Safety of Urate Elevation in Parkinson's Disease

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.

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