Safety of Urate Elevation in Parkinson's Disease (SURE-PD)

• ClinicalTrials.gov Identifier: NCT00833690
• Recruitment Status: Completed
• First Posted: February 2, 2009
• Results First Posted: June 5, 2014
• Last Update Posted: June 5, 2014
• Sponsor: The Parkinson Study Group
• Collaborators: Massachusetts General Hospital; Harvard School of Public Health (HSPH); University of Rochester; Michael J. Fox Foundation for Parkinson's Research
• Information provided by (Responsible Party): Michael Schwarzschild, The Parkinson Study Group

Tracking Information

• First Submitted Date: January 27, 2009
• First Posted Date: February 2, 2009
• Results First Submitted Date: December 26, 2013
• Results First Posted Date: June 5, 2014
• Last Update Posted Date: June 5, 2014
• Study Start Date: June 2009
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 30, 2014)

• Tolerability [ Time Frame: 6 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 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).
• Tolerability [ Time Frame: 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 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: January 29, 2009)

• Tolerability as defined as the extent to which an assigned treatment can be continued without dose reduction for more than 4 weeks due to adverse experience(s). [ Time Frame: 12 weeks and 2 years ]
• Safety as defined as absence of serious adverse experiences that collectively warrant terminating an inosine treatment dose or the trial, as determined by the Data and Safety Monitoring Committee. [ Time Frame: 12 weeks and 2 years ]

Current Secondary Outcome Measures (submitted: May 30, 2014)

• CSF Urate (All Patients) [ Time Frame: 12 weeks ]
  Urate concentration in cerebrospinal fluid (CSF)
• 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ 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. ]
  From blood sample drawn prior to enrollment
• Serum Urate [ Time Frame: Baseline Visit ]
  From blood sample drawn prior to enrollment
• Serum Urate [ Time Frame: Visit 01 (Week 2; 14 +/- 3 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 02 (Week 4; 28 +/- 3 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 03 (Week 6; 42 +/- 3 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 04 (Week 9; 63 +/- 5 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 05 (Week 12; 84 +/- 7 days after Baseline Visit) ]
  From blood sample drawn before taking study drug that day
• Serum Urate [ Time Frame: Visit 06 (Month 6; 180 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 07 (Month 9; 270 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 08 (Month 12; 360 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 09 (Month 15; 450 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 10 (Month 18; 540 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 11 (Month 21; 630 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: Visit 12 (Month 24; 720 +/- 7 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: End of Study Drug Visit (ESD) (Month 9-24; 263-727 days after Baseline Visit) ]
  From blood sample drawn after taking study drug that day
• Serum Urate [ Time Frame: 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 [ Time Frame: Visit 01 from Baseline (i.e., between -45 days and +2 weeks) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 02 from Baseline (i.e., between -45 days and +4 weeks) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 03 from Baseline (i.e., between -45 days and +6 weeks) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 04 from Baseline (i.e., between -45 days and +9 weeks) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 05 from Baseline (i.e., between -45 days and +12 weeks) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 06 from Baseline (i.e., between -45 days and +6 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 07 from Baseline (i.e., between -45 days and +9 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 08 from Baseline (i.e., between -45 days and +12 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 09 from Baseline (i.e., between -45 days and +15 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 10 from Baseline (i.e., between -45 days and +18 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 11 from Baseline (i.e., between -45 days and +21 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Visit 12 from Baseline (i.e., between -45 days and +24 months) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Safety Visit (SV) from Baseline (i.e., between -45 days and +760 days [+1 month after ESD Visit]) ]
  Change from an Average of Baseline and Screening Visits
• Change in Serum Urate [ Time Frame: Safety Visit (SV) from End of Study Drug Visit (ESD); i.e., between +263 and +760 days) ]
  Change from Last Visit on Study Drug

Original Secondary Outcome Measures (submitted: January 29, 2009)

• urate levels in serum/CSF [ Time Frame: 12 weeks and 2 years ]
• oxidative damage biomarker [ Time Frame: 6 months and 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Parkinson Disease

Intervention

• Drug: Placebo
  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
• Drug: inosine
  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
  Other Name: hypoxanthine 9-β-D-ribofuranoside
• Drug: inosine
  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
  Other Name: hypoxanthine 9-β-D-ribofuranoside

Study Arms

• Placebo Comparator: [A:]
  Placebo to produce no urate elevation
  Intervention: Drug: Placebo
• Experimental: [B:]

  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

  Intervention: Drug: inosine
• Experimental: [C.]

  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

  Intervention: Drug: inosine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 8, 2012): 75
• Original Estimated Enrollment (submitted: January 29, 2009): 90
• Actual Study Completion Date: December 2012
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00833690
• Other Study ID Numbers: INO-PD-P2-2008
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Michael Schwarzschild, The Parkinson Study Group
• Original Responsible Party: Michael A. Schwarzschild, MD, PhD, Principal Investigator, Assoc. Professor of Neurology/Harvard Medical School, Assoc. in Neurology/Massachusetts General Hospital, Director, Molecular Neurobiology Lab/Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital
• Current Study Sponsor: The Parkinson Study Group
• Original Study Sponsor: Same as current

Collaborators

• Massachusetts General Hospital
• Harvard School of Public Health (HSPH)
• University of Rochester
• Michael J. Fox Foundation for Parkinson's Research

Investigators

• Principal Investigator: Michael A Schwarzschild, MD, PhD; Massachusetts General Hospital

• PRS Account: The Parkinson Study Group
• Verification Date: May 2014