Clinical trial NCT02642393
Conditions: Parkinson's Disease
Keywords: SURE-PD3 Parkinson's disease PD Inosine Urate Parkinson Study Group (PSG)
Sponsor: Michael Alan Schwarzschild
Start date: 2016-06-01; Completion date: 2019-06-01
Enrollment: 298 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: Placebo will be dosed to match the capsule titrations of the inosine group.
Interventions: intervention 1: Inosine intervention 2: Placebo
Intervention descriptions: intervention 1: capsules containing 500 mg of inosine intervention 2: capsules containing \~500 mg of lactose and appearing indistinguishable from inosine capsules

Protocol documents:
Prot_001.pdf: 
Confidential 
The information contained herein is confidential and proprietary in nature, and will not be disclosed to any third 
party without written approval of authorized designee.  This document may be disclosed to the appropriate 
institutional review boards or to duly authorized representatives of the US Food and Drug Administration or a 
national regulatory authority under the condition that they maintain confidentiality. 
 
 
A randomized, double-blind, placebo-controlled trial of urate-elevating inosine treatment to slow 
clinical decline in early Parkinson’s disease 
 
 
 
Study Chair 
Michael A. Schwarzschild, MD PhD 
Chair, Parkinson Study Group Executive Committee 
Neurologist, Massachusetts General Hospital 
 
 
Study Co-Chair 
Alberto Ascherio, MD DrPH 
Professor of Epidemiology and Nutrition 
Neuroepidemiologist, Harvard School of Public Health 
 
 
Data Coordinating Center (DCC) Director and Biostatistician 
David Oakes, PhD 
Professor of Biostatistics 
Department of Biostatistics, University of Rochester 
 
 
Clinical Coordinating Center (CCC) Biostatistician 
Eric A. Macklin, PhD 
Statistician, Parkinson Study Group Executive Committee 
MGH Biostatistics Center, Massachusetts General Hospital 
 
 
Supported by 
The National Institute of Neurological Disorders and Stroke (NINDS) 
 
 
Sponsor (Sponsor-Investigator) 
Michael A. Schwarzschild 
IND # 100,896 
 
 
Version 
4.0 
 
 
Date 
November 28 2017 
 
NCT02642393


 
 
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SITE INVESTIGATOR AGREEMENT 
 
Protocol #: INO-PD-P3-2014 
Version 4.0 
28 November 2017 
 
IND # 100896 
 
Title: A randomized, double-blind, placebo-controlled trial of urate-elevating inosine treatment to 
slow clinical decline in early Parkinson’s disease 
 
 
I have carefully read this protocol including all appendices and agree that it contains all the 
necessary information for conducting the study safely.  
 
I will conduct this study in strict accordance with this protocol and according to the current Good 
Clinical Practice (GCP) regulations and guidelines and local and national regulatory 
requirements. Any changes in procedure will only be made if necessary to eliminate immediate 
hazards or to protect the safety, rights or welfare of subjects.  
 
I will provide copies of the protocol and all other information relating to the pre-clinical and prior 
clinical experience, which were furnished to me, to all physicians and other study personnel 
responsible to me who participate in this study. I will discuss this information with them to assure 
that they are adequately informed regarding the study drug and conduct of the study.  
 
I will ensure that the drugs supplied to me for this study will be used only for administration to 
subjects enrolled in this study protocol and for no other purpose.  
 
I agree to keep records on all subject and study information (case report forms, informed consent 
statements, drug shipment, drug return forms, and all other information collected during the 
study) in accordance with the current GCP, local and national regulations.  
 
 
 
PSG Site Number:    ___________ 
 
 
Print Site Name:   ___________________________________________________ 
 
 
 
Print Site Investigator Name: ____________________________________________ 
 
 
Site Investigator Signature:   _____________________________ Date: __________ 
 
 
 


 
 
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TABLE OF CONTENTS 
SITE INVESTIGATOR AGREEMENT ................................................................................................................... 2 
ABBREVIATIONS ...................................................................................................................................................... 7 
1. 
STUDY OBJECTIVES .................................................................................................................................... 12 
1.1 
PRIMARY OBJECTIVE ..................................................................................................................................... 12 
1.2 
SECONDARY OBJECTIVES ............................................................................................................................... 12 
2. 
BACKGROUND .............................................................................................................................................. 12 
2.1 
RATIONALE .................................................................................................................................................... 12 
2.1.1 Rationale for Elevating Urate in Parkinson’s Disease ............................................................................. 12 
2.1.2 Rationale for Selecting Inosine as a Means to Elevate Urate ................................................................... 16 
2.2 
SUPPORTING DATA ........................................................................................................................................ 17 
2.2.1 Human Nutritional and Clinical Experience with Inosine ........................................................................ 17 
2.2.2 Human Experience with Elevated Urate ................................................................................................... 20 
2.2.3  Experience with Inosine to Elevate Urate in PD (Phase 2 Development) ............................................... 25 
3. 
STUDY DESIGN .............................................................................................................................................. 32 
3.1 
OVERALL STUDY DESIGN AND PLAN ............................................................................................................. 32 
 ..................................................................................................................................................................................... 32 
FIGURE 10. DIAGRAM AND TIMELINE OF TREATMENT ............................................................................................. 32 
3.2 
RATIONALE FOR KEY/NOVEL DESIGN FEATURES .......................................................................................... 33 
3.2.1 
Target Population – Four Defining Features ................................................................................. 33 
3.2.1.1   Early PD ............................................................................................................................................................. 33 
3.2.1.2   Lower Serum Urate ........................................................................................................................................... 34 
3.2.1.3   Safety Exclusions ............................................................................................................................................... 34 
3.2.1.4   Enrichment for PD by Neuroimaging ................................................................................................................. 34 
3.2.2 
Inosine Dosing Selection ................................................................................................................. 36 
3.2.3 
Primary Outcome and Analysis ...................................................................................................... 37 
3.2.4 
Additional Key Safety Features ....................................................................................................... 39 
3.2.4.1   Pre-Study Determinations of Food and Drug Interaction .................................................................................. 39 
3.2.4.2   Modification of Uric Acid Stone Risk Factor Management Plan ........................................................................ 39 
3.2.4.3   Reducing Risk of Possible Cardiovascular Adverse Effects ................................................................................ 40 
3.3 
STUDY DURATION AND PERIODS .................................................................................................................... 40 
4   SELECTION AND ENROLLMENT OF SUBJECTS ...................................................................................... 41 
4.1 
INCLUSION CRITERIA ..................................................................................................................................... 41 
4.2 
EXCLUSION CRITERIA .................................................................................................................................... 42 
4.3 
TREATMENT ASSIGNMENT PROCEDURES ....................................................................................................... 43 
4.3.1  Identification, Recruitment and Retention of Candidates ........................................................................ 43 
4.3.2 Monitoring and Adaptation of Recruitment & Retention .......................................................................... 47 
4.3.3  Consent Procedures ................................................................................................................................. 47 
4.3.4 Identification Number and Intervention Group Assignment Procedure .................................................... 48 
5. 
STUDY INTERVENTIONS ............................................................................................................................ 48 
5.1 
STUDY INTERVENTIONS, ADMINISTRATION AND DURATION .......................................................................... 48 
5.1.1  Intervention (study drug) .......................................................................................................................... 48 
5.1.2  Administration and dosing of study drug ................................................................................................. 49 
5.1.2.1  Initiation of Dosing at Baseline Visit ................................................................................................................... 49 
5.1.2.2  Initial Dosing Following Baseline Visit ................................................................................................................ 49 
5.1.2.3  Study Drug Dosage Titration Algorithms ............................................................................................................ 51 
5.1.2.4 Missed Doses .......................................................................................................................................... 52 


 
 
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5.1.2.5  Dose Reductions/Suspensions ............................................................................................................... 52 
5.1.2.6 Dose Re-challenge and Resumption ....................................................................................................... 53 
5.1.2.7 Question of Need for Downward Titration ............................................................................................. 53 
5.1.3  Potential Adverse Effects (AEs) of Study Drug ........................................................................................ 54 
5.1.3.1 Potential AEs of Active Drug (Inosine) ................................................................................................................. 54 
5.1.3.2 Potential AEs of Placebo (Lactose) ...................................................................................................................... 54 
5.2 
HANDLING OF STUDY MEDICATIONS ............................................................................................................. 54 
5.3 
CONCOMITANT MEDICATIONS ....................................................................................................................... 55 
5.3.1 
Required Therapy ............................................................................................................................ 55 
5.3.2 
Prohibited Medications ................................................................................................................... 55 
5.3.2.1   Disallowed Medications Prior to Study Entry .................................................................................................... 55 
5.3.2.2   Disallowed Medications during the Study ......................................................................................................... 55 
5.3.3 
Allowed Concomitant Medications ................................................................................................. 56 
5.3.3.1  Initiation of Antiparkinsonian Medication ......................................................................................................... 56 
5.3.3.2   Initiation of Thiazide Therapy during the Study ................................................................................................ 56 
5.4 
ADHERENCE ASSESSMENTS ........................................................................................................................... 56 
6.1 
SAFETY ASSESSMENTS ................................................................................................................................... 57 
6.1.1 
Clinical Variables ........................................................................................................................... 57 
6.1.2 
Vital Signs, their Orthostatic Changes, Weight and Height ............................................................ 57 
6.1.3 
Clinical Laboratory Assessments .................................................................................................... 57 
6.1.4 
12-Lead Electrocardiogram (ECG) ................................................................................................ 58 
6.1.5 
Physical Examination ..................................................................................................................... 58 
6.1.6 
Neurological Examination .............................................................................................................. 58 
6.1.7 
Adverse Events ................................................................................................................................ 58 
6.2 
OTHER ASSESSMENTS .................................................................................................................................... 58 
6.2.1   Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) ................................................. 58 
6.2.2 
Modified Schwab & England Activities of Daily Living Scale ........................................................ 59 
6.2.3 
Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) scale .......................................... 59 
6.2.4 
Modified Hoehn and Yahr Scale ..................................................................................................... 59 
6.2.5 
Assess Need for Dopaminergic Therapy ......................................................................................... 59 
6.2.6 
Mini-Mental State Examination (MMSE) ....................................................................................... 60 
6.2.7 
Montreal Cognitive Assessment (MoCA) ........................................................................................ 60 
6.2.8 
Quality of Life in Neurological Disorders (Neuro-QOL)................................................................ 60 
6.2.9 
Diagnostic Features Assessment ..................................................................................................... 60 
6.2.10 
Primary Diagnosis Assessment ....................................................................................................... 60 
6.2.11 
Dopamine Transporter (DAT) Neuroimaging ................................................................................. 61 
6.2.11.1      Required Dopamine Transporter (DAT) Neuroimaging for Eligibility Determination .............. 61 
6.2.11.2      Optional Follow-up DAT Neuroimaging .................................................................................... 61 
6.2.12 
Blindedness Evaluation ................................................................................................................... 61 
6.2.13 
Exploratory Assessments ................................................................................................................. 62 
6.2.14 
Optional Blood Collection for Biomarker Research ....................................................................... 62 
6.2.15 
Optional Smartphone Outcomes Research Participation ............................................................... 62 
7. 
STUDY SCHEDULE ....................................................................................................................................... 64 
7.1 
PRE-RANDOMIZATION EVALUATIONS ............................................................................................................ 64 
7.1.1 
Screening Visit One (Visit SC1) ...................................................................................................... 64 
7.1.2 
Post SC1 Telephone Call ................................................................................................................ 65 
7.1.3 
Screening Visit Two (SC2) .............................................................................................................. 65 
7.1.4 
Post SC2 Telephone Call ................................................................................................................ 66 
7.1.5 
DAT scan (DS1) .............................................................................................................................. 66 
7.1.6 
Post DS1 Telephone Call between DS1 .......................................................................................... 66 
7.1.7 
Baseline Visit Telephone Call Immediately Prior to Baseline ........................................................ 66 
7.1.8 
Baseline Visit (Visit BL) .................................................................................................................. 66 
7.2 
ON-INTERVENTION EVALUATIONS ................................................................................................................. 68 


 
 
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7.2.1 
Visit 01 (Week 3) ............................................................................................................................. 68 
7.2.2 
Post Study Visit Telephone Calls .................................................................................................... 68 
7.2.3 
Visit 02 (Week 6) ............................................................................................................................. 68 
7.2.4 
Visit 03 (Week 12) ........................................................................................................................... 69 
7.2.5 
Visit 04 (Month 6) ........................................................................................................................... 70 
7.2.6 
Visit 05 (Month 9) ........................................................................................................................... 70 
7.2.7 
Pre-V06 Telephone Call .................................................................................................................. 71 
7.2.8 
Visit 06 (Month 12) ......................................................................................................................... 71 
7.2.9 
Visit 07 (Month 15) ......................................................................................................................... 72 
7.2.10 
Visit 08 (Month 18) ......................................................................................................................... 72 
7.2.11 
Visit 09 (Month 21) ......................................................................................................................... 73 
7.2.12 
Visit 10 (Month 24) ......................................................................................................................... 73 
7.3 
ON STUDY/OFF-INTERVENTION EVALUATIONS ............................................................................................. 74 
7.3.1 
Optional DAT scan (DS2; Month 25-26) ........................................................................................ 74 
7.3.2 
Telephone Evaluation 1 (TE1; Month 25) ....................................................................................... 74 
7.3.3 
Telephone Evaluation 2 (TE2; Month 26) ....................................................................................... 74 
7.4 
FINAL ON-STUDY EVALUATIONS ................................................................................................................... 75 
7.4.1 
Safety Visit (SV; Month 27) ............................................................................................................. 75 
7.5 
ON-STUDY/NON-STANDARD EVALUATIONS .................................................................................................. 75 
7.5.1 
Unscheduled Visit (Visit U01, U02, etc.) ........................................................................................ 75 
7.5.2 
Discontinuation of In-Person Follow-Up Visit (Visit DF) .............................................................. 76 
7.5.3 
Telephone Visits after Permanent Discontinuation of In-Person Follow-Up ................................. 77 
7.6 
PREMATURE STUDY WITHDRAWAL ............................................................................................................... 77 
7.7 
SCHEDULE OF ACTIVITIES .............................................................................................................................. 78 
8.    MANAGEMENT OF ADVERSE EXPERIENCE ........................................................................................... 79 
8.1 
ADVERSE EVENT / EXPERIENCE (AE) DEFINITION ......................................................................................... 79 
8.2 SERIOUS ADVERSE EVENTS / EXPERIENCES (SAES) .......................................................................................... 79 
8.3 RECORDING OF ADVERSE EVENTS / EXPERIENCES ............................................................................................. 80 
For each adverse event or experience, the relationship to the study drug must be recorded on the AE Log as 
one of the defined in Table 6. ............................................................................................................................. 81 
8.3.2 Adverse Event/Experience Severity Definitions ........................................................................................ 81 
8.4 KNOWN ADVERSE EVENT / EXPERIENCE PROPHYLAXIS PLAN ........................................................................... 82 
8.4.1 Monitoring of Urine pH and Uric Acid Crystalluria ................................................................................ 82 
8.4.2 Algorithm for Triggering Urine Alkalinization Method ............................................................................ 82 
8.4.3 Hyperkalemia and Other Laboratory Abnormalities ................................................................................ 85 
8.4.3.1 
Hyperkalemia ............................................................................................................................................. 85 
8.4.3.2 
Rise in Serum Creatinine or Fall in Hematocrit or Hemoglobin ................................................................. 85 
8.5 KNOWN ADVERSE EVENT / EXPERIENCE MANAGEMENT PLAN ......................................................................... 85 
8.5.1 Urolithiasis................................................................................................................................................ 85 
8.5.2 Acute Gouty Arthritis ................................................................................................................................ 86 
8.6 RESPONSIBILITIES OF THE SITE INVESTIGATOR FOR REPORTING SAES .............................................................. 86 
8.7 FOLLOW-UP OF UNRESOLVED AES AND SAES .................................................................................................. 87 
8.8 EMERGENCY ACTIONS ....................................................................................................................................... 87 
8.9 ANALYSIS OF ADVERSE EVENTS / EXPERIENCES................................................................................................ 89 
9.   CRITERIA FOR DRUG DISCONTINUATION AND SUBJECT WITHDRAWAL ................................... 89 
10.   STATISTICAL CONSIDERATIONS ............................................................................................................. 90 
10.1   GENERAL DESIGN ISSUES ............................................................................................................................... 90 
10.1.1   Trial Design .......................................................................................................................................... 90 
10.1.2   Primary Outcome .................................................................................................................................. 90 
10.1.3   Analysis Samples ................................................................................................................................... 91 
10.1.4   Interim Analysis .................................................................................................................................... 91 


 
 
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10.2   OUTCOMES ..................................................................................................................................................... 92 
10.2.1   Primary Outcome .................................................................................................................................. 92 
10.2.2   Secondary Outcomes ............................................................................................................................. 92 
10.2.2.1 
   Safety ...................................................................................................................................................... 92 
10.2.2.2 
   Tolerability .............................................................................................................................................. 92 
10.2.2.3 
   Symptomatic effect ................................................................................................................................. 92 
10.2.2.4 
   Efficacy outcomes ................................................................................................................................... 92 
10.2.2.5 
   Two-period evaluations ........................................................................................................................... 92 
10.3   SAMPLE SIZE AND ACCRUAL .......................................................................................................................... 93 
10.3.1   Effect Size .............................................................................................................................................. 93 
10.3.2   Sample Size ........................................................................................................................................... 94 
10.3.3   Secondary Outcomes ............................................................................................................................. 95 
10.4   DATA MONITORING........................................................................................................................................ 95 
10.4.1   Data and Safety Monitoring Board ....................................................................................................... 95 
10.4.2   Feasibility .............................................................................................................................................. 96 
10.4.3   Safety ..................................................................................................................................................... 96 
10.4.4   Blinded Sample Size Re-Estimation ...................................................................................................... 96 
10.4.5   Efficacy or Futility ................................................................................................................................ 96 
10.5    DATA ANALYSES ........................................................................................................................................... 97 
10.5.1   Primary Analysis ................................................................................................................................... 97 
10.5.2   Alternative Analyses .............................................................................................................................. 97 
10.5.3   Subgroup Analyses ................................................................................................................................ 98 
10.5.4   Disability Warranting Dopaminergic Therapy ..................................................................................... 98 
10.5.5   Combined Function and Treatment ....................................................................................................... 98 
10.5.6   Secondary Efficacy Outcomes ............................................................................................................... 98 
10.5.7   Safety and Tolerability Outcomes ......................................................................................................... 99 
10.5.8   Symptomatic Effects .............................................................................................................................. 99 
10.5.9   Disease Modification ............................................................................................................................ 99 
10.5.10   Smart4SURE Substudy ........................................................................................................................ 99 
10.5.11   Serial DAT Scan Substudy................................................................................................................. 100 
11. DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE       REPORTING ...... 101 
11.1   RECORDS TO BE KEPT .................................................................................................................................. 101 
11.1.1  
Study File and Site Documents ..................................................................................................... 101 
11.1.2  
Maintenance and Retention of Records ........................................................................................ 101 
11.2   ROLE OF DATA MANAGEMENT AND STUDY MONITORING ........................................................................... 102 
11.2.1  Central Data Management ................................................................................................................... 102 
11.2.2 
Site Investigator Responsibilities .................................................................................................. 103 
11.2.3 
Case Report Forms ....................................................................................................................... 103 
11.2.4 Electronic Signatures ............................................................................................................................ 103 
11.2.5 Primary Source Documents .................................................................................................................. 104 
11.2.6 CRF Worksheets .................................................................................................................................... 104 
11.2.7 
Study Monitoring .......................................................................................................................... 104 
11.2.8 Monitoring Visits ................................................................................................................................... 105 
11.2.9 Closeout Visit ........................................................................................................................................ 105 
11.2.10    Study Committees ............................................................................................................................. 105 
11.2.10.1    Steering Committee ................................................................................................................................... 105 
11.2.10.2    Data and Safety Monitoring Board ............................................................................................................. 105 
11.3 QUALITY ASSURANCE .................................................................................................................................. 105 
11.3.1  
QA Audits/Site Visits ..................................................................................................................... 105 
11.3.2  Regulatory Inspections ......................................................................................................................... 106 
12.       HUMAN SUBJECTS ................................................................................................................................... 106 
12.1 COMPLIANCE STATEMENT ........................................................................................................................... 106 


 
 
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12.2   INFORMED CONSENT .................................................................................................................................... 106 
12.3   INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE .......................................................... 106 
12.4   PROTOCOL AMENDMENTS ............................................................................................................................ 107 
12.5   SUBJECT CONFIDENTIALITY ......................................................................................................................... 107 
12.6   STUDY MODIFICATION/DISCONTINUATION .................................................................................................. 107 
13. 
PUBLICATION OF RESEARCH FINDINGS ........................................................................................... 108 
14.   REFERENCES ................................................................................................................................................ 109 
 
 
ABBREVIATIONS 
8-OHdG 
 
8-hydroxy-deoxyguanosine 
AE 
 
 
Adverse Event/Experience  
AT 
 
 
As-treated 
BBB 
 
 
Blood Brain Barrier 
BID 
 
 
Twice per day  
BL 
 
 
Baseline 
BMI 
 
 
Body Mass Index 
BP 
 
 
Blood Pressure 
C 
 
 
Celsius 
CBC 
 
 
Complete Blood Count 
CCC 
 
 
Clinical Coordinating Center 
CDE 
 
 
Common Data Element 
CHD 
 
 
Coronary Heart Disease 
Chem  
 
Chemistry  
CI 
 
 
Confidence Interval 
CNS 
 
 
Central Nervous System 
CRF 
 
 
Case Report Form 
CSF 
 
 
Cerebrospinal Fluid 
CTCC  
 
Clinical Trials Coordinating Center 
CVD 
 
 
Cardiovascular Disease 
DAT 
 
 
Dopamine Transporter 
DATATOP 
 
Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s Disease 
DBP 
 
 
Diastolic Blood Pressure 
DCC 
Data Coordinating Center 
DS1 
DAT scan 1 (screening) 
DS2 
DAT scan 2 (optional) 
DSMB  
 
Data and Safety Monitoring Board  
dL 
 
 
Deciliter 
ECG   
 
Electrocardiogram  
eCRF   
 
Electronic Case Report Form  
eDC  
 
 
Electronic Data Capture  
eDE  
 
 
Electronic Data Entry  
FDA   
 
Food and Drug Administration  
FRAP  
 
Ferric Reducing Antioxidant Power (or Ferric Reducing Ability of Plasma) 
GCP  
 
 
Good Clinical Practice  
GDS-S   
 
Geriatric Depression Scale – Short version 
GFR 
 
 
Glomerular Filtration Rate 
HDFP  
 
Hypertension Detection and Follow-up Program  
HDPE  
 
High-density polyethylene 
HIPAA  
 
Health Insurance Portability and Accountability Act  


 
 
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HPFS   
 
Health Professionals Follow-up Study 
HR  
 
 
Hazard Ratio 
Hr 
 
 
Hour 
ICH 
 
 
International Conference on Harmonization  
ID 
 
 
Identification 
IEC  
 
 
Independent Ethics Committee 
IMP 
 
 
Inosine monophosphate (a.k.a. inosinic acid or inosinate)  
IND  
 
 
Investigational New Drug  
IRB  
 
 
Institutional Review Board  
K 
 
 
Potassium  
kg  
 
 
Kilogram 
LFT 
 
 
Liver Function Test  
MAO   
 
Monoamine Oxidase  
MCID  
 
Minimum clinically important difference 
MDS-UPDRS  
Movement Disorders Society UPDRS 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
mEq 
 
 
Milliequivalent  
mITT   
 
Modified Intent-to-treat 
mL  
 
 
Milliliter  
MMSE  
 
Mini-Mental State Examination  
MoCA   
 
Montreal Cognitive Assessment 
MRFIT  
 
Multiple Risk Factors Intervention Trial 
MS  
 
 
Multiple Sclerosis 
NET-PD 
 
National Institutes of Health Exploratory Trials in PD  
NHS 
 
 
Nurses Health Study 
NIH 
 
 
National Institutes of Health 
NINDS  
 
National Institute of Neurological Disorders and Stroke 
OTC 
 
 
Over-the-counter 
PD 
 
 
Parkinson(’s) disease  
PDQ-39 
 
Parkinson’s Disease Questionnaire – 39 item version 
pH 
 
 
‘power of Hydrogen’ (negative log of hydrogen ion concentration) 
PK 
 
 
Pharmacokinetics 
PAU 
 
 
Persistently acidic urine 
PI  
 
 
Principal Investigator 
PO 
 
 
By mouth 
PRECEPT 
 
Parkinson Research Examination of CEP-1347 Trial  
PRO 
 
 
Patient-reported outcome 
PSG 
 
 
Parkinson Study Group  
PW 
 
 
Premature Withdrawal 
QA 
 
 
Quality Assurance  
QC  
 
 
Quality Control  
QID 
 
 
Four times per day  
QoL  
 
 
Quality of Life  
RBD 
 
 
REM (Rapid Eye Movement) Behavior Disorder 
SBP 
 
 
Systolic Blood Pressure 
S&E ADL 
 
Schwab and England Activities of Daily Living Scale 
SAE  
 
 
Serious Adverse Event/Experience  
SAP  
 
 
Statistical Analysis Plan 
SC  
 
 
Steering Committee 
SC1 (SC2) 
 
Screening Visit 1 (or 2) 
SD  
 
 
Standard Deviation   


 
 
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Smart4SURE 
 
Smartphone substudy and app for the SURE-PD3 trial 
SPECT  
 
Single Photon Emission Computerized Tomography 
SU 
 
 
Serum urate 
SURE-PD 
 
Safety of URate Elevation in Parkinson’s Disease 
SURE-PD3 
 
Study of URate Elevation in Parkinson’s Disease, phase 3 
SV 
 
 
Safety Visit (at month 27) 
SWEDD 
 
Scans Without Evidence of Dopaminergic Deficit 
TE1 (or TE2) 
 
Telephone Evaluation 1 (or 2) 
TID 
 
 
Three times per day 
TSH 
 
 
Thyroid-Stimulating Hormone (thyrotropin) 
UAC 
 
 
Uric acid crystalluria  
UPDRS 
 
Unified Parkinson’s Disease Rating Scale   
VS 
 
 
Vital Signs 


 
 
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SYNOPSIS 
 
Study Title:  A randomized, double-blind, placebo-controlled trial of urate-elevating inosine treatment to 
slow clinical decline in early Parkinson’s disease 
 
Study Acronym:  SURE-PD3 (Study of URate Elevation in Parkinson’s Disease, phase 3) 
 
Study Objectives 
  Primary – 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. 
 
  Secondary – To determine:  
a) safety and tolerability of urate-elevating inosine treatment,  
b) short-term (3 mo) wash-in and wash-out effects on MDS-UPDRS and other outcomes,  
c) time to disability warranting dopaminergic medication, and  
d) long-term (2 yr ±3 mo of wash-out) effects on:  
i) need for initiating dopaminergic medication changes,  
ii) specific non-motor measures of cognitive, mood and autonomic function (vital signs 
and orthostatic changes), and  
iii) quality of life and functional disability measures. 
 
 
Design and Outcomes  
Multicenter, randomized, double-blind, placebo-controlled trial with clinical decline 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.  
 
Secondary outcome variables include safety, disability warranting initiation of dopaminergic therapy, 
quality of life and functional disability measures, and specific non-motor measures of cognition, mood 
and autonomic function. 
 
 
Diagram of Timeline & Treatment  


 
 
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Interventions, Evaluations and Duration 
Capsules containing 500 mg of inosine (active drug) or lactose (placebo) will be taken orally up to two 
capsules three times per day (i.e., up to 3 gm/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 all study visits (V’s 
in the above diagram) 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 
(w/o) by telephone calls (T’s in the above diagram) 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. 
 
Study Population 
To enroll ~270 subjects with early PD (not yet requiring treatment with levodopa or dopamine agonist) 
and with lower serum urate, ~667 people diagnosed with probable early PD will be consented at ~60 US 
Parkinson Study Group (PSG) clinical sites. Initial screening for serum urate levels at or below 5.7 mg/dL 
(approximate population median) and other clinical eligibility criteria (e.g., to exclude those at high risk 
of adverse effects of urate elevation) will identify 300 probable candidates. They will undergo 
neuroimaging of dopamine transporter (DAT) ligand binding uptake to enhance diagnostic confidence by 
excluding ~10% who have scans without evidence of dopaminergic deficit (SWEDDs). The resultant 
cohort of ~270 subjects with lower serum urate predictive of more rapid clinical progression will be well 
suited to study whether urate-elevating inosine treatment can slow clinical progression in early PD.  
 
Sample Size 
Power for the primary outcome of rate of change in MDS-UPDRS over 24 months is based on a random 
slopes model with shared baseline. The model will include fixed effects of time, treatment x time, gender, 
gender x time, baseline MAO-B inhibitor use, and baseline MAO-B inhibitor use x time and random site- 
and subject-specific intercepts and slopes. Use of a shared baseline adjusts for baseline MDS-UPDRS 
score in addition to the adjustment for gender and baseline MAO-B inhibitor use. Other baseline 
covariates may be included in the final model based on any revision in our understanding of predictors of 
PD progression prior to finalizing the analysis plan and breaking the blind. MDS-UPDRS assessments 
completed after a subject has initiated dopaminergic therapy will be censored. Based on applying the 
same primary analysis model to data from SURE-PD, the following variance components were estimated 
for MDS-UPDRS trajectories (assuming a 1.29x conversion factor from UPDRS scores): site-level 
variance (intercept = 12.6, slope = 0.0159 / month, covariance = -0.446), subject-level variance (intercept 
= 99.8, slope = 0.297 / month, covariance = 3.70), and residual variance = 17.9. Similarly informed by 
experience in SURE-PD we assumed that 70% of subjects would initiate dopaminergic therapy plus up to 
8% additional loss to follow-up prior to initiating dopaminergic therapy. With quarterly follow-up for 
MDS-UPDRS, the variance and censoring estimates above, a final two-sided test at alpha = 0.046, 
allowing for two non-binding interim analyses at one-sided alpha = 0.001 each, the study would have 
80% power with n = 270 subjects randomized 1:1 to placebo or urate elevation if the true effect of 
treatment were to reduce 2-year increase in MDS-UPDRS by 6.3 points, a 20% reduction in the expected 
rate of progression. This is robust to variable gender-specific enrollment rates and treatment efficacy as 
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1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
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. 
 
We hypothesize that inosine will reduce the two-year change in total MDS-UPDRS score by 6 points 
versus placebo, representing a 20% reduction in rate of progression. 
 
1.2 
Secondary Objectives 
To determine:  
a) safety and tolerability of urate-elevating inosine treatment,  
b) short-term (3 mo) wash-in and wash-out effects on MDS-UPDRS and other outcomes,  
c) time to disability warranting dopaminergic medication, and  
d) long-term (2 yr ± 3 mo of wash-out) effects on:  
i) need for initiating dopaminergic medication changes,  
ii) specific non-motor measures of cognitive, mood and autonomic function (vital signs and 
orthostatic changes), and  
iii) quality of life and functional disability measures. 
 
