A Double-Blind, Placebo-Controlled, Phase II Study to Determine the Efficacy, Safety, Tolerability and Pharmacokinetics of a Controlled Release (CR) Formulation of Mazindol in Adults with DSM-5 Attention-Deficit/Hyperactivity Disorder (ADHD)

Abstract

BackgroundMazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) formulation of mazindol was developed to allow once-daily dosing.ObjectiveThe aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD.DesignWe conducted a randomized, double-blind, placebo-controlled 6-week trial.MethodsSubjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1–3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression–Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed.ResultsEighty-five participants were randomized (n = 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active–placebo) of − 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR.ConclusionMazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III.(Clinicaltrials.gov Registration No. NCT02808104)

Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents

“…In a Phase 2 flexible-dose, 6-week RCT in adults with ADHD, mazindol controlled-release (MZD-CR, Nolazol®, NLS Pharmaceutics) was associated with significantly greater improvements in ADHD scores vs placebo (effect size, 1.09). 50 The proportion of patients with excellent response (≥50% change from baseline) at 6 weeks was 55% vs 16%. A significant difference favoring MZD-CR was observed at the end of week 1.…”

“…Immediate-release mazindol (MZD-IR) was marketed for the short-term treatment of obesity in adults but was withdrawn from the market for commercial reasons in the early 2000s. 50 As an IR formulation, mazindol is historically considered a weak stimulant (CIV) due to a lower potential for abuse and addiction vs the classical CII stimulants. In more contemporary studies, MZD displays multimodal pharmacologic activities that include NET, DAT, and SERT inhibition (relative affinity, 100:12:2), 51 as well as modulation of serotonin (5-HT 1A , 5-HT 7 ), muscarinic, histamine H 1 , μ-opioid, and orexin-2 receptors.…”

“…In more contemporary studies, MZD displays multimodal pharmacologic activities that include NET, DAT, and SERT inhibition (relative affinity, 100:12:2), 51 as well as modulation of serotonin (5-HT 1A , 5-HT 7 ), muscarinic, histamine H 1 , μ-opioid, and orexin-2 receptors. 50 In a pilot, 1-week, open-label study in children with ADHD (N = 21) and MZD-IR (1 mg q.d.) was associated with significant improvement in ADHD scores.…”

“…Immediate-release mazindol (MZD-IR) was marketed for the short-term treatment of obesity in adults but was withdrawn from the market for commercial reasons in the early 2000s 50 . As an IR formulation, mazindol is historically considered a weak stimulant (CIV) due to a lower potential for abuse and addiction vs the classical CII stimulants.…”

Symptomatic and Functional Response and Remission From the Open-Label Treatment-Optimization Phase of a Study With DR/ER-MPH in Children With ADHD

“…to define response or 40%-50% to define a more robust response, either alone or in combination with a Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). [15][16][17][18][19][20][21][22][23][24] Weiss and colleagues 25 identified a decrease of 40% in ADHD-RS-IV total score as being most closely aligned with individuals being very much or much improved (CGI-I score = 1 or 2). Some have proposed utilizing more robust thresholds to achieve scores within the range of unaffected individuals, which has been termed symptomatic or functional remission.…”