PDF(Pubmed)
Abstract：
OBJECTIVE: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
CONCLUSIONS: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT03439670.
METHODS: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
CONCLUSIONS: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT03439670.
METHODS: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
摘要：
目的：瓦莫罗酮是糖皮质激素受体的解离激动剂，与泼尼松相比，在杜兴氏肌营养不良症（DMD）中表现出相似的疗效和降低的安全性。进行这项研究是为了确定vamororone在48周内的疗效和安全性，并研究交叉参与者（泼尼松与vamororone；安慰剂与vamororone）。
方法：随机，双盲,安慰剂对照和泼尼松对照的2剂vamororone的临床试验进行了DMD的参与者，基线时年龄从4岁到小于7岁。干预措施为2mg/kg/d的vamororone和6mg/kg/d的vamororone，持续48周（1:24周+2:24周）和0.75mg/kg/d的泼尼松和安慰剂前24周（交叉前）。通过粗大运动结果评估疗效，通过不良事件评估安全性，生长速度，体重指数（BMI），和骨转换生物标志物。该分析集中在第2期。
结果：共有121名DMD患者被随机分组。剂量为6mg/kg/d的Vamoolone显示出所有运动结果的改善至第48周（例如，对于主要结果，从仰卧[TTSTAND]速度站立的时间，第24周最小二乘均值[LSM][SE]0.052[0.0130]上升/s与第48周LSM[SE]0.0446[0.0138])。48周后,2mg/kg/d剂量的vamororone显示出与6mg/kg/d相似的改善，用于北极星动态评估（NSAA）（vamororone6mg/kg/d-vamororone2mg/kg/dLSM[SE]0.49[1.14];95％CI-1.80至2.78，p=0.67），但对其他运动结果的改善较少。安慰剂对6mg/kg/d的vamororone组显示出治疗20周后的快速改善，接近TTSTAND治疗48周6mg/kg/d的vamororone治疗的益处，跑/走10米的时间，和NSAA。泼尼松与vamorolone6mg/kg/d组交叉后线性生长显着改善，和快速逆转泼尼松诱导的骨转换生物标志物在两个交叉组中的下降。治疗24周后，两组的BMI均增加，然后稳定。
结论：在治疗24周时，使用6mg/kg/d的vamororone观察到的运动结局的改善一直维持到治疗48周。对于大多数（3/5）运动结果，与剂量为2mg/kg/d的沃莫罗酮相比，剂量为6mg/kg/d的沃莫罗酮显示出更好的维持效果。当治疗过渡到vamororone时，泼尼松的骨发病率（生长迟缓和血清骨生物标志物的下降）被逆转。
■ClinicalTrials.gov标识符：NCT03439670。
方法：这项研究提供了I类证据，对于患有DMD的男孩，剂量为6mg/kg/d的瓦莫罗酮的疗效维持了48周。
方法：随机，双盲,安慰剂对照和泼尼松对照的2剂vamororone的临床试验进行了DMD的参与者，基线时年龄从4岁到小于7岁。干预措施为2mg/kg/d的vamororone和6mg/kg/d的vamororone，持续48周（1:24周+2:24周）和0.75mg/kg/d的泼尼松和安慰剂前24周（交叉前）。通过粗大运动结果评估疗效，通过不良事件评估安全性，生长速度，体重指数（BMI），和骨转换生物标志物。该分析集中在第2期。
结果：共有121名DMD患者被随机分组。剂量为6mg/kg/d的Vamoolone显示出所有运动结果的改善至第48周（例如，对于主要结果，从仰卧[TTSTAND]速度站立的时间，第24周最小二乘均值[LSM][SE]0.052[0.0130]上升/s与第48周LSM[SE]0.0446[0.0138])。48周后,2mg/kg/d剂量的vamororone显示出与6mg/kg/d相似的改善，用于北极星动态评估（NSAA）（vamororone6mg/kg/d-vamororone2mg/kg/dLSM[SE]0.49[1.14];95％CI-1.80至2.78，p=0.67），但对其他运动结果的改善较少。安慰剂对6mg/kg/d的vamororone组显示出治疗20周后的快速改善，接近TTSTAND治疗48周6mg/kg/d的vamororone治疗的益处，跑/走10米的时间，和NSAA。泼尼松与vamorolone6mg/kg/d组交叉后线性生长显着改善，和快速逆转泼尼松诱导的骨转换生物标志物在两个交叉组中的下降。治疗24周后，两组的BMI均增加，然后稳定。
结论：在治疗24周时，使用6mg/kg/d的vamororone观察到的运动结局的改善一直维持到治疗48周。对于大多数（3/5）运动结果，与剂量为2mg/kg/d的沃莫罗酮相比，剂量为6mg/kg/d的沃莫罗酮显示出更好的维持效果。当治疗过渡到vamororone时，泼尼松的骨发病率（生长迟缓和血清骨生物标志物的下降）被逆转。
■ClinicalTrials.gov标识符：NCT03439670。
方法：这项研究提供了I类证据，对于患有DMD的男孩，剂量为6mg/kg/d的瓦莫罗酮的疗效维持了48周。