2.     BACKGROUND 
2.1 
Rationale 
2.1.1 Rationale for Elevating Urate in Parkinson’s Disease 
As an apparent consequence of mutations in the urate oxidase gene 
during primate evolution,1 urate (a.k.a. uric acid) in humans circulates 
at high concentrations near the limits of its solubility and constitutes 
the end product in the metabolism of purines such as adenosine. (Fig. 
1.) Urate has an antioxidant efficacy comparable to that of ascorbate2 
and accounts for most of the antioxidant capacity in human plasma.3 
Thus its high level may serve as one of our major defenses against 
oxidative damage caused by reactive oxygen and nitrogen species. 
Urate also displays potent iron-chelating actions independent of its 
direct antioxidant properties.4 Because oxidative and nitrative stress5,6 
(including that accelerated by oxidized free iron) and possibly 
adenosinergic mechanisms7,8 are thought to contribute to the loss of 
dopaminergic neurons in individuals with Parkinson’s disease (PD), 
urate or its precursors could be an important determinant of disease 
susceptibility and progression in PD. Indeed a potential role for urate 
is consistent with the demonstration of low levels of urate in 
cerebrospinal fluid9 and post-mortem substantia nigra and striatum10,11 
of patients with PD. Moreover, in cellular models of PD 
administration of urate reduced oxidative stress, mitochondrial 
dysfunction and cell death in dopaminergic cell lines exposed to the 
pesticide rotenone, MPP+, 6-hydroxydopamine, glutamate, H2O2 or 
adenosine  
inosine 
hypoxanthine 
xanthine 
urate 
allantoin 
urate 
oxidase 
mutations 
Fig. 1. Metabolism of purines 
(e.g., adenosine) in humans. 
Enzymatic oxidation of urate does 
not occur in humans due to urate 
oxidase gene mutations.  
xanthine  
oxido- 
reductase 
adenosine 
deaminase 


 
 
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iron ions,12-15 and conferred protection against dopaminergic neuron death in primary cell cultures16,17. 
Animal models of PD have provided direct evidence that urate and its elevation protect nigrostriatal 
dopaminergic neurons in vivo.18,19 Interestingly, several laboratories have independently reported that 
neuroprotection by urate may rely more on indirect rather than its direct antioxidant properties, as the 
protective actions of urate can require nearby astrocytes14,17,216,217 as well as the activation of the Nrf2 
transcriptional antioxidant response pathway217,218. 
 
A) Blood urate and PD risk – Our epidemiology research group led by Alberto Ascherio (Co-chair of the 
SURE-PD3 trial Steering Committee) has confirmed and extended earlier observations 20,21 that lower 
blood urate levels in healthy individuals are a risk factor for developing PD later in life. In our 
prospective study22, 23 of a larger population -- 18,000 men followed for more than 8 years in the 
Health Professionals Follow-up Study (HPFS) -- we found that men in the top quartile of plasma 
urate concentration had a 55% lower risk of PD than men in the bottom quartile (Fig. 2A). The 
decrease in PD risk among men with high levels of urate was stronger among men with blood 
collected at least four years before the diagnosis of PD (Fig. 2B), suggesting that the lower serum 
urate among individuals with PD precedes the onset of neurological symptoms and is thus unlikely to 
be a consequence of changes in diet, behavior, or medical treatment early in the course of the disease. 
Further, this inverse association was independent of age, body mass index (BMI), smoking, caffeine 
consumption and other aspects of lifestyle that have been related to both PD and uricemia. Taken 
together in a meta-analysis23 the available prospective data on urate and PD risk demonstrated a 
substantially lower risk of PD in people who have higher plasma urate levels, with a 20% reduction in 
the pooled rate ratio of PD for each standard deviation (1.3 mg/dL) increase in blood urate 
concentration (p < 0.0001).23 With more recent prospective cohort studies28,212,213 the evidence for 
serum urate as an inverse risk factor for PD has overall strengthened, particularly in men.28 In women 
the link appears weaker,28,212,213 possibly reflecting the substantially lower levels of serum urate in 
women rather than the absence of a relationship (see below). Moreover, in numerous case-control 
studies lower serum urate has been linked to PD in both women and men.214 Similarly, the risk of PD 
was reduced in people with gout as shown in two independent prospective cohort studies, 253,254 
though not in a third study255. 
 
In addition to blood urate its genetic and environmental (dietary) determinants have also been 
linked to PD risk or diagnosis, supporting the possibilities of causality and modifiable risk. 
SLC2A9 is a urate transporter and variation in its gene is statistically the strongest known genetic 
determinants of blood urate levels in humans.205 SLC2A9 polymorphisms predictive of higher 
serum urate have been linked to a later age at onset in PD.206 Similarly, a composite genetic index 
of lower serum urate comprising single nucleotide polymorphisms in SLC2A9 and other genes linked 
Figure 2. Serum urate is associated with reduced risk of PD.  A. Rate ratio (RR) for PD by quartile of 
urate concentration among controls adjusted for age, pack-years of smoking, and quintile of caffeine intake 
in HPFS study.  B. Only cases whose blood was drawn >4 years before PD diagnosis and matched controls 
were included. RR is indicated above each bar. (Adapted from ref. # 23.) 


 
 
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to serum urate was significantly higher in PD than in control subjects,207 though in another study 
single nucleotide polymorphisms of SLC2A9 were largely unassociated with PD208.  
Complementing these ‘urate gene’ links to PD, dietary sources of higher urate were found to be 
strongly associated with a reduced risk of PD in the prospectively followed HPFS cohort.139 
B) 
Blood 
urate 
and 
PD 
progression 
– 
This 
epidemiological association with PD risk in healthy 
populations prompted us to investigate whether urate 
might also be linked to PD progression amongst those 
already diagnosed with PD. Working with the 
Parkinson 
Study 
Group 
(PSG), 
a 
non-profit, 
cooperative group of PD clinicians from medical 
centers in the United States and Canada who are 
dedicated to improving treatment of the disease, we 
have been able to address this question in two long-
term, rigorously managed clinical trials. One is known 
as PRECEPT (for Parkinson Research Examination of 
CEP-1347 Trial)30 and the other as DATATOP (for 
Deprenyl and Tocopherol Antioxidative Therapy of 
Parkinson’s Disease).31-34 Together these cohorts 
comprise over 1600 cases of early PD.  In our 
analyses with the biostatistics group of David Oakes 
(serving as PI of the the Data Coordinating Center 
[DCC] at Univ. of Rochester for the trial) we have 
found that higher blood urate levels are indeed 
strongly associated with a slower progression of PD 
symptoms 
and 
signs, 
both 
clinically 
and 
radiographically.35,36 Eight hundred and six (806) 
patients with early PD were enrolled in the PRECEPT 
study, a two-year double-blind, placebo-controlled, 
randomized trial of CEP-1347 (a c-Jun N-terminal 
kinase pathway inhibitor).30 Serum urate was 
measured as a component of safety monitoring. The 
hazard ratio (HR) of reaching the primary study 
endpoint, i.e. the development of disability sufficient 
to require dopaminergic therapy, declined with 
increasing serum urate (p for trend <0.0001).35 The 
age- and gender-adjusted HR for individuals in the top 
quintile of uricemia (>6.7 mg/dL) compared with 
those in the bottom quintile (<5.1 mg/dL) was 0.51 
(95% confidence index: 0.37 to 0.72; p<0.0001). 
Interestingly, in an analysis by gender, an even 
stronger and progressive reduction in the hazard of 
reaching 
the 
endpoint 
with 
increasing 
urate 
concentration was found in men (trend p<0.0001), but 
no significant association was appreciated in women 
(p, trend=0.33). The evidence for interaction was 
suggestive but not statistically significant (p for 
interaction [sex x urate] = 0.15). 
Moreover, a similar robust inverse association35 was 
All 
Men  
Women  
p < 0.0001 
p < 0.0001 
p = 0.17 
A 
B 
C 
Figure 3. Serum urate as a predictor of PD 
disability 
progression 
in 
the 
pooled 
PRECEPT35 and DATATOP36 cohorts. 
Tabulated hazard ratios of reaching the 
primary endpoint of disability sufficient to 
require dopaminergic therapy according to 
quintiles of serum urate for All subjects (A), 
Men (B) or Women (C).  Data are presented 
as means and 95% confidence intervals. P 
values are for trends across quintiles. For men 
(B) n’s for increasing quintiles = 84, 170, 245, 
258, and 271; for women (C) n’s for 
increasing quintiles = 255, 127, 81, 46, and 42. 
n = 1,579 
n = 1,028 
n = 551 


 
 
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observed between baseline urate and loss of striatal iodine-123–labeled 2-E-carboxymethoxy-3-E-(4-
iodophenyl)tropane ([123I]E-CIT) uptake, a marker for the presynaptic dopamine transporter, in a 
subset of PRECEPT subjects.  Overall, the mean change was –2.5% among patients in the top quintile 
of serum urate versus –9.3% for those in the bottom quintile (p=0.002). Just as for the clinical 
endpoint, a highly significant association was found in men but not in women.35 
Analysis of serum urate values in the DATATOP cohort31-34 enrolled 25 years ago also showed that 
higher blood urate at baseline was associated with slower rates of PD progression (again particularly 
amongst men) as assessed by the same clinical endpoint used in PRECEPT (n=776; trend p=0.002),36 
allowing for pooled analysis and substantiation of a decreasing rate of disability progression as a 
function of serum urate levels early in PD (Fig. 3). Interestingly, serum urate was highly predictive of 
slower rate of clinical decline among those not randomized to vitamin E (e.g., as measured in total 
UPDRS change, with those in the highest serum urate quintile declining at one third the rate of those 
in the lowest; p<0.001). By contrast, among those randomized to receive vitamin E serum urate was 
not related to total UPDRS change, with no difference between extreme quintiles (p=0.9), consistent 
with a competitive interaction between putative protective effects of urate acting as an endogenous 
antioxidant and vitamin E administered as an antioxidant. Indeed, in contrast to the null primary 
DATATOP trial results for the full cohort, among those in the lowest quintile of serum urate vitamin E 
treatment appeared to significantly slow the rate of clinical progression (p<0.01)36 albeit in a post hoc 
secondary analysis without adjustment for multiple comparisons. 
Importantly, it remains unclear whether there exists a true gender difference in the relationship 
between urate and PD progression, or whether the relationship is simply less apparent in women due 
to gender differences in urate levels.  Of note, a significant interaction between gender and urate was 
not appreciated in either of these populations (e.g., p for interaction = 0.5)36. Indeed, a relationship 
would be expected to appear weaker in women not only because there were half as many women as 
men in the DATATOP and PRECEPT cohorts (Fig. 3), but also because women have a substantially 
lower mean serum urate level than men.  Consequently, women in both of these studies comprise a 
very small proportion (≤15%) of the two highest population quintiles of serum urate (see Fig. 3 legend 
for n’s by quintile for each gender).  Because the inverse association between urate and PD is 
appreciable only above the population mean (i.e., the curve describing the relationship appears 
relatively plateaued below the mean and much more steeply sloped downward above the mean; Fig. 3) 
– as was similarly found for PD risk (Fig. 2A)23 – it can be expected that if a similar inverse urate-PD 
progression relationship exists in women and men, then it should be much less apparent in women.  
Interestingly, if the inverse association were in fact due to a neuroprotective effect of urate at serum 
concentrations above ~ 6 mg/dL, one could reasonably argue that a higher proportion of women with 
PD than men with PD would stand to gain from a protective urate elevation strategy of boosting serum 
urate to the 7-8 mg/dL range (i.e., because a much higher proportion of men already reside at these 
levels), consistent with preliminary data from the SURE-PD phase 2 study (see below).   
Newly reported data from a third independent cohort of prospectively followed de novo PD (i.e., those 
newly diagnosed and not yet required antiparkinsonian medication) has shown that baseline serum 
urate is also a predictor of favorable progression of multiple non-motor features of the disease, which 
included cognitive, mood and autonomic function domains.219 As disability from PD is increasingly 
appreciated to result from non-dopaminergic neuron involvement220 producing progressive non-motor 
features221,222 in addition to dopaminergic neuron degeneration and deficits, these findings further 
support the potential impact of pursuing the hypothesis that the ‘urate-PD’ association is causal. 
To address the causality of the link between higher serum urate and slower progression of PD we 
conducted a Mendelian randomization study223 of 735 DATATOP and PRECEPT participants with 
available DNA, using a genetic variant of the urate transporter SLC2A9 (see preceding Sec. 2.1.1A) as 


 
 
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an unconfounded proxy for serum urate concentrations. Consistent with prior population-based 
studies, variations in SLC2A9 were strongly associated with serum urate levels. The number of 
SLC2A9 alleles linked to lower serum urate also correlated with a faster clinical progression. 
Specifically, for a 0.5 mg/dL genetically conferred decrease in serum urate, the hazard ratio (HR) for 
developing disability warranting dopaminergic therapy was 1.27 (95% CI = 1.00–1.61, p=0.05). Of 
note, the marginal statistical significance notwithstanding, the magnitude of the apparent benefit of the 
urate-lowering SLC2A9 variant appears substantial, corresponding to a 76% reduction in the rate of 
clinical progression for a 3.0 mg/dL increase in serum urate, which is the average inosine-induced 
increase expected in SURE-PD3 (based on a mean baseline urate of 4.5 mg/dL102 and a mean target of 
7.5 mg/dL). Overall, these results strengthen but do not prove the hypothesis that higher serum urate 
can slow clinical progression in early PD.  
C) CSF urate and PD progression – Because cerebrospinal fluid (CSF) more closely reflects the 
microenvironment of degenerating neurons than does blood,37 we measured urate concentration in 
stored baseline CSF samples from the DATATOP study,31 to conduct a preliminary investigation of 
whether higher urate CSF levels also predict a slower rate of clinical disease progression in PD. Urate 
was measured by HPLC with electrochemical detection.33 Despite some two decades of storage at -80 
oC, CSF urate measured in 2008 in samples collected in 1987-1988 from DATATOP subjects at 
baseline correlated with that analyzed after only ~3 years of storage in 1991 (r2 = 0.52), and with 
serum urate measured fresh during the trial in 1987-1988 (r2 = 0.51) (K. Xu, W. Matson, A. Ascherio 
and M. Schwarzschild, unpublished data). Higher baseline levels of CSF urate were found to be 
predictive of a slower rate of clinical decline (assessed either by time to disability warranting to 
initiation of symptomatic dopaminergic medication, or by change in UPDRS scores), with a 
significantly slower decline in those in the highest quintile of CSF urate compared to the lowest.36 As 
noted above for serum urate the CSF urate-progression relationship was even stronger among those 
not receiving vitamin E and absent in those randomized to receive it.36 
 
D) Significance for neurotherapeutics  The convergence of these clinical and epidemiological as well as 
laboratory data has implicated urate as an attractive candidate neuroprotectant for PD. Growing 
reservations over reliance on animal models of PD to predict therapeutic potential are being 
raised24,38,39 in the wake of clinical failures of several candidate neuroprotectants. For example, anti-
apoptotic (CEP-1347 and TCH346), anti-excitotoxic (riluzole), lipophilic antioxidants (D-tocopherol 
and coenzyme Q10), neuroimmunophilin (GPI-1485), neurotrophic (GDNF) and mitochondrial 
stabilizing (creatine) agents have shown no disease-modifying efficacy in randomized controlled trials 
for PD. Of note, all these compounds appeared promising based on their prior vetting in preclinical PD 
models, though none was associated with improved clinical outcomes in PD. Thus the development of 
a urate-elevating strategy for PD – based in part on the unprecedented availability of human data 
linking urate to favorable PD progression – is particularly timely and compelling.  
 
2.1.2 Rationale for Selecting Inosine as a Means to Elevate Urate  
We considered three general pharmacological strategies to elevate urate in PD patients. First and most 
intuitive is administration of urate itself.  Although urate may not freely cross the blood-brain barrier 
(BBB),40 the main prohibitive factor is poor oral bioavailability.  In humans oral urate up to 4 gm/day 
does not significantly elevate blood urate levels due to its degradation in the gastrointestinal tract, likely 
by uricase-expressing bacteria.41 
 
Second, although enzymatic degradation of urate does not occur in humans (due to our urate oxidase 
mutations)1 and thus cannot be targeted, the clearance of urate can in fact be reduced by enhancement of 
renal urate resorption. For example, commonly taken thiazide diuretics reliably elevate serum urate 


 
 
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through this mechanism.42,43 However, thiazide diuretics generally produce only mild urate elevations (< 
1 mg/dL) at doses that cause significant reductions in blood pressure, which could be a particular liability 
in PD patients who are at increased risk of orthostatic hypotension. An additional theoretical concern over 
serum urate-elevating agents like thiazides that rely on transporter-blocking mechanisms44 is the 
uncertainty over the directionality of their effects on urate transport across the BBB and into or out of 
relevant CNS or cellular compartments.  
 
Third, urate precursor administration can provide a simple 
mass action approach to elevating urate levels.  The nucleoside 
inosine, the immediate deamination product of adenosine 
metabolism (see Figs. 1 and 4), was a particularly attractive 
candidate because it is orally bioavailable and CNS-penetrant.40 In 
addition, substantial human experience had shown inosine to be 
effective at chronically, stably and relatively safely elevating 
serum urate – at least in young athletes and patients with multiple 
sclerosis (MS).41,45-48 Inosine’s reputation as an athletic 
performance enhancer has led to its widespread marketing and use 
as a nutritional supplement. However, exercise physiology studies 
on healthy subjects under laboratory conditions have not 
substantiated any enhancement in athletic performance.48-50 In 
these studies inosine doses as high as 10 gm/day x 10 days50 
produced no apparent adverse effects. 
 
Based on these pharmacological and toxicological considerations 
oral inosine was selected as the most rational initial strategy for 
elevating serum and CSF urate in PD patients. 
 
2.2 
Supporting Data 
2.2.1 Human Nutritional and Clinical Experience with Inosine  
 
A)  Nutritional Supplement Use of Inosine 
1) ‘Performance Enhancer’     
Reflecting its common intended use in the US as an athletic performance enhancer,51 inosine is 
defined in a US President’s Council on Physical Fitness and Sports informational publication 
posted by the US Department of Health and Human Services:52 “Inosine is a nucleoside with a 
variety of proposed ergogenic effects, including enhancement of aerobic endurance performance 
by facilitating the delivery of oxygen to the muscles during exercise. Although scientific research 
is limited, two well-controlled [authors’ phrasing] studies did use the recommended 
supplementation protocol (see B1 below in this section, 2.2.1) for endurance athletes and reported 
no beneficial effects of inosine on cardiovascular-respiratory or metabolic functions during 
submaximal or maximal exercise, nor was there any effect on time to complete a simulated three 
mile race on a treadmill. Both studies actually suggested inosine could be ergolytic for certain 
athletic endeavors involving anaerobic glycolysis (Starling, R., et al., 1996; Williams, M., et al., 
1990).”48-50 More succinctly, a major health care professional resource Thomson Healthcare states 
that, “Inosine is a nucleoside (one of the basic compounds comprising cells) that is used for 
tiredness and to increase athletic performance. There are, however, no clinical studies that 
support the use of Inosine for any condition.”53  
Figure 4.  Structural formula of 
inosine (hypoxanthine 9-β-D-
ribofuranoside) from 
http://pubchem.ncbi.nlm.nih.gov/co
mpound/inosine. 


 
 
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Although the extent of its use for this purpose in the US is difficult to reliably document, its 
common listing and wide availability on its own or as a component of athletic performance 
supplements by nutritional supplement retailers (e.g., 8 listed for inosine in multiple formulations 
on Amazon.com)54 are consistent with its common use in the US.  
Similarly, because it has not been regulated as a drug in the US, information or statistics on its 
safety in common use is limited. General statements of its relative safety as a nutritional 
supplement at doses tested in the exercise physiology literature (see below, 2.2.1-A.2.a.) reflect the 
lack of major adverse effects from acute or subacute dosing with multiple grams-per-day usage. 
For example, “The Health Professional's Guide to Dietary Supplements” notes, “In general, 
supplemental inosine appears to be safe in doses of 5-6 grams for several weeks.”55 
 
2) Food Additive/Component (Umami Taste of Inosine Monophosphate) Inosine is the natural 
dephosphorylation product of inosine monophosphate (IMP; also known as inosinic acid or 
inosinate) as well as the deamination product of adenosine metabolism. IMP is commonly used as 
a food additive because of its flavor enhancing properties. IMP is a key component of the ‘umami 
taste’,56 a primary taste (in addition to bitter, salty, sour and sweet) and generally described as 
beefy, brothy or savory.  A substantial portion of dietary IMP is converted to inosine prior to 
ingestion (during the manufacture process)57-59 and/or through human metabolism60 
(dephosphorylating nucleotidase activity). 
 
Although exposures to inosine via IMP are generally much lower than that for the SURE-PD3 trial 
of inosine, oral administration of IMP in safety tests in animals or humans are consistent with a 
favorable safety profile of inosine at doses relevant to the planned trial. Healthy volunteers were 
given up to 2.5 gm/day IMP over 7 consecutive days with no ill effects despite a doubling of 
serum urate from 3.6 to 6.9 mg/dL.61,62 A publicly posted evaluation of IMP by the United States 
Food and Drug Administration (FDA) (Center for Food Safety and Applied Nutrition, Food and 
Drug Administration, Washington, DC, USA) stated, “The Committee concluded that, on the basis 
of the available data, the combined total daily intake of disodium 5'-guanylate and disodium 5'-
inosinate [IMP] is not of toxicological significance,...”,63 though common exposure to IMP is 
likely at the sub-gram level. 
 
B) Human Research Studies 
1)  Studies of Inosine Use in Exercise Physiology   
Published studies of oral inosine effects on athletic performance have all shown that multi-gram 
doses are well tolerated acutely, but have provided no evidence of putative ergonomic benefit. In 
order of decreasing cumulative inosine exposure, these are: 
x McNaughton L, Dalton B, Tarr J. (1999).50 Inosine supplementation has no effect on aerobic or 
anaerobic cycling performance. Int J Sport Nutr 9:333-344.  
o 10.0 gm/day (5.0 gm b.i.d.) inosine x 10 days 
o associated with rise in serum urate from 7.3 (baseline) to 13.9 mg/dL 
o no adverse events were reported; however the sample size was small: n=7 healthy fit 
subjects (all active cyclists training at 340 ± 36 km/wk) followed for 10 days 
 
x  Starling, R. et al. (1996).49 Effect of inosine supplementation on aerobic and anaerobic cycling 
performance. Med Sci Sports Exerc 28:1193-1198.  
o 5.0 gm/day inosine x 5 days 
 


 
 
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x  Williams, M. et al. (1990).48 Effect of oral inosine supplementation on 3-mile treadmill run 
performance and VO2 peak. Med Sci Sports Exerc. 22:517-522.  
o 6.0 gm/day inosine x 2 days 
 
2) Clinical Trials of Inosine 
i)  Inosine for Multiple Sclerosis (US/European trials) 
To our knowledge five clinical trials have been undertaken to evaluate the effects of urate-
elevating doses of inosine in multiple sclerosis (MS). Inosine has been administered in this 
population (mean subject age ~40; ~75% women) for prolonged periods (1-3 years) at up to 4 
gm/day (b.i.d. dosing).  
  
Although the safety results for two of the studies41,45 noted no adverse effects (including 
urolithiasis, gout, renal disease and cardiovascular disease), more preliminary and more 
recently published data from the other 3 trials25,26,47 indicate an adverse event of urolithiasis has 
occurred in up to 25% of the study subjects.  In a Univ. of Penn. study (IND#57,871)47 
urolithiasis was associated with excessive hyperuricemia (i.e., above this study’s planned target 
range) prior to implementing standard preventative recommendations for kidney stones. In this 
study 4 of 16 (25%) subjects on inosine developed urolithiasis (4 during active drug treatment), 
which resolved readily with medical measures.  
 
In a Spanish study,46 two (11%) of the subjects treated with inosine developed renal colic 
(personal communication, D. Muñoz), presumably due to renal lithiasis.  These episodes 
resolved without need for hospitalization.  In the largest (Belgian) study,26 urolithiasis also 
occurred but only in three subjects (3.8%) on inosine therapy, with one subject (1.2%) on 
placebo developing urolithiasis as well, over two years. Of note, in all five of these prior studies 
there were no apparent efforts to reduce the risk through screening, monitoring or prophylaxis 
of low urine pH, a major risk factor in the formation of uric acid urolithiasis.64   
                                                                
Elevation of urate levels in MS has been studied under two INDs. In IND #54,969 (Dr. Hilary 
Koprowski, sponsor), urate was administered to subjects with severe MS.  Under INDs #54,969 
and #57,871 (Dr. Hilary Koprowski, sponsor) inosine administration to subjects with MS was 
proposed and conducted in order to elevate serum urate levels.  A letter of authorization to 
cross-reference those INDs was provided by Dr. Koprowski. 
 
 
 
ii) Inosine for Other Conditions – The use of inosine has been reported in peer-reviewed 
literature in other clinical indications, including Tourette syndrome (at doses corresponding to 
4-6 gm/day x 1 year)65 and myocardial infarction (up to 0.8 gm/day x 1 month in subjects with 
cardiovascular disease [CVD])66-69. Preclinical data70-72 on potential benefits of inosine for 
spinal cord injury and stroke recovery have been reported; no trials have been registered for 
these indications.  
 
iii) Inosine Pranobex for Immune Disorders – Inosine pranobex is a drug approved and 
marketed since 1971 for use now in 43 countries outside the US (including Canada, France, 
Germany, Italy, Japan and the UK) for the treatment of immune disorders.73 It comprises 
inosine together with 2-hydroxypropyldimethylammon-ium 4-acetamidobenzoate in a 1:3 
molar ratio (such that 10.0 gm of inosine pranobex contains 2.54 gm inosine). Inosine 
pranobex is also known as Isoprinosine, Inosiplex and Immunovir (CAS: 36703-88-5). The 
US National Library of Medicine defines inosine pranobex as, “An alkylamino-alcohol 
complex of inosine used in the treatment of a variety of viral infections. Unlike other antiviral 
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on the virus directly.”74 The immunological disorders for which inosine pranobex may be an 
effective treatment are primarily viral illnesses such as HIV infection,75 herpes simplex virus 
infections, 
genital 
warts,76 
influenza, 
zoster, viral 
hepatitis, 
subacute 
sclerosing 
panencephalitis.77 On September 20, 1988 the FDA designated inosine pranobex as orphan 
product status for the indication of “treatment of subacute sclerosing panencephalitis”.78 
www.clinicaltrials.gov lists seven completed trials of inosine pranobex.79 
 
Usual oral dosage of inosine pranobex corresponds to an inosine dose of approximately 0.8-1.8 
gm/day,77,80 which generally produces a mild elevation of serum urate without significant 
adverse effects. For example, in a study of 3 gm/day inosine pranobex (corresponding to an 
inosine dose of 0.8 gm/day) serum urate rose from 4.0 to 5.4 mg/dL over 3 months (without 
gout or urolithiasis).81  In the European Isoprinosine Trial82 the equivalent of 1.1 gm/day 
inosine administered over two years to subjects with multiple sclerosis produced a serum urate 
elevation of 42% in men (4.4Æ6.2 mg/dL), and of 15% in women (3.5Æ4.0 mg/dL) (R. 
Gonsette, European Isoprinosine Trial PI, personal communication).  
 
Inosine pranobex at typical doses in clinical use is considered to have a good clinical safety 
profile. A review in Drug Safety entitled, “Adverse effects and drug interactions of clinical 
importance with antiviral drugs” noted that, “Only inosine pranobex is largely free from 
toxicity.”83 For example, in a major study of the effects of inosine pranobex on the 
development of AIDS, “No serious side effects were observed” in the 429 subjects taking 3 
gm/day inosine pranobex for 24 weeks.75 However, differences in the dose of inosine itself, the 
duration of drug exposure and study population age limit the relevance of the comparison 
between such studies of inosine pranobex to our trial of inosine for PD. 
 
2.2.2 Human Experience with Elevated Urate  
 
A)  Epidemiology of Urate and Disease (other than PD) 
Higher Serum Urate: Clinical Consequences and Associations – The planned intervention, oral 
inosine titrated to moderate elevation of serum urate levels is expected to increase risks of gout and 
uric acid kidney stones, which are caused by local increases in urate or uric acid concentration.  As 
discussed below, the risk of uric acid urolithiasis can be markedly reduced by avoiding or raising low 
urinary pH, whereas the risk of gout can be minimized but not eliminated by avoiding prolonged 
elevation of serum urate concentrations above ~8 mg/dL (the upper limit of the target range). In 
contrast, there is no conclusive evidence that increasing serum urate will affect the risk of 
cardiovascular events or other diseases.  Nevertheless, we will preemptively exclude from the trial 
individuals at high cardiovascular risk and will closely monitor the subjects for any evidence of harm.  
Most importantly, we expect that the hypothesized slowing of PD progression produced by urate 
elevation will more than compensate for the known adverse effects of higher urate levels, which are 
reversible or treatable. 
 
1) Epidemiology of Urate and Gout 
Although it is widely accepted that high levels of serum urate predispose to gout, there are few 
published prospective epidemiologic studies that have investigated the relationship between prior 
urate levels and the risk of incident gout.   
 
As part of the Framingham Study, a total of 5,127 individuals were examined biennially for a 
follow-up of 12 years.84 The incidence of gout increased with increasing levels of urate.  Over this 
period, gout developed in 18 (1.1%) of 1,615 men with urate < 6 mg/dL; 26 (7.3%) of 354 men 


 
 
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with urate between 6 and 6.9 mg/dL, and 11 (14.2%) of 78 men with urate between 7.0 and 7.9 
mg/dL.  The corresponding annual incidence rates were thus approximately 0.1%, 0.6%, and 1.1 
%.  The incidence rate of gout increased sharply at urate levels above 8 mg/dL, with 8 (36%) of 22 
men in this range developing gout.  In women, gout developed in 3 (0.1%) of 2,405 with urate < 6 
mg/dL; 5 (7.0%) of those with urate between 6.0 and 6.9 mg/dL; and 3 (27.2%) of those with urate 
between 7.0 and 7.9 mg/dL.  The corresponding annual incidence rates were thus approximately 
0.01%, 0.6%, and 2.6%. Only one woman had a serum urate level above 8 mg/dL and she did not 
develop gout. 
 
In a study of 2,046 initially healthy men in the Normative Aging Study followed for about 15 
years there were 87 incident cases of gout. The annual incidence of gout was 4.9% in men with 
serum urate values of 9.0 mg/dL or more, compared with an annual incidence of 0.5% for serum 
urate levels of 7.0 to 8.9 mg/dL, and an annual incidence of only 0.1 % for serum urate levels < 
7.0 mg/dL.85 Among men with serum urate levels ranging between 7.0 and < 8.0 mg/dL (the target 
interval in SURE-PD3), the annual incidence of gout was 0.4% in the Normative Aging Study. 
 
In a Chinese prospective study among men with hyperuricemia (defined as serum concentrations  
> 7.0mg/dL at baseline) 42 cases of incident gout were documented during the 5-year follow-up.86 
Annual incidence rates of gout in this study were 2.2% for serum urate levels of 7.0-7.9 mg/dL, 
5.5% for 8.0-8.9 mg/dL, and 12.2% for > 9.0 mg/dL.   
 
Thus, the associated risk of gout might be considered an acceptable risk if the benefits of increasing 
urate by administration of inosine can be demonstrated to delay the progression of PD.  Based on 
available epidemiological evidence, one may expect an excess of 0.3 to 2.6 episodes of gout for 100 
persons per year in the group targeted to 7.0-8.0 mg/dL of serum urate.  However, there was no 
episode of gout or gout-like symptoms among PD patients with over 25,000 subject-days of exposure 
to urate-elevating inosine in our phase 2 trial102, and similarly none were reported among ~200 MS 
patients in multiple prior trials of urate-elevating inosine (despite numerous kidney stone AEs among 
these subjects)25,26,41,45,46.  Also of note, inosine is unlikely to cause gout per se, as inosine-induced 
hyperuricemia is expected to be reversible and gout is defined as a disease of recurrent episodes of 
urate crystal-induced arthritis and its degenerative consequences. 
 
