Safety, Tolerability, and Sensorimotor Effects of Extended-Release Dalfampridine in Adults With Cerebral Palsy: A Pilot Study

• Published in: Clinical therapeutics Vol. 39; no. 2; pp. 337 - 346
• Main Authors: Bethoux, Francois, MD, Fatemi, Ali, MD, Fowler, Eileen, PhD, Marciniak, Christina, MD, Mayadev, Angeli, MD, Waksman, Joel, PhD, Zackowski, Kathleen, PhD, Suarez, Gustavo, MD, Blight, Andrew R., PhD, Rabinowicz, Adrian L., MD, Carrazana, Enrique, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2017; Elsevier Limited
• Subjects: 4-Aminopyridine - administration & dosage; Adult; Cerebral palsy; Cerebral Palsy - drug therapy; Cross-Over Studies; dalfampridine extended release; Delayed-Action Preparations; Double-Blind Method; Drug dosages; Feet; Female; Humans; Internal Medicine; Male; Medical Education; Middle Aged; Patients; Pilot Projects; proof-of-concept; safety; sensorimotor function; Studies; tolerability; Walking; Walking - physiology; Young Adult; cerebral palsy; dalfampridine extended release; sensorimotor function; safety; proof-of-concept; tolerability
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2016.12.015

Abstract Purpose The goal of this study was to evaluate the safety and tolerability of dalfampridine extended release (D-ER) in a pilot study of adults with cerebral palsy (CP) and limited ambulatory ability, and to explore drug effects on sensorimotor function. Methods An initial double-blind, single-dose crossover study was performed in 11 individuals randomized 1:1 to receive D-ER (10 mg) or placebo, followed by a 2-day washout period and the opposite treatment, with evaluation for safety and tolerability. A twice daily dosing, double-blind, placebo-controlled, crossover study was then performed. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: 1 week of D-ER (10 mg BID) or placebo, followed by a 1-week washout and 1 week of the opposite treatment. Key inclusion criteria were age 18 to 70 years, body mass index 18.0 to 30.0 kg/m2 , diagnosis of CP, and ability to perform all study procedures. Key exclusion criteria were severe CP, moderate or severe renal impairment, history of nonfebrile seizures, and prior dalfampridine use. Primary outcomes were safety profile and tolerability. Exploratory functional outcomes comprised changes in upper and lower extremity sensorimotor function (grip and pinch strength tests), manual dexterity (Box and Block Tests), and walking speed (Timed 25-Foot Walk). The most pronounced measured functional deficit in each individual was defined as the exploratory primary functional end point. Full crossover data were analyzed by using a mixed effects model. Findings Among the 24 total participants who were randomized to treatment and completed the twice daily dosing phase study, their mean age was 38.6 years (range, 20–62 years), 54% were women, and 83% had spastic CP. Adverse events were consistent with previous D-ER trials, most commonly headache (13% D-ER, 4% placebo), fatigue (13% D-ER, 0% placebo), insomnia (8% D-ER, 4% placebo), diarrhea (4% D-ER, 4% placebo), and nausea (4% D-ER, 4% placebo). The mixed model analysis of full crossover data identified no significant difference between D-ER and placebo in the primary functional analysis (the most pronounced deficit; P = 0.70) or in the secondary analyses (hand strength [ P = 0.48], manual dexterity [ P = 0.13], or walking speed [ P = 0.42]). Implications In this preliminary study of adults with CP, a BID dose of 10-mg D-ER was generally safe and well tolerated. The exploratory functional assessments for upper and lower sensorimotor deficits did not establish that the study population was markedly responsive to D-ER relative to placebo. These findings do not provide the proof-of-concept that would support further evaluation of D-ER as a potential intervention to improve function in adults with CP. ClinicalTrials.gov identifier: NCT01468350. ( Clin Ther . 2017;39:XXX–XXX) © 2017 Elsevier HS Journals, Inc.