A Randomized, Double-blind, Placebo-controlled, Dose-ranging Trial of Oral Inosine to Assess Safety and Ability to Elevate Urate in Early Parkinson's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 75
- 试验地点
- 16
- 主要终点
- Tolerability
研究概览
简要总结
The purpose of this study is to determine the safety and tolerability of inosine and its ability to raise urate levels in blood and cerebral spinal fluid in individuals with early Parkinson disease. This will determine whether it is appropriate to proceed with a larger study of inosine's ability to modify the rate of disability progression in PD.
详细描述
Background & Rationale:
Convergent epidemiological and clinical observations have identified urate - a major antioxidant and the end product of purine metabolism in humans - as the first molecular predictor of both the risk and the progression of typical Parkinson's disease (PD). Among some 1600 early PD patients enrolled in prior clinical trials, those with baseline serum urate levels in the highest quintile (i.e., in the upper normal range) displayed a 40% slower rate of clinical (disability) progression compared to those with baseline urate at or below the median (with p<0.000001 for trend across quintiles). Similarly, amongst those who underwent serial SPECT brain scans for changes in dopamine transporter (DAT) binding, those with higher baseline serum urate levels displayed a slower rate of radiographic progression (loss of striatal DAT). Moreover, urate levels in baseline cerebrospinal fluid (CSF) samples also correlate inversely with rates of clinical progression. Although this link between urate and a slower decline in PD appears reproducible and robust, the critical question of causality remains to be answered by a well-designed clinical trial. The biological plausibility of neuroprotection by urate strengthens the rationale for expedient pursuit of a trial. The availability of established pharmacological approaches to elevating urate makes such a trial feasible. In particular, inosine, an orally bioavailable, central nervous system (CNS)-penetrant purine precursor of urate, offers a practical strategy as it can readily elevate serum urate, has been widely consumed as a nutritional supplement, and has been administered chronically in several multi-year clinical trials for multiple sclerosis. Before embarking on a neuroprotection trial of inosine for PD, careful assessment of the safety, validity and methodology of this approach in PD patients is warranted.
Specific Aims:
The main goal of the study is to determine whether inosine is suitable for phase III evaluation of its ability to modify the rate of disability progression in PD. Specific primary aims entail the determination of the safety and tolerability of oral inosine, and its ability to elevate urate levels in serum or CSF; and the selection of an optimal dosing regimen. Secondary aims entail the further optimization of a possible phase III study design.
Methods:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 30 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Idiopathic PD with at least two of the cardinal signs of PD (resting tremor, bradykinesia, rigidity)
- •Currently not taking or needing any treatment for PD other than an monoamine oxidase-B (MAO-B) inhibitor
- •Age 30 or older at the time of PD diagnosis
- •Diagnosis of PD made within past 3 years
- •Serum urate ≤ 5.8 mg/dL at initial screening
排除标准
- •History of kidney stones, gout, stroke, or heart attack
- •History of renal disease or certain cardiovascular problems within the past year
- •Acidic urine (pH ≤ 5.0), uric acid, or urate crystalluria at screening
- •Use of certain medications including co-enzyme Q, creatine, more than 50 IU of vitamin E daily, and more than 300 mg of vitamin C daily. (A standard daily multivitamin is permitted.)
- •Use of anti-PD and other medications targeting central nervous system dopamine transmission
- •Known unstable medical or psychiatric condition that may compromise participation in the study
- •Women who are pregnant or lactating
研究组 & 干预措施
[A:]
Placebo to produce no urate elevation
干预措施: Placebo (Drug)
[B:]
Inosine to produce a mild urate elevation
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a mildly elevated serum urate range of 6.1 - 7.0 mg/dL
干预措施: inosine (Drug)
[C.]
Inosine to produce a moderate urate elevation
500 mg of active substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing titrated to a moderately elevated serum urate range of 7.1 - 8.0 mg/dL
干预措施: inosine (Drug)
结局指标
主要结局
Tolerability
时间窗: 24 months
Defined as the extent to which assigned treatment could continue without prolonged dose reduction (\>48 consecutive days or \>73 cumulative days, which is 10% of total 2-year follow-up) due to AEs, and was assessed after 6 and 24 months on study drug. Units of measure are percentage points (i.e., % of participants in the group).
Safety
时间窗: 24 months
Defined as absence of serious adverse experiences (SAEs) that warranted terminating an inosine treatment arm or the trial, as determined by the Data and Safety Monitoring Committee.
次要结局
- CSF Urate (All Patients)(12 weeks)
- CSF Urate (Females)(12 weeks)
- CSF Urate (Males)(12 weeks)
- CSF Urate as a Proportion of Baseline Serum Urate (All Patients)(12 weeks)
- CSF Urate as a Proportion of Baseline Serum Urate (Females)(12 weeks)
- CSF Urate as a Proportion of Baseline Serum Urate (Males)(12 weeks)
- Serum Urate(Safety Visit (SV); 30 +/- 3 days following ESD or Month 24 Visit)
- Change in Serum Urate(Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days))
研究者
Michael Schwarzschild
Principal Investigator
The Parkinson Study Group