Study of Urate Elevation in Parkinson's Disease, Phase 3
- Registration Number
- NCT02642393
- Lead Sponsor
- Michael Alan Schwarzschild
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 298
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo will be dosed to match the capsule titrations of the inosine group. Inosine Inosine 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.
- Primary Outcome Measures
Name Time Method Rate of Clinical Decline two years The primary outcome of the trial is rate of change in the Movement Disorders Society Unified PD Rating Scale (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. Parts I-III of the MDS-UPDRS include ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse symptoms. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores for Parts I-III are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms.
- Secondary Outcome Measures
Name Time Method Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) two years Rate of change in Quality of Life in Neurological Disorders (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. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. It comprises 17 domains of HRQL covering physical, psychological and social health. Domains tested include anxiety, cognitive function, communication, depression, emotional and behavioral dyscontrol, fatigue, lower extremity function- mobility, positive affect and well- being, stigma, upper extremity function- fine motor and ADL, sleep disturbance, satisfaction with social roles and activities, and ability to participate in social roles and activities. Higher raw scores are associated with more of the concept being measured. All scales range from 8 to 40 except for Positive Affect and Well-Being which ranges from 9 to 45.
Rate of Developing Adverse Effects 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.
Percentage of Participants Developing Disability Warranting Dopaminergic Therapy Over Time two years The percentage of participants with disability warranting the initiation of dopaminergic therapy in each treatment group at time from baseline visit (in 180 day increments).
Symptomatic Effects 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 assessed by short-term change in Movement Disorders Society Unified PD Rating Scale \[MDS-UPDRS\] I-III total 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. The MDS-UPDRS includes ratings of non-motor experiences of daily living, motor experiences of daily living, and a motor examination. The MDS-UPDRS is assessed on a 5-point Likert scale ranging from 0 to 4 where higher scores imply worse features. Parts I-III contain 59 total questions (13 in Part I, 13 in Part II, and 33 in Part III). Total scores are calculated as simple sums of component items with mean imputation by Part if no more than 1, 2, or 7 items are missing for Parts I through III, respectively. Total scores may range from 0 to 236, with 0 meaning no symptoms and 236 meaning worse symptoms.
Percentage Developing Adverse Effects 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 the percentage of subjects experiencing individual types of AE, as classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and system organ class.
Clinical Efficacy: Rate of Change in Parkinson's Disease Questionnaire - 39 Item Version (PDQ-39) Scale two years Rate of change in Parkinson's Disease Questionnaire - 39 item version (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. The PDQ-39 asks 39 questions organized over eight domains (scales): mobility (10 items), activities of daily living (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognition (4 items), communication (3 items), and bodily discomfort (3 items). Each item has five possible ordinal responses, from never to always, depending on frequency of the symptom over the preceding month. The eight scales' scores are generated by Likert's method of summated ratings and then transformed to a single figure that ranges from 0 to 100. Higher scores are associated with more symptoms.
Clinical Efficacy: Rate of Change in Quality of Life in Neurological Disorders (Neuro-QOL) Depression Module two years Rate of change in Quality of Life in Neurological Disorders (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. Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life (HRQoL) of people with neurological disorders. Higher raw scores are associated with more of the concept being measured. The depression module score ranges from 8 to 40.
Clinical Efficacy: Rate of Change in Montreal Cognitive Assessment (MoCA) two years Rate of change in points on the Montreal Cognitive Assessment (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. The MoCA assesses attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Points are awarded for the correct completion of MoCA tasks. Scores for each task are summed for a total score (range 0-30). Higher scores indicate greater cognitive capacity.
Percentage of Subjects Tolerant of the Treatment three months; two years Tolerability of a treatment will be defined as a percentage 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 percentage who are tolerant is significantly greater than 50% by one-tailed testing at p \< 0.05.
Clinical Efficacy: Rate of Change in Schwab and England Scale 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. The Schwab and England scale is a Site Investigator and subject assessment of the subject's level of independence. The subject will be scored on a percentage scale reflective of his/her ability to perform acts of daily living. Printed scores with associated descriptors range from 0% to 100% in increments of 5%, with higher percentages associated with more independence. A score of 0% implies "vegetative functions such as swallowing, bladder and bowel functions are not functioning; bedridden". A score of 100% implies "subject has full ability and is completely independent; essentially normal".
Trial Locations
- Locations (62)
University of Southern California
🇺🇸Los Angeles, California, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Neurosciences Institute at Central DuPage Hospital
🇺🇸Winfield, Illinois, United States
Rocky Mountain Movement Disorder Center
🇺🇸Englewood, Colorado, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
University of Maryland, Baltimore
🇺🇸Baltimore, Maryland, United States
Banner Sun Health Research Institute
🇺🇸Sun City, Arizona, United States
SUNY Downstate Medical Center
🇺🇸Brooklyn, New York, United States
Baylor Scott & White Health
🇺🇸Temple, Texas, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Michigan State University
🇺🇸East Lansing, Michigan, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Henry Ford Health System
🇺🇸West Bloomfield, Michigan, United States
Butler Hospital
🇺🇸Providence, Rhode Island, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Sentara Neurology Specialists
🇺🇸Virginia Beach, Virginia, United States
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Texas Houston Medical School
🇺🇸Houston, Texas, United States
Mayo Clinic Arizona
🇺🇸Scottsdale, Arizona, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of California Davis
🇺🇸Sacramento, California, United States
Weill Cornell Medical Center
🇺🇸New York, New York, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
University of Tennessee Health Science Center
🇺🇸Memphis, Tennessee, United States
Wesley Neurology Clinic, PC
🇺🇸Cordova, Tennessee, United States
VCU Parkinson's & Movement Disorder Center (McGuire Veterans Hospital)
🇺🇸Richmond, Virginia, United States
Inland Northwest Research
🇺🇸Spokane, Washington, United States
Northwest Neurological PLLC
🇺🇸Spokane, Washington, United States
University of California San Diego
🇺🇸La Jolla, California, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Hartford HealthCare Movement Disorders Center
🇺🇸Vernon, Connecticut, United States
The University of Vermont
🇺🇸Burlington, Vermont, United States
Albany Medical College
🇺🇸Albany, New York, United States
Cleveland Clinic Lou Ruvo Center for Brain Health
🇺🇸Las Vegas, Nevada, United States
University of Puerto Rico
🇵🇷San Juan, Puerto Rico
Overlook Medical Center, Atlantic Neuroscience Institute
🇺🇸Summit, New Jersey, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
University of South Florida
🇺🇸Tampa, Florida, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Duke University
🇺🇸Durham, North Carolina, United States
University of Cincinnati/Cincinnati Children's Hospital
🇺🇸Cincinnati, Ohio, United States
Oregon Health & Sciences University
🇺🇸Portland, Oregon, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
University of Louisville
🇺🇸Louisville, Kentucky, United States
Oschner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States