2)  Epidemiology of Urate and Renal Lithiasis 
Formation of uric acid stones. Higher urate generation leads not only to higher urate levels in the 
serum, but also in the urine (uricosuria) and consequently the risk of kidney stones, specifically 
those comprising uric acid crystals.  However the main determinant of uric acid stone formation is 
not uricosuria, but an acidic urinary pH. 29,64,87,88 Uric acid stone formation can thus be prevented 
even in individuals with high urine urate, provided their urinary pH is greater than 5.5.89  Although 
cases of nephrolithiasis were reported in some of the previous trials using inosine (see above), no 
monitoring of urinary pH was implemented in any of those studies.   Our strategy for preventing 
uric acid nephrolithiasis in SURE-PD3 includes exclusion of subjects with acidic urine, 
monitoring of urinary pH,90 and raising of urinary pH by administration of potassium citrate or 
other alkalinization therapy if it falls below 5.5 (or 6.0 in the presence of uric acid crystalluria).89,91  
In the past, concerns were raised that uricosuria could also contribute to the formation of calcium 
oxalate stones,92 but this relationship was not supported by the results of further study.93  
 
3) Correlations between Serum Urate and Hypertension 
A positive association between baseline serum urate and risk of developing hypertension has been 
consistently observed in numerous longitudinal studies, and seems to be independent from other 
known risk factors.94-99 In recent studies in which relative risk estimates were adjusted for baseline 
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hypertension seems to be linear, without obvious threshold effects.  The relative risk associated 
with a 1.0 mg/dL difference in serum urate concentrations ranged from 1.09 (95% CI: 1.02 to 
1.17) among 3,073 men followed for six years as part of the Multiple Risk Factors Intervention 
Trial (MRFIT)99 to 1.31 among 2,520 individuals (men and women) followed for 10 years as part 
of the Beaver Dam Study;95 the pooled relative risk was 1.13 (95% CI: 1.06 to 1.20) in a 2011 
meta-analysis.100 Results of the same meta-analysis suggested that the association between urate 
and hypertension tends to be stronger at younger ages and in women. An increase in blood 
pressure has also been found among individuals who did not develop hypertension during the 
follow-up.  For example, a 1.0 mg/dL increase in serum urate concentration was found to be 
associated with a 2.5 mm Hg increase in systolic blood pressure (SBP) and a 1.2 mm Hg increase 
in diastolic blood pressure (DBP) after 5-years of follow-up in the Beaver Dam Study,95 whereas a 
smaller average increase was reported over a one year period in the MRFIT (0.33/0.16 mm Hg, 
SBP/DBP).99 
 
However, recent studies in humans with MS47,101 and PD102 (see below) on the effects of urate-
elevating inosine found no detectable effect on blood pressure (SBP, DBP or their orthostatic 
changes) of inosine that elevated serum urate by up to 4 mg/dL to achieve chronic stable levels of 
7-8 mg/dL. Thus any increase in blood pressure attributable to urate elevation that might be 
observed in SURE-PD3 would likely be modest.  Further, among individuals with PD, blood 
pressure tends to decline early in the disease course.103 Nevertheless, blood pressure will be closely 
monitored during the trial and anti-hypertensive treatment will be initiated or adjusted as needed. 
 
4)  Other Potential Adverse Effects of Elevated Serum Urate  
The association between serum urate and health outcomes has been investigated in numerous 
longitudinal studies spanning over five decades, but whether high serum urate is an independent 
risk factor for chronic diseases other than kidney stones, gout, or hypertension remains 
controversial.  Although individuals with high serum urate in several studies were found to have 
higher rates of heart disease and stroke, these adverse associations were largely explained by the 
correlation between urate and other risk factors, including obesity, hypertension, high plasma 
lipids, renal insufficiency and other markers of increased cardiovascular risk or general poor 
health.  In some studies a positive association between serum urate and cardiovascular morbidity 
or mortality remained after adjustment for other risk factors, but this adjustment was in all cases 
incomplete -- potential confounders were either poorly measured or completely ignored.  Among 
the potential confounders not considered are levels of physical activity and dietary factors.  A 
summary of literature on urate and cardiovascular risk is provided below. 
 
i) 
 Coronary heart disease (CHD) – In several rigorous longitudinal investigations, most 
notably in the Framingham Study,104 there was no independent relation between baseline 
serum urate and risk of coronary events (relative risk for highest category of urate versus 
lowest = 0.91; 95% CI: 0.83 to 0.99), coronary mortality (0.95; 0.86 to 1.06), or all cause 
mortality (0.97; 0.91 to 1.03).  In contrast, several other investigations reported an 
increased risk of cardiovascular outcomes, although the associations were strongly 
attenuated after adjustment for other risk factors.  A meta-analysis of 16 longitudinal 
studies including 9,458 cases of coronary heart disease and 155,084 controls was 
published in 2005 -- the relative risk comparing individuals in the highest third of serum 
urate serum concentrations to those in the lowest third was 1.13 (CI: 1.07 to 1.20), but it 
was only 1.02 (CI: 0.91 to 1.14) in the eight studies with more complete adjustment for 
possible confounders.105 In a separate review, the association between serum urate 
concentrations and cardiovascular events was reported to be small in healthy individuals, 
but possibly important in high-risk patients.106  In 2010 Kim et al.107 have conducted a new 
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risks (RR) were reported for hyperuricemic vs. non-hyperuricemic individuals, with the 
definition of hyperuricemia varying across studies. The pooled relative risk of incident 
CHD 
after 
adjustment 
for 
traditional 
risk 
factors 
(age, 
sex, 
hypertension, 
hypercholesterolemia, obesity, and smoking) was 1.09 (95% confidence interval: 1.03 to 
1.16).  Sex-specific adjusted relative risks were 1.04 (0.90 to 1.17) in men (based on 7 
studies) and 1.07 (0.82 to 1.32) in women (based on 4 studies).  The pooled and adjusted 
RR for CHD mortality was 1.16 (1.01 to 1.30) in men (based on 8 studies) and 1.67 (1.30 
to 2.04) in women (based on four studies).  
 
A few studies published after this meta-analysis have reported mixed findings, but most 
have been too small to substantially impact the overall meta-analysis results.108-116 The 
largest studies have been based on historical databases, in which information on potential 
confounders is most likely incomplete. In a historical cohort based on laboratory and 
insurance claims among 148,217 patients in the U.S., serum urate was associated with 
cardiovascular morbidity, particularly among individuals with reduced glomerular 
filtration rate.117 Two investigations were conducted in Taiwan. Among 128,569 adults 
recruited in a cohort in 1994-6 and followed through a National Health Insurance 
database, the relative risk for ischemic heart disease was 1.25 (1.11 to 1.40) in men with 
serum urate ≥ 7.0 mg/dL and 1.19 (1.02 to 1.38) in women with serum urate ≥ 6.0 mg/dL 
as compared to those with lower levels.118 In a separate investigation based on the 
secondary data analyses of over 350,000 medical records, serum urate displayed a U-
shaped relation with both all-cause mortality and cardiovascular mortality – the lowest risk 
was reported for levels between 5 and 6.9 mg/dL.119,120 In a 2013 meta-analysis of 
randomized trials in which serum urate was measured at baseline and at the end of follow-
up, no significant association was found between changes in serum urate and 
cardiovascular outcomes.121 Finally, a 2013 meta-analysis reported estimates on the 
association between uricemia and cardiovascular mortality or all-causes mortality.  For the 
highest urate level as compared to the lowest, the relative risk for all-causes mortality was 
1.23 (1.08 to 1.42) in men, and 1.05 (0.79 to 1.39) in women;  for cardiovascular mortality 
the relative risk was 1.30 (1.07 to 1.59) in men, and 1.35 (1.06 to 1.72) in women.122 
 
ii) 
Stroke – The relation between hyperuricemia and risk of stroke has been summarized in a 
2009 meta-analysis including data from a total of 16 prospective studies and over 230,000 
individuals.  After adjustment for traditional risk factors, the pooled relative risk of stroke 
was 1.47 (1.19 to 1.76), with results similar in men and women.123 An increased risk of 
stroke in individuals with higher urate levels has been confirmed in subsequent studies. In 
a cohort of 5,700 people in Norway, a 1 SD increase in serum urate (~ 1.5 mg/dL) was 
associated with a relative risk of 1.22 (1.09 to 1.35).124 Similarly, a recent population-
based study found hyperuricemia to be related to white matter atrophy (assessed by 
magnetic resonance imaging) and worse cognition, an association that was only partially 
attenuated by adjustment for several markers of vascular disease.209 
 
The results of these studies should be interpreted cautiously, because serum urate positively 
correlates with several risk factors for cardiovascular disease, including among others, obesity, 
high plasma triglycerides, high blood pressure, low level of physical activity, metabolic syndrome, 
and several dietary factors.  As expected, therefore, individuals with high levels of serum urate 
tend to have a higher risk of CHD or stroke, but this risk is strongly attenuated after adjustment for 
other cardiovascular risk factors.  Moreover, serum urate increases with declining renal function, 
which is also a poor prognostic factor for chronic diseases and survival.   Whether hyperuricemia 
is a contributory cause rather than just a consequence of kidney failure remains uncertain. 
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information or measurement error in the confounders.125,126 Conspicuously absent among adjusting 
factors are physical activity and diet, which are strong determinants of risk of CHD and 
stroke.127,128 It remains therefore possible that the positive association between serum urate and 
cardiovascular risk or overall mortality seen in some studies is artifactual, due simply to 
confounding risk factors. 
 
In spite of these limitations, an adverse effect of urate on cardiovascular events cannot be 
excluded.  Because many large investigations did not find a significant association, such effects 
would most likely be modest.  The actual number of events attributable to the intervention would 
depend not only on the relative risk, but also on the underlying incidence of cardiovascular events 
in the study population.  For example, if inosine treatment increased the risk of major 
cardiovascular events (including nonfatal stroke, nonfatal myocardial infarction, or death from any 
cardiovascular cause) by 20%, the number of expected cases attributable to the treatment would be 
1.5 per 1,000 persons per year in a population with a baseline rate of 7.7 per 1,000, the rate based 
on 2,607 events observed during the 20-year follow-up of nearly 18,000 men aged 40 to 84 at 
baseline in the Physician Health Study.129  
 
It should be emphasized again that there is no convincing evidence that elevating serum urate will 
increase the risk of cardiovascular events.  The number of excess cases provided as an example 
above is thus hypothetical.  However, to try to further minimize risk, individuals with a history of 
major cardiovascular morbidity or decreased kidney function will be excluded from SURE-PD3, 
and all subjects will be closely monitored for increases in blood pressure and other early signs of 
coronary or cerebrovascular events.  
 
5) Serum Urate and Mortality Among Patients with PD 
For the purpose of the planned trial, a key question is whether a slowing of PD progression that 
may result from increasing serum urate would offset the increased risk of kidney stones, gout, and 
possibly hypertension and other adverse events due to elevated serum urate.  Data on serum urate 
and survival in PD could be analyzed for 768 of the 804 subjects with early PD enrolled in the 
DATATOP trial, for whom serum urate at baseline and 13-year survival are available.36 Two 
hundred and ninety two patients died during the follow-up (211 among men); the hazard ratio for 
all-cause mortality, adjusted for age, treatment group, pack-years of smoking, did not significantly 
increase with serum urate levels.   The hazard ratio comparing patients in the top quintile of serum 
urate to those in the bottom was 0.89 (95% CI: 0.53 to 1.50) in men and 1.96 (95% CI: 0.89 to 
4.33) in women.36 These data, like the epidemiological studies discussed above, are of an 
observational nature, and potentially confounded by other risk factors for cardiovascular disease 
and renal function.   
 
B)  Drug-Induced Urate Alterations and Clinical Consequences 
 
1)  Randomized Trials of Drugs that Elevate Serum Urate (Thiazide-Type Diuretics)  
An increase in serum urate is a well-known side effect of thiazide diuretics, which are used by 
millions of individuals in the U.S. and other countries as a first line drug for the treatment for 
arterial hypertension.  In individuals with high blood pressure, treatment with thiazides clearly 
reduces morbidity and mortality in spite of modest increases in serum urate levels.   
 
Detailed analyses on the effects of serum urate at baseline and following treatment with a thiazide 
diuretic (primarily clorthalidone, at 50 mg/day) were conducted among 3,693 participants in the 
Hypertension Detection and Follow-up Program (HDFP).130 Half of the participants in the HDFP 
were randomly assigned to receive intensive antihypertensive treatment given in special clinics 
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HDFP drug protocol was chlorthalidone, 50mg/d; reserpine, methyldopa, or hydralazine 
hydrochloride were added as needed.  After 4-months of follow-up, 1,230 (59.5%) of the 2,068 
men were being treated with a thiazide diuretic.  Among these men, 506 (41.1%) had serum urate 
concentrations ≥ 8.0 mg/dL.  Among women, 905 (55.7%) of 1,625 were treated with thiazide 
diuretics, among whom serum urate concentrations were ≥ 8.0 mg/dL in 140 (15.5%).  The HDFP 
protocol required temporary discontinuation of thiazides if symptoms of gout appeared.  Only 15 
of the 3,693 individuals at risk had their thiazide diuretic therapy suspended for this reason.   
 
The one-year change in serum urate among men treated with thiazides was 1.3 mg/dL in men in 
the lowest quartile of serum urate at baseline (mean at baseline 4.9 mg/dL) and 0.85 among men in 
the highest quartile at baseline (mean at baseline 7.7 mg/dL).  Similar increases in serum urate 
following thiazide treatment were observed in women, although baseline levels were lower.  
Overall, no significant association was found between serum urate and changes in creatinine levels 
(as a marker of renal damage) in either men or women.  Among men, no significant association 
was found between serum urate at baseline and overall survival, but a positive association was 
found in women.  As for the studies above, however, this association was more likely due to 
confounding by hyperlipidemia and other risk factors.  Conclusions of the authors was: “…in the 
HDFP, analysis of data regarding the elevation of uric acid associated with the administration of 
thiazide diuretics in the treatment of hypertension provides little evidence of an adverse effect for 
the patient without renal damage or history of gout”. 
 
 
2) Randomized Trials of Drugs that Reduce Serum Urate (Allopurinol, Oxypurinol, 
Probenecid, Urate Oxidase) 
Because of the association between serum urate and hypertension discussed above, it has been 
hypothesized that drugs that reduce serum urate either by inhibiting its synthesis (e.g., allopurinol), 
catalyzing its degradation (urate oxidase), or increasing its renal excretion (e.g., probenecid) could 
contribute to treatment or prevention of hypertension.  However, despite their consistent ability to 
lower urate, these agents have shown variable effects on blood pressure/vascular function in 
controlled trials;131-134 new studies of allopurinol are ongoing.79 Similarly, a recent study of another 
xanthine oxidase inhibitor oxypurinol in congestive heart failure135 found no evidence of 
hypothesized health benefits over 6 months despite a reduction in serum urate levels by 2 mg/dL. 
Possible beneficial effects of allopurinol have been reported in some observational studies.  In a 
retrospective study in Canada, use of allopurinol in patients with heart failure gout was associated 
with lower risk of readmission for heart failure or death.136  In a recent case-control study, the odds 
ratio for a first myocardial infarction associated with allopurinol use was 0.80 (0.59 to 1.09); this 
inverse association reached borderline significance when using less stringent matching criteria.137 
It should be noted, however, that these studies do not directly test the hypothesis that urate itself is 
a cause of hypertension or cardiac dysfunction, because inhibition of xanthine oxidase may also 
directly reduce the generation of oxygen radicals and thereby affecting endothelial and 
cardiovascular function.131 
2.2.3  Experience with Inosine to Elevate Urate in PD (Phase 2 Development)  
In preparation for the planned clinical efficacy trial of inosine we conducted a phase 2 study to assess its 
safety, tolerability and urate-elevating capability in early PD, and to inform the design of the phase 3 trial. 
The Safety of URate Elevation in PD (SURE-PD)102 study was a randomized, double-blind, placebo-
controlled, dose-ranging trial of inosine. Seventy-five adults (mean age 62; 55% women) with early PD 
not yet requiring symptomatic treatment and a serum urate concentration below 6 mg/dL (the approximate 
population median) were enrolled for up to 25 months at 17 credentialed clinical study sites of the 
Parkinson Study Group (PSG). Subjects were randomized to one of three treatment arms: placebo or 


 
 
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inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 
500 mg capsules taken orally up to two thrice daily. They were followed for up to 24 months (median 18) 
on study drug plus 1 wash-out month. The pre-specified primary outcomes were absence of unacceptable 
serious adverse events (safety), continued treatment without adverse event requiring dose reduction 
(tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal 
fluid (CSF).  The trial was registered at ClinicalTrials.gov under NCT00833690.79 
 
The SURE-PD study has yielded extensive data that support and inform an advance to phase 3 
development: 
 
A)  Safety and Tolerability Outcomes Serious adverse events (17), including infrequent 
cardiovascular events, occurred at the 
same or lower rates in inosine groups 
relative to placebo (Table 2). No subject 
developed gout and three receiving inosine 
developed symptomatic urolithiasis (Table 
3). These stones were reported only in 
women after more than 4 months of 
receiving the study drug102 and may have 
been dose dependent (0, 1, and 2 events in 
the placebo, mild, and moderate groups, 
respectively; 
Table 
2). 
Need 
for 
alkalinization was rare because urine pH 
was unaffected by inosine.102 Urine 
collected at each visit was also assessed 
for the presence of various crystals, and 
their potential use in monitoring inosine-
induced urolithiasis risk was investigated. 
Although no crystal type was predictive of 
urolithiasis, 
uric 
acid 
crystals 
were 
observed in urine from 10 subjects with a 
dose-dependent distribution (0 placebo, 3 
mild, and 7 moderate).102 The 1 subject 
who 
developed 
a 
documented 
symptomatic uric acid stone (after 14 
months of inosine in the moderate urate 
elevation arm) had tested positive for uric 
acid crystalluria and had relatively low 
urine pH hovering at 5.5 (just above the 
trigger for alkalinization). Stones in 2 
other subjects were likely not uric acid 
because the composition of one was 
documented as “65% calcium oxalate 
dihydrate + 35% carbonate apatite,” and 
the other though not analyzed was from a 
subject whose urine pH was ~6.5, which is 
usually incompatible with uric acid stone 
formation.   
 
Secondary safety outcomes, including 
those associated with hyperuricemia,122,126 
Table 2. Serious Adverse Events (AEs) in SURE-PD 
Table 3. AEs of Special Concern in SURE-PD 
a Medical Dictionary for Regulatory Activities system organ class and preferred terms. 
bValues show total number of events (% of participants). 
c Arthralgia of toes combines the following preferred terms in instances where the 
verbatim complaints mentioned feet or toes: arthralgia and pain in extremity. 
d Swelling of toes combines the following preferred terms in instances where the verbatim 
complaints mentioned feet or toes: joint swelling and local swelling. 
Abbreviations: Ino→Mild, inosine dosed to mildly elevate urate; Ino→Mod, inosine dosed 
to moderately elevate urate.   [Adapted from Ref. 102.] 


 
 
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did not differ between treatment groups. For example, serial vital signs, serum assays, and 
electrocardiograms (ECGs) showed no effect of inosine on blood pressure (or its orthostatic changes), 
body mass index, serum glucose and cholesterol levels, or ECG parameters.102 And despite the 
increased frequency of urolithiasis while receiving inosine, there were no other renal SAEs and renal 
function as assessed by serum creatinine and estimated glomerular filtration rate remained unchanged 
from baseline in all groups.  
 
Treatment was tolerated by 95% of subjects at 6 months (Fig. 5A), and no subject withdrew due to an 
adverse event.  Similarly, retention and compliance were excellent, with 99% completing the study102 
and 100% of placebo subjects maintaining a mean serum urate within the baseline range (<6.0 mg/dL), 
consistent with no surreptitious use of OTC inosine. Thus a high proportion tolerated and maintained 
the assigned treatment, and overall safety results were reassuring. Nevertheless, urolithiasis remains a 
Figure 5. Tolerability of Inosine and Its Effects on Serum and CSF Urate Levels. 
A, Tolerability of the study drug from baseline to drug discontinuation displayed as Kaplan-Meier survival curves over the 
maximum 2-year period for participants taking placebo or inosine dosed to mildly or moderately raise serum urate. Tick 
marks indicate censored events (see the Methods section). B, Estimated time course of serum urate levels across study 
visits with the study drug initiated at the baseline (BL) visit and continued for as long as 24 months (V12) until 1 month 
before the final (safety) visit (SV). Means and 95% confidence intervals from a mixed model are displayed. For visits V1 to 
V12, serum was collected after morning study drug intake, except for the “trough” sample at week 12 (V05). The shaded 
range of serum urate concentrations represents exclusionary values at the screening visits (SC1 and SC2). C, The CSF 
urate concentrations and ranges (bars, with boxes and dots representing the interquartile and median values, respectively) 
after 12 weeks of receiving the study drug. P < .001 for the mild and moderate inosine groups compared with placebo. D, 
Correlation between CSF and serum urate levels at the 12-week visit for individuals identified by their treatment groups 
and sex. F indicates female and M, male.  [Adapted from Fig. 2 of ref. 102.] 


 
 
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substantial risk that warrants consideration of options for further mitigation (see below, Sec. 3.2.4). 
 
B)  ‘Target Engagement’ Efficacy of Inosine  
1)  Urate Elevation in Serum (Fig. 5B) 
A lesson learned from earlier failures of phase 3 trials for disease modification in PD is the 
importance of demonstrating target engagement at the doses tested for a candidate neurotherapeutic, 
to the extent feasible. For example, in retrospect a weakness of the PRECEPT trial was the 
uncertainty over whether the candidate protectant, a mixed lineage kinase (MLK) inhibitor, actually 
entered the CNS and/or inhibited MLK activity30 – even in the periphery where it may have been 
readily measured. Current efforts to identify the most promising neuroprotectants for clinical 
development in neurodegenerative disease consider evidence that a candidate agent penetrates the 
relevant compartment (e.g., CNS) and that it engages its putative target in some manner to be key 
criteria224,225.  
 
Inosine differs from most other candidate disease-modifying drugs in that its development is 
uniquely driven by robust epidemiological and clinical biomarker data. Based on the reproducible 
linkage between serum or CSF urate and favorable PD outcomes, the elevation of urate itself rather 
than any of its possible mechanistic actions is arguably the most relevant target of inosine treatment 
to demonstrate, short of disease modification. Indeed, although the promise of urate-elevating 
inosine treatment is bolstered by consistent laboratory evidence of urate’s neuroprotective actions,12-
19 whether they rely on its direct antioxidant,2 metal chelator,4 Nrf2 activator217,218 or other properties 
is uncertain and therefore may be unnecessary (even if reassuring) to demonstrate in patients. 
Participants randomized to mild or moderate elevation treatment arms were titrated to an average 
inosine dose of 1.18 or 1.51 gm/day, and achieved average increases in serum urate of 2.3 and 3.0 
mg/dL, respectively (p<0.001).102 Serum urate levels were significantly elevated above placebo as 
soon as the 2-week visit (V01, Fig. 5B). They were relatively constant starting at the 2-week visit 
among those in the mild elevation group and continued to rise during titration until the 4-week visit 
(V02) among those in the moderate elevation group. The 12-week visit (V05) was the only one for 
which participants were asked not to take their study drug beforehand, accounting for the apparent 
dip in serum urate at the time of this trough measurement. Serum urate had fully reverted to baseline 
levels by the time of the safety visit, one month after discontinuation of study drug.102  
  
2)  Urate Elevation in CSF (Fig. 5C, 5D) 
CSF urate levels were measured once (at the 12-week visit) in 44 (59%) of the participants.102 For 
the others consent to lumbar puncture was not given (29%) or lumbar punctures were contraindicated 
(e.g., participants on warfarin; 4%) or were attempted but failed (7%). Among those measured, levels 
were 40% and 50% higher in mild and moderate elevation treatment groups, respectively, relative to 
placebo participants (p=0.006 and p<0.001, respectively; Fig. 5C). There was evidence of a 
difference by gender. CSF urate levels were lower among female than male placebo participants, and 
were significantly elevated in the active arms relative to placebo only among female participants 
(p<0.001 for females in both inosine arms; p=0.6 and 0.4 for males in the lower and higher inosine 
arms). Twelve-week serum and CSF urate levels in women and men were modestly correlated (r = 
0.43, Fig. 5D).  
 


 
 
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3) Proof-of-Principle for Potential Antioxidant 
Mechanism (Fig. 6) Inosine had a robust effect 
on plasma ferric reducing antioxidant power 
(FRAP)199, 
as 
expected 
given 
the 
major 
contribution that urate makes to plasma total 
antioxidant capacity in humans.3 Mild and 
moderate inosine elevated FRAP levels by ~35% 
and 50% at 6 months compared to baseline values 
and the elevations persisted until the third and 
final FRAP measurement between 12 and 24 
months,256 indicating that the putative benefit is 
not attenuated by compensatory mechanisms.  By 
contrast, neither CSF FRAP nor the urinary 
excretion 
of 
8-hydroxy-deoxyguanosine 
(8-
OHdG), a DNA repair product that has been 
proposed as a marker of DNA oxidative 
damage,200  was detectably affected by inosine.256   
 
 
C)  Preliminary Clinical Efficacy Data Analyses 
1) Acute efficacy (measured by change in total UPDRS score over 1-3 months): 
No symptomatic effect was apparent during initiation of inosine treatment (p value=0.45 for 
change in slope of total UPDRS from baseline to 3 months for mild versus placebo, and p=0.23 for 
moderate versus placebo) or during the 1-month wash-out period (p=0.71 and p=0.30).102 
 
2) Long-Term Efficacy: 
Although not powered to determine the effects of inosine on long-term changes in clinical outcome 
measures, preliminary data were collected. Time to need for dopaminergic therapy, which was the 
primary endpoint in DATATOP and PRECEPT trials, was reached in 63% of the randomized 
participants over an average of 18 months and did not differ significantly among the treatment 
groups (Fig. 7A).  
 
Plausible efficacy of serum urate elevation to delay symptomatic progression was assessed using a 
futility analysis approach equivalent to that employed for the primary analysis in the National 
Institutes of Health Exploratory Trials in PD (NET-PD) program201,202 except that the active 
groups were compared to our own relatively small placebo group rather than to historical controls, 
a more conservative comparison relative to practice in NET-PD.202 The two active groups were 
compared to a futility boundary (FB) calculated as 70% of the estimated progression among our 
placebo participants over 12 months. Both mild and moderate elevation treatments were non-futile 
based on this comparison for six parkinsonism (sub)scales including total UPDRS scores (Fig. 7B). 
Figure 6. Inosine dose-dependently and 
chronically 
elevates 
plasma 
antioxidant 
capacity (measured as FRAP). *p<0.001 
compared to baseline value; p=0.025 mod. vs 
mild Inosine group values at 6 months.256 


 
 
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To reduce the bias introduced by carrying forward the last UPDRS score for participants who 
develop need for dopaminergic treatment before the end of the observation period, we also 
employed two random-slopes models with follow-up truncated at the time of dopaminergic therapy 
initiation: one with no treatment x gender interaction but allowing unstructured profiles over time 
(i.e., separate treatment x visit estimates; Fig. 7C) and one including gender-specific effects of 
treatment but assuming linear trends in symptom scores over time (Fig. 7D). Like the futility 
analysis, these complementary approaches suggested attenuated clinical progression with 
increasing inosine doses, although the treatment differences were not significant.  
 
Note however that these analyses are substantially underpowered to determine an effect of inosine 
on rates of clinical progression over 2 years, with a sample over 7-fold smaller than would be 
required for 80% power. Whereas each inosine or placebo arm in SURE-PD included ~25 early PD 
subjects, we have estimated that each arm in the SURE-PD3 trial will require an n of 135 early PD 
subjects with demonstrated DAT deficits, corresponding to n=168 un-enriched early PD subjects 
(see Fig. 11 below). Even this 7-fold (168/25) sample size difference likely underestimates the 
inadequacy of SURE-PD’s sample size for efficacy analysis given that SURE-PD likely under-
dosed inosine for the higher urate elevation target (7.1 – 8.0 mg/dL) based on random urate 
sampling (vs. trough sampling in this trial; see Sec. 3.2.2 below). 
 
Figure 7. Secondary Analyses of Clinical 
Outcomes in the SURE-PD Study. 
A, Kaplan-Meier curves showing time to disability 
warranting dopaminergic therapy for up to 2 years 
of follow-up for each of the 3 treatment groups.    
B, Futility analysis of the change in total Unified 
Parkinson's Disease Rating Scale (UPDRS) scores 
over 12 months or until need for dopaminergic 
therapy, based on National Institutes of Health 
Exploratory Trials in PD (NET-PD) methods. Much 
or most of the 95% confidence interval for the mild 
or moderate inosine treatment groups, respectively, 
falls below the futility boundary (FB), defined as 
70% of the placebo group’s mean rate of change. 
C, The 24-month change of total UDPRS score 
estimated from a mixed-model analysis of variance 
(ANOVA) allowing unstructured profiles over time 
suggests a trend of decreasing rate with increasing 
inosine dose. D, A weaker trend is observed when 
using a complementary random-slopes model 
incorporating sex-specific effects and assuming 
linearity in change over time. E, Rates of mood 
change 
during 
the 
study 
as 
assessed 
by 
differences in Geriatric Depression Scale short form 
(GDS-S)189 scores over an average of 18 months’ 
follow-up. Receiving either dose of inosine, the rate 
appears slower (comparison-wise P < .001) 
compared with placebo. [Adapted from Fig. 3 in ref. 
102.] 


 
 
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In additional exploratory 
efficacy analyses stratified 
by gender, the rate of 
deterioration as measured 
by change in total UPDRS 
scores appeared to decrease 
significantly 
with 
increasing serum urate in 
women, but not in men 
(Fig. 
8). 
Whether 
this 
difference is related to the 
greater CSF urate elevation 
demonstrated in women (as 
above, 
Fig. 
5D), 
an 
unexpectedly 
greater 
biological response to urate 
among women, or the small 
sample 
size 
(e.g., 
contributing 
to 
an 
anomalous cluster of men 
on placebo with no UPDRS 
change (Fig. 8, right panel) 
is 
not 
clear. 
This 
preliminary suggestion of 
greater efficacy of urate-
elevating inosine in women 
than in men runs counter to 
the stronger epidemiological associations between urate and favorable PD risk or progression in 
men. The seeming paradox may be explained by naturally lower urate levels in women and the 
potential benefit of urate only at higher urate concentrations (contributing to significantly greater 
absolute increases in serum and CSF urate in women in SURE-PD102). Given this divergence of 
findings, no clear conclusions can be drawn from available data regarding gender-dependent 
differences in the effect of elevated urate levels. They do not warrant focusing an efficacy trial 
exclusively on either women or men. We believe that an equal potential remains for a protective 
effect of elevated urate for both women and men. 
 
There was no evidence of an effect of active treatment on cognitive function as assessed by MoCA 
Rasch scores203 although only non-demented individuals were enrolled and the placebo group 
showed no cognitive decline during the study. Mood as assessed on the GDS-S declined during the 
trial only among placebo participants, suggesting perhaps a preventative effect on depression of 
urate-elevating inosine (Fig. 7E; comparison-wise p <0.001 for each inosine group versus placebo). 
A possible prophylactic effect on the development of depression would be convergent with recent 
data from laboratory, epidemiological and PD biomarker studies. Inosine was recently found to 
produce beneficial effects in different animal models of depression.226 Additionally, lower urate has 
been linked to depression in a cross-sectional study.227 Also, as noted above, higher serum urate has 
been reported to predict a reduced risk of non-motor symptoms in PD, with lower urate levels 
among those PD patients who subsequently developed anxiety/depression domain deficits.219 
 
Based on the results of phase 2 study, inosine was found to be generally safe, tolerable, and effective in 
raising serum and CSF urate levels in early PD. The findings support advancing to more definitive 
development of inosine as a potential disease-modifying therapy for PD. 
Figure 8.  Exploratory long-term outcome: Rate of deterioration 
(change in total UPDRS) diminishes as urate increases in women, 
but not men in SURE-PD.102 For each subject the increase in serum 
urate from the baseline to the average of on-treatment values was plotted 
against the individual’s change in total UPDRS score using the 
conservative mixed model slope estimate shown in Fig. 7D. The placebo 
group data (circles) appear on the left of each plot given the expected 
lack of any urate change. Although a clustering of men in the placebo 
group showed no decline during the trial (filled circles in lower left) 
contributing to an overall trend toward worsening with increasing urate 
among men, it was not significant. 


