Raphael Schiffmann1,2, Mary E Wallace3, Daisy Rinaldi4, Isabelle Ledoux5, Marie-Pierre Luton4, Scott Coleman6, H Orhan Akman7, Karine Martin8, Jean-Yves Hogrel5, Derek Blankenship3, Jacob Turner3, Fanny Mochel4,9,10. 1. Baylor Scott & White Research Institute, Dallas, TX, USA. Raphael.schiffmann@BSWhealth.org. 2. Institute of Metabolic Disease, 3812 Elm Street, Dallas, TX, 75226, USA. Raphael.schiffmann@BSWhealth.org. 3. Baylor Scott & White Research Institute, Dallas, TX, USA. 4. INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Brain and Spine Institute, Paris, France. 5. Institute of Myology, Neuromuscular Physiology and Evaluation Lab, F-75013, Paris, France. 6. Department of Orthopedics, Baylor University Medical Center, Dallas, TX, USA. 7. Department of Neurology, Columbia University Medical Center, New York, NY, USA. 8. Clinical Research Unit, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France. 9. Reference Center for Neurometabolic Diseases, Pitié-Salpêtrière University Hospital and Neurometabolic Research Group, University Pierre and Marie Curie, Paris, France. 10. Department of Genetics, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France.
Abstract
BACKGROUND:Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. METHODS AND RESULTS: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 ± 164 m (range 95-672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) -11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. CONCLUSIONS: We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960.
RCT Entities:
BACKGROUND:Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. METHODS AND RESULTS: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 ± 164 m (range 95-672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) -11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. CONCLUSIONS: We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960.
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