背景:Prader-Willi综合征(PWS)是一种罕见的神经行为-代谢疾病,由染色体15q11-q13区域缺乏父系表达基因引起,以张力减退为特征,神经认知问题,行为困难,内分泌疾病,如果不控制能量摄入,会导致严重的肥胖。在一项针对PWS参与者的3期安慰剂对照研究中,先前已评估了二氮嗪胆碱缓释(DCCR)片剂对PWS患者的饮食过多和其他行为并发症的影响。4岁及以上伴饮食亢进(C601),在一项开放标签延伸研究中,C602.
方法:为了更好地了解DCCR的长期影响,来自PATH的PWS队列,一项自然史研究,招募年龄在5岁及以上的PWS参与者,遇到了C601时代,体重和基线饮食亢进纳入标准,并且有2次饮食亢进评估间隔≥6个月,与C601/C602队列进行比较。使用临床试验的饮食过度问卷测量饮食过度(HQ-CT,范围0-36)。主要分析使用观察到的值,没有对缺失数据进行明确的填补。进行了敏感性分析,其中C601/C602队列中所有缺失的HQ-CT评估都被指定为最高可能值(36)。代表最坏的情况。使用Prader-Willi综合征概况问卷(PWSP)评估其他行为变化。
结果:相对于PWS自然史研究队列的PATH,DCCR治疗的C601/C602队列在26周时HQ-CT评分显着改善(LSmean[SE]-8.3[0.75]vs.-2.5[0.43],p<0.001)和52周(LSmean[SE]-9.2[0.77]vs.-3.4[0.47],p<0.001)。在最坏情况下的归因敏感性分析中,队列之间的比较仍然显着。与PWS参与者的PATH相比,C601/C602参与者在26周(所有p<0.001)和52周(所有p≤0.003)的PWSP所有领域也有显着改善。
结论:对PWS患者长期给予DCCR会导致PWS的饮食亢进和其他行为并发症的变化,这与该综合征的自然史不同,如PATH的PWS队列所示。DCCR给药的联合作用应减轻综合征对患者的负担,看护者和他们的家人,从而可能使患有PWS的人及其家人受益。
背景:临床研究C601最初于2018年2月22日在ClinicalTrials.gov上注册(NCT03440814)。临床研究C602最初于2018年10月22日在ClinicalTrials.gov上注册(NCT03714373)。PATH最初于2018年10月24日在ClinicalTrials.gov上注册(NCT03718416)。
BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled
study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension
study, C602.
METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history
study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP).
RESULTS: Relative to the PATH for PWS natural history
study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants.
CONCLUSIONS: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families.
BACKGROUND: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical
study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).