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 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
75
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
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
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
University of Southern California
Los Angeles, California, United States
Eastern Connecticut Neurology Specialists, LLC
Manchester, Connecticut, United States
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).
Time frame: 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).
Time frame: 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.
Time frame: 24 months
CSF Urate (All Patients)
Urate concentration in cerebrospinal fluid (CSF)
Time frame: 12 weeks
CSF Urate (Females)
Time frame: 12 weeks
CSF Urate (Males)
Time frame: 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).
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Institute for Neurodegenerative Disorders
New Haven, Connecticut, United States
Parkinson's Disease and Movement Disorders Center of Boca Raton
Boca Raton, Florida, United States
Rush University Medical Center
Chicago, Illinois, United States
Ochsner Clinic Foundation
New Orleans, Louisiana, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Boston University Medical Center
Boston, Massachusetts, United States
Michigan State University
East Lansing, Michigan, United States
Struthers Parkinson's Center
Golden Valley, Minnesota, United States
...and 6 more locations
Time frame: 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).
Time frame: 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).
Time frame: 12 weeks
Serum Urate
From blood sample drawn prior to enrollment
Time frame: 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
Time frame: Baseline Visit
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 01 (Week 2; 14 +/- 3 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 02 (Week 4; 28 +/- 3 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 03 (Week 6; 42 +/- 3 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 04 (Week 9; 63 +/- 5 days after Baseline Visit)
Serum Urate
From blood sample drawn before taking study drug that day
Time frame: Visit 05 (Week 12; 84 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 06 (Month 6; 180 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 07 (Month 9; 270 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 08 (Month 12; 360 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 09 (Month 15; 450 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 10 (Month 18; 540 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 11 (Month 21; 630 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: Visit 12 (Month 24; 720 +/- 7 days after Baseline Visit)
Serum Urate
From blood sample drawn after taking study drug that day
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days)