Safety of Urate Elevation in Parkinson's Disease (SURE-PD)

• Tolerability as defined as the extent to which an assigned treatment can be continued without dose reduction for more than 4 weeks due to adverse experience(s). [ Time Frame: 12 weeks and 2 years ] [ Designated as safety issue: Yes ]
• Safety as defined as absence of serious adverse experiences that collectively warrant terminating an inosine treatment dose or the trial, as determined by the Data and Safety Monitoring Committee. [ Time Frame: 12 weeks and 2 years ] [ Designated as safety issue: Yes ]

• urate levels in serum/CSF [ Time Frame: 12 weeks and 2 years ] [ Designated as safety issue: No ]
• oxidative damage biomarker [ Time Frame: 6 months and 2 years ] [ Designated as safety issue: No ]

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.

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 the DATATOP and PRECEPT 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 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, 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:

A placebo-controlled double-blind dose-ranging randomized trial of inosine will be conducted in early PD. Ninety untreated subjects diagnosed with idiopathic PD and with a serum urate below the population mean (~6 mg/dL) will be enrolled at 17 North American sites and randomized to one of three treatment groups (n=30): 1) placebo, 2) inosine dosed to produce a mild elevation in serum urate, and 3) inosine dosed to produce a moderate elevation. Tolerability, validity (urate elevation), dosage and symptomatic efficacy will be assessed after 12 weeks of treatment. Contingent on adequate tolerability and validity as assessed in this short-term analysis, the study will continue for 2 years total duration with 2 groups (placebo and a merged single inosine dosing group) or the original 3 to assess long-term tolerability and safety, which will focus on main known risks of urolithiasis and gouty arthritis and the theoretical risk of cardiovascular disease.

Significance:

This study will determine whether a phase III trial of inosine as a potential neuroprotectant in PD is warranted. If it is, then the present study could shorten substantially the lead time, and through optimization of key design features would enhance the likelihood of its safety and success.

• Drug: Placebo
  500 mg of inactive substance per capsule; 1 to 6 capsules per day (in up to 3 divided doses) for 2 years; dosing adjusted algorithmically to parallel that in the inosine arms
• Drug: inosine
  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
  Other Name: hypoxanthine 9-β-D-ribofuranoside
• Drug: inosine
  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
  Other Name: hypoxanthine 9-β-D-ribofuranoside

• Placebo Comparator: [A:]
  Placebo to produce no urate elevation
  Intervention: Drug: Placebo
• Experimental: [B:]
  Inosine to produce a mild urate elevation
  Intervention: Drug: inosine
• Experimental: [C.]
  Inosine to produce a moderate urate elevation
  Intervention: Drug: inosine

Inclusion Criteria:

• 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 MAO-B inhibitor
• Age 30 or older at the time of PD diagnosis
• Diagnosis of PD made within past 3 years
• Specified serum urate levels at screening visits

Exclusion Criteria:

• 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

• Massachusetts General Hospital
• Harvard School of Public Health
• University of Rochester
• Michael J. Fox Foundation for Parkinson's Research