ATLANTA – Results from new research point to a possible alternative to stimulants for the treatment of attention-deficit hyperactivity disorder in children and adolescents.
Two phase III studies presented at the annual meeting of the American Psychiatric Association show that a once-daily pediatric formulation of modafinil is well tolerated and improves attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents.
Modafinil is currently marketed by Cephalon under the brand name Provigil in 100-mg and 200-mg strengths. Provigil is indicated for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea, hypopnea syndrome, and shift work sleep disorder.
The company, which funded the phase II trials, is seeking approval from the Food and Drug Administration to market modafinil in 85-mg, 170-mg, 255-mg, 340-mg, and 425-mg strengths. If approved, the drug would be indicated for treatment of ADHD in children and adolescents aged 6–17 years.
The company is planning to launch the drug under the brand name Attenace by early 2006.
In one study, 189 patients with ADHD aged 6–17 years were randomized to a 7-week double-blind, fixed-dose treatment with either modafinil or placebo. This protocol was followed by a 2-week withdrawal period in which half of the modafinil-treated patients were placed on placebo without tapering, and half were continued on the drug, said Joseph Biederman, M.D., the lead investigator in the study and professor of psychiatry at Harvard University in Boston.
Modafinil was administered once daily, starting at 85 mg/day, and was rapidly titrated over 7–9 days to dosages of either 340 mg/day for patients who weighed less than 30 kg or 425 mg/day for patients who weighed 30 kg or more.
The results of the study were assessed using the school and home ADHD Rating Scale-IV total score change from baseline to last treatment visit.
After 1 week, the 125 modafinil-treated patients had significantly greater improvements in school scores, compared with the 64 placebo patients, and those results were maintained through week 7.
On the school scale, patients on modafinil experienced a 17.2-point drop in symptoms, compared with an 8.2-point drop for patients on placebo. Modafinil also significantly improved total scores from parents, compared with placebo.
The side effects included insomnia and appetite decrease. Overall, the side effects were generally mild and occurred at initiation of the treatment. There were two serious adverse events not associated with the trial, said Dr. Biederman, who is an advisory board member for Cephalon and receives research/grant support from the company.
The researchers also assessed ADHD symptoms and physical/emotional response after rapid discontinuation. During the 2-week withdrawal phase there were no reported symptom rebounds, no adverse events related to withdrawal, and no physical or emotional responses.
Modafinil appears to work like a gentler stimulant, Dr. Biederman said in an interview.
The findings present possible new treatment options, he said. Although stimulants are effective, they are not universally effective. About 30%–40% of patients are nonresponsive to stimulants, he said, and some patients also have tolerability problems.
Stimulants also have the potential for acute deterioration and symptom rebound if treatment is interrupted or discontinued without tapering, Dr. Biederman said.
In the second study, researchers considered the effect of a flexible dose of modafinil in children and adolescents.
The study included 198 patients aged 6–17 years who were started on a dose of 85 mg/day of modafinil, which was titrated over 22 days based on clinical effectiveness. The maximum dose was 425 mg/day with once-daily dosing, said James Swanson, Ph.D., of the University of California at Irvine Child Development Center, who was the lead investigator.
The results were assessed using the school and home ADHD Rating Scale-IV, the Clinical Global Impression of Improvement (CGI-I), and Test Variables of Attention (TOVA).
The home score showed a mean drop of 17.6 points in symptoms for the 131 patients receiving modafinil at a mean stable dose of 361 mg/day, compared with a 7.5-point drop in symptoms for the 67 patients on placebo. The improvement in the total school score was also significantly greater for modafinil patients, Dr. Swanson reported.
Modafinil was shown to significantly improve inattention and hyperactivity/impulsivity, and there was an improvement in overall clinical condition and in the TOVA measurements of ADHD.
The researchers focused not only on decreasing symptoms of ADHD, but on increasing positive interaction and social skills, and they saw an increase in positive behaviors, he said.
The side effects included insomnia, headache, and appetite problems, which are similar to the side effects for stimulants, said Dr. Swanson, who is an advisory board member with Cephalon, receives research/grant support from the company, and is a member of the company's speakers' bureau.