Background:Current drug treatments have little efficacy in advanced-to-end-stage Parkinson’s disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. Objective:To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD. Methods:A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. 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. Results: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. Conclusion:PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

中文翻译：

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D 1/D 5 多巴胺部分激动剂 PF-06412562 治疗晚期帕金森病：可行性研究

背景：目前药物治疗对晚期至终末期帕金森病（advPD）疗效甚微，尚无针对advPD的介入试验报道。D1 多巴胺激动剂有可能提供益处。目的：确定选择性D1/D5多巴胺部分激动剂PF 06412562治疗advPD的可行性和安全性。方法：一项针对 advPD 患者的为期两周、随机、双盲、交叉 Ib 期研究将标准护理 (SoC) 卡比多巴/左旋多巴与 PF 06412562 进行比较。每周进行第一天基线评估，并进行隔夜左旋多巴冲洗，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）。结果：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级中支持 PF-06412562，每名护理人员的评级中有 4 名参与者支持 PF-06412562。结论：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。