 
 
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3. STUDY DESIGN 
3.1 
Overall Study Design and Plan 
A multicenter, randomized, double-blind, placebo-controlled trial of urate-elevating inosine to slow 
clinical decline over two years will be conducted on ~270 subjects with early PD.  Clinical decline is 
assessed as change in the primary outcome variable of the 
Movement Disorders Society-Unified Parkinson’s Disease 
Rating 
Scale 
(MDS-UPDRS),138 
a 
composite 
scale 
comprising patient- and clinician-reported parkinsonian 
outcomes. Secondary outcome variables include disability 
warranting initiation of dopaminergic therapy, specific non-
motor measures of cognitive, mood and autonomic function, 
and quality of life and disability measures. 
During the enrollment period, approximately 667 subjects 
will be screened from approximately 60 Parkinson Study 
Group (PSG) clinical centers in the US (Fig. 9). 
Approximately 270 of these subjects with early PD and 
serum urate ≤5.7 mg/dL will be randomly assigned in a 1:1 
ratio to oral placebo:inosine capsules. Inosine will be dosed 
by titration to achieve an elevation of serum urate to trough 
levels of 7.1 to 8.0 mg/dL, and placebo will be dosed to 
match the capsule titrations of the inosine group. After 
screening and randomization at baseline visit, subjects will 
undergo follow-up evaluations in clinic on treatment at 
Weeks 3, 6, 12 and Months 6, 9, 12, 15, 18, 21, and 24. A 3-
month wash-out period off treatment will include two 
monthly telephone evaluations and a final in-person 
evaluation at Month 27. (See timeline in Fig. 10.)  
 
 
 
 
 
 
 
 
 
 
 
Figure 
10. 
Diagram and Timeline of Treatment 
 
Figure 9. Major screening steps and 
impact. To achieve enrollment of 270 eligible 
subjects it is anticipated that ~667 consented 
subjects will be required, with screening visit 1 
(SC1) excluding 50% based on higher serum urate, 
SC2 excluding 10% more based on the general 
clinical features (including safety lab data), and a 
subsequent dopamine transporter (DAT) brain scan 
excluding an additional 10%. 


 
 
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3.2 
Rationale for Key/Novel Design Features 
 
The rationale for the planned phase 3 trial of inosine for slowing clinical decline in PD builds on earlier 
advances in preclinical to phase 2 clinical development, as detailed above (Sec. 2.2.3):  
x 
The rationale for elevating urate in PD is based on a convergence of laboratory, epidemiological 
and clinical data supporting its neuroprotective potential.  
x 
The rationale for selecting inosine as the means to elevate urate in PD is based upon knowledge 
of purine metabolism (Fig. 1), pharmacological data, non-clinical human experience, and clinical 
studies of non-parkinsonian subjects. 
x 
The rationale for advancing from a phase 2 to 3 clinical study is based on the positive results of 
the former (i.e., the SURE-PD trial) in supporting inosine’s safety, tolerability and validity as a 
urate-elevating strategy. In addition, the planned phase 3 design has benefited substantially from 
the successful design optimization features of SURE-PD. Specifically, phase 2 results have 
indicated that the higher inosine dosing regimen investigated in that trial is superior to the lower 
target range tested (based on greater serum urate increase without reduced tolerabililty). In 
addition to dose-selection, SURE-PD data have guided an improved strategy for prevention of 
uric acid urolithiasis and other protocol refinements. 
 
3.2.1 
Target Population – Four Defining Features 
3.2.1.1   Early PD 
People with early PD, and specifically those who have not yet developed sufficient motor symptom 
disability to require treatment with major antiparkinsonian agents, have been targeted in phase 3 as well 
as phase 2 development of inosine for several reasons: 
 
Generically, 
x 
Earlier disease implies a greater therapeutic impact for a putative neuroprotective strategy 
(i.e., more neurons to save). 
x 
Earlier, untreated disease affords the opportunity to employ validated metrics (e.g., the MDS-
UPDRS) of clinical disease burden and progression, which can be greatly confounded later in 
the disease by substantial and variable effects of antiparkinsonian medications like levodopa.  
 
Specific to inosine development, 
x 
Epidemiological evidence linking higher urate to reduced risk of developing PD are reflective 
of influences on disease pathophysiology early in the degenerative process, which may differ 
from that underlying clinical progression late in the disease. 
x 
Clinical evidence linking higher serum and CSF urate in early, untreated PD to favorable rates 
of clinical or radiographic progression argue further and more directly for targeting this early 
stage of clinical decline.  
 
Accordingly, as a general principle of guiding the design of this study we are seeking to replicate the 
features of DATATOP and PRECEPT studies – such as the early, untreated PD subpopulation that both 
targeted -- as faithfully as possible.  If the slower rate of progression among their subjects with higher 
urate represents a causal relationship then the best way to test this hypothesis is to recapitulate the 
features of those trials except that we will control rather than observe the concentration of urate, allowing 
us to determine its effects rather than simply its associations.   


 
 
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3.2.1.2   Lower Serum Urate 
A unique additional defining feature of the targeted PD population is its lower serum urate levels (≤5.7  
mg/dL on initial screening). This subset of early PD patients is rationally selected for urate elevation for 
several reasons.  
x 
First, for safety we considered elevating serum urate among those already in the upper range 
of normal at 7-8 mg/dL to clearly hyperuricemic levels above 8 mg/dL to pose an unnecessary 
risk to those subjects, especially because we are relying epidemiological and clinical studies 
with very few data for subjects above 8 mg/dL.   
x 
Second, those with lower serum urate are enriched for faster progressors (by definition of the 
relation between urate and progression), and thus may have more to gain from putative disease 
modifying benefit.   
x 
Third, the non-linear shape of the curve describing the urate-progression (see Fig. 3A 
above)35,36 and the urate-PD risk20,21,23,139 relationships further supports the rationale for 
enrolling all those below the 5.8 mg/dL (near the boundary between the 3rd and 4th quintiles in 
Fig. 3A). Because the risk of progression remains relatively high and unchanging (flat) across 
the lowest 3 quintiles for serum urate20,21,23,35,36,139 before dropping down more sharply to 
lower risks in the two highest quintiles (with the highest corresponding to ~7-8 mg/dL) it 
suggests that all in the selected subpopulation could gain a similarly full benefit of urate 
elevation to 7-8 mg/dL -- regardless of whether one starts at 3.5 mg/dL (lowest quintile) or 5.5 
mg/dL (middle quintile).  
3.2.1.3   Safety Exclusions 
Despite reassuring phase 2 safety data for urate-elevating inosine treatment and FDA guidance prompting 
liberalization of prior safety exclusions, several key risk factors for potential urate-related AEs are 
retained among the current eligibility criteria.  These include a history of gout or uric acid kidney stones, 
and low urine pH, which is a major risk factor for uric acid kidney stones.  In addition, a history of major 
cardiovascular events or renal dysfunction remains exclusionary. 
3.2.1.4   Enrichment for PD by Neuroimaging 
Despite the clinical expertise of the movement disorders specialists who have enrolled subjects in some of 
the largest trials of de novo PD, a substantial proportion (~10%) have been found to have dopamine 
transporter (DAT) scans without evidence of dopaminergic deficit (SWEDDs).30,140-144 These subjects are 
unlikely to have PD as reflected in their lack of clinical progression over years and measured by various 
clinical scales including the Experiences of Daily Living components of the MDS-UPDRS,141,145-147 which 
will be employed in the current trial. More recently, in the large observational biomarker cohort known as 
PPMI (Parkinson’s Progression Marker Initiative) 15% of subjects identified as probable early, untreated 
PD subjects were found to have SWEDDs148.  As these subjects do not generally decline further after 
enrollment, their inclusion in disease modification trials undermines the power to test the ability of a 
putative neuroprotectant to slow clinical progression (Fig. 11).  
 


 
 
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Specifically, for the current trial 
design we estimated that the ability 
to exclude 10% of otherwise eligible 
subjects based on a SWEDD would 
significantly reduce the number of 
subjects required to detect a minimal 
clinically important change (MCIC) 
of 6.3 total MDS-UPDRS points 
produced by urate-elevating inosine 
treatment after 2 years.  The power 
achieved 
with 
the 
planned 
enrollment of ~270 subjects with 
DAT scan-documented evidence of a 
striatal dopamine deficit would have 
required 66 more subjects to achieve 
in the absence of this screening 
method (Fig. 11).  Accordingly the 
SURE-PD3 trial design entails an 
additional screening evaluation at a 
local 
neuroimaging 
center 
to 
measure DAT ligand binding in the 
striatum as an anatomical marker of 
residual dopamine.   
 
Conversely, the novelty of implementing DAT imaging for diagnostic enrichment in PD intervention 
trials also reflects prior concerns for drawbacks to its inclusion. We have considered these and found that 
in the context of the current trial they are mitigated or do not apply: 
x 
 Reduced relevance of a DAT-scan enriched population to ‘real world’ PD, in which DAT 
scans (appropriately) are not routinely used or indicated for the diagnosis of PD. On the 
contrary, we contend that incorporating DAT scans for screening in de novo PD trials corrects 
an artifact of these trials rather than distorting the composition of early PD in clinical practice.  
Despite the considerable clinical expertise of Site Investigators who have conducted major 
clinical trials targeting de novo PD subjects (for the reasons noted above in 3.2.1a), these 
studies have consistently enrolled a substantial proportion (estimated 8-15%) who turn out to 
be unlikely to have PD.30,141-144,148 For example in the PRECEPT trial 10% of subjects had 
DAT scans without evidence of dopaminergic deficit (SWEDDs) at baseline30 and on follow-
up imaging years later148.  Recruitment pressure to diagnose early PD for such research 
protocols may encourage premature diagnosis of probable PD that would not normally be 
made at this point, at least not without assessment for responsiveness to dopaminergic drugs. 
This practical standard of diagnostic evaluation cannot typically be pursued in such de novo 
trials, for which these drugs are exclusionary. Thus in the artificial clinical context of disease 
modification trials for de novo PD, DAT scan imaging may compensate for the absence of 
clinical testing of dopamine replacement therapy and for unnatural pressures to enroll newly 
diagnosed early PD.  
x 
 Restricted availability of DAT neuroimaging. Earlier DAT imaging protocols relying on 
single photon emission computerized tomography (SPECT) of radioligands for DAT (like β-
CIT uptake scans in the PRECEPT trial) required specialized centralized imaging centers that 
necessitated long-distance travel by subject and their caregivers. However, in recent years 
standardized SPECT imaging scanners and protocols have become widely available 
throughout the US.   For example, 80% of the sites selected for participation in SURE-PD3 
Figure 11. Sample size reduction afforded by exclusion of 
SWEDD subjects. The treatment effect size (difference in the change 
of MDS-UPDRS over 2 years) that can be detected with 80% power 
decreases with increasing study sample size. The curve depicting this 
relationship under standard de novo subject screening protocols 
(dashed line) can be shifted to the left by excluding subjects who have 
DAT scans without evidence of a dopaminergic deficit (SWEDDs; solid line). 
For the targeted effect size of 6.3 points (see Sec. 10) the use of DAT scans to 
exclude an estimated 10% with SWEDDs would reduce the sample size by 
20% from 336 to 270. 


 
 
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reported having a DAT neuroimaging center at their institution, and the remaining 20% 
reported having access to a certified center an average of 11 miles away.   
x 
 Untenably high cost of DAT neuroimaging. DAT scans at an estimated $4.5k in direct costs 
for each (~$2k radionuclide + ~$1.6 local neuroimaging center fee + ~0.9k central 
neuroimaging core) in a study of 300 subjects constitute a major budgetary component. 
However these cost would be fully offset and yield a net savings in project costs in the current 
study.  Overall economy can result from improved statistical power or sample size reduction 
(by 66 subjects or 20% in this study, as above), with associated reduction in per-subject-fee 
payments, central management, vendor fees and project timeline. In addition the limitation of 
DAT neuroimaging to a single scan per subject as in this project, reduces costs substantially 
further compared to studies where DAT imaging is employed serially (a use that may offer 
ancillary value but falls outside the scope of this protocol). Lastly, the potential contribution of 
the radionuclide component by one of several commercial suppliers may reduce the costs 
further. Thus these contained costs may be significantly less than the savings due to a 
substantially reduced sample size and its resulting efficiencies.  
3.2.2 
Inosine Dosing Selection 
Uniquely for a drug trial in PD, subjects randomized to active drug (inosine) receive a variable dose 
titrated to a concentration range of serum urate rather than a set number of capsules or milligrams of the 
study drug. The dosing strategy is driven by evidence (reviewed above) that both safety and putative 
clinical efficacy follow serum urate values much more closely than the amount of inosine administered. 
The SURE-PD study pursued a secondary dose-finding goal (see Sec. 2.2.3 above) by comparing the 
safety and urate-elevating actions of two incremental dosing regimens that titrate the number of inosine 
capsule to elevate serum urate into target ranges of either 6.1 to 7.0 mg/dL, or 7.1 - 8.0 mg/dL.102 SURE-
PD data support excellent safety and tolerability for both mild and moderate urate elevation, whereas the 
higher dosing of inosine was confirmed to produce a greater increase in serum urate approaching levels 
that were associated with the lowest risk of disease progression in the PRECEPT and DATATOP 
cohorts.35,36 Accordingly, moderate elevation of serum urate (into the 7.1-8.0 mg/dL range) is 
selected as the target for study drug dosing among those randomized to inosine treatment in phase 3.102 
 
Several additional dosing refinements are incorporated into the phase 3 design based on knowledge 
gained from phase 2 development: 
x 
Tailored wash-in titration – In SURE-PD a conservatively slow titration schedule was 
employed to accommodate uncertainty over the variation and volatility of urate elevation upon 
initiation of inosine dosing, which began with a fixed low starting dose (500 mg bid) and ceiling 
doses mandated for all subjects during the wash-in phase. Analysis of SURE-PD provided 
evidence that baseline characteristics could be used to help predict an individual’s dosing 
requirement to achieve a targeted serum urate elevation. Specifically, baseline serum urate levels, 
gender and diuretic use (but not weight, measured 24-hour urine urate output, estimated 
glomerular filtration rate, and triglycerides) were found to meaningfully inform an individual’s 
future dosing requirements. Accordingly, the current protocol incorporates an algorithm to tailor 
initial inosine dosing based on these or other baseline characteristics of each subject, and thereby 
enhance the efficiency and safety of inosine wash-in. An identical algorithm will be implemented 
for subjects in the placebo arm.   
x 
Fewer initial visits – In SURE-PD a cautious study drug wash-in strategy included frequent 
blood draws and evaluations totaling 5 visits in the first 3 months after the baseline visit. 
However steady-state levels were rapidly achieved in the moderate urate elevation target range of 
7.1-8.0 mg/dL (by the second visit on study drug; see Fig. 5B, Sec. 2.2.3). Accordingly, the initial 


 
 
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density of evaluations has been reduced to 3 visits with blood draws in the first 3 months (see 
Sec. 7.7) on treatment in the phase 3 protocol. 
x 
Trough urate sampling – In the SURE-PD (phase 2) trial inosine was titrated to serum urate 
levels measured in blood drawn at the time of their visits, irrespective of when subjects had taken 
their morning study drug capsule(s). For improved safety and potentially efficacy, trough urate 
sampling (i.e. just before the first daily inosine dose) will be adopted in phase 3 and is expected to 
reduce under- and over- shooting the serum urate target range, and therefore to reduce fluctuation 
in dosage (capsules/day). Because in practice blood collection for trough urate levels may occur a 
few hours after the first daily dose is normally taken at home (but delayed on study visit days) 
this value obtained may slightly underestimate the trough value with regular inosine scheduling, 
but the small difference is not materially relevant. 
Note that the change from ad hoc sampling in SURE-PD (phase 2) to trough sampling in this 
phase 3 trial will also lead to a greater actual increase in serum urate despite the target range 
being nominally unchanged at “7.1-8.0 mg/dL”.  The difference can be appreciated by noting the 
~0.7 mg/dL drop in serum urate at the week 12 visit (V05 in Fig. 5B, Sec. 2.2.3), the one visit in 
SURE-PD at which serum urate was measured at trough (i.e., when subjects were instructed to 
hold off taking their medications that day until after the blood draw, due to a pharmacokinetic 
[PK] series being conducted at this visit).  Because the ad hoc sampling of urate in SURE-PD 
while highly variable in its timing actually averaged ~3 hr after the last study drug dose and given 
the PK demonstration of a time-to-peak serum urate concentration of ~3 hr after inosine dosing 
(unpublished data, SURE-PD Investigators), it is likely that the true average daily serum levels in 
these subjects were closer to the trough-sampled values at V05.  Thus it is expected that adoption 
of trough sampling will produce ~0.7 mg/dL higher serum urate levels compared to those 
achieved in the phase 2 study. Consequently the targeted trough level range of 7.1 – 8.0 mg/dL 
should now more closely match the uppermost quintile in the PRECEPT study (median value 7.5 
mg/dL), in which the lowest rates of clinical and radiographic progression were observed.35  
Importantly, the resultant greater urate elevation in SURE-PD3 would increase the risks of AEs 
compared to those assessed in SURE-PD. However the small increase in risk expected with 
trough dosing was deemed acceptable upon FDA review of the SURE-PD safety data assuming 
adequate justification for the threshold for above-range serum urate levels (>9.0 mg/dL) that 
trigger dose reductions (Sec. 5.1.2) in terms of estimated Cmax (peak concentration) after inosine 
doses. We fit a linear regression of Cmax estimates against trough serum urate levels from the 
timed PK series in SURE-PD. For a trough serum urate of 9.0 mg/dL, the estimated mean Cmax 
and standard error were 10.6 mg/dL and 0.20 mg/dL. The root mean square error was 0.633 
mg/dL, yielding a total variance for the prediction interval of 0.44. By those estimates, the 
probability of a Cmax ≥13 mg/dL, the alert level employed by the National Health and Nutrition 
Examination Survey (NHANES) program of the Centers for Disease Control and Prevention 
(CDC),215 is 0.00016, or 1 in 6400. This may slightly underestimate the risk of Cmax levels ≥13 
mg/dL due to measurement error in the trough serum urate levels used in the regression, possible 
underestimation of Cmax levels from the time series, and possible asymmetry in the among-
person distribution of Cmax levels conditional on a given trough, but having observed no serum 
urate levels greater than 11.6 mg/dL in SURE-PD, suspending treatment for any serum urate 
value >9.0 mg/dL appears more than adequate to keep the proportion of participants in the current 
study with transient (Cmax) peak levels above 13 mg/dL below 1 or 2 percent. 
 3.2.3 Primary Outcome and Analysis 
x 
Justification of primary outcome variable: MDS-UPDRS – Although the original UPDRS was 
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(DATATOP and PRECEPT) linking urate to slower PD progression, features of the revised MDS 
version warrant its use in place of the original as our primary variable of clinical PD status: 
o The MDS-UPDRS was developed to improve upon the original UPDRS by better 
assessing the more recently appreciated breadth of non-motor features. (See Sec. 6.2.1 for 
scale overview.)  
o Responsive to NIH guidance and to increased appreciation of the value of incorporating 
patient-reported outcomes (PROs) to enhance the relevance and validity of study results, 
approximately 40% of its items constitute PROs150 (vs. none in the original UPDRS).  
o Importantly for our phase 3 trial, although the MDS-UPDRS is closely modeled on and 
highly correlated138,149 with the original UPDRS, it appears to have greater sensitivity for 
monitoring clinical progression compared to original UPDRS.145 
o The MDS-UPDRS has been validated across its multiple motor and non-motor domains, 
and across cultures in independent studies.138,151,152 
o Availability of standardized training and certification 
153 facilitates quality and 
consistency of its administration. Training resources are accessible for both in–person 
and online training/reinforcement. 
o Increasingly adopted for use in PD clinical research, including as primary endpoint for 
trials designed to evaluate long-term disease-modification as well as for symptomatic 
effects.154 The MDS-UPDRS is now recommended155 (along with the original UPDRS) as 
a core instrument among NINDS common data elements (CDEs) for PD studies. 
x 
Justification of primary analysis: difference in change in MDS-UPDRS over 2 years -- 
Neuroprotective candidates with dopaminergic properties, even those with only mildly 
symptomatic antiparkinsonian effects (e.g., selegeline, rasagiline), have proven challenging to 
assess for their disease-modifying potential. As a result more complex (e.g., delayed-start) study 
designs have been pursued in attempts to tease apart symptomatic and neuroprotective effects.156-
159 However, the complexities of these designs then created their own challenges of 
interpretation.160  By contrast, for candidate protectants lacking symptomatic efficacy the most 
rational phase 3 efficacy designs may rely on a simpler structure of parallel groups assessed using 
a ‘change in a rating scale over time’.154 Thus while decidedly problematic in the study of a 
symptomatic agents for their influence on long-term clinical course, this parallel group design 
remains the historically best studied and most common ‘neuroprotection’ trial design in PD.156,157 
It is well suited to putative protectants like inosine that are unlikely to acutely impact 
dopaminergic neurotransmission or parkinsonian symptoms.  
Accordingly, changes in scores on an appropriate clinical rating scale – the MDS-UPDRS as 
justified above—will be compared between early PD subjects randomized to placebo or urate-
elevating inosine treatment over a 24 month period for the primary efficacy analysis of the trial. 
The design and primary analysis are further supported by: 
o Evidence of non-futility of inosine (and possible efficacy in subgroup analyses) using 
change in UPDRS scores from the preceding phase 2 experience in the SURE-PD 
study102. (See Sec. 2.2.3). A recently proposed ‘road map’ to clinical development of 
candidate disease-modifying agents158 highlights the efficiency of sequential 
investigations and the value of advancing to fuller efficacy trials with an outcome 
analysis similar to that used in demonstrating non-futility. 
o Observational data35,36 from the DATATOP and PRECEPT trial cohorts linking higher 
urate with favorable rates of progression assessed as difference in UPDRS change over 
two years, approximating the planned primary efficacy analysis. Although higher urate 


 
 
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was also a significant predictor of delayed disability (warranting dopaminergic 
medication) in these cohorts, comparing MDS-UPDRS change has advantages as our 
primary outcome variable. Change in a continuous variable over time can offer greater 
statistical power over that achieved with a dichotomous endpoint like disability 
warranting dopaminergic therapy.159,161 Differences in proportions reaching this disability 
milestone will included among secondary analyses of the trial.  
o Recent/current use of this parallel group design with change in UPDRS over time in the 
primary efficacy analysis in the QE3, FS-ZONE and STEADY-PD III trials of non-
dopaminergic agents (coenzyme Q10, pioglitazone and isradipine) posited to have 
disease-modifying properties.162 
o Wash-out period option for confirming lack of symptomatic efficacy, though not part of 
the primary analysis, may strengthen the evidence against an acute antiparkinsonian 
action of inosine. In the SURE-PD trial no effect of urate-elevating inosine treatment was 
apparent during the 3-month treatment initiation period or conversely during the 1-month 
wash-out.102 If a lack of symptomatic efficacy were replicated using MDS-UPDRS with 
the greater sample size of the phase 3 trial, then a positive result of divergent rates of 
change over two years in the primary analysis would be more suggestive of a disease-
modifying benefit of urate-elevating inosine treatment. However, even under this 
scenario in the absence of a commensurate effect on an associated meaningful biomarker 
of PD progression the results would not suffice to prove slowing of the disease. An 
indication for disease modification would thus likely require additional clinical 
investigation. 
3.2.4 
Additional Key Safety Features 
3.2.4.1   Pre-Study Determinations of Food and Drug Interaction  
In order to further reduce the variability in inosine bioavailability and urate elevation, and the associated 
AE risk, standard drug-drug and drug-food interaction studies (per FDA guidance163) will be completed in 
advance of the trial.  Evidence for substantial interactions will prompt modified dosing instructions 
limiting concomitant dosing with specified medication and/or requiring subjects to take study drug on an 
empty stomach (or consistently with or without food).   
3.2.4.2   Modification of Uric Acid Stone Risk Factor Management Plan 
The likelihood of gouty arthritis and uric acid urolithiasis – the two major known side effects of 
hyperuricemia –increase with age.64,89,164-166 Accordingly, these are the main inosine-induced AEs 
anticipated in this study of early PD patients, who are expected to be over 60 years of age on average.30,31 
To help avoid them, any history of gout or uric acid urolithiasis will remain an eligibility exclusion 
criterion, as will a screening urine test result showing low pH (≤5.0), a major risk factor for uric acid 
urolithiasis. 29, 64, 87,88  
Although no cases of gouty arthritis developed during SURE-PD, three subjects developed urolithiasis on 
inosine treatment and uric acid composition was documented in one.102 Because urine pH can be readily 
identified and raised with common oral alkalinization treatments64,89 the phase 3 trial will employ 
additional measures to monitor for uric acid urolithiasis risk and a lower threshold for initiating standard 
alkalinization therapy.  Based on SURE-PD data linking the presence of uric acid crystalluria (UAC) and 
low urine pH to the subsequent development of uric acid stones, urine samples provided at each visit will 
be processed centrally for blinded UAC determinations as well as pH measurements. These data will be 
followed and alkalinization will be triggered by persistently acidic urine (PAU) with or without the 
presence of UAC as follows (detailed in Sec. 8.4): 


 
 
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x 
Urine pH ≤5.0 in 2 consecutive samples 
x 
Urine pH ≤5.5 in ~3 consecutive samples (or fewer in the placebo group as needed to 
maintain a similar likelihood of alkalinization in the placebo and inosine groups; see Sec. 
8.4.2) 
x 
Uric acid crystalluria + urine pH ≤5.5 in 1 of the last 2 samples 
Alkalinization therapy will be continued, advanced or reduced based on an algorithm that considers urine 
pH and crystalluria responses. Subjects on alkalinization therapy will also be carefully monitored for any 
adverse effects of alkalinization. Although asymptomatic renal stones can be detected by ultrasonography, 
its sensitivity is relatively low91 and is considered an appropriate monitoring test only when urine pH is 
below 5.5 in those who are otherwise at high risk of uric acid urolithiasis.64 Computerized tomography 
scans have the greatest sensitivity for uric acid renal stones (which are not radioopaque on plain 
films),91,167 but drawbacks including the serial low level radiation exposure that would be required for 
monitoring offset any diagnostic benefit in the present study. All subjects will also be counseled on 
avoiding dehydration, an avoidable and remediable risk factor for both gout and urolithiasis.29 
By reducing the number of UA urolithiasis AEs, these bolstered prevention measures will help minimize 
unblinding. Similarly, knowledge gained from experience with inosine in phase 2 will reduce unblinding 
as we have observed that stones can form on placebo,26 do not necessarily contain UA,102 and would 
normally be managed without disclosure of treatment assignment (see Sec. 8.8). 
3.2.4.3   Reducing Risk of Possible Cardiovascular Adverse Effects 
Also of particular relevance to the PD population is the risk of cardiovascular disease (CVD), which is an 
important even if uncertain risk of higher urate levels, as detailed above. Individuals with higher serum 
urate have a significantly increased risk of hypertension, coronary heart disease, and stroke.168,169 
Although these associations may in part be confounded by obesity and other risk factors,98,105 potential for 
a long-term neuroprotective effect of urate or its precursors must be weighed against potential adverse 
cardiovascular effects.  It is worth noting that amongst PD patients in developed countries CVD is 
common and indeed is a leading cause of death.170-172 Moreover, CVD and its major sequelae of 
myocardial and cerebral infarction are far less reversible than urate-related crystal disease.  On the other 
hand, recent data from a small study of urate-elevating inosine in MS138 and from the SURE-PD trial 
showed no evidence of blood pressure elevation compared to placebo despite months to years of 
substantial elevation of serum urate levels. 
The main approach to reducing possible CVD risk during the SURE-PD trial was through the exclusion 
of those with a significant history (Sec. 4.2), particularly prior myocardial infarction or stroke and heart 
failure with an ejection fraction <45%. The lack of evidence for inosine-associated CVD events in the 
SURE-PD trial reflects a sample size and follow-up period that are too small to offer substantial 
reassurance. Accordingly, these exclusion criteria will remain unaltered in the phase 3 trial. Assessments 
for development of CVD during the trial will include frequent review of all AEs, and regular blood 
pressure and electrocardiographic monitoring.  
Although serum urate has also been linked to metabolic syndrome and diabetes,173,174 which is itself a 
major risk factor for CVD, SURE-PD data102 showed no effect of long-term urate-elevating inosine 
treatment on body weight or blood sugar.  In any event, risk of type II diabetes-related CVD will also be 
reduced through exclusion of those with evidence of CVD. 
3.3 
Study Duration and Periods 
The total time of active participation in the study (including screening, treatment and wash-out periods) is 
2.25 years for each subject completing the study (see Schedule of Activities; Sec. 7.7), and includes:  


 
 
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x 
Screening of up to 60 days from Screening Visit 1 (SC1) to enrollment at Baseline Visit. Because 
of the substantial (~50%) chance that the results of serum urate screening test will be exclusionary 
(Fig. 9, Sec. 3.1), the screening process at PSG sites is split into two visits with testing on a brief 
initial visit (SC1) primarily limited to the serum urate measurement. For those subjects who pass 
SC1, most of the remaining screening procedures are conducted on a longer second screening visit 
(SC2) and if still eligible then a subsequent DAT brain scan at a local neuroimaging center. 
x 
Treatment (Period 1) of 720 ± 7 days (~24 months) approximates the 2-year observation periods 
of the DATATOP36, PRECEPT35 and SURE-PD102 studies, on which the present trial is modeled. 
Extending follow-up beyond 24 months would provide diminishing returns as the primary 
outcome variable of MDS-UPDRS score is censored from the primary analysis after initiation of 
symptomatic antiparkinsonian therapy, which is expected to have occurred in the majority (two 
thirds) of placebo subjects by that point. Randomized, placebo-controlled, double-blind treatment 
is initiated at the baseline visit (BL) and gradually advanced and titrated up to a maximum 6 
capsules/day or until the target serum urate range of 7.1-8.0 mg/dL is reached in the inosine-
treated group. After wash-in/titration visits (V01, V02) at 3 and 6 weeks after BL, scheduled visits 
(V03 - V10) will occur at 3-month intervals for clinical and safety assessments, including a serum 
urate measurement for any algorithmic dosage adjustments needed to maintain levels within the 
7.1-8.0 mg/dL target range for those in the inosine group. Mirrored adjustment in the number of 
placebo capsules/day help ensure subject and site staff remain blind to treatment assignment. 
x 
Wash-out (Period 2) of 90 ± 7 days, ending ~27 months after enrollment.  Three monthly 
evaluations will be conducted after discontinuation of study drug at V10 (after 24 months of 
treatment), two by phone (TE1 and TE2 at months 25 and 26, respectively) and the final visit (SV) 
in person at month 27. The multiple visits will allow for serial assessments of the need for 
dopaminergic therapy during and after the reversal of any short-term effect of inosine or its 
withdrawal, as well as for any late adverse effects of the treatment or its withdrawal.  
 
4   SELECTION AND ENROLLMENT OF SUBJECTS 
 
After screening approximately 667 consented subjects, ~270 women and men (age 30 or older) with early 
idiopathic PD are expected to enroll at approximately 60 PSG study sites (see Fig. 9 in Sec. 3). At the 
time subjects undergo randomization they will have not yet developed sufficient disability to require 
treatment with dopaminergic agents other than MAO-B inhibitors, and they will not appear likely to 
develop it imminently (i.e., within 3 months).  
 
Subjects withdrawn from the study will not be replaced.  
4.1 
Inclusion Criteria 
Study subjects meeting all of the following criteria will be allowed to enroll in the study:  
1. Willingness and ability to give written informed consent and to comply with trial procedures. 
2. Fulfillment of diagnostic criteria for idiopathic PD with at least two of the cardinal signs of PD 
(resting tremor, bradykinesia, rigidity) present at 2nd screening and baseline evaluations, as 
assessed by the Site Investigator. 
3. Absence of current or imminent (within 90 days of enrollment) PD disability requiring 
dopaminergic therapy, as assessed by the Site Investigator. 
4. Modified Hoehn and Yahr Scale Stage 1 to 2.5 inclusive. 


