A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD.

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.

Real-World Efficacy and Safety of Extended-Release Methylphenidate (PRC-063) in the Treatment of ADHD in Pediatric and Adult Subjects: Results of a Phase IV Multicenter Comparison With Lisdexamfetamine Dimesylate.

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.

Efficacy and Safety of a Long-Acting Multilayer-Release Methylphenidate Formulation (PRC-063) in the Treatment of Adolescent Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Clinical Trial with a 6-Month Open-Label Extension.

Objectives: To study the safety and efficacy of the long-acting methylphenidate formulation PRC-063 in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: Adolescents 12 to ≤17 years who met Diagnostic and Statistical Manual of Mental Disorders (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). Results: 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, p = 0.0067). For individual PRC-063 doses, improvements in ADHD-5-RS total score versus placebo were significant for 45 mg (p = 0.0155) and 70 mg (p = 0.0401), but not for 25 or 85 mg. A significant improvement for PRC-063 versus placebo was recorded for C3SR Inattention (p = 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 (p = 0.0004). Further improvements in ADHD symptoms based on ADHD-5-RS were observed from 1 month through 6 months of open-label treatment (p < 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. Conclusion: 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.

Efficacy and Safety of PRC-063, Extended-Release Multilayer Methylphenidate in Adults with ADHD Including 6-Month Open-Label Extension.

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.

Efficacy and Safety of Multilayer, Extended-Release Methylphenidate (PRC-063) in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder: A Laboratory Classroom Study.

Objective: To determine the safety and efficacy of PRC-063, a once-daily, multilayer, extended-release (ER) formulation of methylphenidate (MPH) hydrochloride, in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children in a randomized, double-blind, parallel group, dose-optimized, placebo-controlled phase 3 study. Methods: Boys and girls aged 6-12 years diagnosed with ADHD were enrolled. During a 6-week, open-label, dose-optimization phase, subjects began treatment at 25 mg/day of PRC-063 and were titrated until an optimal dose (maximum 85 mg/day) was reached. During the double-blind period, subjects were randomized to receive treatment with their optimal dose of PRC-063 or placebo for 1 week. Efficacy was assessed in a laboratory classroom setting on the final day of the double-blind treatment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale and Permanent Product Measure of Performance (PERMP). Safety was assessed measuring adverse events (AEs), vital signs, and electrocardiograms. Results: The study was completed by 147 subjects. In the primary efficacy analysis, significant improvements were demonstrated with PRC-063 versus placebo (p < 0.0001) when SKAMP-Combined scores were averaged over the 13-hour full-day laboratory classroom (least squares mean difference = -8.6, 95% confidence interval = -10.6 to -6.6). Mean average PERMP-Total scores were also significantly improved with PRC-063 versus placebo at all time points postdose (p < 0.01). The onset of treatment effect was present by 1-hour postdose (the first time point measured) and duration of efficacy was up to and including 13 hours postdose. AEs reported in ≥5% of subjects during the dosing optimization period were decreased appetite, abdominal pain upper, affect lability, weight decreased, headache, irritability, and insomnia. Conclusions: PRC-063 was effective in improving attention and reducing symptoms of ADHD versus placebo and had a rapid onset and extended duration of effect. AEs were consistent to those reported with other ER MPH treatments. Clinical Trial Registry: NCT03172481.

Randomized Controlled Crossover Trials of the Pharmacokinetics of PRC-063, a Novel Multilayer Extended-Release Formulation of Methylphenidate, in Healthy Adults.

PURPOSE/BACKGROUND: 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. METHODS/PROCEDURES: 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. FINDINGS/RESULTS: 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. IMPLICATIONS/CONCLUSIONS: Our data indicate that PRC-063 can be taken with or without food or by sprinkling capsule contents on food.

The Time Course of Effect of Multilayer-Release Methylphenidate Hydrochloride Capsules: A Randomized, Double-Blind Study of Adults With ADHD in a Simulated Adult Workplace Environment.

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.

Comparative bioavailability of single-dose methylphenidate from a multilayer-release bead formulation and an osmotic system: a two-way crossover study in healthy young adults.

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/m(2) (range, 19.0-28.5 kg/m(2)). 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 AUC(0-4) (P < 0.001), AUC(0-8) (P < 0.001), AUC(0-12) (P < 0.001), and AUC(4-12) (P = 0.037); the AUC(8-12) was not significantly different between the 2 formulations. Values were significantly higher for the MLR methylphenidate formulation relative to the OROS methylphenidate formulation for C(max0-4) (P < 0.001) and C(max4-12) (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.

