A 9-week, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to evaluate the efficacy and safety of modafinil as treatment for adults with ADHD.

OBJECTIVE: This study evaluated the efficacy and tolerability of modafinil at a range of doses, versus placebo, in alleviating symptoms of ADHD in adults. METHOD: Adult patients with ADHD were randomized in 1:1:1:1:1 fashion to double-blind treatment with modafinil 255, 340, 425, or 510 mg daily or placebo for 9 weeks. The primary efficacy outcome was the change from baseline at final visit in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. RESULTS: A total of 338 patients were enrolled, of whom 330 received at least 1 dose of study medication (modafinil or placebo). No statistically significant difference in the AISRS total score was observed at final visit between any modafinil group and placebo; however, some observations among patients who completed the trial may warrant further investigation. CONCLUSION: Modafinil was reasonably tolerated but did not demonstrate a benefit on ADHD symptoms in adults.

Fentanyl buccal tablet compared with immediate-release oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic cancer and noncancer pain: a randomized, double-blind, crossover study followed by a 12-week open-label phase to evaluate patient outcomes.

OBJECTIVE: Evaluate analgesic efficacy, functional benefit, and patient satisfaction with fentanyl buccal tablet vs immediate-release oxycodone for breakthrough pain (BTP). DESIGN: Randomized, double-blind, active-controlled crossover trial and 12-week open-label extension. SETTING: Forty-two U.S. sites. PATIENTS: Opioid-tolerant patients with predominantly chronic noncancer pain experiencing BTP. INTERVENTION: Patients were randomized to open-label titration periods with fentanyl buccal tablet followed by oxycodone or vice versa for BTP management. After titrating to a successful dose of both medications (single dose providing adequate analgesia without unacceptable adverse events), patients were re-randomized to treat 10 BTP episodes with one medication and 10 with the other. OUTCOME MEASURES: The primary efficacy measure was pain intensity (PI) difference 15 minutes postdose. Secondary measures included PI difference 5, 10, 30, 45, and 60 minutes postdose; sum of PI differences 30 and 60 minutes postdose; ≥33% and ≥50% reduction in PI; and pain relief. Questionnaires assessed functional status/satisfaction. RESULTS: Of 213 patients enrolled, 149 achieved a successful dose of both medications; 131 completed the double-blind phase and 112 the open-label phase. PI difference at 15 minutes (mean [standard deviation]) was greater with fentanyl buccal tablet (0.88 [1.20]) vs oxycodone (0.76 [1.13]; P < 0.001). Patients preferred fentanyl buccal tablet (47%) over oxycodone (35%); 18% had no preference. Patients and clinicians reported consistently better functional improvement and satisfaction with fentanyl buccal tablet vs short-acting opioids (P < 0.05). CONCLUSIONS: Fentanyl buccal tablet was associated with rapid onset of analgesia and improvements in functional status and patient satisfaction compared with immediate-release oxycodone.

A phase 3, double-blind, randomized, placebo-controlled study of armodafinil for excessive sleepiness associated with jet lag disorder.

OBJECTIVE: To assess the effect of armodafinil, the longer-lasting isomer of modafinil, on jet lag disorder. PARTICIPANTS AND METHODS: This double-blind, randomized, parallel-group, multicenter study was conducted between September 18, 2008, and February 9, 2009. Adults with a history of jet lag symptoms on previous flights through multiple time zones flew from the United States to France (a 6-hour time zone change) for a 3-day laboratory-based study period. Participants received armodafinil (50 or 150 mg/d) or placebo each morning. Wakefulness was assessed by the coprimary outcomes, mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of all MSLT sessions across days 1 and 2) and Patient Global Impression of Severity in relation to jet lag symptoms (averaged across days 1 and 2). RESULTS: A total of 427 participants received armodafinil at 50 mg/d (n=142), armodafinil at 150 mg/d (n=143), or placebo (n=142). Armodafinil at 150 mg/d provided a significant benefit in sleep latency on the MSLT (days 1-2: mean, 11.7 minutes vs 4.8 minutes for placebo; P<.001) and participants' perception of their overall condition in relation to jet lag symptoms (Patient Global Impression of Severity, days 1-2: mean, 1.6 vs 1.9 for placebo; P<.05). The most frequently reported adverse events for armodafinil at 150 mg/d were headache (27%), nausea (13%), diarrhea (5%), circadian rhythm sleep disorder (5%), and palpitations (5%). CONCLUSION: Armodafinil increased wakefulness after eastward travel through 6 time zones. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00758498.

A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study.

