Difference in chronological changes of outcome measures between untreated and placebo-treated patients of spinal and bulbar muscular atrophy
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Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, and bulbar involvement. The aim of this study was to analyze the differential change of various outcome measures by comparing the progression of motor impairment in the two independent groups: placebo-treated group (PTG) and natural history group (NHG). For the PTG, we analyzed 99 patients who participated in a previous double-blind phase III clinical trial and received placebo. For the NHG, a total of 34 patients were followed with no specific treatment. The characteristics of both groups did not differ at baseline except for disease duration. Although the 6 min walk distance (6MWD) showed almost the same progression in both groups (−14.7 ± 7.3 m in NHG, −14.0 ± 4.7 m in PTG; NS), there was a significant difference of progression in the ALSFRS-R between the NHG and PTG (−1.18 ± 0.38, −0.14 ± 0.24; p = 0.03). A similar tendency was also seen in the subgroup analysis of the patients whose disease durations were less than 10 years. Although the relationship between the ALSFRS-R and 6MWD at week 48 was similar to that at baseline in the NHG, the slope of the regression at week 48 was significantly milder than at baseline in the PTG (p = 0.04). In conclusion, these two groups demonstrated a large difference in the chronological analysis of a motor function score, but showed similar changes in objective measures of walking capacity. These findings should be thoroughly considered when designing clinical trials for slowly progressive neurodegenerative diseases such as SBMA.
KeywordsSpinal and bulbar muscular atrophy Natural history Placebo effect Negative expectation Clinical trial
We wish to thank all the JASMITT investigators for collecting data of PTG. We acknowledge and thank all patients and their families for participating in this study. We also acknowledge and wish to thank Hiroaki Oe and Shinya Sakai, the biostatisticians of EPS Co., Ltd., for statistical advice. This work was supported by the Program for Improvement of Research Environment for Young Researchers from Special Coordination Funds for Promoting Science and Technology (SCF) commissioned by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grant-in-Aids from Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant numbers 21689024 and 22110005); Large Scale Clinical Trial Network Project subsidized by the Ministry of Health, Labour and Welfare (MHLW) and supported by Health and Labour Sciences Research Grants, Japan; and JST, CREST, Japan.
Conflict of interest
G.S. has received research grant and honoraria from Takeda pharmaceuticals. All other authors declare that they have no conflict of interests.