Safety of Urate Elevation in Parkinson's Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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.

Official Title
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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

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: inosine
* Drug: inosine


Participation Criteria
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Eligibility Criteria
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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 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 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

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: [A:]<br>Placebo to produce no urate elevation | Drug: Placebo<br>* 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<br>|
| Experimental: [B:]<br>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 | Drug: inosine<br>* 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<br>* Other names: hypoxanthine 9-β-D-ribofuranoside;|
| Experimental: [C.]<br>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 | Drug: inosine<br>* 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<br>* Other names: hypoxanthine 9-β-D-ribofuranoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability | 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 adverse experiences (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). | 6 months | 
| Tolerability | 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). | 24 months | 
| Safety | 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSF Urate (All Patients) | Urate concentration in cerebrospinal fluid (CSF) | 12 weeks | 
| CSF Urate (Females) |  | 12 weeks | 
| CSF Urate (Males) |  | 12 weeks | 
| CSF Urate as a Proportion of Baseline Serum Urate (All Patients) | Although CSF urate was not measured at baseline, the change of CSF urate from baseline may be indirectly estimated by the ratio of CSF urate (at the 12 week visit when a lumbar puncture was performed) to the serum urate measured in the same subject at baseline. Baseline serum urate and CSF urate concentrations are directly correlated with one another (i.e., individuals with higher serum urate concentrations tend to have higher CSF urate concentrations) even though the concentration of urate in CSF is typically  10% of that in serum. The ratio of CSF urate to baseline serum urate can be expressed as the percentage of the value of urate concentration measured in serum at baseline that is measured in CSF (at week 12). | 12 weeks | 
| CSF Urate as a Proportion of Baseline Serum Urate (Females) | Although CSF urate was not measured at baseline, the change of CSF urate from baseline may be indirectly estimated by the ratio of CSF urate (at the 12 week visit when a lumbar puncture was performed) to the serum urate measured in the same subject at baseline. Baseline serum urate and CSF urate concentrations are directly correlated with one another (i.e., individuals with higher serum urate concentrations tend to have higher CSF urate concentrations) even though the concentration of urate in CSF is typically  10% of that in serum. The ratio of CSF urate to baseline serum urate can be expressed as the percentage of the value of urate concentration measured in serum at baseline that is measured in CSF (at week 12). | 12 weeks | 
| CSF Urate as a Proportion of Baseline Serum Urate (Males) | Although CSF urate was not measured at baseline, the change of CSF urate from baseline may be indirectly estimated by the ratio of CSF urate (at the 12 week visit when a lumbar puncture was performed) to the serum urate measured in the same subject at baseline. Baseline serum urate and CSF urate concentrations are directly correlated with one another (i.e., individuals with higher serum urate concentrations tend to have higher CSF urate concentrations) even though the concentration of urate in CSF is typically  10% of that in serum. The ratio of CSF urate to baseline serum urate can be expressed as the percentage of the value of urate concentration measured in serum at baseline that is measured in CSF (at week 12). | 12 weeks | 
| Serum Urate | From blood sample drawn prior to enrollment | Screening Visits, up to 45 days prior to Baseline Visit. Specifically, Screening Visit 1 occurred between day -45 and -4; Screening Visit 2 occurred between day -43 and -2. | 
| Serum Urate | From blood sample drawn prior to enrollment | Baseline Visit | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 01 (Week 2; 14 +/- 3 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 02 (Week 4; 28 +/- 3 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 03 (Week 6; 42 +/- 3 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 04 (Week 9; 63 +/- 5 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn before taking study drug that day | Visit 05 (Week 12; 84 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 06 (Month 6; 180 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 07 (Month 9; 270 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 08 (Month 12; 360 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 09 (Month 15; 450 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 10 (Month 18; 540 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 11 (Month 21; 630 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | Visit 12 (Month 24; 720 +/- 7 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn after taking study drug that day | End of Study Drug Visit (ESD) (Month 9-24; 263-727 days after Baseline Visit) | 
| Serum Urate | From blood sample drawn a month after stopping study drug | Safety Visit (SV); 30 +/- 3 days following ESD or Month 24 Visit | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 01 from Baseline (i.e., between -45 days and +2 weeks) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 02 from Baseline (i.e., between -45 days and +4 weeks) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 03 from Baseline (i.e., between -45 days and +6 weeks) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 04 from Baseline (i.e., between -45 days and +9 weeks) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 05 from Baseline (i.e., between -45 days and +12 weeks) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 06 from Baseline (i.e., between -45 days and +6 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 07 from Baseline (i.e., between -45 days and +9 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 08 from Baseline (i.e., between -45 days and +12 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 09 from Baseline (i.e., between -45 days and +15 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 10 from Baseline (i.e., between -45 days and +18 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 11 from Baseline (i.e., between -45 days and +21 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Visit 12 from Baseline (i.e., between -45 days and +24 months) | 
| Change in Serum Urate | Change from an Average of Baseline and Screening Visits | Safety Visit (SV) from Baseline (i.e., between -45 days and +760 days [+1 month after ESD Visit]) | 
| Change in Serum Urate | Change from Last Visit on Study Drug | Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Parkinson disease, PD, inosine, urate, uric acid, cerebrospinal fluid