BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016.

Background:The benefits of exercise on long-term health and well-being are well established. The possible benefits of exercise in Spinal Muscular Atrophy (SMA) have not been explored in a controlled clinical trial format.Objective:To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients.Methods:Fourteen participants, ages 10–48 years, were randomized to control and exercise cohorts after a 1 month lead-in period. The exercise group received 6 months of intervention. Thereafter, both groups received the intervention for the remaining 12 months. Participants were monitored for a total of 19 months. Exercise included individualized home-based cycling and strengthening. The primary outcome measure was distance walked during the six-minute walk test (6MWT). Secondary outcomes included strength, function, exercise capacity, quality of life and fatigue.Results:Twelve participants completed the first 7 months of the study, and 9 completed all 19 months. At baseline, the groups were similar on all clinical variables. There were no group changes at any time point in the 6MWT, fatigue, or function. Percent-predicted VO2 max improved 4.9% in all participants in 6 months (p = 0.036) (n = 10).Conclusion:Daily exercise is safe in ambulatory SMA and should be encouraged. We did not uncover any deleterious effects on strength, function, or fatigue. Our study documented a reduction in oxidative capacity and a blunted conditioning response to exercise possibly representing an important insight into underlying pathophysiological mechanisms. These findings also may be linked causally to mitochondrial depletion in SMA and warrant further study.

Background: Fatigue is a common complaint in spinal muscular atrophy (SMA). Fatigability is well described in ambulatory SMA but the relationship to perceived fatigue has not been evaluated. Understanding this relationship has proven challenging for most disorders. Objective: To assess the relationship of perceived fatigue to fatigability, function, and quality of life in SMA. Methods: Thirty-two participants with SMA (21.9% type 2, 78.1% type 3) were recruited. Perceived fatigue and fatigability, function, and quality of life were assessed using standardized questionnaires and assessments. Associations were analyzed using Pearson correlation coefficients (p = 0.05). Also, the effects of age, type, and ambulatory status were determined on perceived fatigue. Results: All SMA participants reported fatigue. Perceived fatigue was not associated with function, quality of life, or fatigability in ambulatory SMA patients. Neither age, type, nor ambulatory status influenced perceived fatigue. Conclusions: Perceived fatigue can be quantified in SMA. Interestingly, perceived fatigue did not correlate with fatigability or function, suggesting that cognitive, homeostatic, or psychologic factors may be more relevant as co-morbid factors. Clinical trials targeting perceived fatigue in SMA should focus on these patient-reported assessments. A multilevel approach is required to separate the various mechanisms involved in perceived fatigue.

In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA.