placebo-controlled, crossover phase. Primary outcome measure was the Permanent Product Measure of Performance (PERMP) total score measured pre-dose and from 1 to 16 hr post-dose. Results: Of the 59 randomized participants, 45 participants completed the study. While receiving PRC-063, adults had greater mean PERMP total scores across all time points compared with placebo (268.7 ± 11.24 vs. 255.6 ± 10.87; p = .0064). Common adverse events were decreased appetite, headache, and insomnia. There was no significant impact on overall sleep quality (p = .9542). Conclusion: PRC-063 significantly improved PERMP scores with an onset within 1 hr post-dose, and maintained improvement throughout the 16 hr post-dose study period compared with placebo in adults with ADHD.
Objective:
To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a phase IV, ...open-label study.
Method:
The primary endpoint was the change in the ADHD-DSM-5 Rating Scale (ADHD-5-RS) total score from baseline to Month 4. Secondary endpoints included a non-inferiority comparison between PRC-063 and LDX and measures of functioning and evening behavior.
Results:
One hundred forty-three pediatric and 112 adult subjects were enrolled. Mean ADHD-5-RS scores (standard deviation) were reduced in pediatric (−16.6 10.4) and adult (−14.8 10.6) subjects treated with PRC-063 (p < .001). PRC-063 was non-inferior to LDX in the pediatric population but not in the adult population. Significant improvements were demonstrated in quality of life and functionality. Both medications were well-tolerated; more adverse events led to study discontinuation in pediatric subjects treated with LDX versus PRC-063.
Conclusion:
PRC-063 and LDX significantly improved ADHD symptomatology and functioning and were well-tolerated.
PRC-063 is a once-daily, extended-release oral formulation of methylphenidate hydrochloride developed to provide early and prolonged symptom improvement in patients with ...attention-deficit/hyperactivity disorder.
We conducted 3 randomized, open-label crossover studies of the pharmacokinetics of PRC-063 in healthy, nonobese men and women aged 18 to 45 years. PRC-063 (100 mg/d) was compared with immediate-release methylphenidate (20 mg, 3 times daily) when administered on a single day under fasted and fed conditions and at steady state (day 5 of repeat dosing under fasted conditions). The pharmacokinetics of PRC-063 administered as capsule contents sprinkled on apple sauce, yoghurt, or ice cream were also investigated.
PRC-063 demonstrated biphasic absorption, with 2 distinct peak plasma concentrations. Intake of a high-fat, high-calorie meal did not increase the peak plasma methylphenidate concentration (Cmax) or extent of absorption (area under the curve), however; it resulted in slower uptake versus a fasted state. During repeated dosing, steady state was reached with no further accumulation of methylphenidate from day 3. At steady state, PRC-063 gave higher evening and trough plasma methylphenidate levels than immediate-release methylphenidate (3 times daily). The pharmacokinetics of PRC-063 sprinkled on food were comparable to that of intact capsules. Reported adverse events (AEs) were consistent with the established safety profile of methylphenidate. There were no serious AEs, but 3 subjects discontinued the repeat-dosing study because of AEs assessed as possibly related to study treatment.
Our data indicate that PRC-063 can be taken with or without food or by sprinkling capsule contents on food.
To evaluate the efficacy and safety of a new biphasic multilayer-release (MLR) methylphenidate formulation in a double-blind, placebo-controlled crossover study of adults with ...attention-deficit/hyperactivity disorder (ADHD).
Adults 18 to 60 years of age with a DSM-IV diagnosis of ADHD entered a no-medication baseline week and were then randomly assigned to once-daily MLR methylphenidate or matching placebo. Patients were titrated to optimal effect over 1 to 3 weeks followed by 2 weeks of treatment on a stable dose. The same titration protocol was repeated with the alternate treatment. Clinical Global Impressions scale (CGI) and Conners' Adult ADHD Rating Scales (Self-rated, CAARS-S, and Observer-rated, CAARS-O) were collected at weekly clinic visits. The study was conducted between October 2003 and April 2004.
Fifty patients were randomly assigned to treatment, and 39 were analyzed in a per-protocol population (23 men, 16 women; mean age = 37.9 years). CGI-Improvement scores of subjects taking MLR methylphenidate were significantly improved compared with placebo (Global Improvement: 2.6 vs. 3.7; p = .0015). MLR methylphenidate produced improvements over placebo on the ADHD Index T scores of the CAARS-S (12.2 vs. 5.4 change from baseline score; p = .0083) and the CAARS-O (10.9 vs. 6.6 change from baseline score; p = .1404). The most frequent adverse events for MLR methylphenidate and placebo were headache (26% and 24%, respectively), anorexia (22% and 6%), insomnia (22% and 8%), nervousness (20% and 4%), and nausea (16% and 8%). There were no serious adverse events.