 
 
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5. Age 30 or older at the time of PD diagnosis. 
6. Diagnosis of PD made within 3 years prior to 1st Screening Visit. 
7. Non-fasting serum urate ≤ 5.7 mg/dL at 1st Screening Visit (SC1). 
8. If the subject is female, then: 
a) Being surgically sterile (hysterectomy or tubal ligation), or  
b) Being postmenopausal (last menstruation was two years or more prior to 2nd Screening 
Visit), or  
c) For those of childbearing potential 
• Using a reliable form of contraception for 60 days or more prior to Baseline Visit 
and agreeing to continue such use for 30 days post last dose of study drug.  
Reliable forms of contraception include: abstinence; implanted, injected or oral 
contraceptives (birth control pills), intrauterine device in place for at least 3 months 
prior to Baseline Visit, vaginal ring with spermicide, barrier with spermicide such 
as male or female condom, diaphragm or cervical cap, transdermal patch; male 
partner with vasectomy. 
• And having a negative pregnancy test at the 2nd Screening Visit. [Note that a 
urine pregnancy test will be performed at screening on all women who are not at 
least two years postmenopausal or surgically sterile.]  
4.2 
Exclusion Criteria 
Study subjects meeting any of the following criteria during screening evaluations will be excluded from 
entry into the study: 
1. Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, 
cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease. 
2. Dopamine transporter brain scan without evidence of dopamine deficit. 
3. History of gout. 
4. History of uric acid or urate urolithiasis, or recurrent urolithiasis all of unknown type. 
5. A screening test positive for uric acid crystalluria, urine pH ≤ 5.0, or an estimated glomerular 
filtration rate (GFR) < 60 ml/min/1.73 m2. 
6. History of myocardial infarction or stroke. 
7. Symptomatic congestive heart failure with a documented ejection fraction below 45%. 
8. History of severe chronic obstructive pulmonary disease. 
9. History of nephrectomy. 
10. Mini Mental State Exam score < 25; i.e., a score of 0 to 24. 
11. Use of any anti-parkinsonian medication (including levodopa, dopamine agonists, amantadine, 
entacapone and the anticholinergic agents trihexyphenidyl and benztropine) other than monoamine 
oxidase-B inhibitors within 60 days of Baseline, or in excess of 90 days. 
12. Change in the dosage of (or initiation of) a monoamine oxidase-B inhibitor within 90 days prior to 
Baseline, i.e., entry on a MAO-B inhibitor requires a stable dosage for the 90 days prior to 
Baseline. 


 
 
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13. Use of the following within 30 days prior to the Baseline Visit: inosine, allopurinol, febuxostat, 
probenecid, more than 50 IU of vitamin E daily, or more than 300 mg of vitamin C daily (though a 
daily standard multivitamin such as Bayer One-A-Day® or Centrum® is permissible), reserpine, 
methylphenidate, amphetamines, cinnarizine, monoamine oxidase-A inhibitors, tetrabenazine, 
neuroleptics or other dopamine blocking drugs.  
14. Use of the following within 90 days prior to the DAT neuroimaging screening evaluation: 
modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, or 
amphetamine derivative. 
15. Unstable dosing of a thiazide -- such as hydrochlorothiazide (e.g., Esidrex), chlorothiazide (e.g., 
Diuril), chlorthalidone (e.g., Hygroton), indapamide (e.g., Lozol), metolazone (e.g., Zaroxolyn), 
which are permissible as long as the subject is on a stable dose from 1 week prior to the 1st 
Screening Visit through the Baseline Visit. 
16. Known unstable medical or psychiatric condition that may compromise participation in the study. 
(Note that difficulty swallowing large capsules might preclude participation due to the size of the 
study drug capsules.) 
17. Clinically serious abnormality in the screening visit laboratory studies or ECG, as determined by 
the Site Investigator. 
18. Participation in another investigational treatment study within 30 days prior to the Baseline Visit. 
19. Known hypersensitivity or intolerability to inosine. 
20. Known hypersensitivity to DaTscanTM (either to the active substance of 123I-ioflupane or any of the 
excipients).  
4.3 
Treatment Assignment Procedures 
Each subject who meets all eligibility criteria and who has signed and continues to give informed consent 
will be randomized to receive either oral inosine or matching placebo for approximately 24 months of 
treatment.   
4.3.1  Identification, Recruitment and Retention of Candidates 
Subjects will be recruited to enroll at approximately 60 PSG clinical sites in the US. Each site employs a 
PSG-credentialed Site Investigator and a study coordinator, and has been selected by the Steering 
Committee for this trial from ~120 US PSG sites based on recruitment record from prior trials as well as 
compliance with prior study protocols and regulations, higher proportion of underrepresented ethnic and 
racial minorities among the patient population, and availability of necessary resources (e.g., local DAT 
scan accessibility).  As credentialed PSG investigators all Site Investigators are well trained in the 
diagnosis and management of PD, are experienced in the conduct of clinical research, and will be certified 
in the administration of the MDS-UPDRS138.  
 
Providing 60 sites an average enrollment period of 18 months yields realistic average site rates of 
recruitment (7 consented/site/year) and enrollment (3 randomized/site/year) despite the narrow eligibility 
criteria, which account for the expected exclusion of 60% of consented subjects during screening.  The 
projection of 3.0 enrollments/site/year was calculated as 270 enrolled/60 sites/1.5 years, and is realistic as 
it closely matches the enrollment achieved under the final protocol of our preceding SURE-PD study. 
Note that the need to mobilize and motivate a large group of high quality PD clinical sites to serve as both 
backup and active sites is a particular challenge to which the PSG clinical trial network is well suited 
based on the track record and commitment of its member investigators and coordinators, who author all 
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Based on our prior experience with clinical trials in PD, including SURE-PD, we anticipate that most 
subjects will be recruited locally for this trial through the site’s center and institutional network. Training 
and recruitment materials will be developed based on our experience with SURE-PD and informed by the 
experience of collaborating recruitment specialists of the NINDS Office of Clinical Research, Michael J. 
Fox Foundation, Parkinson’s Disease Foundation (PDF), NCRI and the trial Steering Committee.  IRB-
approved materials will be tailored to target both potential subjects (e.g., waiting room brochures, 
PowerPoint slides) and clinicians at the study sites and within their referral networks (e.g., bullet point 
cards highlighting key points of the trial’s purpose, eligibility criteria and contact info).   
 
x 
Local outreach will be conducted by site staff and partnered patient support groups and 
advocates (through PSG collaboration with the PDF and its PAIR advocacy program175) with the 
encouragement and support of the Clinical Coordinating Center (CCC). Activities will range from 
letters to local movement disorder physicians and general neurologists, clinical site institutional 
webpage postings, area clinician symposia highlighting the study, local media engagement, and 
PD support group meetings.   
 
x 
Informatics- and network-based candidate identification initiatives will build on novel 
strategies explored during the SURE-PD trial. Outlined below are two innovative methods for 
accelerating candidate referral – one relying on advances in large healthcare database searches, 
and one on a national neuroimaging network with early access to de novo PD subjects. 
x 
A healthcare network database and its user interface originally developed for digital ‘chart 
review’ research at MGH and known as the Research Patient Data Registry (RPDR)228,229 was 
employed late in the SURE-PD trial under a 2011 IRB protocol amendment at MGH to boost the 
rate of subject enrollment there. The approach effectively identified early untreated PD patients 
who may have been recently diagnosed by a primary care physician or general neurologist, who 
was then contacted to encourage referral to the trial as appropriate. Such de novo patients may be 
interested in participating but unaware of their candidacy, and often may not be referred to a 
movement disorders trial site until months or years later, when their narrow window of candidacy 
may have closed due to clinical progression and initiation of antiparkinsonian medications.  
Depending on the size of a healthcare database/network its accessibility could increase a 
site’s subject accrual several fold. In the last few years the software platform for RPDR (now 
known as i2b2 for ‘Integrated informatics from bench to bedside’230,231) has been adapted by Dr. 
Shawn Murphy and colleagues at MGH for distribution to other healthcare network databases and 
installed at institutions worldwide,232 including 66 in the US (~32 of which are PSG sites 
participating in this phase 3 trial). I2b2 fully complies233 with patient privacy standards of the 
Health Insurance Portability and Accountability Act (HIPAA), and has successfully identified 
recruitable cohorts with cancer, depression and epilepsy.234,235 
After obtaining local IRB approval each participating site that adopts this optional 
method would conduct automated ~monthly screens of their broader healthcare network’s 
database with a query structure including several basic features: 
x 
+  PD diagnosis code within past 3 years, 
x 
No PD diagnosis code > 3 years ago, 
x 
No exclusionary PD medication (e.g., levodopa, dopaminergic agonists), 
x 
No exclusionary medical condition (e.g., gout, myocardial infarction). 
The diagnosing physician of each identified candidate will be contacted by site staff with a 
personalized, template-based email or phone call explaining the subject’s potential eligibility and 
options for referral, if the provider concurs, to the local trial site. 
Of note, this recruitment strategy may provide a novel solution to the persistent challenge 
of improving enrollment rates among underrepresented minority populations. A repeatedly 


 
 
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identified impediment is the lower rate of referral to specialist care in general236,237 and PD trials 
in particular among African-American and Hispanic patients.238,239 Despite increasing attention to 
this challenge it has proven resistant to bolstered efforts and interventions designed to enhance 
minority enrollment in PD research studies.240,241 Hence, a near real-time, informatics-based 
method of recruitment from across a site’s broader healthcare network offers an innovative 
alternative strategy, as it may accelerate or engender minority referrals, which otherwise might 
not have occurred in time or at all.  
Lastly, the efficiency of this informatics-based referral process, which entails 
numerous clinical sites may be enhanced through a centralized program linking multiple 
i2b2-enabled sites, and known as SHRINE (for Shared Healthcare Information 
Network).242 SHRINE was recently established by Dr. Murphy’s team at MGH together 
with the CTSA-supported Harvard Catalyst program, which now provides this service to 
investigators as a means to aggregate queries and responses from multiple i2b2 databases 
across multiple institutions. Pilot programs successfully demonstrated the feasibility of 
linking i2b2-enabled sites nationally for identifying disease-specific cohorts ranging from 
atrial fibrillation to autism to epilepsy patients243,244 and suitable for subject recruitment. 
x 
Additional strategies for subject identification may be tailored to this phase 3 inosine trial based 
on its unique eligibility criteria.  A dopaminergic deficit on DAT neuroimaging is a particularly 
discrete criterion that will generally be fulfilled as the final step in the study screening procedure 
prior to enrollment for eligible subjects.  However, DAT scans are also obtained as part of routine 
clinical care in the setting of diagnostic uncertainty over early PD and related conditions. A 
positive result (low levels of DAT ligand uptake into the striatum) can indicate or confirm a 
clinical diagnosis of probable PD (e.g., when the scan is ordered to distinguish between PD 
versus essential tremor, and other forms of parkinsonism are less likely).  Neuroimaging centers 
within 60 miles of an active trial site (~180 = ~3/site x 60 sites) will be invited to provide an IRB-
approved digital trial flyer (with trial description, eligibility criteria and contact info) with each 
positive DAT scans report sent to the ordering clinician.  S/he can then determine whether the 
trial may be appropriate and of value for the patient and how to inform the patient.  
Neuroimaging centers in the vicinity of participating clinical sites may be contacted 
individually by site staff.  Alternatively, a more efficient centralized approach may be employed 
through collaboration with a commercial radiotracer provider, which would provide a 
digital/paper flyer to the neuroimaging center along with each delivered dose of DAT 
radionuclide. The provider would identify imaging centers for this program based on knowledge 
of the overlap between the national network of DAT scan-certified neuroimaging centers and the 
trial’s roster of activated clinical sites. Privacy of potential subjects identified in this manner 
would be preserved because their identities and test results would not be provided by the 
neuroimaging center to any trial staff or to the radiotracer company. 
 
x 
National/centralized outreach will include:  
o announcements on NIH’s clinical trials registration website, the PSG website (which is 
also linked from other PD advocacy organization’s websites), FoxTrialFinder.org176 and 
in PD newsletters and web postings.  
o a dedicated trial website will be developed and serve as the digital hub featuring layered 
trial information and site contact to facilitate both lay and clinician referrals of 
candidates. A toll-free ‘800#’ will be routed to NCRI staff. 
x 
social media outreach program will direct traffic to the trial website or 800#. A core media 
element will be a brief, professionally produced informational/promotional video on the trial, and 
will reside on MGH’s Youtube account as well as on the trial website.  It will expand on our 
experience 
developing 
a 
prior 
video 
posted 
late 
in 
SURE-PD 
recruitment 
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advocate as well as investigator presenters. Partnering individuals and institutions (those of the 60 
active clinical sites as well as foundations; e.g., see PDF President’s letter) will post content to 
their Twitter, Facebook, Vine, Flickr, etc. accounts, linking to trial website and/or the Youtube 
video (and in turn the website).  
x 
well-publicized safety guidance on the risks of self-treating with inosine outside of a carefully 
conducted clinical study (which can rigorously avoid, monitor and manage AE risk factors); it 
may help preserve eligibility of the de novo PD population while fostering public safety. SURE-
PD-related press releases and educational postings (including a series developed by the Michael J. 
Fox Foundation as grantor) explicitly tempered enthusiasm with caution and highlighted safety 
priorities. This public information stance is an important responsibility because regular, 
knowledgeable monitoring of serum urate and urine pH is required to avoid SAEs of inosine 
taken to meaningfully elevate urate.  
However, despite the availability of inosine as an over-the-counter (OTC) nutritional 
supplement its widespread use among de novo subjects is unlikely to occur or pose a significant 
challenge to study recruitment. Given the complexities and inherent risks of self-treating with 
inosine to elevate urate, together with our continued emphasis on disseminating balanced 
scientific information on the topic, it is expected that few PD patients will be ineligible due to 
OTC inosine use. Although little information is available on trends in nutritional supplement 
consumption, a review of the publicly accessible database of medication and supplement usage by 
9,052 people with PD who participate in the self-selected ‘PatientsLikeMe’ PD community250 
found that 0 listed use of inosine (ten months after publication of SURE-PD results). By 
comparison, the same PD cohort included 21 on isradipine, 80 on vitamin E, 382 on coenzyme 
Q10, and 909 on rasagiline. The lack of reported inosine usage in PD likely reflects truly low 
usage, given that by contrast, inosine was listed as taken (up to 2,000 mg/day) by 10 of 6,883 in 
the ‘PatientsLikeMe’ ALS community on the same website.250 The apparent rarity of PD patients 
taking inosine may relate to the above safety guidance, possibly in combination with the cautious 
(reduced risk-taking) personality features often ascribed to people with PD251 – especially those 
not taking dopaminergic agonists such as de novo patients.252 By contrast, greater usage in the 
ALS population may reflect its relatively dire prognosis, which lowers the threshold for accepting 
AE risks of unproven therapies.  
Lastly, because serum urate levels will be routinely screened and monitored, any 
surreptitious use of OTC inosine may be readily detected at screening and during enrollment 
(when SURE-PD data showed no evidence of OTC usage; see Sec. 2.2.3A above). Thus ‘drop-in’ 
non-compliance is unlikely to be a significant problem, but if it were it would be readily detected 
and then addressed through ‘as-treated’ secondary statistical analyses (Sec. 10.1.3 and 10.5.2).   
 
Systematic retention measures will be similarly deployed. Key strategies that contributed to excellent 
retention (>98%) in SURE-PD will be replicated and additional approaches employed given that larger 
trials can be more susceptible to attrition:  
x 
Our core, critical retention strategy of ensuring a highly motivated and informed site staff was 
successful in SURE-PD and will again be prioritized.  
x 
In addition, a debit card-based, HIPAA-compliant subject reimbursement system tailored to 
clinical trials (Payoneer®; New York, NY) was implemented to enhance retention as well as 
recruitment in SURE-PD, and was universally appreciated by study subjects based on site staff 
feedback. Similarly, site staff endorsed its operational efficiency and their minimal burden due to 
its central administration (with weekly reloading of debit cards by coordination center staff using 
anonymized subject ID numbers).  
x 
Additional retention plan elements emphasized based on experience with recent early stage PD 
trials include:  
o tailoring communications with subjects (study drug dose adjustments, visit reminders, 
etc.) to their preferences; e.g., via phone, email or text,  


 
 
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o ensuring that the Investigator devotes time to meet with the subject at each visit,  
o efficiently managing visit time –  avoid rushing subjects and minimize their wait times,  
o providing flexibility in accommodating patients’ schedules ; e.g., with after-hours visits 
for patients working 9-5 jobs, 
…essentially all courtesies that convey respect for the subjects and their major contributions 
to the research. 
4.3.2 Monitoring and Adaptation of Recruitment & Retention 
Upon obtaining IRB approval, each site will begin tracking all identified potential study subjects.  
Candidates who are asked to participate in this trial will be recorded on a Confidential Participant Log, 
which is kept by the site study staff in a secure location.  In addition de-identified information regarding 
how subjects learned about the trial, referral sources, reasons for ineligibility and reasons for non-
participation by eligible subjects will be tracked on the Screening/Demographics form in the eClinical 
system for all subjects who have signed a consent and are screened for the study.  These secure reporting 
forms will be updated regularly by site staff with current numbers of identified potential candidates, 
consented, and at each stage of screening (SC1, SC2 and DAT scan 1 [DS1]) prior to enrollment. They 
will be reviewed and incorporated into monthly study-wide tabulations of recruitment and enrollment 
statistics for distributions to site staff, coordination center staff, trial Steering Committee (SC), Data and 
Safety Monitoring Board (DSMB) and NINDS.  
 
A recruitment and retention committee (RRC), which as a subcommittee of the SC will report directly to 
it, will meet regularly prior to and during the active enrollment and follow-up periods (specifically, at 
least every other month until full enrollment) in order to optimize recruitment and retention.  The RRC 
will comprise relevant members of the SC (trial PI, prior SURE-PD project manager and patient research 
advocate), key trial staff (coordination center project managers and representative site investigators and 
coordinators) and collaborators (recruitment and retention specialists from the Michael J. Fox Foundation 
and NINDS).  In addition to ensuring the design and implementation of planned recruitment strategies, 
the RRC will continually review recruitment and enrollment activity statistics and also any changes in the 
broader recruitment landscape (e.g., shifts in prescribing patterns that impact eligibility criteria, or the 
advent of competing trials, opportunities for media engagement). As warranted it will make 
recommendations for modification of recruitment and retention practices to coordination center staff (e.g., 
to facilitate creative publicity strategies) and the SC (e.g., to consider altering eligibility criteria or 
activating backup sites). 
 
In addition to frequent central review of recruitment and retention status, regularly scheduled conference 
calls will be held for all Investigators and Coordinators to discuss retention strategies and share 
successes/failures with each other and coordination center staff. These exchanges will include a particular 
focus on effectiveness of strategies for enhanced recruitment and retention of participants in minority 
populations.  In parallel, project managers will routinely monitor each site’s subject, consent, enrollment 
and premature withdrawal rates, reporting outliers directly to the RCC and PI. For a site with a problem in 
any category, a rapid assessment of the cause and action plan will be reviewed with the site. 
4.3.3  Consent Procedures 
During or before a screening visit, the subject will be thoroughly informed of all aspects of the study, 
including all scheduled visits and activities, and will be able to ask questions. The subject will be 
requested to sign and date the informed consent form prior to undergoing any study-specific procedures.  
The original signed and dated informed consent form must be retained by the Investigator in the subject’s 
file and a copy must be provided to the subject. Subjects may also consent to optional substudies: a) blood 
collection for future biomarker research (see Section 16.2.14), with consent obtained at SC1 at the time of 
parent trial consent, b) smartphone-based outcomes research (see Section 16.2.15), with consent obtained 
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that used for the parent study, and/or c) second DAT neuroimaging to assess change from pre-baseline 
imaging (see Section 16.2.11.2), with consent obtained at or prior to visit V10. 
4.3.4 Identification Number and Intervention Group Assignment Procedure 
Subjects will be given three types of identification numbers: 
1. 9-digit CTCC Unique ID 
x 
If agreeable, at the time the consent form is signed the subject will be assigned a unique 9-digit 
ID number that can be used to connect the subject’s SURE-PD3 research data to other studies 
conducted by the University of Rochester’s Clinical Trials Coordinating Center (CTCC) in which 
s/he may participate. 
2. 4- digit Subject ID Number 
x 
At the time the consent form is signed, all subjects will be assigned a 4-digit Subject ID 
Number by the site, from a list generated by the DCC and  provided to sites by the CCC.  
This number will be used on all data forms. 
3. 5-digit Enrollment/Randomization Number 
x 
Study drug will be pre-coded by the DCC with Enrollment ID/randomization kit numbers 
(based on the randomization plan generated by the University of Rochester Biostatistics 
Department). Pre-assigned drug kits will be supplied to the site Investigator.   
x 
The treatment for each subject will be assigned by a randomized code.  A blocked 
randomization scheme will be used to ensure approximately even distribution of subjects in 
treatment groups at each site.   
x 
Once the subject qualifies for the randomized phase of the study, the site Investigator or 
Study Coordinator will enter data into the eClinical system and the subject will be assigned a 
unique 5 digit Enrollment ID, which will match a study drug kit. These numbers are assigned 
in a randomized order, rather than sequentially. 
x 
The randomization algorithm and subject enrollment process will be implemented through the 
Internet accessible Electronic Data Capture (EDC) system using authenticated, password-
protected accounts for each study site.  The EDC system will automatically validate 
inclusion/exclusion criteria and generate visit date windows.  
x 
Once the online enrollment process is completed, the site will print an Enrollment 
Verification Report that verifies the subject has been randomized.  The report will note the 
Enrollment ID Number that was assigned that corresponds to the drug kit number and the 
upcoming study visit windows.  If a site’s EDC system is not operating, the site may 
alternatively call the DCC for subject enrollment during designated working hours. 
x 
Once a subject has been allocated an Enrollment ID Number this number cannot be assigned 
to another subject. 
 
5. 
STUDY INTERVENTIONS 
5.1 
Study Interventions, Administration and Duration 
5.1.1  Intervention (study drug) 
Study drug will be supplied as identical appearing capsules for oral administration.  
x 
Active study drug capsules will contain: 500 mg inosine and 10 mg magnesium stearate. 
x 
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5.1.2  Administration and dosing of study drug 
Subjects will be randomly assigned to receive one of the two following regimens (1:1 ratio) for taking 
study drug, administered in doses of one or two 500 mg capsules: 
 
x 
Inosine dosed to elevate serum urate to 7.1 – 8.0 mg/dL 
1-6 capsules (0.5 to 3.0 gm of inosine) per day in 3 divided doses (0-2 caps t.i.d.); dosing is 
titrated to serum urate levels 
 
x 
Placebo 
1-6 capsules (0.5 to 3.0 gm of lactose) per day in 3 divided doses (0-2 caps t.i.d.); dosing is 
algorithm-driven to mimic that of inosine regimens 
5.1.2.1  Initiation of Dosing at Baseline Visit 
x 
First capsule will be taken with fluids during the Baseline Visit under the guidance of site staff. 
x 
At that time, staff will provide subject education on study drug administration, explaining: 
o That each dose of 1-2 capsules is to be taken with a glass of water or other unsweetened, 
non-alcoholic beverage. 
o Inosine may be taken with or without food, but because it may cause mild stomach upset 
in some it will be recommended to at least start by taking it with meals (unless otherwise 
indicated by the results of inosine-food interaction studies). It will be stressed that – 
whether taken with meals or not – every dose of 1-2 capsules should be taken with fluids 
as above for adequate hydration to reduce the risk of kidney stones and gout.177,178 
o If warranted, tips for overcoming difficulty swallowing the relatively large-sized study 
capsules. 
o Compliance and study drug storage requirements. 
o Return of study bottles at each visit (whether or not empty). 
o Need for immediate reporting of any AEs to the Site Investigator or Coordinator. 
o Importance of not taking study drug on study visit days until immediately after the visit 
blood draw (with any further daily doses distributed over the remainder of day following 
the visit). 
o Titration schedule of study medication, as below. 
 
5.1.2.2  Initial Dosing Following Baseline Visit 
Following administration of the first dose, each subject will begin taking an initial daily dosage (# of 
capsules per day) that is individualized. These subject-specific initial dosages are derived from several 
factors that were identified (upon analysis of SURE-PD data) as predictors of the daily dosage required to 
achieve serum urate elevation into a specified range. Factors associated with larger increases in serum 
urate for a given dose were a) higher screening serum urate levels, b) female gender, and c) diuretic use. 
Upon randomization of a subject the DCC will automatically send site staff an initial daily dosage plan 
individualized to the subject (along with an enrollment number and study drug kit assignment). The initial 
daily dosage plan will be one of five (labeled by letters A to E in Table 4) with two stages.  The first stage 
will employ a relatively low starting dosage for 1 week (through day 6 after BL; BL = day 0), before 
increasing the daily dosage one week after the BL visit (per schedule in Table 4), except that subjects who 
are on Plan A will stay on 1 capsule/day after day 6.  
 


 
 
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Table 4: Initial daily dosage (capsules/day) 
Plan 
Day 0 (Baseline) 
Day 1 - 6 
Day 7+ 
A 
  1 at visit only 
1 
1 (no change) 
B 
  1 at visit only 
1 
2 
C 
  1 at visit + 1 at dinner time 
2 
3 
D 
  1 at visit + 1 at dinner time 
2 
4 
E 
  1 at visit + 1 at dinner time 
3 
5 
 
During this initial dosing period (starting on Day 1) and throughout the study the daily dosing schedule 
will be determined by total daily capsule (cap) dosage as described in Table 5. Following the initial 
dosing period subjects will remain on the same daily dosage, as tolerated, until a dose adjustment is 
triggered in response to serum urate measured in blood drawn at subsequent visits (see below). 
 
Table 5: Daily dosing schedule based on total daily capsule count  
caps/day 
Breakfast time 
Lunch time 
Dinner time 
1 
1 
- 
- 
2 
1 
- 
1 
3 
1 
1 
1 
4 
1 
1 
2 
5 
2 
1 
2 
6 
2 
2 
2 
Unless otherwise indicated by the results of inosine-food interaction studies, doses will be organized by 
approximate mealtimes as subjects are instructed to initially take doses with meals to reduce any risk of 
dyspepsia. Dose times may vary but consecutive doses should be maintained at least 4 hours apart.  
At study visits on treatment (V01-V09) subjects will hold their dose(s) until after the blood draw for 
trough serum urate sampling, when they will promptly take their first dose of the day.  Any subsequent 
doses for that day will be distributed across the remainder of the day (i.e., with all the day’s doses delayed 
rather than skipped; e.g., for a subject taking at least 3 capsules/day, and therefore on a t.i.d. schedule, 
who undergoes a visit blood draw at 11 AM s/he will then take the first dose of the day [with fluids 
during the visit], then the second dose at ~dinner time, and then the third/final dose before bed). A normal 
dosing schedule will be resumed the following day. 
At the discretion of the Investigator, the administration of any two-capsule dose of study drug (i.e., for 
subjects taking 4 or more caps/day) may be split if it were associated with a minor AE that does not 
warrant dose reduction. If a two-capsule dose is split then the 2nd capsule may be taken after any delay as 
long as it is taken at least 4 hours ahead of the next dose. 


 
 
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5.1.2.3  Study Drug Dosage Titration Algorithms  
A titration algorithm will be employed to lower inosine dosing for over-range levels (>8.0 mg/dL) as well 
as to increase inosine dosing for those that are under 7.1 mg/dL. A parallel titration algorithm for dosing 
of subjects on placebo will be used to match their daily capsule dosage to that of subjects on active drug. 
The resultant adjustments in study drug dosage will be made after each on-treatment visit via person-to-
person phone call (or receipt-confirmed forms of email, text message, voice message, etc) from staff to 
subject within 3 days of receiving a dose adjustment notification from the DCC. At the visits subjects will 
be instructed to continue their current dosing unless they receive a call (or are otherwise contacted if they 
mutually agree to an alternative means of communication).  When staff contact a subject electronically or 
otherwise leave a message, the staff must receive from subjects an acknowledgement of receipt of the 
message and a plan to initiate the change at a specific time and date. Contact will normally only be made 
when a dose adjustment is warranted, or if a test result warrants a dose change/suspension or other 
intervention (such as a urine alkalinization).  
 
The Site Investigator and Coordinator will be contacted with instructions by the DCC (by automated 
email) that will indicate what the study drug dosing should now be and whether this is a change. When 
subjects are then contacted they should be instructed of the/any dose change and that it should be put into 
effect immediately (at their next dose). All post-visit contacts, their timing and outcome should be logged 
in the subject’s source documents and the Dose Management Log electronic Case Report Form (eCRF) 
updated appropriately if a dose adjustment is ordered. 
 
Specific dose adjustments will be made in response to serum urate results at on-treatment visits V01 to 
V09 (and at any unscheduled on treatment) as follows: 
 
Subjects randomized to active drug: 
o Serum urate < 67% increase from baseline level (calculated as average of SC1, SC2 and BL visit 
values) to lower limit of target range (7.1 mg/dL) ==> increase by 2 caps/day, except:   
 If subject is already on 5 caps/day, then increase by 1 cap/day up to 6 caps/day.  
 If subject is already on 6 caps/day (possible only after V01) then continue at this dose. 
o Serum urate 67-99% increase from baseline level to lower limit of target range ==> increase by 1 
cap/day, except:  
 If subject is already at 6 caps/day then continue at this dose. 
o Serum urate within target range ==> no change. 
o Serum urate >upper limit of target range (8.0 mg/dL) and ≤ 9.0 mg/dL ==> reduce by 1 cap/day the 
dose being taken at the most recent visit (unless the subject was already down to 1 cap/day in which 
case s/he will continue at 1 cap/day).  
o Serum urate > 9.0 mg/dL ==> hold treatment (i.e., take 0 caps/day) x 6 days, and then resume 
treatment at 1 less cap/day than the prior dose (i.e., at the most recent visit), except:   
 If that reduction results in no caps being taken, then continue the hold (i.e., 0 caps/day) x 6 more 
days, then resume treatment at 1 cap/day and return for an unscheduled visit (e.g., U01) in 4 
weeks, employing the same titration study drug adjustment algorithm as presented here (Sec. 
5.1.2.3) after the unscheduled visit labs are received. 
 If a subject returns 3 consecutive serum urate levels > 9.0 mg/dL on 1 cap/day, then the study 
drug will be permanently discontinued due to “excess sensitivity to study drug” (not an AE).    


 
 
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Subjects randomized to placebo:  
To preserve blinding to treatment assignment study drug titration will be according to the same titration 
schedule used for active subjects, but those titrations will be based on a hypothetical serum urate (SU) 
level calculated as an adjustment from the placebo subject's observed SU level at any given time point. 
The adjustment will initially be a fixed increment calculated as a function of the subject’s current placebo 
dose. After accumulating some experience with how actual inosine doses affect both mean SU levels and 
among-subject variation in SU levels, then the increment calculation may be adjusted. Thus the system is 
designed with the additional flexibility to include some degree of variation among subjects and a non-
constant effect of inosine over time. The following algorithm will be used: 
1. For placebo subject i at visit j: hypothetical SU[ij] = observed SU[ij] + (U[i] + v[j] + w[ij]) * # of 
placebo capsules in current dose. 
2. U[i] ~ Normal(mean S, variance T); S will be a function of gender, baseline SU, and diuretic use or 
other participant characteristics; initially T = 0, later T may be greater than 0 based on 
accumulating data in the trial. 
3. Initially v[j] = 0 and w[ij] = 0; later v[j] or w[ij] may differ from 0 in order to best match placebo 
pill counts to those required for titration of participants in the active arm. 
 
5.1.2.4 Missed Doses 
 
The subject should not take a double dose to make up for a missed dose. If a subject forgets to take a 
particular dose, it should not be made up with the next scheduled dose. Subjects may take a forgotten dose 
as long as the delayed dose is taken at least 1 hour before the next regularly scheduled dose.  
 
