Massachusetts General Hospital, Boston, Massachusetts.
Harvard School of Public Health, Boston, Massachusetts.
JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528.
Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).
To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.
DESIGN, SETTING, AND PARTICIPANTS: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.
Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.
The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.
Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.
clinicaltrials.gov Identifier: NCT00833690.
汇聚的生物学、流行病学和临床数据将尿酸升高确定为减缓帕金森病 (PD) 残疾进展的候选策略。
确定尿酸前体肌苷在早期 PD 中的安全性、耐受性和尿酸升高能力，并评估其适合性和潜在的设计特征，以进行疾病修饰试验。
设计、设置和参与者：尿酸升高在 PD 中的安全性 (SURE-PD) 研究是一项肌苷的随机、双盲、安慰剂对照、剂量范围研究，于 2009 年至 2011 年招募参与者，并在全美帕金森研究小组的 17 个认证临床研究点进行门诊随访，最长随访时间为 25 个月。招募了 75 名同意参加的早期 PD 成年人（平均年龄 62 岁；55%为女性），这些人尚未需要进行症状治疗，且血清尿酸浓度低于 6mg/dL（约为人群中位数）。
参与者被随机分配到 3 个治疗组之一：安慰剂或肌苷，肌苷的剂量调整为产生轻度（6.1-7.0mg/dL）或中度（7.1-8.0mg/dL）血清尿酸升高，使用 500mg 胶囊，每天最多服用 2 粒，每天 3 次。在接受研究药物治疗和 1 个月洗脱期的同时，他们接受了长达 24 个月（中位数为 18 个月）的随访。
预先指定的主要结局是无不可接受的严重不良事件（安全性）、继续治疗而无需要减少剂量的不良事件（耐受性）以及血清和一次（3 个月）脑脊液中尿酸的连续升高。结果：在肌苷组中，包括罕见的心血管事件在内的严重不良事件（17 例）发生率与安慰剂组相同或更低。没有参与者发生痛风，3 名接受肌苷治疗的参与者发生了有症状的尿路结石。在 6 个月时，95%的参与者耐受治疗，没有参与者因不良事件退出。与安慰剂相比，肌苷组的血清尿酸分别升高 2.3mg/dL 和 3.0mg/dL（各 P<0.001），且两种肌苷组的脑脊液尿酸水平均升高（P=0.006 和<0.001）。次要分析表明肌苷治疗对减缓残疾没有无效。
肌苷在早期 PD 中通常是安全、耐受和有效的，可升高血清和脑脊液中的尿酸水平。这些发现支持进一步开发肌苷作为 PD 的潜在疾病修饰治疗。
clinicaltrials.gov 标识符：NCT00833690。
