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)

Tim L Wigal, Jeffrey H Newcorn, Nelson Handal, Sharon B Wigal, Ioulietta Mulligan, Virginia Schmith, Eric Konofal, Tim L Wigal, Jeffrey H Newcorn, Nelson Handal, Sharon B Wigal, Ioulietta Mulligan, Virginia Schmith, Eric Konofal

Abstract

Background: Mazindol 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.

Objective: The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD.

Design: We conducted a randomized, double-blind, placebo-controlled 6-week trial.

Methods: Subjects 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.

Results: Eighty-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.

Conclusion: Mazindol 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).

Conflict of interest statement

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Schulman Institutional Review Board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study prior to any study procedures.

Funding

This study was sponsored by NLS-1 Pharma AG. The open access fee was paid by NLS-1 Pharma AG.

Conflict of interest

The study was sponsored by NLS-1 Pharma AG. All coauthors are paid consultants of NLS-1 Pharma AG. EK is the inventor of the patent for the use of mazindol in ADHD and VS is the inventor of the patent for mazindol CR. Other COIs including as Consultant, Advisory Board, Research Support: Akili Interactive (TW JN SW), Alcobra (JN), Arbor (JN), Cingulate (JN SW), Enzymotec (JN), Ironshore (TW SW JN), KenPharm (JN), Lundbeck (JN), Medic (JN), Neos (JN), Neurovance (TW SW), NFL (JN), Pfizer (SW) Purdue (TW SW), Rho (SW), Rhodes (TW SW JN), Shire (TW SW JN), Sunovion (TW SW JN), Supernus (JN), Tris Pharma (TW SW).

Figures

Fig. 1
Fig. 1
Disposition of participants. AE adverse event, CR controlled release
Fig. 2
Fig. 2
Mean profiles for ADHD-RS-DSM5 score by treatment: intent-to-treat population. Bars represent standard error. ADHD-RS-DSM5 Attention-Deficit/Hyperactivity Disorder Rating Scale for DSM-5, CR controlled release

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