OBJECTIVE: This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of several modafinil dosing regimens in children with attention-deficit/hyperactivity disorder (ADHD) to determine whether modafinil can be given once daily in pediatric ADHD. METHOD: Children and adolescents (age range, 6-13 years) (N = 248) with DSM-IV-defined ADHD were enrolled in a 4-week, double-blind, placebo-controlled study, conducted February-May 2002. The group was assigned to receive oral (100-mg tablets) modafinil 300 mg once daily (300 mg in the morning followed by placebo at midday), modafinil 300 mg as a divided dose (100/200 mg or 200/100 mg), or matching placebo. In children weighing > or = 30 kg, a higher dose of 400 mg (200/200 mg) was evaluated. Efficacy measures included the teacher-rated School Version and clinician-rated Home Version of the ADHD Rating Scale-IV and the parent-completed Conners' ADHD/DSM-IV Scales. RESULTS: 223 children completed the study. Those who received modafinil 300 mg once daily showed a significantly greater improvement (change from baseline) than those who received placebo in symptoms of ADHD across all rating scales and subscales (all p < .05). Divided 300-mg doses of modafinil provided some significant but inconsistent improvements in ADHD symptoms. In children weighing > or = 30 kg, modafinil 400 mg (200/200 mg) was significantly superior to placebo on clinician- and parent-completed scales (all p < .05). Insomnia was the only adverse event to occur with significantly greater frequency in a modafinil group (200/100) than in the placebo group (14% vs. 2%) (p = .03). CONCLUSION: Modafinil significantly improved ADHD symptoms in children. Once-daily dosing (300 mg) provided the most consistent improvement in symptoms. All dosing regimens of modafinil were well tolerated.

A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. RESULTS: Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). CONCLUSION: Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation.

OBJECTIVE: The objective of this fixed-dose study was to determine the efficacy and safety of a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). In addition, the effect of abrupt discontinuation of modafinil was evaluated in a 2-week observation period. METHOD: Patients aged 6 to 17 years with DSM-IV-TR-defined ADHD were randomly assigned to 7 weeks of double-blind treatment with modafinil or placebo in a 2:1 ratio, followed by abrupt discontinuation of modafinil and a 2-week, double-blind observation period in which 46% of patients receiving modafinil were switched to placebo without tapering and half continued to receive modafinil. Study drug was administered once daily and titrated over the first 7 to 9 days to daily doses of 340 mg for patients < 30 kg or 425 mg for patients > or = 30 kg. Assessment instruments included the Attention-Deficit/ Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impressions-Improvement scale (CGI-I). The study was conducted from November 2003 to June 2004. RESULTS: A total of 190 patients were randomly assigned to receive modafinil (340 mg, N = 44; 425 mg, N = 82) or placebo (N = 64). 189 patients were evaluated for safety. Modafinil significantly improved symptoms of ADHD as shown by reductions in ADHD-RS-IV School Version total scores compared with placebo at all visits (p < or = .009), including the final visit of the double-blind phase (p < .0001). With modafinil, ADHD-RS-IV School Version mean total scores changed from 37.8 at baseline to 29.3 at week 1 and 20.7 at final visit; corresponding placebo values were 36.6, 32.8, and 28.4, respectively; effect size at final visit was 0.76 (95% CI = 0.63 to 0.88). Total scores on the ADHD-RS-IV Home Version were also significantly reduced at all visits (p < or = .022) and final visit (p = .001) in patients receiving modafinil compared with those receiving placebo. Significantly higher proportions of patients receiving modafinil were rated "much improved" or "very much improved" in overall clinical condition (CGI-I) at all visits compared with patients receiving placebo (p < .001). No withdrawal symptoms were observed when modafinil was abruptly discontinued at the beginning of the final 2-week observation period. Modafinil was generally well tolerated. Insomnia, headache, and decreased appetite were the most commonly reported adverse events. Sixty-three percent of patients who received modafinil completed the study; 13% discontinued because of lack of efficacy; 10%, because of adverse events; and 13%, for other reasons (e.g., consent withdrawn, lost to follow-up). CONCLUSION: Modafinil significantly improved symptoms of ADHD both at school and at home and was well tolerated by children and adolescents. Abrupt discontinuation of modafinil was not associated with symptoms of withdrawal or with rebound of symptoms of ADHD.

Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study.

