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Results From CARNI-VAL Clinical Trial Published: A Twelve Month Prospective, Open-label Trial of VPA and L-carnitine in Ambulatory Children with Spinal Muscular Atrophy

FSMA | July 6, 2011

The second set of results from the Families of Spinal Muscular Atrophy funded CARNI-VAL clinical trial in ambulatory children published in PLoS ONE. The trial was completed by the Project Cure SMA Clinical Trial Network. The trial was registered at clinicaltrials.gov with identifier: NCT00227266.

Multiple lines of evidence, including treatment of patient-derived cell lines, animal models and open-label pilot human trials, have suggested that valproic acid (VPA) might have a therapeutic benefit in patients with spinal muscular atrophy. The SMA CARNIVAL TRIAL was a trial designed to evaluate the effectiveness of combined oral VPA and l-carnitine in two different groups of children with SMA. Group 1 of this trial targeted non-ambulatory SMA children 2-8 years of age, randomized to receive placebo or treatment for the first six months, then active treatment for an additional six months (Please see group 1 results in an earlier article in this issue of Compass). Group two of this study was a twelve month open-label trial of VPA and L-carnitine in ambulatory children with SMA. Group two of the study involved an ambulatory group of 33 genetically proven SMA “standers and walkers” (type 3), between the ages 3-17 years.

Participants underwent two initial baseline assessments of functional over a 4-6 week period and then were placed on VPA and L-carnitine for 12 months. Functional assessments were performed at baseline, 3, 6 and 12 months. Several primary functional assessments (outcomes / trial endpoints) were used, including safety, adverse event data, and efficacy. Efficacy (potential benefit) was measured by change in motor function at 6 and 12 months using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed tests of gross motor function, and a fine motor module. Secondary outcome measures were tested at 6 and 12 month. These included maximum ulnar compound muscle action potential amplitudes (CMAP; see article in this issue of Compass describing what CMAP measures and indicates about motor neuron functionality), muscle strength by handheld dynamometry, pulmonary function measures, and patient and care-giver Pediatric Quality of Life Inventory scores.

Twenty-nine patients completed the 12 month open label study. VPA and carnitine were generally well tolerated, with only 1 patient developing a serious adverse event (dehydration) during the study. At least one adverse event occurred in 85% of all subjects but these were mild and similar to those seen in the group 1 study. The most common adverse events were pneumonia, gastrointestinal symptoms, fever and fractures; all except gastrointestinal symptoms were considered unlikely due to study medication. Excessive weight gain and abdominal pain were the most frequent drug-related adverse events. There was no significant change in any of the primary outcome measures at six or 12 months. There were some changes in secondary measurements. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP amplitude did significantly improve at six and 12 months, suggesting a possible modest biologic effect directly on motor neurons, but that change was not clinically meaningful in improving participant function.

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