Importance Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration ClinicalTrials.gov Identifier: NCT02642393.

中文翻译：

---

尿酸升高肌苷对早期帕金森病进展的影响：SURE-PD3 随机临床试验。

尽管尿酸升高与结晶病、心血管和代谢紊乱有关，但根据生物学、流行病学和临床数据，尿酸升高一直被视为帕金森病 (PD) 的潜在疾病缓解策略。目的 确定尿酸前体肌苷持续升高尿酸治疗是否可以减缓早期帕金森病进展。设计、参与者和环境 早期 PD 口服肌苷治疗的随机、双盲、安慰剂对照 3 期试验。2016 年 8 月至 2017 年 12 月期间，共有 587 名受试者同意，其中 298 名患有 PD 且尚未需要多巴胺能药物、纹状体多巴胺转运蛋白缺乏且血清尿酸低于人群中位浓度 (<5.8 mg/dL) 的患者在美国 58 个地点进行了随机分组。随访至 2019 年 6 月。 干预措施 肌苷，通过盲法滴定给药，将血清尿酸浓度提高至 7.1-8.0 mg/dL (n = 149) 或匹配安慰剂 (n = 149)，持续长达 2 年。主要结果和措施 主要结果是运动障碍协会统一帕金森病评定量表（MDS-UPDRS；第 I-III 部分）总分的变化率（范围 0-236；分数越高表示残疾程度越高；临床重要差异最小6.3分）在多巴胺能药物治疗开始之前。次要结局包括用于衡量目标参与度的血清尿酸盐、用于衡量安全性的不良事件以及针对残疾、生活质量、认知、情绪、自主功能和作为神经元完整性生物标志物的纹状体多巴胺转运蛋白结合的 29 项疗效衡量指标。结果 根据预先指定的中期无效性分析，该研究提前结束，273 名 (92%) 随机参与者（49% 为女性；平均年龄 63 岁）完成了研究。随机接受肌苷组（MDS-UPDRS 评分，每年 11.1 [95% CI，9.7-12.6] 分）和安慰剂组（MDS-UPDRS 评分，9.9 [95% CI，8.4-11.3] 分）的受试者之间的临床进展率没有显着差异每年点数；差异，每年 1.26 [95% CI，-0.59 至 3.11] 点；P = .18）。肌苷组血清尿酸持续升高 2.03 mg/dL（从基线水平 4.6 mg/dL；增加 44%），而安慰剂组血清尿酸变化为 0.01 mg/dL（差异为 2.02 mg） /dL [95% CI，1.85-2.19 mg/dL]；P<.001）。次要疗效结果（包括多巴胺转运蛋白结合丧失）没有显着差异。与安慰剂相比，随机接受肌苷治疗的参与者出现的严重不良事件较少（每 100 患者年 7.4 例 vs 13.1 例），但肾结石较多（每 100 患者年 7.0 例 vs 1.4 例）。结论和相关性 在最近诊断为 PD 的患者中，与安慰剂相比，肌苷治疗并未导致临床疾病进展率存在显着差异。研究结果不支持使用肌苷作为早期帕金森病的治疗方法。