5.1.2.5  Dose Reductions/Suspensions 
 
A.  Dose Reductions 
 
In addition to serum urate-triggered algorithmic dose reductions (See 5.1.2.3), placebo and active drug 
may also be reduced during the study if a subject develops a persistent AE that the Enrolling Investigator 
believes warrants a study drug reduction. Non-Investigator-approved dose reductions may be retroactively 
assessed and determined to be appropriate by the Site Investigator, for example a dose reduction initiated 
by another physician upon the subject’s hospitalization for an AE. 
 
The duration of the decrement should be the minimum period required to ensure subject safety and 
comfort. Whether or not the Investigator or another clinician initiates an AE-triggered dose reduction, the 
Site Investigator should follow the subject as closely as reasonable during the dose reduction period to 
ensure a prompt re-challenge when appropriate (see Section 5.1.2.6). If an AE-triggered dose reduction or 
suspension (see 5.1.2.5.B1) is sufficiently long, study drug will be deemed “intolerable” as part of the key 
trial assessment of tolerability (see Section 10.2.2.2).  
 
The extent of the decrement is at the discretion of the Investigator, and can range from reducing a specific 
dose (e.g., halving or eliminating the last dose of the day) to eliminating all doses (effectively ‘dose 
suspension’; see 5.1.2.5.B1). 
 
Clinician-initiated dose reductions and their duration are to be recorded on the Dose Management Log 
and reported to the CCC within 24 hours of initiation. In the event that an AE-triggered dose reduction of 
any type lasts longer than 72 hours, then the Site Coordinator or Investigator is to contact the Medical 
Safety Monitor or CCC Project Manager to discuss the situation and review management options. 


 
 
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B.  Dose Suspensions – may be AE-triggered, precautionary or logistical as follows:  
1. AE-triggered suspensions – As for AE-triggered dose reductions, AE-triggered suspensions may 
contribute to a determination that the study drug is intolerable (see Section 12.4.2). 
a.  Automatic:  
x 
Myocardial or cerebral infarct (If confirmed, drug will be permanently discontinued. See 
Sections 7.5.1 and 9.0 ) 
x 
Gout attack (suspend at least until acute symptoms resolve) 
x 
Uric acid or urate urolithiasis (suspend at least until any acute symptoms resolve) 
b.  Investigator-initiated: as above in 5.1.2.5.A.                                                                                                            
2. Precautionary suspensions – Investigators may approve a brief non-AE-triggered suspension of 
study drug employed as a medical precaution (e.g., as in a peri-operative suspension of study drug 
required by the subject’s surgeon for an elective procedure, during a day of potential dehydration 
as in religious fasting, etc).  
3.  Logistical suspensions – Brief interruptions in study drug use may be incurred due to 
unavailability (e.g., as in inadvertent destruction, or loss during travel).  Re-supply and 
resumption should occur as soon as possible.  
 
All dose suspensions are to be recorded on the Dose Management Log and reported to the CCC within 24 
hours of initiation. In the event that an AE-triggered suspension of any type lasts longer than 72 hours, 
then the Site Coordinator or Investigator is to contact the Medical Safety Monitor or CCC Project 
Manager to discuss the situation and review management options.  
 
5.1.2.6 Dose Re-challenge and Resumption  
 
Subjects whose dose has been suspended for precautionary or logistical purposes (see Section 5.1.2.5B2 
and 5.1.2.5B3) should resume drug as soon as the precautionary or logistical concerns have been 
adequately addressed.  They should resume drug at the level being taken at the time of the suspension.  
 
Subjects whose dose has been reduced or suspended due to an adverse effect (see Sections 5.1.2.5A and 
5.1.2.5B1) must tolerate the reduced or suspended drug level for two or more full days (i.e., equal to or 
greater than 48 hours) before being re-challenged.  After this time the re-challenge may begin with a 
partially or fully resumed dose of the study drug (i.e., the dose being taken at the time of reduction or 
suspension).  Whether the re-challenge is immediately at the full dosage (i.e., resumption) or gradually 
escalating is at the discretion of the Site Investigator. Re-challenge and resumption should be pursued 
with expedience while ensuring the subject’s likely safety and comfort. If the AE recurs as the dosage is 
increased, the subject should continue on the maximally tolerated dosage up to the full dose.   
 
All dose re-challenges and resumptions are to be recorded on the Dose Management Log and reported to 
the CCC within 24 hours of initiation.  Having to back down on the dosage during a re-challenge is 
considered another dose reduction and should be reported to the CCC as such and recorded on the Dose 
Management Log.   
 
Note that persistent dosing below the full study drug regimen (as dictated by serum urate-titrated dosing 
plan; Section 5.1.2.3) would lead to a determination that the intended dose was “intolerable” as per 
Section 10.2.2.2. 
 
5.1.2.7 Question of Need for Downward Titration 
 


 
 
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There is no downward titration necessary when study drug is reduced, suspended temporarily, or 
permanently discontinued.  
 
 
 
5.1.3  Potential Adverse Effects (AEs) of Study Drug 
5.1.3.1 Potential AEs of Active Drug (Inosine) 
Anticipated AEs of inosine are expected to be primarily mediated by urate, to which it is rapidly 
metabolized. Established AEs of elevating urate are disorders of crystallization, as reviewed above. The 
two main disorders are gout (a form of arthritis triggered by urate crystals forming in a joint) and uric acid 
urolithiasis (uric acid crystalizing at low urine pH to form stones). Although gout is often a progressive 
degenerative arthritis, any inosine-induced episodes of acute gouty arthritis would be expected to be fully 
reversible upon discontinuation of inosine and thus would not require additional medication.  Similarly 
urolithiasis is often a recurrent nephropathic disease, whereas uric acid stones induced by inosine would 
not be expected to recur if inosine were discontinued. Nevertheless the study incorporates numerous 
safeguards against these conditions, particularly uric acid urolithiasis given our phase 2 data indicating 
that a small but significant portion of the study cohort may develop stones.  (See Sec. 2.2.3.) 
 
In addition, as surveyed above in Sec. 2, numerous other medical conditions have been linked to higher 
serum urate and include cardiovascular diseases, including hypertension, coronary artery disease, heart 
failure, stroke, and renal dysfunction, and metabolic disorders (metabolic syndrome and diabetes 
mellitus). Although it remains uncertain whether or not urate itself contributes to these conditions and 
their increased risk with higher urate is generally modest, special attention will be paid to both avoiding 
and monitoring for these conditions during the trial. 
5.1.3.2 Potential AEs of Placebo (Lactose)  
No specific AEs of placebo drug are anticipated. Note that symptoms due to lactose intolerance (a 
theoretically placebo-specific potential AE) are unlikely given that the maximum single dose of 1 gm 
lactose (two 0.5 gm placebo capsules) is well below the limit of lactose sensitivity (typically >12 
gm/serving) in lactose-intolerant people.179,180 By comparison, 50 gm lactose is considered the standard 
challenge dose in lactose intolerance tests. 
5.2 
Handling of Study Medications 
Study drug will be manufactured in the same opaque white, hard gelatin capsules for both placebo and 
active drug formulations. Their indistinguishable appearance will be confirmed initially after 
manufacturing and at least annually thereafter during the study through a scheduled stability testing 
program.  Study drug will be packaged with 100 capsules per bottle, which will be white high-density 
polyethylene (HDPE) with a standard lid closure. All study drug formulation, encapsulation and bulk 
packaging (into bottles) will be conducted by a single contract manufacturer.  
 
Study drug will undergo final packing, labeling and distribution to clinical sites by a central pharmacy.  
Six study drug bottles of placebo or active drug will be assembled into a kit box and labeled to meet 
applicable US regulatory requirements. Each kit box is good for at least 3 months of dosing. Each subject 


 
 
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who completes the study without early drug discontinuation will receive from 2 to 8 kit boxes (12 to 48 
bottles) in total depending on the dose level maintained.  
 
The central pharmacy will label and supply subject kits for each study center according to the 
randomization list provided by the project DCC Biostatistics Core. Each kit and its bottles will be 
identified via a 5-digit Enrollment ID Number as defined by this randomization list to maintain study 
blindedness. Pre-assigned start-up study drug kits will be supplied to the Site Investigator once 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval is granted and all 
regulatory documents are filed and contractual arrangements are in place.  Additional start-up kits will be 
provided by the central pharmacy as site enrollment warrants. The central pharmacy will send additional 
supplies for a given enrolled subject in advance of each dispensing visit.     
 
In accordance with local regulatory requirements, the Site Investigator or designated site staff must 
document the amount of investigational product dispensed and/or administered to study subjects, the 
amount received from the central pharmacy, and the amount destroyed upon completion of the study. The 
Site Investigator is responsible for ensuring product accountability records are maintained throughout the 
course of the study. The inventory will include details of the study drug and dispensed to subjects, batch, 
and ID numbers. All unused capsules and bottles must be kept until reconciliation of delivery records 
with accountability logs by the monitor. Subjects will be asked to maintain a daily drug diary to confirm 
drug was taken as prescribed. After the monitor has performed accountability, the site will be instructed 
by the CCC or designee to either destroy the remaining study medication per institutional policy or return 
it to the central pharmacy. An accounting must be made of any drug deliberately or accidentally 
destroyed. Discrepancies between the amount of study drug received and dispensed drug must be 
reconciled. 
 
5.3 
Concomitant Medications 
5.3.1 
Required Therapy 
There is no required therapy to take on a regular basis in addition to study drug.  Subjects with 
persistently acidic urine will be prescribed potassium citrate (or an alternative medication) as a urine 
alkalinization method to reduce the risk of uric acid stone formation. See Sec. 8.4.2. 
5.3.2 
Prohibited Medications  
5.3.2.1   Disallowed Medications Prior to Study Entry  
Subjects who have used certain medications as specified under the study exclusion criteria (Sec. 4.2) will 
not be eligible for participation in this study. 
5.3.2.2   Disallowed Medications during the Study  
Use of the following medications is not allowed during the study. The use of any disallowed medication 
must be documented.  
x 
Multivitamins and/or mineral preparations, other than a standard daily multivitamin*. 
x 
Antioxidants such as vitamin E, vitamin C and inosine (other than as may be in study drug, a 
standard daily multivitamin or a normal diet)* 
x 
Neuroleptics (typical and atypical), metoclopramide 
x 
Methylphenidate, amphetamine, cinnarizine, reserpine, tetrabenazine, MAO-A inhibitors, or 
appetite suppressants*  
x 
The urate-reducing agents, allopurinol, febuxostat and probenecid. 


 
 
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*Please see Section 18, Concomitant Medications, in the site Manual of Procedures located on the 
study ePortal section: for further details related to these disallowed medications. 
5.3.3 
Allowed Concomitant Medications  
All concomitant medications that the subject is taking at study initiation must be recorded on the 
Concomitant Medication Log. The log will include a list of all medications taken during the 30-day 
period prior to the 2nd Screening Visit. Any changes in concomitant medications or new medications 
added, including use with an intercurrent illness, must be recorded in the case report forms. All 
concomitant medications must be used in accordance with approved labeling and as prescribed. 
5.3.3.1  Initiation of Antiparkinsonian Medication 
Although anti-PD medications other than monoamine oxidase B inhibitors are not permitted at entry, anti-
PD medications may be initiated during the study.  The decision to initiate antiparkinsonian treatment 
must be made by the Site Investigator at an in-person visit (regular or unscheduled), and only after a 
determination that the subject has developed the need for dopaminergic therapy. For this study 
‘dopaminergic therapy’ is defined as symptomatic treatment with an antiparkinsonian drug (levodopa, a 
dopamine agonist, amantadine or an anticholinergic agent trihexyphenidyl or benztropine), other than a 
MAO-B inhibitor taken at enrollment.  Increasing an entry dosage of a MAO-B inhibitor or initiating a 
MAO-B inhibitor during the study will be considered as requiring dopaminergic therapy. Once treatment 
has been initiated, dosage adjustments may be ordered by telephone. Dosing of a monoamine oxidase B 
inhibitor that was taken at enrollment should remain unaltered until (additional) dopaminergic therapy is 
initiated or until the subject’s final study visit.  
5.3.3.2   Initiation of Thiazide Therapy during the Study  
Initiation of treatment with a prescription thiazide -- such as hydrochlorothiazide (e.g., Esidrex), 
chlorothiazide (e.g., Diuril), chlorthalidone (e.g., Hygroton), indapamide (e.g., Lozol), metolazone (e.g., 
Zaroxolyn) -- will be allowed. However, thiazide therapy can cause an increase in serum urate (usually <1 
mg/dL).  Accordingly, a regular or unscheduled visit with serum urate measurement by the central lab 
must occur between 1 and 4 weeks after initiation of any thiazide to afford timely algorithmic adjustment 
of study drug dosing. Although diets can also influence serum urate,139 they are generally stable and any 
changes are expected to prompt titration of study drug dosing based on placebo and inosine dosing 
algorithms. 
5.4 
Adherence Assessments 
At each study visit, the Site Investigator and/or Study Coordinator will assess the subject’s compliance 
with the study requirements. This will include checks of protocol compliance, concomitant medication 
use, and use of study drug in order to assess the reliability of subject-generated data. The primary 
mechanism for assessing compliance with use of study drug will be capsule counts i.e., the number of 
capsules dispensed and returned at each visit will be documented in the Study Drug Dispensing/Return 
Log. Subjects are instructed to return all study bottles (whether empty, partially used, or unused) at each 
visit on study drug (V01-V09) and upon its discontinuation (V10). 
 
Non-compliance will be defined as taking less than 80% or more than 125% of study medication as 
determined by capsule counts.  If a study subject is non-compliant with study medication, the Site 
Investigator and staff should re-educate and train the subject in administration of study drug. Subjects 
who fail to comply with the study requirements may be withdrawn from the study. Data indicating non-
compliance will be used in the end of study analysis, when they may be related to pharmacodynamic 
evidence of non-compliance (e.g., lack of increase in serum urate on maximum inosine dosage).   
 
 


 
 
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6. 
 CLINICAL AND LABORATORY EVALUATIONS 
6.1 
Safety Assessments 
6.1.1 
Clinical Variables 
In addition to the data from assessments listed below, subjects will provide information on their 
demographics, past medical history, including PD, socio-economic history, smoking, alcohol and caffeine 
usage, as well as concomitant medication usage and compliance with study procedures. 
6.1.2 
Vital Signs, their Orthostatic Changes, Weight and Height 
Blood pressure (supine and standing), heart rate (supine and standing), and body weight will be measured 
at Screening Visit 2, Baseline Visit, Week 12, Month 12, Month 24 and Month 27. Height will be 
measured at the Baseline Visit only.  
6.1.3 
Clinical Laboratory Assessments 
The following laboratory tests will be performed at Screening Visit 1 and 2, Baseline before first dose of 
study drug is administered, at Weeks 3-12, Months 6-24, and Month 27 for safety (as indicated below and 
on the Schedule of Activities; Sec. 7.7): 
o Serum Uric Acid [all visits] 
o Complete blood count (CBC) with differential (hematocrit, hemoglobin, platelet count, RBC 
indices, Total RBC, Total WBC, and WBC & differential) [at baseline and after 3 months and 2 
years on treatment; and at all other visits for subjects on potassium citrate alkalinization therapy] 
o Basic blood chemistry panel: bicarbonate, blood urea nitrogen (BUN), chloride, creatinine, 
glucose, potassium, sodium, GFR [at 2nd screening visit, all on-treatment visits, and safety visit] 
o Specialty blood chemistry: Liver function tests (LFTs)/Lipids/ thyroid-stimulating hormone 
(TSH); LFTs: alanine aminotransferase (ALT (SGPT)), aspartate aminotransferase  (AST 
(SGOT)), albumin, alkaline phosphatase, calcium, magnesium, phosphate, total bilirubin and total 
protein; Lipids comprise cholesterol, HDL, LDL and triglycerides [at baseline and after 3 months 
and 2 years on treatment] 
o Urinalyses: bilirubin, blood, clarity, color, glucose, ketones, nitrate, pH, protein, specific gravity, 
urobilinogen and WBC screen; plus urine sediment exam for uric acid crystalluria [at 1st 
screening visit, all on-treatment visits, and safety visit]. 
o Subjects may be asked to obtain additional urine samples at home if they begin 
alkalinization therapy (see section 8.4.2 for futher instruction), or they may be given the 
option to obtain additional urine samples at home as deemed appropriate by the Site 
Investigator (for example, to ensure subjects are adequately hydrated as assessed by urine 
specific gravity).  If the reason the subject is being asked to collect a urine sample is to 
monitor their hydration level, study staff should ask subjects to collect this sample 
anywhere from one week after a visit to one week before the next visit (further guidance 
can be found in the Manual of Procedures section 13.4).  Subjects will be instructed by 
sites as to how to obtain and send the at-home urine samples to the central lab. 
o 24-Hour urine analysis: chloride, creatinine, pH, potassium, sodium and urate, with total volume 
[at baseline and 1 year visit] 


 
 
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o Urine pregnancy test for women of childbearing potential (WOCBP) [if warranted at 2nd 
screening visit and as necessary thereafter at on-treatment visits] 
All subjects will have safety laboratory tests at the designated visits outlined in the protocol. These 
samples will be analyzed at a central laboratory.  The Site Investigator may order additional testing, if 
needed, to further assess an adverse event (AE), or if there were any suspicion that a subject may be 
pregnant, throughout the course of the study. 
6.1.4 
12-Lead Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed at Screening Visit 2, Month 12 and Month 24 or the 
Discontinuation of In-Person Follow-up Visit for subjects unwilling to continue in-person visits.  Results 
will be based upon the Site Investigator’s interpretation of the standard machine readings and the reading 
provided by the central cardiology lab service.  It is the Site Investigator’s decision as to whether the ECG 
needs to be interpreted by a cardiologist in addition to the one reading by the central laboratory.  A copy 
of the tracings will be kept on site as part of the source documents.  
6.1.5 
Physical Examination 
A physical examination will be performed and recorded at Screening Visit 2.  The following systems will 
be examined: skin, head/neck/lymphatic, eyes, ears/nose/throat, cardiovascular, lungs, abdomen, 
musculoskeletal, neurological and psychiatric.   
6.1.6 
Neurological Examination 
A neurological examination will be performed and recorded at Screening Visit 2.  
6.1.7 
Adverse Events 
Adverse events (AEs) will be documented at each study visit, starting with the signing of informed 
consent.  Events that occur prior to administration of first dose of study drug will be noted accordingly. 
Information on adverse effects of study medication and on intercurrent events will be determined at each 
visit by direct questioning of the subjects, review of concomitant medications, and vital sign results.  
6.2 
Other Assessments 
6.2.1   Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) 
The MDS-UPDRS138 will serve as the primary outcome variable of the study (as justified in detail in Sec. 
3.2.3) and will be conducted at all standard visits beginning with the 2nd screening visit. The MDS-
UPDRS was designed by movement disorders experts to address weaknesses of the original UPDRS (e.g., 
by adding questions on constipation and sialorrhea) while preserving its overall format. The MDS-
UPDRS has four parts:  
x 
Part I (non-motor experiences of daily living), comprising 
o Part IA concerning behaviors that are assessed by the Site Investigator with all pertinent 
information from patients and caregivers 
o Part IB that is completed by the patient with or without the aid of the caregiver, but 
independently of the Site Investigator. 
x 
Part II (motor experiences of daily living), designed to be a self-administered questionnaire like 
Part IB, but similarly can be reviewed by the Site Investigator to ensure completeness and clarity. 
x 
Part III (motor examination) has instructions for the rater to give or demonstrate to the patient; 
it is completed by the clinician rater. 


 
 
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x 
Part IV (motor complications) with instructions for the rater and also instructions to be read to 
the patient. This part integrates patient-derived information with the rater's clinical observations 
and judgments and is completed by the rater.  
  
Subjects will self-administer Parts IB and II, but will review responses for accuracy and clarity with the 
Site Investigator or Coordinator.  Parts IA, III and IV must be conducted by the Site Investigator.  Parts I, 
II, and III will be conducted at study visits as indicated on the Schedule of Activities (Sec. 7.7). Part IV 
will be conducted at visits where MDS-UPDRS Parts I-III are conducted/collected but only on subjects 
who have started on symptomatic therapy after the Baseline visit.  Use of MDS-UPDRS is responsive to 
core instrument recommendations for the Quality of Life subdomain of the NINDS CDEs for PD, and to 
FDA guidance encouraging use of patient-reported outcomes (PROs) as a substantial portion of the 
responses are patient-reported. The same Site Investigator should assess all subjects on parts IA and III of 
the MDS-UPDRS at all study visits. 
6.2.2 
Modified Schwab & England Activities of Daily Living Scale  
The Schwab & England scale181,182 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 100% to 0% in increments of 10%, 
where 100% is “subject has full ability and is completely independent; essentially normal” and 0% is 
“vegetative functions such as swallowing, bladder and bowel functions are not functioning; bedridden”. 
Scores should be coded in increments of 5, (i.e. 095, 090, 085).  This joint subject/Site Investigator 
assessment will be conducted periodically at the visits indicated in Sec. 7.7. 
 
6.2.3 
Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) scale 
The PDQ-39 asks 39 questions organized over eight domains: mobility (10 items), activities of daily 
living (6 items), emotional well-being (6 items), stigma (4 items), social support (3 items), cognitions (4 
items), communication (3 items), and bodily discomfort (3 items). The PDQ-39 is the most widely used 
health related-QoL instrument in PD, and is considered to have generally good psychometric properties 
and content validity.183,184 Use of PDQ-39 is responsive to core instrument recommendations for the 
Quality of Life subdomain of the NINDS CDEs for PD, and to FDA guidance encouraging use of PROs. 
This assessment will be collected from subjects periodically at the visits indicated in Sec. 7.7. 
6.2.4 
Modified Hoehn and Yahr Scale 
The Modified Hoehn and Yahr Scale181, 185 is an 8-level PD staging instrument.  Stage 0 is “no signs of 
disease” and the highest stage (5) is “wheelchair bound or bedridden unless aided.”  This Site Investigator 
assessment will be conducted periodically at the visits indicated in Sec. 7.7.  
6.2.5 
Assess Need for Dopaminergic Therapy 
At each visit beginning with Baseline Visit, the Site Investigator will assess the subject’s need for 
dopaminergic therapy. (See Sec. 5.3.3.1 for definition of dopaminergic therapy.) A questionnaire will be 
used to facilitate the Site Investigator’s decision. As in the DATATOP31,32 and PRECEPT30 trials, this will 
be based on PD disability posing a threat to the subject’s current occupational status, current abilities 
(potential capacities) related to occupational matters, to handle routine personal finances and domestic 
responsibilities, and activities of daily living.  
Subjects who are judged to require dopaminergic therapy at Baseline or are thought likely to need therapy 
within the 3 months after Baseline, will be excluded from participation in this study.  Subjects who are 
judged to require dopaminergic therapy after starting study drug will continue in the study after anti-
parkinsonian therapy is instituted.   


 
 
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6.2.6 
Mini-Mental State Examination (MMSE)  
The Mini-Mental State Examination186 is a 30-point scale that is widely used for the evaluation of 
degenerative dementia in patients with a variety of neurologic and psychiatric disorders, and is designated 
an NINDS CDE for PD. The MMSE includes evaluations of orientation to time and place, immediate 
recall, attention, delayed recall, naming, repetition, stage command, reading, copying and writing. The 
test is referred to as “mini” because it focuses only on the cognitive aspects of mental functions and does 
not include questions related to mood, abnormal mental experiences, or the form of thinking. The total 
score ranges from 0 to 30 (highest function). 
Subjects will complete the MMSE at the Screening Visit 2.  Subjects with an MMSE score less than 25 
will be excluded from participation in the study.   
6.2.7 
Montreal Cognitive Assessment (MoCA) 
In early Parkinson’s disease, when cognitive deficits occur, they are subtle and mild and the subjects 
usually perform in the normal range of the widely used Mini-Mental State Exam.  The Montreal 
Cognitive Assessment187 is a rapid screening instrument like the MMSE, but was developed to be more 
sensitive to patients presenting with mild cognitive complaints. It is designated an NINDS CDE for PD. 
Compared to the MMSE the MoCA may be more sensitive to mild cognitive deficits in PD.188 The MoCA 
assesses short term and working memory, visual-spatial abilities, executive function, attention, 
concentration, language and orientation.  The total score ranges from 0 to 30 (highest function).   The 
MoCA will be administered at Baseline, Week 12, Month 12, Month 24 and Month 27 or the 
Discontinuation of In-person Follow-up Visit for subjects unwilling to continue in-person visits. 
6.2.8 
Quality of Life in Neurological Disorders (Neuro-QOL) 
Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related quality of life 
of people with neurological disorders.190,191 It facilitates comparisons between diseases and within 
individual patients over time. Developed through a collaborative NINDS-sponsored research initiative, 
Neuro-QOL is an NINDS CDE and has been validated in multiple patient populations including PD.190,192 
It comprises item banks and scales (with short form versions covering physical, psychological and social 
domains) that assess symptoms and concerns that are meaningful across disorders, while others are of 
particular relevance to specific patient populations. In a PD population, Neuro-QoL measures including 
its short forms have demonstrated high internal consistency, with acceptable test-retest reliability and 
support for convergent validity with PD specific measures including PDQ-39 and MDS-UPDRS.190 An 
instrument comprising multiple short form domains will be employed before and after the study drug 
treatment period (at SC2 and SV) while the depression domain will be employed on its own at additional 
visits during the treatment period, as indicated in Sec. 7.7. 
6.2.9 
Diagnostic Features Assessment 
The Diagnostic Features form is a companion to the Primary Diagnosis form.  It is a review by the Site 
Investigator of factors that do and do not suggest a diagnosis of Parkinson disease.   This assessment is 
completed at Month 27 or the Discontinuation of In-person Follow-up Visit for subjects unwilling to 
continue in-person visits.  
6.2.10 Primary Diagnosis Assessment 
The Primary Diagnosis form captures, in the Site Investigator’s opinion, a current percentile probability 
the subject has idiopathic Parkinson disease based on available information. Ranges include: 90-100%; 
50-89%, 10-49% and 0-9%. In addition the Site Investigator selects the most likely primary diagnosis 
from a listing that includes idiopathic PD, many other neurological disorders, and the option of no 
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diagnosis will be captured at Month 27 or the Discontinuation of In-person Follow-up Visit for subjects 
unwilling to continue in-person visits.   
6.2.11 Dopamine Transporter (DAT) Neuroimaging 
The radionuclide-labeled dopamine transporter (DAT) ligand DaTscanTM (123I-ioflupane   injection) is 
approved by the FDA for striatal DAT visualization using single photon emission computed tomography 
(SPECT) brain imaging to assist in the evaluation of adult patients with suspected parkinsonian 
syndromes. DaTscanTM is approved to help differentiate essential tremor from tremor due to parkinsonian 
syndromes (including idiopathic PD, multiple system atrophy and progressive supranuclear palsy) and not 
for the diagnosis of PD among parkinsonian syndromes. Nevertheless, DAT brain scans (using any of 
several radioligands) in clinical research have consistently identified a small but substantial (~10%) 
portion of subjects who are enrolled in clinical trials based on an expert clinician diagnosis of probable 
early PD but who turn out to be unlikely to have PD.30,140,143,145-147 In addition, quantitiative changes in 
striatal DAT bindng sites assessed by serial DaTscanTM imaing studies over years provide a biomarker of 
progressive nigrostriatal dopaminergic neuron degeneration, which correlated inversely with serum urate 
levels at baseline in the PRECEPT study.36  
 
6.2.11.1 Required Dopamine Transporter (DAT) Neuroimaging for Eligibility Determination 
DAT scans will be performed prior to the baseline visit, and will generally be conducted as the final 
screening evaluation (DS1) at a certified neuroimaging center at or near the clinical site. A determination 
of whether DaTscanTM imaging supports a diagnosis of PD and therefore study eligibility will be made by 
the study imaging core. Its experienced nuclear medicine specialists (trained in the visual read method 
appropriate for DATscanTM imaging) will perform the qualitative eligibility assessment. Each scan will be 
assessed independently by two readers. If the readers disagree then a third, expert reader will be used to 
adjudicate and the majority read outcome will determine whether the scan is classified positive or 
negative. In order to avoid false negative reads, if the readers agree that the result is positive then no 
further assessment is required; however if they agree it is negative, then a third, expert reader will 
reassess the image and make a final determination of whether the scan is classified positive or negative. 
 
6.2.11.2   Optional Follow-up DAT Neuroimaging 
An additional follow-up DaTscanTM imaging study will be performed one to two months following the 
final study clinic visit (V10), and before the final safety visit (SV), for active SURE-PD3 subjects who 
have consented to participate in a serial DAT scan substudy, who have been on study drug through at 
least the 1-year visit (V06), and who are not expected to use any of the following within 90 days prior to 
DS2: modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, or 
amphetamine derivative.  The substudy will quantify changes in DAT binding between the pre-study drug 
exposure and post-study drug exposure timepoints.  
6.2.12 Blindedness Evaluation 
At week 6 and either month 24 or an Unscheduled Visit due to study drug discontinuation or a 
Discontinuation of In-person Follow-up Visit (whichever of the 3 visits comes first), the Site Investigator, 
Coordinator, and subject will complete a blindedness evaluation in which each is asked to give his/her 
independent impression of the subject’s treatment assignment and the primary and secondary reasons for 
this opinion. Subjects’ responses will not be available to the site Investigator or Coordinator when they 
make their assessments. 


 
 
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6.2.13 Exploratory Assessments  
Three brief, self-administered questionnaires will be included to explore whether readily ascertained 
historical factors modify or otherwise interact with inosine effects.  
x 
REM Behavior Disorder (RBD) Question – A single semi-quantitative RBD question will be 
asked at SC1, BL, and 3 mo, 12 mo, 24 mo, and 27 mo visits. 
x 
PD Risk Factors Questionnaire – A self-administered questionnaire assessing exposures and 
experiences linked to the risk of PD will be collected at BL. The questionnaire was developed by 
the PSG and derived from NINDS CDEs. 
x 
PD - Expectancy Questionnaire – A self-administered questionnaire assessing expectations of 
study drug effect will be collected at BL. 
6.2.14 Optional Blood Collection for Biomarker Research 
The following optional blood samples will be collected, at the visits indicated, from subjects who have 
‘opted in,’ by written consent, to participate in a biomarker research substudy of SURE-PD3. 
x 
Blood (5-10 ml) for DNA [collected at BL] 
x 
Blood (5-10 ml) for plasma biomarkers [collected at BL, 24 mo and 27 mo visits]* 
 
*If the participant permanently discontinues study drug, for any reason, before the 24 mo visit, 
the 24 mo blood sample should be taken at an unscheduled study visit on the day they plan to 
discontinue the study drug (instead of at the 24 mo visit. Please see section 7.5.1 for more about 
this unscheduled visit). 
6.2.15 Optional Smartphone Outcomes Research Participation 
Eligible, consenting subjects may participate in a research substudy designed to assess the feasibility of 
using smartphone metrics as decentralized assessments of motor and non-motor outcomes of clinical 
progression in early PD257-259. Self–administered questionnaires and tests are completed by participants 
using a smartphone application adapted for the SURE-PD3 trial and known as Smart4SURE, as is the 
substudy. The primary aim of the Smart4SURE substudy is: 
x 
to assess the feasibility of incorporating smartphone application-based outcome measures in 
phase 3 ‘disease-modifciation’ trials for people with PD. If feasibility were supported by the 
substudy results, they may facilitate adoption of smartphone metrics as secondary or eventually 
primary outcomes in future neurotherapeutics trials for PD.   
Key secondary aims of the substudy are: 
x 
to correlate the cross-sectional assessments and the longitudinal changes documented by 
smartphone sensors and questionnaires with related elements of SURE-PD3’s primary (MDS-
UPDRS) and secondary outcome measures. 
x 
to compare rates of change in motor performance and in cognitive and other non-motor functions 
among substudy participants randomized to inosine versus placebo (i.e., an exploratory test of the 
parent study’s central hypothesis for these novel measures). 
without interfering with the parent project’s goals. Substudy participation is voluntary. After subject 
training at the 2nd screening visit (SC2), or if necessary at a subsequent visit, smartphone assessments will 
be conducted off-site at each participating subject’s convenience. Accordingly Smart4SURE is not 
expected to appreciably increase burden to subjects or site staff during regular study visits, nor to 
compromise the clinical assessments conducted during visits. Serial assessments for Smart4SURE consist 
primarily of: 


 
 
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x 
Activity Sessions comprising ~15 minutes of motor and cognitive tests (including finger tapping, 
voice, tremor, gait and memory) to be conducted at least monthly but no more frequently than 
weekly. At least one activity session should be completed prior to the baseline visit for subjects 
who consented prior to their baseline visit. 
x 
Surveys comprising ~20 minutes of responding to questions from a) the patient-reported parts (1b 
and 2) of the MDS-UPDRS145,150, b) an 8-item PD quality of life (QoL) survey260,261, and c) an 18-
item apathy evaluation262-267. The surveys are to be conducted at least every 3 months but no more 
frequently than monthly.  At least one survey should be completed prior to the baseline visit for 
subjects who consented prior to their baseline visit. 
To be eligible the subject should expect to have access to a Smart4SURE-compatible smartphone and 
service plan (neither of which will be provided, replaced or otherwise paid for or supported by the study) 
and should be interested and able to commit the time needed to conduct serial activity sessions usually at 
least monthly and to complete the serial surveys usually at least every three months. Smart4SURE 
subjects can miss scheduled smartphone activities and still continue in the substudy. Similarly, substudy 
participants may withdraw from the Smart4SURE substudy at any time without jeopardizing participation 
in the parent trial.


