Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I

Kristin J Krosschell; John T Kissel; Elise L Townsend; Sarah D Simeone; Ren Zhe Zhang; Sandra P Reyna; Thomas O Crawford; Mary K Schroth; Gyula Acsadi; Priya S Kishnani; Jürgen-Christoph Von Kleist-Retzow; Barbara Hero; Guy D'Anjou; Edward C Smith; Bakri Elsheikh; Louise R Simard; Thomas W Prior; Charles B Scott; Bernard Lasalle; Ai Sakonju; Brunhilde Wirth; Kathryn J Swoboda; Project Cure SMA Investigator's Network

doi:10.1002/mus.25776

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I

Muscle Nerve. 2018 Feb;57(2):193-199. doi: 10.1002/mus.25776. Epub 2017 Sep 18.

Authors

Kristin J Krosschell¹, John T Kissel², Elise L Townsend³, Sarah D Simeone⁴, Ren Zhe Zhang⁴, Sandra P Reyna⁵, Thomas O Crawford⁶, Mary K Schroth⁷, Gyula Acsadi⁸, Priya S Kishnani⁹, Jürgen-Christoph Von Kleist-Retzow¹⁰, Barbara Hero¹⁰, Guy D'Anjou¹¹, Edward C Smith⁹, Bakri Elsheikh², Louise R Simard¹², Thomas W Prior¹³, Charles B Scott¹⁴, Bernard Lasalle¹⁵, Ai Sakonju¹⁶, Brunhilde Wirth^{17

18}, Kathryn J Swoboda⁴; Project Cure SMA Investigator's Network

Affiliations

¹ Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
² Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
³ Department of Physical Therapy, Institute of Health Professions, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Simches 5-240, Boston, Massachusetts, 02114, USA.
⁵ Department of Neurology, University of Utah, Salt Lake City, Utah, USA.
⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁷ Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
⁸ Connecticut Children's Medical Center, Hartford, Connecticut, USA.
⁹ Department of Pediatrics, Duke University, Durham, North Carolina, USA.
¹⁰ Department of Pediatrics, Hospital of the University of Cologne, Cologne, Germany.
¹¹ Department of Pediatrics, Saint-Justine Hospital, Montreal, Quebec, Canada.
¹² Biochemistry and Medical Genetics, University of Manitoba, Winnepeg, Manitoba, Canada.
¹³ Department of Molecular Pathology, The Ohio State University, Columbus, Ohio, USA.
¹⁴ CBS Squared, Inc, Fort Washington, Pennsylvania, USA.
¹⁵ Department of Bioinformatics, University of Utah, Salt Lake City, Utah, USA.
¹⁶ Department of Neurology, State University of New York, Syracuse, New York.
¹⁷ Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne.
¹⁸ Institute of Genetics, University of Cologne, Cologne, Germany.

PMID: 28833236
DOI: 10.1002/mus.25776

Abstract

Introduction: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA).

Methods: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude.

Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts.

Discussion: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Keywords: L-carnitine; clinical trials; infants; natural history; spinal muscular atrophy type I; valproic acid.

Publication types

Clinical Trial, Phase II
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Carnitine / adverse effects
Carnitine / therapeutic use*
Cohort Studies
Drug Therapy, Combination
Female
GABA Agents / adverse effects
GABA Agents / therapeutic use*
Humans
Infant
Male
Negative Results
Respiration, Artificial
Retrospective Studies
Spinal Muscular Atrophies of Childhood / drug therapy*
Spinal Muscular Atrophies of Childhood / physiopathology
Survival Analysis
Treatment Outcome
Valproic Acid / adverse effects
Valproic Acid / therapeutic use*
Vitamin B Complex / adverse effects
Vitamin B Complex / therapeutic use*

Substances

GABA Agents
Vitamin B Complex
Valproic Acid
Carnitine

Grants and funding

R01 HD054599/HD/NICHD NIH HHS/United States