The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study.
The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study.
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DOI：
10.3233/jpd-202188
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Mailman RB
中科院分区：
文献类型：
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作者：
Huang X;Lewis MM;Van Scoy LJ;De Jesus S;Eslinger PJ;Arnold AC;Miller AJ;Fernandez-Mendoza J;Snyder B;Harrington W;Kong L;Wang X;Sun D;Delnomdedieu M;Duvvuri S;Mahoney SE;Gray DL;Mailman RB
目前的药物治疗对于晚期至终末期帕金森病（advPD）疗效有限且副作用难以忍受。 D1 激动剂有可能提供症状益处，但没有关于该人群的安全性和可行性的数据。在 advPD 患者中进行了一项为期两周的随机、双盲、交叉 Ib 期研究，以比较标准护理 (SoC) 卡比多巴/左旋多巴与 PF-06412562（一种选择性 D1/D5 多巴胺受体部分激动剂）。每周进行第一天基线评估，过夜左旋多巴冲洗，然后在第 2 天和第 3 天使用 SoC 或 PF-06412562（分次剂量 25+20 mg）进行治疗，然后在第 4 天出院。主要终点是安全性和耐受性。次要终点是由临床医生和护理人员评定的全球临床印象变化（GCI-C）。 8 名 advPD 患者及其护理人员同意参与，其中 6 名患者被随机分配（平均病程：22 年）。没有人自愿退出。一名基线第 1 天脱水、肾前性肾损伤和自主神经功能障碍的参与者在第 1 周接受 PF-06412562 后出现症状性严重低血压，并退出研究。所有其他不良事件均被评为轻度（PF-06412562：n=1，SoC：n=0）、中度（PF-06412562：n=1，SoC：n=1）或严重但不严重（PF-06412562：n=3，SoC：n=2）。没有观察到有临床意义的实验室变化。在完成研究的 5 名参与者中，GCI-C 在每名临床医生的评分中偏爱 PF-06412562，每名护理人员的评分中偏爱 4 名参与者。 PF-06412562 在 advPD 患者中具有耐受性。这项研究为未来针对这一需求未得到满足的人群进行安全性和有效性研究提供了可行性。临床试验.gov：NCT03665454
Current drug treatments have limited efficacy and intolerable side effects in advanced-to-end-stage Parkinson’s disease (advPD). D1 agonists have the potential to provide symptomatic benefit, but there are no data on safety and feasibility in this population. A two-week, randomized, double blind, crossover phase Ib study was performed in advPD patients to compare standard-of-care (SoC) carbidopa/levodopa with PF-06412562, a selective D1/D5 dopamine receptor partial agonist. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25+20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n=1, SoC: n=0), moderate (PF-06412562: n=1, SoC: n=1), or severe but non-serious (PF-06412562: n=3, SoC: n=2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians’ and four participants per caregivers’ rating. PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs. ClinicalTrials.gov:NCT03665454