Confidential 
The information contained herein is confidential and proprietary in nature, and will not be disclosed to any third 
party without written approval of authorized designee.  This document may be disclosed to the appropriate 
institutional review boards or to duly authorized representatives of the US Food and Drug Administration or a 
national regulatory authority under the condition that they maintain confidentiality. 
 
 
7. 
STUDY SCHEDULE 
7.1 
Pre-Randomization Evaluations 
Prior to performing any study activity, the candidate will be thoroughly informed of all aspects of the 
study, including all scheduled visits, activities and procedures, and will be requested to sign and date the 
IRB-approved informed consent form. All subjects will be given a photocopy of the signed consent form. 
 
In this study the Site Investigator will be responsible for  
x 
Assuring that the subject has given informed consent; 
x 
Determining subject eligibility; 
x 
Conducting the physical (medical) and neurological examinations; 
x 
Conducting the MDS-UPDRS Parts IA, III and IV;  
x 
Assessing Modified Hoehn and Yahr stage and Modified Schwab and England Activities of Daily 
Living; 
x 
Assessing the need for dopaminergic therapy; and, 
x 
Assuring subject safety.   
 
After a subject discontinues study drug, the Site Investigator will also assess blindedness to treatment 
assignment and probability of PD as the accurate diagnosis. 
 
Screening activities for this study will include two screening visits at the clinical site (Visit SC1 and Visit 
SC2) and one DAT neuroimaging study (DS1), which will take place within 60 days prior to the Baseline 
Visit.  It is anticipated that many subjects will not be eligible to participate due to their serum urate level 
and/or their history of exclusionary medical conditions.  Therefore, the first screening visit is designed as 
a relatively quick, preliminary screen focused on obtaining a blood sample to measure serum urate, and 
thus to spare those subjects who are excluded based on this result the unnecessary physical and 
neuropsychiatric assessments as well as additional laboratory and ECG procedures.   
 
Following these two clinical site screening visits, those subjects who remain eligible will undergo a DAT 
scan as a third screening activity (DS1). Promptly after receipt of results from each of the three screening 
activities (SC1, SC2 and DS1), site staff will contact subjects to inform them either of exclusionary 
results that preclude their enrollment, or of their continued eligibility and in that case, to schedule or 
confirm their next screening activity or baseline visit.  
 
All the inclusion criteria must be met and none of the exclusion criteria may apply unless the site is given 
a waiver (exception) for a particular criterion by the Medical Safety Monitor, a physician whose sole role 
in the study is to ensure participant well-being.  All results from both screening visits and the DAT scan 
visit must be available before the final determination of a subject’s eligibility for the study, which will be 
made at the baseline visit (BL).  
 
7.1.1 
Screening Visit One (Visit SC1)  
The following procedures and evaluations are to be performed at Screening Visit One (SC1): 
x 
Request/obtain written informed consent for the study 
x 
Assign 4-digit Subject ID Number    
x 
Obtain 9-digit CTCC Unique ID Number  


 
 
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x 
Obtain demographic information  
x 
Review assessable inclusion/exclusion criteria 
x 
Obtain blood for serum urate testing 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Provide RBD Question to subject for self-administration  
x 
Schedule time to contact subject after serum urate results have been received 
x 
Tentatively schedule SC2 
7.1.2 
Post SC1 Telephone Call  
A follow-up phone call will take place once the serum urate and urine test results have been received and 
reviewed.  The following will be performed during the call: 
x Review the results with the subject 
x Inform the subject of his/her eligibility for proceeding to SC2 
x 
Inform or remind the subject – if eligible and interested in participating in the Smart4SURE 
substudy – of the need to bring his or her substudy-compatible (and adequately charged) 
smartphone to SC2 in order enroll in and train for the substudy at SC2. 
7.1.3 
Screening Visit Two (SC2) 
SC2 must occur after SC1 and before the DS1 visit. Subjects are to proceed to SC2 only if they met 
preliminary eligibility at SC1, including serum urate level. 
 
The following procedures and evaluations are to be performed at SC2: 
x 
Review assessable inclusion/exclusion criteria 
x 
Obtain medical history 
x 
Review and document concomitant medications 
x 
Assess and document adverse events/experiences (AEs) 
x 
Conduct neurological exam  
x 
Conduct physical exam 
x 
Assess PD features    
x 
Administer MDS-UPDRS Parts IA and III  
x 
Provide MDS-UPDRS Parts IB and II and Neuro-QOL to subject for self-administration 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Administer Mini-Mental State Exam (MMSE)  
x 
Obtain weight and orthostatic vital signs (supine and standing blood pressure and heart rate – 
refer to operations manual for standardized procedure) 
x 
Conduct 12-Lead Electrocardiogram (ECG) 
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain urine for pregnancy test for all women unless they are at least two years postmenopausal, 
or surgically sterile 
x 
For an interested, eligible subject obtain written informed consent for the optional Smart4SURE 
substudy 
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
(Please note: If necessary, consent and training for the Smart4SURE substudy can take place at an 
additional visit to the study site after SC2).  
x 
Distribute container for 24-hour urine collection at home and instruct subject in collection/storage 
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x 
Schedule time to contact subject after SC2 serum urate and other lab and ECG results have been 
received 
x 
Tentatively schedule DAT scan and Baseline Visit (with at least 5 business days between them) 
 
7.1.4 
Post SC2 Telephone Call  
A follow-up phone call will take place once the serum urate, laboratory results and ECG results have been 
received and reviewed.  The following will be performed during the call: 
x Review the results with the subject 
x Inform the subject of his/her eligibility for proceeding to DS1 
7.1.5 
DAT scan (DS1) 
DS1 must occur after SC2 and before the Baseline visit. Subjects are to proceed to DS1 only if they met 
preliminary eligibility after the results of the SC2 labs and ECG have been received and reviewed by the 
Site Investigator. 
 
DAT scan screening will be conducted at a qualified neuroimaging center. Results will be analyzed by the 
study imaging core to determine whether there is evidence of a dopamine deficit, which is required for 
eligibility.  
7.1.6 
Post DS1 Telephone Call between DS1 
A follow-up phone call will take place once the DS1 results have been received and reviewed.  The 
following will be performed during the call: 
x Review the results with the subject 
x Inform the subject of his/her eligibility for proceeding to BL 
x Remind the subject (if proceeding to BL) to collect the 24-hour urine on the day before 
the BL visit, and to bring the container to the visit 
7.1.7 
Baseline Visit Telephone Call Immediately Prior to Baseline 
Two or three days before the Baseline Visit is scheduled to occur, the subject should be contacted to 
remind him/her to collect the 24-hour urine on the day before the visit and to bring the container to the 
visit.  
7.1.8 
Baseline Visit (Visit BL) 
The Baseline Visit must be within 60 days after SC1 and may not be conducted until the result of the DS1 
scan has been received and reviewed by the Site Investigator.  
 
The following procedures & evaluations are to be performed at the Baseline Visit:  
x 
Review all inclusion/exclusion criteria to ensure subject remains eligible  
x 
Obtain socio-economic information 
x 
Obtain smoking, alcohol & caffeine information 
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Administer MDS-UPDRS Parts IA and III 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
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x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
Provide MDS-UPDRS Parts IB and II, PDQ-39, depression module of the Neuro-QOL, RBD, PD 
Risk Factors, and PD-Expectancy questionnaires to subject for self-administration 
x 
Obtain height, weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Obtain blood for safety lab tests: serum urate, chem 7 panel, LFTs, TSH, lipids, CBC with 
differential 
x 
If the subject has given consent, obtain extra blood samples for (DNA and plasma) banking  
x 
Obtain urine for routine analysis/pH/sediment 
x 
Retrieve 24-hour urine container from subject and process urine sample   
x 
Use electronic enrollment module to randomize to treatment the subject who continues to meet all 
eligibility requirements per the Site Investigator’s final assessment (see Section 4.3.4 for 
information regarding the enrollment module).  The DCC will assign the subject’s 5-digit 
enrollment/randomization number at this time. 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
 
Under no circumstances may study drug be pulled from storage and given to a subject unless that 
drug kit has been assigned to that subject via the enrollment process.  
 
The coordinator should write the subject’s initials and Subject ID Number assigned at SC1 on the drug kit 
when it is taken from storage. 
x 
Dispense sufficient study drug to cover time to next visit 
x 
Observe subject taking one capsule and offer tips193 if difficulty swallowing is a concern. (Note: 
This will be the only capsule taken on enrollment day for subjects whose initial dosing is one 
capsule daily; those whose initial dosing is one capsule b.i.d. or t,i,d, will take one more capsule 
after the visit around dinner time.)  
x 
Provide verbal instructions regarding study drug covering: 
o Storage requirements  
o Importance of always taking capsules with a glass of water or other unsweetened, non-
alcoholic beverage to ensure adequate hydration that should reduce the risk of kidney 
stones and gout.64,177,178 
o May be taken with or without food, but because it can cause stomach upset in some it is 
recommended to at least start by taking it with meals.  
o Titration schedule (see section 5.1.2.2)  
o Importance of not taking any study medication on study visit days until after the blood 
draw. 
o Return of all study bottles at each visit (whether empty, partially used, or unused) 
x 
Distribute written dosing instructions 
x 
Distribute subject reimbursement card and information  
x 
Distribute Study Drug Record sheets and instruct subject how to record doses ordered and taken 
x 
Stress to subject the importance of calling site to report any AEs 
x 
Begin tracking dosing on the Dose Management Log 
x 
Schedule Visit 01 (week 3) for 21 +/- 3 days after the Baseline Visit  


 
 
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7.2 
On-Intervention Evaluations 
7.2.1 
Visit 01 (Week 3) 
Visit 01/Week 3 will occur 21 ± 3 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 01 (week 3):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Schedule Visit 02 (week 6) for 42 +/-5 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
7.2.2 
Post Study Visit Telephone Calls 
Beginning with the Baseline Visit, serum urate test results will not be provided to sites.  Instead the serum 
urate result will only be provided to an unblinded DCC Programmer and used in an algorithm to 
determine if a subject’s study drug should be increased, decreased, or remain steady.  (See Sec. 5.1.2.3)  
 
If serum urate level warrants altering capsule dosing, the DCC will notify both the Site Investigator and 
Coordinator by email within 3 days of the visit.  The Site Investigator or Coordinator should immediately 
notify the subject and update the Dose Management Log.  Dosage increases, reductions, or holds should 
be initiated as soon as the subject is notified.  
 
If the most recent urine pH/sediment results trigger the initiation or change of alkalinization therapy, then 
the Site Investigator or Coordinator should immediately notify the subject on how to begin or modify use 
of potassium citrate (or an alternative alkalinizing agent) according to the alkalinization algorithm in Sec. 
8.4.2. 
 
A follow-up phone call will take place after each study visit once the site is informed of a dosage change. 
The following will be performed and documented during the call: 
x Inform the subject to either increase, reduce or hold their study drug  
7.2.3 
Visit 02 (Week 6) 
Visit 02/Week 6 will occur 42 ± 5 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 02 (Week 6):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  


 
 
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x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess blindedness to treatment assignment (Site Investigator, Coordinator, and subject), unless 
previously assessed during an Unscheduled Visit due to drug discontinuation. 
x 
Schedule Visit 03 (week 12) for 84 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
7.2.4 
Visit 03 (Week 12) 
Visit 03/Week 12 will occur 84 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 03 (week 12):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Obtain blood for safety lab tests: serum urate, chem 7 panel, LFTs, TSH, lipids, CBC with 
differential 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II, RBD, depression module of the Neuro-QOL, and PDQ-39 
questionnaires to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
Schedule Visit 04 (month 6) for 180 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  


 
 
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x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
7.2.5 
Visit 04 (Month 6) 
Visit 04/Month 6 will occur 180 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 04 (month 6):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Schedule Visit 05 (month 9) for 270 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
7.2.6 
Visit 05 (Month 9) 
Visit 05/Month 9 will occur 270 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 05 (month 9):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 


 
 
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x 
Distribute container for 24-hour urine collection at home and instruct subject in collection/storage 
procedures 
x 
Schedule Visit 06 (month 12) for 360 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
7.2.7 
Pre-V06 Telephone Call  
A follow-up phone call will take place 2-3 days BEFORE V06 to remind the subject of the following:  
x Remind the subject to collect the 24-hour urine on the day before the V06 visit, and to 
bring the container to the visit 
7.2.8 
Visit 06 (Month 12) 
Visit 06/Month 12 will occur 360 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 06 (month 12):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Conduct Electrocardiogram (12-lead ECG) 
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Retrieve 24-hour urine container from subject and process urine sample   
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II, RBD, depression module of the Neuro-QOL, and PDQ-39 
questionnaires to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
Schedule Visit 07 (month 15) for 450 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
x 
For an interested, eligible subject, obtain written informed consent for the optional DAT scan 
substudy  
 


 
 
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7.2.9 
Visit 07 (Month 15) 
Visit 07/Month 15 will occur 450 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 07 (month 15):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Schedule Visit 08 (month 18) for 540 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional DAT scan substudy  
 
7.2.10 Visit 08 (Month 18) 
Visit 08/Month 18 will occur 540 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 08 (month 18):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Schedule Visit 09 (month 21) for 630 +/-7 days after the Baseline Visit 


 
 
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x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
Assist a consented Smart4SURE substudy subject in downloading and registering the 
Smart4SURE app on the subject’s smartphone, and conduct an online training session via the app 
if not performed at a prior visit. 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional DAT scan substudy  
7.2.11 Visit 09 (Month 21) 
Visit 09/Month 21 will occur 630 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 09 (month 21):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
Obtain blood for safety lab test CBC with differential if subject treated with potassium citrate 
alkalinization therapy (at any time) since last visit 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Review drug compliance on Study Drug Record with subject and re-educate as necessary 
x 
Distribute additional Study Drug Record sheets 
x 
Review and update Dose Management Log as necessary 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance 
x 
Dispense/re-dispense sufficient study drug to cover time to next visit  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Schedule Visit 10 (Month 24) for 720 +/-7 days after the Baseline Visit 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional Smart4SURE substudy  
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the Smart4SURE substudy Assist a consented Smart4SURE substudy subject in downloading 
and registering the Smart4SURE app on the subject’s smartphone, and conduct an online training 
session via the app if not performed at a prior visit. 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional DAT scan substudy  
7.2.12 Visit 10 (Month 24) 
Visit 10/Month 24 will occur 720 ± 7 days from the Baseline Visit.  The following procedures and 
evaluations are to be performed at Visit 24 (month 24):  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Conduct Electrocardiogram (12-lead ECG) 
x 
Obtain blood for safety lab tests: serum urate, chem 7 panel, LFTs, TSH, lipids, CBC with 
differential 
x 
If the subject has given consent, obtain extra blood sample for (plasma) banking unless one was 
obtained previously during an Unscheduled Visit due to drug discontinuation 
x 
Obtain urine for routine analysis/pH/sediment 


 
 
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x 
Retrieve previously dispensed study drug/bottles and calculate compliance (Note:  The last dose 
of study drug will have been taken on the day prior to Visit 10.  No study drug is to be taken 
during or after the visit.) 
x 
Record last dosing on Dose Management Log 
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II, RBD, depression module of the Neuro-QOL, and PDQ-39 
questionnaires to subject for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
Assess blindedness to treatment assignment (Site Investigator, Coordinator, and subject) unless 
previously assessed during an Unscheduled Visit due to drug discontinuation 
x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
For an interested, eligible subject who has not already enrolled, obtain written informed consent 
for the optional DAT scan substudy  
 
During this visit the following will be scheduled with the subject: 
x 
Telephone Evaluation TE1 (Month 25) for 30 +/-3 days after the current V10 visit  
x 
Telephone Evaluation TE2 (Month 26) for 60 +/-3 days after the current V10 visit 
x 
Safety Visit SV (Month 27) for 90 +/-3 days after the current V10 visit 
x 
Optional DAT scan DS2 (Month 25-26) for 45+/-15 days after the current visit. 
7.3 
On Study/Off-Intervention Evaluations 
7.3.1 
Optional DAT scan (DS2; Month 25-26) 
For subjects who have consented to the optional DAT scan substudy, who have been on study drug 
through at least the 1-year visit (V06), and who have not taken any drug disallowed within 90 days prior 
to DS2 (see Sec. 6.2.11.2), visit DS2 will occur 45+/-15 days after the V10 visit, and before the Safety 
Visit (SV).   
 
The DAT scan process will be conducted at a qualified neuroimaging center. Results will be analyzed by 
the study imaging core. 
 
7.3.2 
Telephone Evaluation 1 (TE1; Month 25) 
Visit TE1/Month 25 will occur 30 +/-3 days after the current V10 visit.  The following procedures and 
evaluations are to be performed via the TE1 Telephone evaluation (month 25):  
x 
Review and document concomitant medications 
x 
Assess and document AEs 
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
7.3.3 
Telephone Evaluation 2 (TE2; Month 26) 
Visit TE2/Month 26 will occur 60 +/-3 days after the current V10 visit.  The following procedures and 
evaluations are to be performed via the TE2 Telephone evaluation (month 26):   
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 


 
 
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7.4 
Final On-Study Evaluations 
7.4.1 
Safety Visit (SV; Month 27) 
Visit SV/Month 27 will occur 90 +/-3 days after the current V10 visit (810 ± 10 days from the Baseline 
Visit).  The following procedures and evaluations are to be performed at the SV visit (month 27):   
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Obtain blood for safety lab tests: serum urate and chem 7 panel 
x 
If the subject has given consent, obtain extra blood sample for (plasma) banking.  
x 
Obtain urine for routine analysis/pH/sediment 
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II, RBD, Neuro-QOL and PDQ-39 questionnaires to subject 
for self-administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
Assess diagnostic features and PD diagnosis 
x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
Inform the subject – if participating the Smart4SURE substudy – that s/he should complete a final 
smartphone Activity Session and Survey set within one month of the SV (if s/he has not already 
completed them in the past month). 
x 
Complete the Conclusion of Study Participation eCRF 
7.5 
On-Study/Non-Standard Evaluations 
7.5.1 
Unscheduled Visit (Visit U01, U02, etc.) 
An unscheduled visit may be performed at any time during the study at the subject’s request or as deemed 
necessary by the Site Investigator. The date and reason for the unscheduled visit should be recorded in the 
source documentation.  
 
In most cases, an unscheduled visit will be warranted due to an AE, significantly abnormal lab values, 
permanent discontinuation of study drug before 24 month visit, initiation of treatment with a thiazide 1-4 
weeks earlier, or need for an in-person assessment for possible initiation of dopaminergic therapy. 
 
The following procedures and evaluations at a minimum are to be performed at an Unscheduled Visit:  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Obtain serum urate for blinded central analysis if subject initiated thiazide treatment 1-4 weeks 
earlier, or if otherwise warranted based on the Site Investigator’s judgment 
x 
Update the Dose Management Log as needed 
 
If the reason for the unscheduled visit is that the participant is permanently discontinuing drug at the visit, 
whether by choice, or for reasons concerning the health or well being of the subject, the following 
additional procedures and evaluations should be completed:  
x 
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x 
Retrieve all previously dispensed study drug and calculate compliance (Note: If study drug has 
not already been discontinued and there is no medical reason to warrant otherwise, the final dose 
will be taken when the last dose of the day is normally taken on the day prior to the visit .  No 
study drug is to be taken during or after the study visit.) 
x 
Record last dosing on Dose Management Log 
x 
If participant consented to the optional future biomarker study a blood sample will be taken 
(please see section 6.2.14 for information about altered sample collection schedule) 
 
In addition as warranted by the purpose of the unscheduled visit, the following procedures and 
evaluations may be performed at the discretion of the Site Investigator: 
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Obtain blood and/or urine for additional study chemistry or hematology tests, or other laboratory 
testing if warranted based on the Site Investigator’s judgment 
 
7.5.2 
Discontinuation of In-Person Follow-Up Visit (Visit DF) 
The Discontinuation of In-person Follow-up (DF) Visit should be conducted at the time the decision to 
stop in-person follow-up is made or as soon thereafter as possible.  The DF Visit (and subsequent Safety 
Visit) should be conducted whether this decision is made when drug is discontinued or later after some 
visits off drug have already occurred.   
The following procedures and evaluations are to be performed at the Discontinuation of In-person 
Follow-up Visit:  
x 
Review and document concomitant medications 
x 
Assess and document AEs  
x 
Obtain weight and orthostatic vital signs (blood pressure, heart rate) 
x 
Conduct Electrocardiogram (12-lead ECG) 
x 
Obtain blood for safety lab tests: serum urate, chem 7 panel, LFTs, TSH, lipids, CBC with 
differential 
x 
Obtain urine for routine analysis/pH/sediment 
x 
Retrieve previously dispensed study drug/bottles and calculate compliance (Note:  The last dose 
of study drug will have been taken on the day prior to visit or earlier.  No study drug is to be 
taken during or after the visit.) 
x 
Record last dosing on Dose Management Log 
x 
Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
x 
Administer MDS-UPDRS Part IA and III 
x 
Provide MDS-UPDRS Parts IB and II, RBD and PDQ-39 questionnaires to subject for self-
administration 
x 
Administer MDS-UPDRS Part IV, if dopaminergic therapy was previously initiated during study 
x 
Assess Modified Hoehn and Yahr Scale  
x 
Assess Modified Schwab & England Activities of Daily Living  
x 
Assess diagnostic features and PD diagnosis 
x 
Assess blindedness to treatment assignment (Site Investigator, Coordinator, and subject)  
x 
Administer Montreal Cognitive Assessment (MoCA) 
x 
Review with the subject the plan for quarterly telephone visits (see Sec. 7.5.3) 
Call the CCC within 24 hours to report the discontinuation of in-person follow-up 
Note:  If a subject who permanently discontinues study participation via in-person visits also declines a 
Safety Visit and also declines future telephone visits, then the Conclusion of Study Participation eCRF 
should be completed at the Discontinuation of In-person Follow-up Visit and the premature withdrawal 
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is reported.  In addition, any AE that remains active at the Discontinuation of In-person Follow-up Visit 
for such a subject must be followed for 30 days or until resolved or stabilized, whichever occurs first. 
7.5.3 
Telephone Visits after Permanent Discontinuation of In-Person Follow-Up 
For any subject who permanently discontinues in-person follow-up prior to Month 24, study participation 
will continue via telephone visits.  Calls from the Site Investigator or Coordinator will occur during the 
pre-established study visit windows for all remaining study visits through Month 27. 
 
The purpose of these telephone visits will be to: 
1. Review any AEs that have occurred since the last visit or phone call  
2. Review and document concomitant medications used during this time period 
3. Assess need for dopaminergic therapy (if need has not been determined at a previous visit) 
7.6 
Premature Study Withdrawal 
The following events will be considered a premature study withdrawal, and the CCC must be notified of 
such within 24 hours of the Site Investigator’s awareness of the following: 
x 
A subject who has completed 24 months on study drug does not complete the Month 27 Safety 
Visit.  
x 
A subject who is participating in the study via in-person visits discontinues those visits prior to 
his/her Month 24 visit and declines to continue study participation via telephone visits. 
x 
A subject who is participating in the study via telephone visits discontinues prior to his/her Month 
27 call. 
 
The following will NOT be considered a premature study withdrawal: 
x 
A subject permanently discontinues study drug but does continue participation in the study via 
in-person visits.   
x 
A subject permanently discontinues study drug and does not complete a Discontinuation of In-
Person Follow-up Visit and/or a Safety Visit, but does continue participation in the study via 
telephone visits.  
 
Each of these cases will be considered a reportable drug discontinuation but not a reportable premature 
withdrawal.  The non-conducted Discontinuation of In-Person Follow-up, and/or Safety visit(s) will be 
recorded as missed visit(s). 
 
 
 
 
 
 
 
 


 
 
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7.7 
Schedule of Activities 
 


 
 
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8.    MANAGEMENT OF ADVERSE EXPERIENCE 
 
Chronic oral inosine treatment poses small but likely increased risks of gout and urolithiasis because 
inosine here is intended and expected to elevate serum urate levels significantly.  A less substantiated but 
important possible risk of elevating urate is cardiovascular disease (CVD), based on an association in 
some studies between urate levels and the risk of CVD. Accordingly, precautions at the levels of subject 
selection, monitoring, prophylaxis, and/or treatment have been included to mitigate the risk of potential 
adverse effects. 
8.1 
Adverse Event / Experience (AE) Definition 
An adverse event or experience is any symptom, sign, illness, or event that develops or worsens during 
the course of the study, whether or not the experience is considered related to study drug. Some examples 
of AEs are:  
x 
Acute gout, uric acid urolithiasis or any other medical problem to which higher urate levels are 
known to contribute 
x 
A myocardial or cerebral infarction, or any other medical problem with which higher urate levels 
have been associated without clear evidence of causality 
x 
A change, excluding minor fluctuations, in the nature, severity, frequency, or duration of a pre-
existing condition  
x 
Development of an intercurrent illness during the study  
x 
Development of symptoms that may or may not be related to the use of a concomitant medication or 
study drug  
x 
Appearance of abnormal laboratory results, or substantial shifts of lab values within the reference 
ranges that the Site Investigator considers clinically important. 
 
Worsening of a PD symptom is to be recorded as an AE only when there is a change in nature, 
severity, or frequency of that Parkinson’s disease symptom beyond what the Site Investigator 
expects is within the normal range of fluctuation for that subject. 
8.2 Serious Adverse Events / Experiences (SAEs) 
A serious adverse drug experience or SAE is defined as any adverse event or experience that occurs at 
any dose that results in any of the following outcomes:  
x 
Death;  
x 
A life-threatening adverse event or experience;  
x 
Inpatient hospitalization or prolongation of existing hospitalization;  
x 
A persistent or significant disability/incapacity; or  
x 
A congenital anomaly/birth defect.   
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include (but are not limited to) 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, convulsions that 
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This category also includes any event the Site Investigator or the Medical Safety Monitor judges to be 
serious or that would suggest a significant hazard, contraindication, side effect or precaution. It can also 
involve the withdrawal of a subject from study drug due to abnormal lab values, excluding Screening 
Visit lab results.  
8.3 Recording of Adverse Events / Experiences 
The site study staff will assess AEs at each subject visit by recording all voluntary complaints of the 
subject and by assessment of clinical features. At each study visit, the subject should be questioned 
directly regarding the occurrence of any AE since their last visit.  
 
All AEs whether observed by the Site Investigator and/or Coordinator, elicited from or volunteered by the 
subject, and whether ascribed to the study drug or not, should be recorded on the eCRF AE Log and in the 
subject’s clinical chart. The following information is gathered on the Log:  event term, onset date, 
resolution date if any, whether serious or not, severity level, action taken with study drug, outcome, and 
the Site Investigator’s opinion of the possible relationship between the AE and the study drug or 
participation in the study.  If a subject is withdrawn from drug or the study because of an AE, it must be 
recorded on the eCRF as such. 
 
All serious adverse events/experiences, as defined above, must be reported to the Medical Safety Monitor 
and the CCC within 24 hours of the site’s awareness, whether or not the Site Investigator feels that the 
experience is related to study drug, or was expected.   Within that 24 hour period the Site Investigator 
must also complete a SURE-PD3 SAE Report Form and e-mail or fax it to the CCC.  
 
For AE or significant abnormal result that is identified during a visit, telephone call or other study 
activity, the site staff should ensure that the information is available to the subject and his or her primary 
care physician. As appropriate and permitted by the subject, the primary care physician should be notified 
by the research staff via written correspondence for further follow-up. Should the result affect the 
subject’s immediate safety (e.g., severe depressed mood, significant out of range laboratory value), 
appropriate, immediate action should be taken by the Site Investigator to ensure the subject’s well-being.  
 
 
 


 
 
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8.3.1 Adverse Event/Experience Causality Definitions 
For each adverse event or experience, the relationship to the study drug must be recorded on the 
AE Log as one of the defined in Table 6.  
8.3.2 Adverse Event/Experience Severity Definitions  
The severity of each adverse event or experience must be recorded as one of the following on the AE 
Log:  
Mild  
 
 
No limitation of usual activities  
Moderate   
 
Some limitation of usual activities  
Severe  
 
 
Inability to carry out usual activities 
 
 
 
Table 6:  Causality Definitions for Adverse Events/Experiences in SURE-PD3 
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8.4 Known Adverse Event / Experience Prophylaxis Plan 
8.4.1 Monitoring of Urine pH and Uric Acid Crystalluria 
Acidic urine is a major, modifiable risk factor for uric acid urolithiasis, which form from uric acid 
crystals. Thus microscopic uric acid crystals in the urine (uric acid crystalluria; UAC) are an intuitive 
additional risk factor for these stones. Our experience in SURE-PD provides empiric evidence that 
identification of uric acid crystalluria by a central laboratory in the setting of low urine pH can in fact 
provide a useful further indication of increased risk of uric acid urolithiasis. Accordingly, urine samples 
will be collected at all on-treatment site visits for central laboratory urinalysis to determine pH and the 
presence of UAC, in a blinded manner.  (See Schedule of Activities, Sec. 7.7.)  Both risk factors will be 
integrated into the following algorithm 
for 
triggering 
urine 
alkalinization 
therapy for uric acid stone prophylaxis. 
8.4.2 Algorithm for Triggering Urine 
Alkalinization Method  
Based on the premise that repeated 
measures of urinary risk factors for stone 
formation will be more reliable than a 
single measure,194,195 persistently acidic 
urine (PAU) will trigger alkalinization 
treatment with potassium citrate (or an 
alternative means of urine alkalinization 
were potassium citrate [51] to be contra-
indicated) according to the schematized 
algorithm of Fig. 12. The threshold for 
alkalinization in response to PAU is 
lowered by greater urine acidity (i.e., the 
lowest pH values), by greater persistence 
of lower values, and by the presence of 
UAC. 
 
x 
Alkalinization Triggers 
o PAU with lowest urine pH -- 
Although the lowest urine pH 
value of ≤5.0 on the initial 
screening visit (SC1) is an 
enrollment exclusion criterion, it 
may occur at the baseline visit or 
as a finding in any subsequent 
urine sample collected throughout the study.  If it occurs in any two consecutive urine samples 
(first possible at the 3-week visit V01) it will trigger alkalinization per the algorithm outlined in 
Fig. 12.    
 
o PAU with sustained lower urine pH – Three consecutive study urine pH values of ≤5.5 will 
trigger alkalinization (as in Fig. 12), unless the DSMB or SC determine that fewer (two) or more 
(four) consecutive study urine pH values of ≤5.5 will trigger alkalinization to better balance the 
benefits and risks of alkalinization in the trial.  
 
