Safety of Urate Elevation in Parkinson's Disease
- Registration Number
- NCT00833690
- Lead Sponsor
- The Parkinson Study Group
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 75
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description [A:] Placebo Placebo to produce no urate elevation [C.] inosine 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 [B:] inosine 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
- Primary Outcome Measures
Name Time Method Tolerability 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 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.
- Secondary Outcome Measures
Name Time Method CSF Urate (All Patients) 12 weeks Urate concentration in cerebrospinal fluid (CSF)
CSF Urate (Females) 12 weeks CSF Urate (Males) 12 weeks CSF Urate as a Proportion of Baseline Serum Urate (All Patients) 12 weeks 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).
CSF Urate as a Proportion of Baseline Serum Urate (Females) 12 weeks 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).
CSF Urate as a Proportion of Baseline Serum Urate (Males) 12 weeks 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).
Serum Urate Safety Visit (SV); 30 +/- 3 days following ESD or Month 24 Visit From blood sample drawn a month after stopping study drug
Change in Serum Urate Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days) Change from Last Visit on Study Drug
Trial Locations
- Locations (16)
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
University of Southern California
🇺🇸Los Angeles, California, United States
Eastern Connecticut Neurology Specialists, LLC
🇺🇸Manchester, Connecticut, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Parkinson's Disease and Movement Disorders Center of Boca Raton
🇺🇸Boca Raton, Florida, United States
Duke University School of Medicine
🇺🇸Durham, North Carolina, United States
Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Struthers Parkinson's Center
🇺🇸Golden Valley, Minnesota, United States
Butler Hospital Movement Disorder Program
🇺🇸Providence, Rhode Island, United States
Scott & White Hospital
🇺🇸Temple, Texas, United States
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Michigan State University
🇺🇸East Lansing, Michigan, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Institute for Neurodegenerative Disorders
🇺🇸New Haven, Connecticut, United States