Clinical trial NCT00833690: Safety of Urate Elevation in Parkinson's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Parkinson Disease
Keywords: Parkinson's disease
Parkinson disease
PD
inosine
urate
uric acid
cerebrospinal fluid
Lead sponsor: The Parkinson Study Group
Sponsor class: NETWORK
Collaborators: name: Massachusetts General Hospital
name: Harvard School of Public Health (HSPH)
name: University of Rochester
name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2009-02-02
Enrollment: 75
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Tolerability
timeFrame: 6 months
measure: Tolerability
timeFrame: 24 months
measure: Safety
timeFrame: 24 months
Secondary outcomes:
measure: CSF Urate (All Patients)
timeFrame: 12 weeks
measure: CSF Urate (Females)
timeFrame: 12 weeks
measure: CSF Urate (Males)
timeFrame: 12 weeks
measure: CSF Urate as a Proportion of Baseline Serum Urate (All Patients)
timeFrame: 12 weeks
measure: CSF Urate as a Proportion of Baseline Serum Urate (Females)
timeFrame: 12 weeks
measure: CSF Urate as a Proportion of Baseline Serum Urate (Males)
timeFrame: 12 weeks
measure: Serum Urate
timeFrame: 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.
measure: Serum Urate
timeFrame: Baseline Visit
measure: Serum Urate
timeFrame: Visit 01 (Week 2; 14 +/- 3 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 02 (Week 4; 28 +/- 3 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 03 (Week 6; 42 +/- 3 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 04 (Week 9; 63 +/- 5 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 05 (Week 12; 84 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 06 (Month 6; 180 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 07 (Month 9; 270 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 08 (Month 12; 360 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 09 (Month 15; 450 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 10 (Month 18; 540 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 11 (Month 21; 630 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: Visit 12 (Month 24; 720 +/- 7 days after Baseline Visit)
measure: Serum Urate
timeFrame: End of Study Drug Visit (ESD) (Month 9-24; 263-727 days after Baseline Visit)
measure: Serum Urate
timeFrame: Safety Visit (SV); 30 +/- 3 days following ESD or Month 24 Visit
measure: Change in Serum Urate
timeFrame: Visit 01 from Baseline (i.e., between -45 days and +2 weeks)
measure: Change in Serum Urate
timeFrame: Visit 02 from Baseline (i.e., between -45 days and +4 weeks)
measure: Change in Serum Urate
timeFrame: Visit 03 from Baseline (i.e., between -45 days and +6 weeks)
measure: Change in Serum Urate
timeFrame: Visit 04 from Baseline (i.e., between -45 days and +9 weeks)
measure: Change in Serum Urate
timeFrame: Visit 05 from Baseline (i.e., between -45 days and +12 weeks)
measure: Change in Serum Urate
timeFrame: Visit 06 from Baseline (i.e., between -45 days and +6 months)
measure: Change in Serum Urate
timeFrame: Visit 07 from Baseline (i.e., between -45 days and +9 months)
measure: Change in Serum Urate
timeFrame: Visit 08 from Baseline (i.e., between -45 days and +12 months)
measure: Change in Serum Urate
timeFrame: Visit 09 from Baseline (i.e., between -45 days and +15 months)
measure: Change in Serum Urate
timeFrame: Visit 10 from Baseline (i.e., between -45 days and +18 months)
measure: Change in Serum Urate
timeFrame: Visit 11 from Baseline (i.e., between -45 days and +21 months)
measure: Change in Serum Urate
timeFrame: Visit 12 from Baseline (i.e., between -45 days and +24 months)
measure: Change in Serum Urate
timeFrame: Safety Visit (SV) from Baseline (i.e., between -45 days and +760 days [+1 month after ESD Visit])
measure: Change in Serum Urate
timeFrame: Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Manchester
country: United States
facility: Eastern Connecticut Neurology Specialists, LLC
state: Connecticut
city: New Haven
country: United States
facility: Institute for Neurodegenerative Disorders
state: Connecticut
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: East Lansing
country: United States
facility: Michigan State University
state: Michigan
city: Golden Valley
country: United States
facility: Struthers Parkinson's Center
state: Minnesota
city: Durham
country: United States
facility: Duke University School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Providence
country: United States
facility: Butler Hospital Movement Disorder Program
state: Rhode Island
city: Temple
country: United States
facility: Scott & White Hospital
state: Texas
Study officials:
affiliation: Massachusetts General Hospital
name: Michael A Schwarzschild, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schwarzschild MA, Macklin EA, Bakshi R, Battacharyya S, Logan R, Espay AJ, Hung AY, Bwala G, Goetz CG, Russell DS, Goudreau JL, Parashos SA, Saint-Hilaire MH, Rudolph A, Hare JM, Curhan GC, Ascherio A; Parkinson Study Group SURE-PD Investigators. Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial. Neurology. 2019 Oct 1;93(14):e1328-e1338. doi: 10.1212/WNL.0000000000008194. Epub 2019 Sep 4.
citation: Parkinson Study Group SURE-PD Investigators; Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528.