OBJECTIVE: In a 4-week, double-blind, placebo-controlled study, the attention-promoting agent modafinil improved symptoms of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents and was well tolerated. To assess the continued efficacy of modafinil and obtain additional safety data, an 8-week, open-label study was conducted as an extension to the double-blind study. METHOD: Two hundred and twenty children and young adolescents (age range, 6-14 years) with ADHD who had completed 4 weeks of the double-blind period or had withdrawn for reasons other than an adverse event were enrolled. Patients received individually titrated doses of modafinil (100-400 mg), administered once daily or as a divided dose. Patients visited the clinic at open-label weeks 2, 4, and 8 for assessments of efficacy. Efficacy was assessed using the parent- or clinician-completed ADHD Rating Scale-IV (ADHD-RS-IV) Home Version, the parent-completed Conners' ADHD/DSM-IV Scale Parent Version (CADS-P), and the clinician-rated Clinical Global Impression of Improvement (CGI-I) scale. Adverse events were monitored. RESULTS: Modafinil improved symptoms on all ADHD rating scales and subscales during the open-label extension. Mean change (baseline to final visit) in Total score on the ADHD-RS-IV was -14.6 (95% CI: -16.40 to -12.70); and -7.6 (95% CI: -8.65 to -6.62) and -6.9 (95% CI: -7.90 to -5.94) in the Inattention and Hyperactivity-impulsivity scores, respectively. The mean Total score [SD] on the CADS-P decreased from baseline (74.4 [10.3]) to the final visit (63.2 [13.1]) (change: -11.2, 95% CI: -13.08 to -9.65). Fifty-three percent of patients were rated as much or very much improved on the CGI-I. Insomnia (13%) and headache (10%) were the most common adverse events. No clinically meaningful changes were observed in physical examination findings, electrocardiography, blood pressure, pulse, or body temperature. Clinically significant changes (increase or decrease) in body weight of 7% or more were observed for 30 patients (14%), with decreases (mean, 3.2 kg) reported for 22 patients (10%) and increases (mean, 3.7 kg) reported for eight patients (4%). CONCLUSION: Modafinil remained efficacious and well tolerated in children with ADHD, improving ADHD symptoms and overall clinical condition during the open-label study. Limitations of the study include open-label dosing and lack of a placebo control.

Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study.

OBJECTIVE: Modafinil, which is structurally and pharmacologically different from other agents that are used for the treatment of children with attention-deficit/hyperactivity disorder (ADHD), selectively activates the cortex and has low potential for abuse. Initial studies of the use of modafinil to treat ADHD showed significant improvements in the core symptoms of the disorder, namely inattention, hyperactivity, and impulsivity. This study evaluated a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with ADHD. METHODS: This 9-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose study evaluated the film-coated tablet formulation of modafinil, which was titrated to an optimal dose on the basis of efficacy and tolerability (range: 170-425 mg once daily). Efficacy was assessed by clinicians who completed the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) based on interviews with teachers (School Version) and parents (Home Version) and the Clinical Global Impression of Improvement scale. Safety evaluation was based on assessments of adverse event reports, laboratory tests, vital signs, and body weight. RESULTS: A total of 248 subjects were randomly assigned in a 2:1 ratio, and 246 were treated with modafinil (n = 164) or placebo (n = 82). Treatment groups were comparable with respect to demographics and baseline characteristics. Intention-to-treat analysis (ITT) showed that compared with placebo, treatment with modafinil significantly improved the core symptoms of ADHD as shown by greater reductions in the ADHD-RS-IV School Version total scores from baseline to final visit (mean change [SD]: -15.0 [11.8] vs -7.3 [9.7]) (effect size: 0.69; 95% confidence interval: 0.57-0.82). Significant improvements were observed with modafinil treatment on the ADHD-RS-IV School Version at week 1, with improvements maintained throughout the study. Similar differences in symptom improvements were observed on the ADHD-RS-IV Home Version between modafinil-treated and placebo-treated patients. Treatment with modafinil also significantly reduced subscale scores for inattention and hyperactivity-impulsivity on both School and Home Versions compared with placebo. At the final visit, 48% of modafinil-treated patients were rated as "much" or "very much" improved in overall clinical condition compared with 17% of placebo-treated patients (Clinical Global Impression of Improvement). Most adverse events were mild to moderate in severity, and the majority resolved during treatment. The most commonly reported adverse events in the modafinil group were insomnia (29%), headache (20%), and decreased appetite (16%). Three percent of modafinil-treated patients and 4% of placebo-treated patients discontinued treatment because of adverse events. CONCLUSIONS: Modafinil film-coated tablets significantly improved ADHD symptoms at school and home as evaluated by clinicians, teachers, and parents. Treatment with once-daily modafinil was generally well tolerated, with few discontinuations as a result of adverse events.