PDF(Pubmed)
Abstract：
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.
To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.
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.
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.
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.
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).
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.
ClinicalTrials.gov Identifier: NCT02642393.
To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.
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.
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.
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.
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).
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.
ClinicalTrials.gov Identifier: NCT02642393.
摘要：
尿酸盐高程,尽管与晶体学有关，心血管,和代谢紊乱，已被视为基于趋同生物学的帕金森病（PD）的潜在疾病改善策略，流行病学,和临床数据。
确定用尿酸前体肌苷的持续尿酸升高治疗是否减缓早期PD进展。
随机化，双盲,安慰剂对照,早期PD口服肌苷治疗的3期试验。共有587人同意,298例PD还不需要多巴胺能药物，纹状体多巴胺转运蛋白缺乏，在2016年8月至2017年12月期间，在58个美国地点随机分配了低于人群中位浓度（<5.8mg/dL）的血清尿酸盐，并随访至2019年6月。
肌苷，通过盲法滴定法将血清尿酸浓度增加至7.1-8.0mg/dL（n=149）或匹配的安慰剂（n=149）长达2年。
主要结果是运动障碍协会统一帕金森病评定量表（MDS-UPDRS；I-III部分）总分（范围，0-236；较高的分数表示更大的残疾；在多巴胺能药物治疗开始之前，最低的临床重要差异为6.3分）。次要结果包括血清尿酸来测量目标参与度，衡量安全性的不良事件，和29项残疾的功效衡量标准，生活质量,认知，心情,自主神经功能,和纹状体多巴胺转运蛋白结合作为神经元完整性的生物标志物。
根据预先规定的临时徒劳分析，这项研究提前结束了，273名(92%)随机参与者(49%为女性；平均年龄，63年）完成研究。随机接受肌苷治疗的参与者之间的临床进展率没有显着差异（MDS-UPDRS评分，每年11.1[95%CI，9.7-12.6]分）和安慰剂（MDS-UPDRS评分，每年9.9[95%CI，8.4-11.3]点；差额，每年1.26[95%CI，-0.59至3.11]点；P=.18）。肌苷组的血清尿酸持续升高2.03mg/dL（从4.6mg/dL的基线水平;增加44％），而安慰剂组的血清尿酸持续升高0.01mg/dL（差异，2.02mg/dL[95%CI，1.85-2.19mg/dL]；P<.001）。包括多巴胺转运体结合丧失在内的次要疗效结果没有显着差异。参与者随机分配给肌苷，与安慰剂相比，严重不良事件较少(7.4vs13.1/100患者-年),但肾结石较多(7.0vs1.4结石/100患者-年).
在最近诊断为PD的患者中，用肌苷治疗，与安慰剂相比，没有导致临床疾病进展率的显著差异。研究结果不支持使用肌苷作为早期PD的治疗。
ClinicalTrials.gov标识符：NCT02642393。
确定用尿酸前体肌苷的持续尿酸升高治疗是否减缓早期PD进展。
随机化，双盲,安慰剂对照,早期PD口服肌苷治疗的3期试验。共有587人同意,298例PD还不需要多巴胺能药物，纹状体多巴胺转运蛋白缺乏，在2016年8月至2017年12月期间，在58个美国地点随机分配了低于人群中位浓度（<5.8mg/dL）的血清尿酸盐，并随访至2019年6月。
肌苷，通过盲法滴定法将血清尿酸浓度增加至7.1-8.0mg/dL（n=149）或匹配的安慰剂（n=149）长达2年。
主要结果是运动障碍协会统一帕金森病评定量表（MDS-UPDRS；I-III部分）总分（范围，0-236；较高的分数表示更大的残疾；在多巴胺能药物治疗开始之前，最低的临床重要差异为6.3分）。次要结果包括血清尿酸来测量目标参与度，衡量安全性的不良事件，和29项残疾的功效衡量标准，生活质量,认知，心情,自主神经功能,和纹状体多巴胺转运蛋白结合作为神经元完整性的生物标志物。
根据预先规定的临时徒劳分析，这项研究提前结束了，273名(92%)随机参与者(49%为女性；平均年龄，63年）完成研究。随机接受肌苷治疗的参与者之间的临床进展率没有显着差异（MDS-UPDRS评分，每年11.1[95%CI，9.7-12.6]分）和安慰剂（MDS-UPDRS评分，每年9.9[95%CI，8.4-11.3]点；差额，每年1.26[95%CI，-0.59至3.11]点；P=.18）。肌苷组的血清尿酸持续升高2.03mg/dL（从4.6mg/dL的基线水平;增加44％），而安慰剂组的血清尿酸持续升高0.01mg/dL（差异，2.02mg/dL[95%CI，1.85-2.19mg/dL]；P<.001）。包括多巴胺转运体结合丧失在内的次要疗效结果没有显着差异。参与者随机分配给肌苷，与安慰剂相比，严重不良事件较少(7.4vs13.1/100患者-年),但肾结石较多(7.0vs1.4结石/100患者-年).
在最近诊断为PD的患者中，用肌苷治疗，与安慰剂相比，没有导致临床疾病进展率的显著差异。研究结果不支持使用肌苷作为早期PD的治疗。
ClinicalTrials.gov标识符：NCT02642393。
