NEW YORK ― In adults with predominantly inattentive attention-deficit/hyperactivity disorder (PI-ADHD), an extended-release formula of metadoxine improved attention after a single dose in a phase 2b study.
The follow-up phase 2b "validates the finding of the effects in PI-ADHD subtype, and the magnitude of the effect in this 1-day treatment trial was similar to what was seen in the 6-week treatment trial," principal investigator Leonard Adler, MD, professor of psychiatry at New York University School of Medicine in New York City, told Medscape Medical News.
The findings were presented here at the American Psychiatric Association's 2014 Annual Meeting.
Alcohol Intoxication Drug
A nonstimulant 5-hydroxytryptamine receptor antagonist, metadoxine's immediate-release formulation is currently used to treat acute alcohol intoxication and withdrawal symptoms in adults.
Metadoxine extended release (MDX, also known as MG01CI) is being developed by Alcobra Inc for ADHD and other cognitive disorders such as fragile X syndrome.
Once thought to only affect children, ADHD is now known to persist into adolescence and adulthood in a sizeable number of cases. It is estimated that 4% to 5% of adults worldwide are affected with ADHD.
In a prior 6-week phase 2 trial involving 120 adults with ADHD, 1400 mg of MDX was safe and significantly improved ADHD symptoms compared with placebo, and suggested a preferential response in those with PI-ADHD, as reported by Medscape Medical News.
Participants in the current study included 36 men and women, aged 18 to 55 years (mean age, 32 years), diagnosed with PI-ADHD with a Clinical Global Improvement–Severity (CGI-S) score of at least 4 and a Test of Variable Attention (TOVA) ADHD score of -1.8 or less at screening. Adults with ADHD combined type, ADHD hyperactive impulsive type, and individuals with any significant medical or psychiatric condition were excluded.
Patients were randomly assigned to alternating sequences of a single weekly dose of MDX 1400 mg, MDX 700 mg, and placebo, each with a 1-week washout. The primary analysis was the mean change in the TOVA ADHD score from baseline to 3.5 hours post dose using a paired t-test to compare MDX 1400 mg with placebo and MDX 700 mg with placebo.
The mean TOVA score at baseline was -8.8. The primary efficacy endpoint of the study was met, as demonstrated by a statistically significant difference between the mean change in TOVA ADHD score following a single dose of 1400-mg MDX vs placebo (mean difference, 2.0), Dr. Adler reported. "The change on the MDX 700, although better than placebo, was not significant," he said.
Table. TOVA ADHD Scores by Treatment (ITT Population)
|Assessment||MDX 1400 mg||MDX 700 mg||Placebo|
|TOVA score post dose||-2.5||-4.1||-4.4|
|Change from baseline||6.5||4.7||4.4|
|95% CI||8.1 - 4.9||6.5 - 2.9||6.7 - 2.2|
|P value (compared with placebo)||< 0.1||.899||-|
ITT, intention to treat; CI, confidence interval
It is also noteworthy, Dr. Adler said, that the TOVA response time variability subscore, which measures the quantity of inattention/sustained attention, was "significantly better" 3 to 5 hours after a single 1400-mg MDX dose vs placebo. Reaction time variability has been previously associated with inattentive symptoms.
The percentage of responders after a single dose of MDX 1400 mg was also significantly greater compared with placebo (97.1% vs 71.4%; P = .0063).
There were no significant differences observed between the MDX 700-mg dose and placebo in the primary or secondary efficacy endpoints. Between the 2 doses of MDX, patients taking the 1400-mg dose demonstrated significantly greater improvements (P < .05) than those taking the 700-mg dose on most endpoints.
Exploratory analyses of the Cambridge Neuropsychological Test Automated Battery (CANTAB) did not yield significant findings.
Mirroring the prior study, the most common treatment-emergent adverse events (AEs) during the active treatment periods were fatigue and headache. All AEs were mild in severity except for 3 moderately severe cases of headache. No serious AEs occurred. One patient who had a history of allergies since childhood developed allergic dermatitis. There were no clinically significant abnormalities in laboratory values, vital signs, or ECG parameters.
Novel Immediate Effect
"This is a very interesting study in that just a single dose of metadoxine can influence performance," Anthony Rostain, MD, from the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, who was not involved in the study, told Medscape Medical News.
"Most nonstimulants do not work immediately; with metadoxine, apparently you get an effect right away. That's very unusual, very interesting, and deserves further study, in particular in people with inattentive-type ADHD," Dr. Rostain said.
"It looks like it's a viable alternative nonstimulant treatment for ADHD. We don't know exactly why it does what it does, but it seems to be a novel way of improving focus. Whatever the mechanism of action, it seems to be apparent very quickly," he added.
"There is always a debate in the literature about how much improvement on a measure of attention play out in the real world, and we need more studies to look at that. But just on its face alone, the fact that there was a distinguishing of performance between placebo or low-dose metadoxine vs the higher-dose metadoxine does substantiate that it has a neurocognitive effect," Dr. Rostain added.
A large, placebo-controlled, randomized phase 3 trial of MDX in adult PI-ADHD is currently recruiting participants.
The study was funded by Alcobra Inc. Dr. Adler reports that he has received grant/research support from Shire Pharmaceuticals Inc and Theravance Inc and has participated in advisory boards and consulted for Alcobra Inc, Shire Pharmaceuticals Inc, Sunovian, and Theravance Inc. Dr. Rostain is on the advisory board of Alcobra Inc.
American Psychiatric Association's 2014 Annual Meeting. Abstract NR6-21. Presented May 5, 2014.
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Cite this: Nonstimulant May Provide Rapid Relief for Adult ADHD - Medscape - May 05, 2014.