Cognitive and behavioral effects of multilayer-release methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Once-daily multilayer-release methylphenidate in a double-blind, crossover comparison to immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to evaluate the comparative efficacy and safety of a novel long-duration multilayer-release (MLR) methylphenidate (MPH) formulation and immediate-release (IR) MPH in attention-deficit/hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: This study was a randomized, double-blind, crossover comparison of once-daily MLR and twice-daily IR-MPH in home and school settings in children with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of ADHD. Patients completed a 1-week baseline followed by two active medication titration phases. Each phase of treatment was 1-4 weeks of titration with an additional stable dose week. The final dose was based on efficacy and adverse events for each patient. Efficacy measures included Clinical Global Impressions (CGI) and Conners' Parent and Teacher Rating Scales (CPRS and CTRS). The Clinical Assessment of Side Effects (CASE) scale assessed frequency of adverse events. RESULTS: Of the 90 enrolled patients, aged 6.4-17.5 years, 79 (88%) completed the study. Stable daily doses were 32.0 and 32.5 mg for MLR and IR-MPH, respectively. All efficacy parameters were significantly improved from baseline. A total of 73.2% and 81.0% of patients on MLR and IR-MPH were rated as "much" or "very much improved" on the CGI. A total of 77.4% and 81.1% of patients were normalized on the CPRS-R and 78.9 and 90.4% of patients were normalized on the CTRS-R for MLR and IR-MPH, respectively. The mean CASE score was not different from baseline for either treatment.

Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study.

OBJECTIVE: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

The objective of this study was to compare the single-dose pharmacokinetics of multilayer-release and immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Patients 6- to 12-years-old with a DSM-IV diagnosis of attention-deficit/hyperactivity disorder were randomized to receive multilayer-release methylphenidate (qd) or immediate-release methylphenidate (bid) at equivalent doses, with a 14-day washout between treatments. Plasma samples were collected predosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Pharmacokinetic analysis was conducted on 14 patients (1 female, 13 male; mean age: 9.6 +/- 2.5 years [range, 6-12]). The mean dose of methylphenidate received by these patients in both phases of the study was 38.6 mg/d (range, 20-80 mg/d). The relative AUC(0-t) and C(max 0-4) ratios for multilayer-release compared with immediate-release methylphenidate were 100.8% and 78.8%, respectively. Multilayer-release methylphenidate produces a biphasic concentration-time profile, with a rapid initial increase in plasma concentration that is maintained throughout the school day.

Efficacy and safety of controlled-release oxycodone and standard therapies for postoperative pain after knee or hip replacement.

BACKGROUND: Standard therapy (ST) for postoperative pain after knee and hip replacement at the Hamilton Health Sciences Henderson Hospital consists of epidural analgesia or patient-controlled analgesia for the first 48 hours, followed by oral or parenteral analgesics, or both, on an as-needed basis. We compared the efficacy and safety of scheduled controlled-release (CR) oxycodone hydrochloride (OxyContin; Purdue Pharma, Pickering, Ont.) and ST for postoperative pain 48 hours after primary knee and hip replacement. METHODS: In 2 separate 3-week studies of similar design, pain intensity, pain relief, length of hospital stay, analgesic use and side effects of CR oxycodone (n = 70) and ST (n = 101) were evaluated. In the CR oxycodone trial, a dose de-escalation protocol was used. RESULTS: At the time of discharge from hospital, patients in the CR oxycodone group recorded lower mean (and standard deviation) pain intensity scores than the ST group (20.2 [17.9] v. 27.7 [21.5] mm on a 100-mm visual analogue scale; p = 0.021). Length of hospital stay was 5.5 and 6.4 days for the CR oxycodone and ST groups respectively (p < 0.001). CR oxycodone patients used less opioid (morphine equivalent) while in hospital than ST patients (p < 0.001), and the average number of daily administrations of analgesics in hospital was 2.1 and 3.5 for CR oxycodone and ST patients respectively (p < 0.001). ST patients reported more nausea and vomiting, pruritus and fever than the CR oxycodone patients, but less somnolence, constipation, dizziness, confusion and tachycardia. CONCLUSIONS: CR oxycodone every 12 hours is as effective as ST in treating postoperative pain but length of hospital stay was shorter and analgesic administration in the hospital was used less frequently, providing potential hospital cost savings and reduced use of health care resources.