Once-daily MLR methylphenidate produces significant improvements in ADHD symptoms and situational behavior in adult patients with ADHD, with a prolonged duration of effect and minimal side effects, thus having the potential to improve compliance and, therefore, treatment outcomes in routine clinical use.
Abstract Objective: This study was conducted to compare plasma levels of methylphenidate over time with single doses of a multilayer-release (MLR) bead formulation and an osmotic, controlled-release ...oral delivery system (OROS) of methylphenidate in young adults. Methods: This was a randomized, 2-way crossover study in which healthy, nonsmoking young adults (age 18-25 years) were randomized to receive methylphenidate MLR 20 mg QD or OROS methylphenidate 18 mg QD, with a 7-day washout between treatments. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 14, 16, and 24 hours after dosing. Analysis of plasma samples was conducted by high-performance liquid chromatography with tandem mass-spectrometry detection. Adverse events were monitored by spontaneous reports, laboratory and biochemistry tests, urinalysis, and physical examinations conducted at screening and at the end of the study. Results: Of the 24 subjects originally enrolled, 3 discontinued for personal reasons after the first phase and were not included in the pharmacokinetic analysis. The per-protocol population (11 females, 10 males) had a mean (SD) age of 22 (2) years (range, 19-25 years) and a mean body mass index of 23.6 (3.0) kg/m2 (range, 19.0-28.5 kg/m2 ). The relative AUC0t and Cmax ratios for the MLR methylphenidate formulation compared with the OROS methylphenidate formulation were 110.88% and 121.84%, respectively. When OROS methylphendate values were dose normalized to 20 mg, the relative AUC0-t and Cmax ratios were 100.72% and 111.82%. The mean Tmax for the 2 formulations was 3.71 (2.03) and 4.96 (2.56) hours. Values were significantly higher with the MLR methylphenidate formulation compared with the OROS methylphenidate formulation for AUC0-4 ( P < 0.001), AUC0-8 (P < 0.001), AUC0-12 ( P < 0.001), and AUC4-12 ( P = 0.037); the AUC8-12 was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for Cmax0-4 ( P < 0.001) and Cmax4-12 (P = 0.002). Thirty-seven adverse events occurred in 11 and 10 subjects during receipt of MLR and OROS methylphenidate, respectively. The most commonly reported adverse events in the intent-to-treat population were catheter-site pain, reported by 8 of 24 subjects (33.3%), and headache, reported by 5 of 24 subjects (20.8%). Conclusions: In these healthy young subjects, MLR methylphenidate was associated with a concentration-time profile that resulted in a higher proportion of the administered methylphenidate dose being delivered in the first 4 hours after dosing compared with OROS methylphenidate while maintaining comparable levels of drug in the latter portion of the dosing interval. This led to maintenance of higher mean levels of methylphenidate throughout the day compared with the closest marketed dose of OROS methylphenidate. The 2 formulations are marketed in dissimilar strengths; however, after correction for administered dose, they yielded similar AUC values.
The aim of this study was to compare the pharmacodynamics of a new multilayer-release (MLR) formulation methylphenidate (MPH; Biphentin) with immediate-release (IR) MPH (Ritalin) in a double-blind, ...cross-over, placebo-controlled study in patients with attention-deficit/hyperactivity disorder (ADHD).
Patients were randomized to equivalent doses of MPH as MLR (once per day), IR (twice per day) or placebo. Each treatment was taken for 1 week prior to repeated behavioral and cognitive laboratory evaluations on a single day in each phase of the crossover.
Two girls and 15 boys 6.8-15.3 years old (mean age 11.3 +/- 2.2 years) participated. Both MLR and IR MPH significantly reduced the Stop Signal Reaction Time (p = 0.0001, p = 0.0005), the Errors of Omission on the Continuous Performance Task (p = 0.0039, p = 0.0001), the IOWA-Conners Inattention/Overactivity Index (p = 0.0001, p = 0.0001), and increased the Clinical Global Impressions (CGI) Efficacy Index (p = 0.0001, p = 0.0017) and reduced the CGI Global Improvement Index (p = 0.0001, p = 0.0006) compared to placebo. Mild adverse events were experienced by 4, 6, and 3 patients on placebo, IR, and MLR MPH, respectively.
MLR MPH given once daily produces equivalent improvements in behavioral and cognitive measures, and has a duration of effect at least as long as that of IR MPH given twice daily.
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