SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy.

INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 20­55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10­20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

Reliability and validity of the TIMPSI for infants with spinal muscular atrophy type I.

PURPOSE: This study examined the reliability and validity of the Test of Infant Motor Performance Screening Items (TIMPSI) in infants with type I spinal muscular atrophy (SMA). METHODS: After training, 12 evaluators scored 4 videos of infants with type I SMA to assess interrater reliability. Intrarater and test-retest reliability was further assessed for 9 evaluators during a SMA type I clinical trial, with 9 evaluators testing a total of 38 infants twice. Relatedness of the TIMPSI score to ability to reach and ventilatory support was also examined. RESULTS: Excellent interrater video score reliability was noted (intraclass correlation coefficient, 0.97-0.98). Intrarater reliability was excellent (intraclass correlation coefficient, 0.91-0.98) and test-retest reliability ranged from r = 0.82 to r = 0.95. The TIMPSI score was related to the ability to reach (P ≤ .05). CONCLUSION: The TIMPSI can reliably be used to assess motor function in infants with type I SMA. In addition, the TIMPSI scores are related to the ability to reach, an important functional skill in children with type I SMA.

Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy.

INTRODUCTION: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. METHODS: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. RESULTS: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. DISCUSSION: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.

Compound muscle action potential and motor function in children with spinal muscular atrophy.

Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action potential (CMAP) data were collected at two visits over a 4-6-week period in children with SMA types II and III, 2-17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non-ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test-retest reliability (ICC = 0.96-0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS-Extend (r = 0.61-0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status.

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy.

The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra- and interrater reliability and the test-retest stability of a modified version of the scale. Both intra- and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20 degrees . These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

BACKGROUND: Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. METHODS: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. RESULTS: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. CONCLUSIONS: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

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. TRIAL REGISTRY: Clinicaltrials.gov NCT00227266.