SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.
BACKGROUND
Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.


METHODS
Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.


RESULTS
At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).


CONCLUSIONS
This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.


BACKGROUND
Clinicaltrials.gov NCT00227266.
Swoboda
Kathryn J
KJ
Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Scott
Charles B
CB
Crawford
Thomas O
TO
Simard
Louise R
LR
Reyna
Sandra P
SP
Krosschell
Kristin J
KJ
Acsadi
Gyula
G
Elsheik
Bakri
B
Schroth
Mary K
MK
D'Anjou
Guy
G
LaSalle
Bernard
B
Prior
Thomas W
TW
Sorenson
Susan L
SL
Maczulski
Jo Anne
JA
Bromberg
Mark B
MB
Chan
Gary M
GM
Kissel
John T
JT
D000367:Age Factors; D001823:Body Composition / Q000187:drug effects; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002331:Carnitine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007223:Infant; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D011788:Quality of Life; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000097:blood / Q000235:genetics; D016896:Treatment Outcome; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D012333:RNA, Messenger; D055533:Survival of Motor Neuron 1 Protein; D014635:Valproic Acid; D002331:Carnitine
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