Study of Urate Elevation in Parkinson's Disease, Phase 3 (SURE-PD3)
A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to determine whether oral inosine dosed to moderately elevate serum urate (from ≤5.7 mg/dL to 7.1-8.0 mg/dL) over 2 years slows clinical decline in early PD.
Clinical decline will be assessed as change in the primary outcome variable of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a composite scale comprising patient- and clinician-reported outcomes.
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Other
|Official Title:||A Randomized, Double-blind, Placebo-controlled Trial of Urate-elevating Inosine Treatment to Slow Clinical Decline in Early Parkinson's Disease|
- Rate of clinical decline [ Time Frame: two years ]The primary outcome of the trial is rate of change in MDS-UPDRS I-III total score over 24 months estimated from a shared-baseline, random-slopes mixed model, censoring follow-up of subjects after initiation of dopaminergic therapy.
- Rate of developing adverse effects [ Time Frame: two years ]Safety also will be evaluated by comparing active vs. placebo treatment with respect to overall adverse event (AE) and serious AE (SAE) rate.
- Proportion developing adverse effects [ Time Frame: two years ]Safety of oral inosine titrated to elevate trough serum urate to 7.1 - 8.0 mg/dL will be evaluated by comparing active vs. placebo treatment with respect to proportions of subjects experiencing individual types of AE, as classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class.
- Proportion of subjects tolerant of the treatment [ Time Frame: three months; two years ]Tolerability of a treatment will be defined as a proportion of all subjects in a treatment group who are tolerant of the treatment at 12 weeks (short-term tolerability) and 24 months (long-term tolerability). A subject who is tolerant of treatment will be defined as one who remains on-study and on the assigned treatment without one or more dose reductions lasting more than 4 weeks cumulative due to AEs. A treatment will be declared tolerable if the proportion who are tolerant is significantly greater than 50% by one-tailed testing at p < 0.05.
- Time to disability warranting dopaminergic therapy [ Time Frame: two years ]Secondary efficacy outcomes will include time from baseline visit to disability warranting the initiation of dopaminergic therapy in each treatment group.
- Clinical efficacy: Rate of change in PDQ-39 [ Time Frame: two years ]Rate of change in PDQ-39 scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group.
- Clinical efficacy: Rate of change in Neuro-QOL [ Time Frame: two years ]Rate of change in Neuro-QOL scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group.
- Clinical efficacy: Rate of change in Neuro-QOL depression module [ Time Frame: two years ]Rate of change in Neuro-QOL depression module scale points (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group.
- Clinical efficacy: Rate of change in Schwab and England scale [ Time Frame: two years ]Rate of change in percentage points on the Schwab and England scale for functional disability (over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group.
- Clinical efficacy: Rate of change in Montreal Cognitive Assessment (MoCA) [ Time Frame: two years ]Rate of change in points on the MoCA scale (for cognition; over the time between baseline visit and final visit on study drug) will be assessed for subjects in each treatment group.
- Clinical efficacy: Proportion of subjects having developed disability warranting dopaminergic therapy [ Time Frame: up to 27 months ]Determinations of disability warranting initiation of dopaminergic therapy will be made every three months during period 1 (24 months on study drug) and monthly during period 2 (following study drug discontinuation, between months 24 and 27) for subjects who have not previously reached this level of disability. Analysis of measures that are equally evaluable at the end of both periods (such as proportion of subjects having developed disability warranting dopaminergic therapy), will be conducted as a three-part test: a) of significantly slower worsening during period 1, b) of non-inferior rates of worsening during period 2, and c) of a significant net benefit at the end of period 2. It could provide evidence of disease modification if all three evaluations were favorable.
- Symptomatic effects [ Time Frame: three months (after both initiation and discontinuation of study drug) ]Symptomatic effects will be estimated by changes in motor and other features (e.g., as assess by short-term change in total MDS-UPDRS score) during the first 3 months of wash-in at the start of period 1 and during the 3-month wash-out of period 2.
|Study Start Date:||June 2016|
|Estimated Study Completion Date:||August 2020|
|Estimated Primary Completion Date:||February 2020 (Final data collection date for primary outcome measure)|
Inosine will be dosed by titrating the number of capsules taken daily to achieve an elevation of serum urate to trough levels of 7.1 to 8.0 mg/dL.
capsules containing 500 mg of inosine
Other Name: hypoxanthine 9-β-D-ribofuranoside
Placebo Comparator: Placebo
Placebo will be dosed to match the capsule titrations of the inosine group.
capsules containing ~500 mg of lactose and appearing indistinguishable from inosine capsules
Other Name: inactive agent
Capsules containing 500 mg of inosine (active drug) or ~500 mg of lactose (placebo) will be taken orally up to two capsules three times per day (i.e., up to 3 g/day) for 24 months. In the inosine-treated group the number of capsules taken per day will be titrated to serum urate levels - measured at trough at study visits no more than three months apart - in order to achieve concentrations of 7.1-8.0 mg/dL. Initial dosing will be tailored to individualized factors including gender and pretreatment serum urate, and then advanced gradually toward the projected target dose. Adjustments in dosing of placebo capsules in the control arm will be algorithm-based to match dosing of inosine capsules in the active drug arm.
Following study drug discontinuation all subjects will be followed during a 3-month wash-out period by telephone calls and a final study visit. All study visits after screening will include measurement of the primary outcome variable (MDS-UPDRS) and most will include secondary outcome variables: adverse events, dose adjustments, disability warranting initiation of dopaminergic therapy, Quality of Life in Neurological Disorders (Neuro-QOL), 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab & England Activities of Daily Living (S&E ADL) scale, Montreal Cognitive Assessment (MoCA), and orthostatic vital signs.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02642393
|Contact: Sheehan F Wheeler||617-726-5714||SFWheeler@mgh.harvard.edu|
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|Study Chair:||Michael A Schwarzschild, MD, PhD||Massachusetts General Hospital (PI of Clinical Coordinating Center), PSG (Chair, SURE-PD3 Steering Committee)|
|Study Director:||Alberto Ascherio, MD, DrPH||Harvard School of Public Health, PSG (Co-Chair, SURE-PD3 Steering Committee)|
|Study Director:||David Oakes, PhD||University of Rochester (PI of Data Coordinating Center), PSG (Study Statistician/Member, SURE-PD3 Steering Committee)|
|Study Director:||Eric A Macklin, PhD||Massachusetts General Hospital, PSG (Study Statistician/Member, SURE-PD3 Steering Committee)|