The efficacy of RELEXXII for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients (6 to 17 years) and adult patients is based upon adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets (referred to as “methylphenidate hydrochloride extended-release tablets” in the section below). The results of these adequate and well-controlled studies are presented below.

Methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in four randomized, double-blind, placebo-controlled studies in pediatric patients 6 to 17 years and two double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.

Pediatric Patients 6 to 12 Years

Three double-blind, active- and placebo-controlled studies were conducted in 416 pediatric patients 6 to 12 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets given once daily (18 mg, 36 mg, or 54 mg), methylphenidate given three times daily over 12 hours (15 mg, 30 mg, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was methylphenidate hydrochloride extended-release tablets versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for methylphenidate hydrochloride extended-release tablets. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at Week 4. 

The scores for methylphenidate hydrochloride extended-release tablets and placebo for the three studies are presented in Figure 2. Error bars represent the mean plus standard error of the mean.

Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate Hydrochloride Extended-Release Tablets Once Daily (18 mg, 36 mg, or 54 mg) and Placebo (Studies 1, 2, and 3)

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the Swanson, Kotkin, Agler, M-Fynn, and Pelham (SKAMP) laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with methylphenidate hydrochloride extended-release tablets versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for methylphenidate hydrochloride extended-release tablets and placebo.

Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

Pediatric Patients 13 to 17 years

In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of ADHD in pediatric patients aged 13 to 18 years at doses up to 72 mg once daily (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg once daily) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of methylphenidate hydrochloride extended-release tablets (18 mg to 72 mg once daily, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo.

Adults

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 mg to 108 mg once daily) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18 mg, 36 mg, and 72 mg once daily).

Study 5 demonstrated the effectiveness of methylphenidate hydrochloride extended-release tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg once daily to 108 mg once daily based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to methylphenidate hydrochloride extended-release tablets and 116 were randomized to placebo. Treatment was initiated at 36 mg once daily and patients continued with incremental increases of 18 mg once daily (36 mg to 108 mg once daily) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo. 

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18 mg, 36 mg, and 72 mg). Patients were randomized to receive methylphenidate hydrochloride extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg once daily (n=102), or placebo (n=96). All three doses of methylphenidate hydrochloride extended-release tablets were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.