12. 
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o PAU with lower urine pH and UAC – If UAC is identified in the sediment of a urine sample, 
than a urine pH value of ≤5.5 either in the same sample or in the sample from the prior urine 
sample will trigger alkalinization (as in Fig. 12).  
 
x 
Alkalinization Impact on Blinding 
Subjects and site staff will be blinded to the specific urine pH and crystalluria test results to 
minimize unblinding to treatment assignment. Because urate-elevating inosine treatment does not 
have an appreciable effect on urine pH as demonstrated in SURE-PD, the rate of alkalinization 
due to low urine pH will be similar in placebo- and inosine-assigned subjects, also mitigating any 
unblinding effect. However, a difference in alkalinization rates may occur, because UAC is 
expected to occur primarily in inosine-treated subjects and would further lower the threshold for 
alkalinization (as above). Accordingly, if alkalinization is initiated in more inosine- than placebo- 
assigned participants then the threshold for initiating alkalinization would be altered in placebo 
participants in order to maintain similar frequencies of alkalinization across treatments. For 
example, if the number of participants in the inosine group who have initiated alkalinization 
exceeds that in the placebo group by 2 or >2, then the placecbo group alkalinization trigger for 
consecutive urine pH values ≤5.5 even in the absence of UAC would be 2 or 1, respectively 
(rather than 3 as in Fig. 12). Further, the DSMB will monitor rates of alkalinization, any 
alkalinization AEs and any urolithiasis AEs (in aggregate and by treatment assignment) and will 
periodically assess whether any change in the alkalinization protocol is warranted during the 
study. 
 
x 
Alkalinization Protocol 
Site staff will receive automated notification from the DCC of the need to initiate alkalinization 
within a few days of the urinalysis that triggers the protocol by the above criteria. The following 
steps should then be taken: 
x 
Site staff will prescribe (via a central pharmacy) “lower-dose” potassium citrate, which 
depends on subject weight (as recorded most recently on a study visit): 
x   Less than 70 kg:   10 mEq, in tablet form, po tid (with meals) 
x   70 kg or greater:  10 mEq, in tablet form, po qid (with meals and at bedtime) 
The potassium citrate prescription may be written for a one month supply of tablets that will 
cover dosing at either the lower or higher dose -- for efficiency given the possibility that the 
subject may double the dose (from lower to higher) within two weeks of initiation.  
Accordingly, recommended prescriptions depending on subject weight are: 
x 
[Less than 70 kg]  10 mEq tabs; # 180; sig: 1-2 po tid (with meals); refills: 5. 
x 
[70 kg or greater] 10 mEq tabs; # 240; sig: 1-2 po qid (with meals and at bedtime); refills: 
5. 
 
x 
Staff will phone the subject to review the purpose, administration, potential adverse effects of 
potassium citrate, and plan rechecking urine pH in two weeks. In addition, staff will review 
recommendations for adequate hydration.  The prescriber should review with the subject:  
x 
Any contraindications to potassium citrate, including a history of peptic ulcer disease, 
current use of an anticholinergic agent (e.g., trihexyphenidyl), hyperkalemia or renal 
insufficiency per most recent electrolyte measurements, or an active urinary tract 
infection.  
o If potassium citrate were deemed contraindicated (or later found insufficient) 
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alternative dosing schedule or an alternative alkalinizing agent such as sodium 
bicarbonate. 
x 
Potential adverse effects of potassium citrate, including minor gastrointestinal 
complaints, such as abdominal discomfort, vomiting, diarrhea, loose bowel movements or 
nausea, and rarely gastrointestinal bleeding. The subject should be instructed to check 
with site staff or another doctor at once if tarry stools or other evidence of gastrointestinal 
bleeding is noticed.  
x 
The possibility of abnormal results of blood lab test that will be monitored regularly on 
subsequent visits, and if this is the first prescription of potassium citrate at either a 10 
mEq or the 20 mEq dose then in 5-10 days at an unscheduled visit. 
x 
The importance of taking each dose faithfully,91 and without crushing, chewing or 
sucking the tablet, and to check with physician if there is trouble swallowing tablets or if 
the tablet seems to stick in the throat. Subjects should not change dosing alkalinization 
medication until instructed to do so based on follow-up urinalysis results. 
x 
Instructions for obtaining and mailing to the central lab a urine sample 2 weeks following 
initiating the alkalinization mediation (using a kit and mailer to be received by courier 
mail). 
 
x 
Site staff will receive automated notification from the DCC within a few days of any home 
(and visit) urine sample analysis for a subject on alkalinization therapy.  The notification will 
include the assumptions of what the subject is currently taking for alkalinization therapy (e.g., 
low or higher dose potassium citriate or the equivalent) and recommendation to continue on 
this dosing, to reduce/discontinue it, or to increase it (according to algorithm outlined in Fig. 
12). 
x 
Staff will phone the subject to review the results, confirm the assumptions of the 
subject’s dosing when the urine sample was collected, and make the indicated 
recommendation to continue on this dosing, to reduce/discontinue it, or to increase it.  
o For subjects on “lower-dose” potassium citrate who are instructed to increase it 
to “higher-dose” potassium citrate, they will be instructed to double their current 
dose. Depending on their weight: 
 
less than 70 kg:   20 mEq, in tablet form, po tid (with meals) 
 
70 kg or greater:   20 mEq, in tablet form, po qid (with meals and at 
bedtime) 
x 
For any deviations from compliance with the medication site staff will contact the CCC 
who may engage the Medical Safety Monitor to obtain guidance.  
x 
Staff will review (as detailed above) the purpose, administration, potential adverse effects 
of potassium citrate, and plan for rechecking urine pH at home in two weeks if the 
subject is to increase or to reduce the alkalinization dose. Home recheck will not be 
performed if the subject is instructed to continue the current alkalinization dose or to 
discontinue it, or if the subject is scheduled for a site visit in the next two weeks. 
x 
Subjects will be instructed to follow this algorithm for alkalinization for the duration of the 
treatment period of the trial.  Any alkalinization therapy ongoing at the time of 24 month visit 
will be discontinued immediately after that visit (or at the time of study drug discontinuation 
if occurring earlier) irrespective of urine pH or sediment results at the visit.   


 
 
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8.4.3 Hyperkalemia and Other Laboratory Abnormalities 
Current full prescribing information for potassium citrate196 indicates that laboratory tests should be 
checked every 4 months for: 
x 
Electrolytes (to monitor for potassium elevation) 
x 
Creatinine (to monitor for renal disease, a risk factor for hyperkalemic complications) 
x 
CBC (to monitor for anemia as an indicator of gastrointestinal bleeding due to mucosal lesions, which 
have been observed rarely on solid potassium treatments – at an estimated frequency of 
approximately 1 lesion per 100,000 patient-years). 
 
Under the study protocol electrolytes and creatinine will be monitored even more frequently via routine 
laboratory testing no more than 3 months apart. A CBC will be added to the central lab tests in subjects 
treated with potassium citrate at any time since their last study visit. 
8.4.3.1 Hyperkalemia 
If hyperkalemia develops while a subject is taking potassium citrate, it should be suspended. Potassium 
testing should be repeated within 7 days of the suspension.   
 
If serum potassium falls back into the normal range, then the potassium citrate will be resumed at a 
reduced dosage in an effort to find a lower dosage that does not produce hyperkalemia but on which urine 
pH remains at 5.5 or above.  
 
If hyperkalemia remains, the potassium citrate will be discontinued.  An alternative, non-potassium-based 
alkalinization measure64 may be tried if the Medical Safety Monitor and Site Investigator believe such a 
measure is warranted.  If a non-potassium-based alkalinization measure is not warranted, then the subject 
should discontinue study drug. 
 
If urine pH remains <5.5 on potassium citrate at the maximum tolerated dosage (i.e., not producing 
hyperkalemia, and up to 100 mEq/day), or on a non-potassium-based-alkalinization measure, then the 
subject will discontinue study drug due to ‘unmitigated PAU.’  
8.4.3.2 Rise in Serum Creatinine or Fall in Hematocrit or Hemoglobin 
If a significant rise in serum creatinine or a significant fall in blood hematocrit or hemoglobin develops 
while a subject is taking potassium citrate, it should be suspended and the source of the abnormality 
determined.   
 
If these abnormalities are attributable to irreversible renal disease or to gastrointestinal bleeding, then the 
potassium citrate should not be resumed.  Consideration may be given to an alternative, non-potassium-
based alkalinization measure if the Medical Safety Monitor and Site Investigator believe such a measure 
is warranted. 
 
If urine alkalinization cannot be resumed or an alternative cannot be instituted, then a urine sample will be 
sent for central laboratory pH testing within 2 weeks.  If urine pH is found to be <5.5 then the subject will 
discontinue study drug due to ‘unmitigated PAU’. 
8.5 Known Adverse Event / Experience Management Plan 
8.5.1 Urolithiasis 
If urolithiasis occurs with symptoms of suggestive pain, hematuria or painless urolithiasis observed or if 
incidentally noted on imaging, the following steps should be undertaken:  


 
 
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x 
Seek prompt medical attention to diagnose and manage elimination of any stone(s)  
x 
Medical evaluation and treatment (preferably at the time of symptom onset) should include 
assessment of  
o 
Serum urate measurement  
o 
Urinalysis for pH; and initiation of alkalinization therapy64,91 as warranted  
o 
Urine sediment examination for crystalluria (and type of any crystals)  
o 
State of hydration assessment (by history and exam); and rehydration,177, 178 as warranted 
x 
Submit stone, if available, for chemical analysis  
x 
Study drug plan: 
o 
Suspend study drug until medical condition is stabilized (including resolution of symptoms that 
may be due to urolithiasis) 
o 
Resume dosing if the analysis of the stone or associated sediment crystalluria indicates no uric 
acid or urate composition, or the subject is found not to have urolithiasis. 
o 
If the analysis of the stone or associated sediment crystalluria indicates uric acid or urate 
composition, or is indeterminant, then: 
 
Resume dosing if a remediable contributor (e.g., unduly elevated serum urate, low urine pH 
and/or dehydration) can be reasonably expected to be better controlled. 
 
Discontinue study drug if there is no evidence of remediable source or precipitant of 
urolithiasis (e.g., no serum urate level above targeted range, no urine pH <6.0, no 
dehydration) 
 
Discontinue study drug if there is evidence of remediable source or precipitant of urolithiasis 
but subject prefers not to continue on drug. 
8.5.2 Acute Gouty Arthritis 
If gout-like acute arthritis develops, the following steps should be undertaken: 
x 
Seek prompt medical attention to diagnose and treat  
x 
Medical evaluation should include prompt serum urate level checks 
x 
Study drug plan: 
o 
Suspend study drug during evaluation period 
o 
Resume drug if the diagnosis of gout is associated with a remediable above-range serum urate 
level that resolves within 4 weeks off study drug.   Drug resumption must be accompanied by 
continuing close monitoring of serum urate. 
o 
Discontinue study drug if the diagnosis of gout is confirmed without a remediable above-range 
serum urate level. 
8.6 Responsibilities of the Site Investigator for Reporting SAEs  
x 
The Site Investigator or Coordinator should record all SAEs that occur during the study period on the 
AE Log and in the appropriate source documents. 
x 
For the purposes of reporting SAEs, the study period is defined as the time when the subject signs the 
informed consent (1st Screening Visit) through Month 27 or in the event of a premature withdrawal, 
for 30 days following the premature withdrawal (if subject is willing).  
x 
The Site Investigator or Coordinator should notify the CCC by telephone within 24 hours of 
becoming aware of the occurrence of an SAE. If calling after hours or on the weekend, a message will 
instruct the caller on how to reach the physician on-call. Upon completion of the telephone report, the 
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entry of the incident, an immediate notification will be disseminated by email to the Steering 
Committee (including PI and Co-PI), DCC PI and project staff, Medical Safety Monitor, site 
monitoring staff, CCC project staff, CCC Biostatistics staff, and DSMB if desired.  
x 
The following information should be supplied if available, and as applicable, at the time of the 
telephone call: site number, subject ID number, subject age and gender, date of randomization, study 
drug start date, whether study drug dosage has been reduced or discontinued, date of last study drug 
dose, date of onset of event, event description, whether event required treatment, death and autopsy 
report, an identification of which criteria for an SAE have been met, the Site Investigator’s current 
opinion of the relationship between the event and the study drug and/or study participation.  
x 
The Site Investigator and Coordinator will complete the SURE-PD3 SAE Report Form and update the 
AE, concomitant medications and dose management eCRFs and e-mail or fax the SAE Report Form 
to the CCC Project Manager within 24 hours of the site’s becoming aware of the SAE. A SURE-PD3 
SAE Report Form must be completed for all SAEs regardless of causality or expectedness.  
x 
The Medical Safety Monitor will review the SAE incident report and SURE-PD3 SAE Report Form 
and related database entries and confer with the Principal Investigator and/or the Site Investigator 
and/or Coordinator as necessary.  
x 
The Principal Investigator or designee will report the SAE to regulatory authorities and the grantor 
(NINDS program staff) as applicable.  
x 
The Site Investigator must also comply with the site’s local Institutional Review Board (IRB) 
regulations regarding the reporting of AEs.   
x 
If follow-up information is required, e.g., hospital discharge report, the Site Investigator and/or 
Coordinator will provide it to the CCC in a timely manner.  
8.7 Follow-Up of Unresolved AEs and SAEs 
x 
All AEs on-going at the time the subject discontinues study drug use must be followed until the 
Month 27 Visit or until resolved or stabilized, whichever occurs first.  In the event a subject 
prematurely withdraws from the study, AEs should be followed for 30 day post study withdrawal (if 
subject is willing). SAEs may need to be followed beyond the 30 day period as requested by the 
Principal Investigator or Medical Safety Monitor. 
x 
Follow-up may involve the Site Investigator’s or Coordinator’s contacting other clinicians responsible 
for the subject’s care to obtain information on diagnoses, investigations performed and treatment 
given.  
8.8 Emergency Actions 
Inosine is widely available as a dietary supplement. It appears to be very well tolerated in the short-
term,48-50 and generally well tolerated in the long term when the only consistently reported adverse effects 
have been kidney stones (apparently uric acid urolithiasis).41,45,46,102  These have occurred at inosine doses 
(up to 4 gm/day) and over time periods (up to two years) that are comparable to those planned in the 
current study. However, most human studies of inosine at such doses have targeted healthy volunteers or 
athletes (with acute or sub-acute administration), or subjects with multiple sclerosis (with chronic 
administration). The preceding phase 2 SURE-PD trial and the present trial are the first to our knowledge 
to systematically target an older subject population.  Accordingly the mitigation and assessment of AEs 
will remain a priority. 
 
There are no known reports of acute overdose with inosine. Maximal doses in the current study (up to 1.0 
gm/dose and up to 3.0 gm/day) are 3-5 times lower than the maximal doses (5.0-6.0 gm/dose and up to 
10.0 gm/day for over a week) administered to a small number of healthy volunteers or athletes, and who 
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In the event of accidental or intentional overdose exceeding the study maximum daily dose of 6 capsules 
(which for active drug constitutes >3.0 gm inosine) in a 24 hour period, then additional fluids (the 
equivalent of at least three 12 oz unsweetened, non-alcoholic beverages in addition to subject’s normal 
fluid intake during the study) should be taken to reduce the risk of any acute hyperuricemic or 
hyperuricosuric AE.  
 
Any overdose exceeding 20 capsules (which for active drug constitutes >10.0 gm inosine) in a 24 
hour period (i.e., the limits of published human experience) should be considered an adverse effect 
potentially warranting emergency medical care and monitoring. Although inosine itself is a natural 
component of human intermediary metabolism, rapid conversion to urate, the end product of the 
inosine pathway, could theoretically lead to transient pathogenic elevation of serum and urinary 
urate beyond the limits of solubility, with attendant arthropathic (gout-like) and nephropathic 
(acute renal failure; as in ‘tumor lysis syndrome’) consequences. Site Investigator/staff should 
facilitate emergency medical services in the event of high level overdose by providing this 
background information, and encouraging consideration of supplemental intravenous hydration 
and close monitoring of serum urate levels. Site staff should be prepared to break the blind for the 
subject at the discretion of the treating emergency service physician, although it is expected that 
empiric monitoring of serum urate would be sufficient for overdose management.  
 
After any acute concerns for the subject’s safety have been addressed, the site staff should work with the 
subject to determine the basis for an overdose if it were not already apparent.  If an overdose were 
deemed accidental, then steps should be taken to avoid any further accidental overdose. If an overdose 
were deemed intentional, then consideration should be given for permanent study drug discontinuation 
(e.g., administratively for non-compliance, medically for major psychiatric AE, etc).  
 
For subjects continuing in the study after an overdose that did not prompt medical attention with serum 
urate monitoring, the regular dosing schedule should be resumed after skipping half the number of doses 
that were taken in excess. (E.g., for a subject taking 4 caps/day who inadvertently took 12 caps one day, 
regular dosing could resume after one day’s hiatus.) For subjects continuing in the study after an overdose 
that prompted medical attention with serum urate monitoring, any resumption of study dosing should be 
determined by the Site Investigator after discussion with the Medical Safety Monitor. 
 
There are no known drug interactions with inosine. Any results indicating otherwise from formal drug-
drug interaction studies conducted on GCP conditions will be incorporated into guidance for subjects. 
Theoretical interactions should be considered with any drug that affects urate levels. Although urate-
lowering drugs will not be allowed, thiazide diuretics can mildly elevate serum urate levels and are 
allowed at enrollment and during the study. Because urate levels are continually titrated to serum urate 
levels, the effects of mildly hyper- or hypo-uricemic agents on serum urate will be compensated.  
 
Neither drug discontinuation, premature withdrawal from the study, nor most clinical emergencies 
necessitate disclosure of treatment assignment. Most emergency situations can be handled by 
withdrawing study drug without disclosure of treatment assignment. However, in rare circumstances 
under which knowledge of the drug assignment is necessary for the treatment of an SAE, Site 
Investigators are encouraged to discuss the situation with the Medical Safety Monitor before deciding 
whether to disclose treatment assignment. Disclosure of individual treatment assignment must be made by 
the Site Investigator responsible for the care of the involved subject (or by the Coordinator or other 
physician as designated by the Site Investigator). Assigned drug treatment must not be revealed to other 
study staff, CCC or DCC staff or to individuals who are not involved directly in the clinical care of the 
subject unless disclosure is critical to the care of the subject.  


 
 
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8.9 Analysis of Adverse Events / Experiences 
On a regular basis the Medical Safety Monitor will evaluate AE and SAE data to determine if there is any 
indication of toxicity associated with inosine.  
 
The Data and Safety Monitoring Board (DSMB) will periodically review blinded, and if necessary, 
unblinded medical event data. SAEs, drug suspensions/rechallenges, drug discontinuations, and premature 
withdrawals will be tracked in real time, and the DSMB alerted if any imbalances arise between treatment 
groups. If there is a significantly (P< 0.05) greater incidence of a major (severe) adverse event in the 
inosine-treated group, the study may be modified after discussion with the DSMB.  
 
9.   CRITERIA FOR DRUG DISCONTINUATION AND SUBJECT WITHDRAWAL  
 
Subjects will be advised in the written informed consent forms that they have the right to permanently 
discontinue study drug and/or withdraw from the study at any time without prejudice, and may be 
withdrawn from drug and/or the study at the discretion of the Site Investigator, CCC Director and/or 
Study Principal Investigator at any time. Subjects who prematurely discontinue study drug will be asked 
to continue study participation via in-person visits if willing, and otherwise via quarterly telephone visits.  
Some premature drug discontinuations and/or study withdrawals may be unavoidable, but the Site 
Coordinator and Site Investigator will work closely with the study CCC, Medical Safety Monitor and 
Study Principal Investigator to attempt to retain subjects, if appropriate.  See Sections 7.5 to 7.6 for 
further discussion of non-standard visits for drug or visit discontinuation and premature withdrawal. 
 
Every effort should be made to obtain the subject’s final laboratory tests and evaluations of clinical status. 
Reasonable effort should be made to contact any subject lost to follow-up during the course of the study 
in order to complete assessments and retrieve any outstanding data, drugs or clinical supplies. In this case, 
the Site Investigator must use reasonable effort to contact the subject in order to finalize study-related 
procedures. Following unsuccessful telephone contact, an effort to contact the subject by mail using a 
method that provides proof of receipt, should be attempted. Such efforts should be documented in the 
source documents.  
 
A subject may discontinue study drug and/or withdraw from the study and/or be withdrawn from drug 
and/or the study for the following reasons:  
 
Administrative 
1. Withdrawal of subject consent  
2. Request of Site Investigator or Study Principal Investigator 
3. Request of primary care physician  
4. Non-compliance  
5. Pregnancy (Study drug will be discontinued in the event of a pregnancy, and every reasonable 
effort should be made to assess the health of the mother/fetus during the pregnancy and its 
outcome.) 
6. Protocol deviation  
7. Premature termination of the study 
 
Adverse Event/Experience  
1. Worsening of pre-existing disease (other than disease under study)  
2. Intercurrent illness  
3. Death  


 
 
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4. Major/clinically significant alteration in laboratory values after beginning study drug  
5. Other AE 
6. Other reasons concerning the subject’s health or well-being 
 
Persistently Acidic Urine 
Study drug will be discontinued for subjects who have persistently acidic urine (PAU) unresponsive to 
alkalinization.  However, neither PAU nor ‘PAU unresponsive to alkalinization’ is considered an AE 
(which is defined for this study in Sec. 8.1.)     
  
All premature study drug discontinuations, study withdrawals, and dropouts (lost to follow-up) must be 
reported to the CCC within 24 hours of the Site Investigator’s decision or his/her becoming aware of the 
subject’s decision.  
 
A Screening/Demographics eCRF must be completed for all individuals who sign the study consent form. 
This includes participants who fail screening or do not proceed to study drug initiation for some other 
reason, as well as those subjects who complete the study or withdraw prematurely. If a subject 
discontinues study drug or withdraws from the study due to an AE, the AE must be documented on the 
eCRF AE Log.  
 
Subjects withdrawn from the study before completion will not be replaced.  
 
10.   STATISTICAL CONSIDERATIONS 
10.1   General Design Issues 
10.1.1   Trial Design 
The trial is a phase 3, randomized, two-arm, parallel-group, placebo-controlled, two-period, multicenter 
clinical trial of oral inosine titrated to elevate trough serum urate to 7.1 to 8.0 mg/dL over 24 months with 
a 3-month wash-out among de novo PD patients exclusive of SWEDDs. The primary aim is to test 
efficacy of serum urate elevation based on rate of change in MDS-UPDRS I-III total score over 24 
months. Randomizations will be stratified by site to avoid chance confounding between site 
characteristics and treatment. 
 
The randomized, two-arm, parallel-group design will provide an unbiased estimate of effectiveness of 
inosine dosed to elevate serum urate in slowing or delaying PD progression over 24 months during period 
1. Tracking symptoms during randomized wash-in and during the non-randomized 3-month wash-out of 
period 2 will allow estimation of symptomatic effects of serum urate elevation and thereby better evaluate 
whether any observed effects on PD progression reflect a disease-modifying effect. Note that although 
suspension of study drug during the wash-out will be unmasked, subjects and staff will remain blinded as 
to whether this represents a transition off of active treatment or of placebo treatment, and thus treatment 
comparison of changes during the 3-month wash-out should remain unbiased. The difference in the 
proportion of subjects requiring dopaminergic therapy after the 3-month wash-out among all those 
randomized will provide an estimate of disease-modification by serum urate elevation free of any 
symptomatic effects of study drug. 
10.1.2   Primary Outcome 
Use of rate of change in MDS-UPDRS I-III total score as our primary efficacy measure is based on an 
interest in an outcome that can be evaluated within 2 years and an interest in a patient-reported outcome. 
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elevation for 24-month change in UPDRS I-III total score. Anticipating that recruitment will require 18 
months, evaluations of the primary outcome needs to be completed in 2 to 2.5 years in order to launch, 
implement, and publish results from the trial within a 5-year grant period.  
 
Assessing change in MDS-UPDRS or other measures of motor symptoms among initially de novo PD 
patients becomes more complex as subjects begin initiating dopaminergic therapy, with roughly two-
thirds expected to have initiated dopaminergic therapy by 2 years in the placebo group. We feel that 
assessing motor symptoms when not on dopaminergic therapy best reflects the efficacy of the intervention 
under study, whereas evaluation in the OFF condition after dopaminergic therapy has already been 
initiated is burdensome to subjects and unreliable due to incomplete and variable wash-out. Evaluating 
motor symptoms in the ON condition is prone to bias due to adjustment of dopaminergic therapy to 
achieve a pre-targeted level of symptoms. We propose instead to analyze MDS-UPDRS measurements 
made prior to initiating dopaminergic therapy, considering use of such treatments a censoring event that 
precludes observation of future untreated MDS-UPDRS scores. While delaying progression over only 2 
years provides less benefit to patients than we would ultimately wish to offer, we feel that a 
demonstration of delay over 2 years in the absence of symptomatic effects is an achievable result, one that 
could provide evidence of disease modification early in the clinical course, and may motivate a longer-
term trial focused on functional and quality of life endpoints. 
10.1.3   Analysis Samples 
A modified intention-to-treat (mITT) sample will include all randomized subjects who received at least 
one dose of study drug, each classified according to their randomized treatment assignment without 
regard to compliance with their assigned treatment. An as-treated (AT) sample will include all subjects 
who received at least one dose of study drug classified according to the actual treatment received and 
reclassifying subjects randomized to inosine who report not taking inosine and reclassifying subjects 
randomized to placebo who report taking inosine or whose serum urate during treatment averages 6.5 
mg/dL or greater (note: no such subjects out of 25 randomized to placebo were observed in SURE-PD). 
Separate analysis will also look only at intervals on study drug, censoring follow-up after study drug 
discontinuation, and at serum urate elevation as achieved, distinct from either randomized or self-selected 
treatment as administered. 
 
The primary efficacy analyses will use the mITT sample to best estimate the expected effectiveness of 
urate-elevating oral inosine supplementation in clinical practice, recognizing that compliance in clinical 
use may differ from compliance in the clinical trial. Analyses of tolerance will also use the mITT sample. 
Analyses of safety will use the AT sample to avoid downwardly biased estimates of adverse outcomes 
associated with inosine exposure due to treatment non-compliance. Secondary analyses of efficacy 
outcomes will also use the AT sample to perhaps better estimate efficacy of inosine supplementation as 
administered and serum urate elevation as achieved. 
10.1.4   Interim Analysis 
In addition to periodic review of accrual and adverse events by an independent DSMB to evaluate 
feasibility and safety, the trial will utilize an information-based group-sequential design with plans for 
two non-binding interim analyses for evaluating efficacy and futility. Adequacy of the planned sample 
size will also be reviewed on an ongoing basis by the Steering Committee based on updated estimates of 
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10.2   Outcomes 
10.2.1   Primary Outcome  
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. Details of the analysis are described in Sec. 10.5.1. 
10.2.2   Secondary Outcomes 
Secondary outcomes include safety and tolerability of the protocol-specified urate-elevating inosine 
treatment, symptomatic effects of urate elevation, and a range of secondary efficacy measures, including 
time to disability warranting dopaminergic therapy, levodopa equivalent dose, cognition, mood, quality of 
life, and functional disability. 
10.2.2.1   Safety 
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 overall AE and SAE rate, time to first SAE, and 
proportions of subjects experiencing (a) each type of AE, classified by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, (b) clinically-significant abnormal labs, and 
(c) clinically significant abnormal vital signs, including orthostatic hypotension defined as positional 
dizziness or other clinical symptoms of orthostatic hypotension or a drop in systolic and diastolic blood 
pressures of 20 mm Hg and 10 mg Hg or more, respectively, when moving from a supine to a standing 
position. 
10.2.2.2   Tolerability  
Tolerance of treatment by an individual subject will be defined as remaining on-study and on their 
assigned treatment without one or more dose reductions lasting more than 4 weeks cumulative due to 
AEs. 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) and 24 months (long-term). A treatment will be 
declared tolerable if the proportion who are tolerant is significantly greater than 50%. 
10.2.2.3   Symptomatic effect 
Symptomatic effects will be estimated by changes in motor symptoms during the first 3 months of wash-
in at the start of period 1 and during the 3-month wash-out of period 2. 
10.2.2.4   Efficacy outcomes 
Additional efficacy outcomes will include time to disability warranting dopaminergic therapy, the 
prescribed levodopa equivalent dose, motor function as measured by MDS-UPDRS ambulation subset 
and the patient-reported sections (IB and II), cognition as measured by MoCA, quality of life as measured 
by PDQ-39 and by Neuro-QOL (including its depression module as a measure of mood), and functional 
disability as measured by Schwab and England. 
10.2.2.5   Two-period evaluations 
Analysis of the persistence of benefit after the 3-month wash-out of period 2 among subjects randomized 
to active treatment during period 1 permits an evaluation of disease-modifying effect of serum urate 
elevation. Not all measures are amenable to two-period evaluation because of the censoring effect of 
initiation of dopaminergic therapy. In particular, with only one-third of subjects expected to have not 
initiated dopaminergic therapy at the end of period 1, few data on MDS-UPDRS trajectories during wash-
out will be available and subjects contributing that data are a non-random subset of slow progressors. For 
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slower worsening during period 1, non-inferior rates of worsening during period 2, and a significant net 
benefit at the end of period 2 would provide evidence of disease modification if all three evaluations were 
favorable. 
10.3   Sample Size and Accrual 
10.3.1   Effect Size 
The effect size for determining power is based on estimates of the minimum clinically important 
difference (MCID) for changes in MDS-UPDRS I-III total scores and on the previously observed 
association between baseline serum urate levels and the rate of change in UPDRS I-III total scores in the 
DATATOP, PRECEPT, and SURE-PD trials. 
 
Hauser et al.197 report that placebo-treated subjects who reported being minimally worse over 26 weeks 
on a global impression of change assessment experienced an average increase in UPDRS I-III total scores 
of 4.9 units. Given our expectation that elevated serum urate will delay progression, not improve 
symptoms, a MCID related to minimal worsening among placebo subjects seems most appropriate in this 
context. Based on estimates by Goetz and colleagues145,149,152,198 for PD patients with mild symptoms 
(Hoehn and Yahr stage I/II), MDS-UPDRS I-III total scores are roughly 30% larger than UPDRS I-III 
total scores (2.5x for 16 questions in Part 1, 
1.1x for 52 questions in Part II, and 1.2x for 108 
questions in Part III, yielding a weighted 
conversion of 1.29x), implying a MCID of 6.3 
MDS-UPDRS I-III total score units.  
 
We expect to enroll subjects with mean baseline 
serum urate of approximately 4.5 mg/dL based 
on data from SURE-PD and then raise levels in 
the active arm 3 mg/dL on average at trough 
sampling.  A 3 mg/dL difference in baseline 
serum urate predicted 8.1 and 2.1 unit per year 
differences in UPDRS I-III total score slopes in 
the DATATOP36 and PRECEPT35 trials. In the 
SURE-PD trial102, subjects randomized to 
moderate serum urate elevation (7 to 8 mg/dL at 
random sampling) progressed 1.1 unit / year 
slower than placebo arm subjects with wide 
confidence bounds (95% CI 4.8 units / year 
slower to 2.8 units / year faster). Note that this 
estimate from SURE-PD (see Fig. 7D) is 
conservative relative to an alternative model for 
the effect of serum urate elevation (see Fig. 7C). 
A random-effects meta-analysis of results from the three studies yields a weighted estimate of 4.5 units 
slower progression in UPDRS I-III total score over 2 years among patients with higher serum urate levels. 
 
We propose that 6.3 units over two years or a difference in slopes of 3.15 units per year is a reasonable 
minimum clinically important difference (MCID) in MDS-UPDRS I-III total scores, equal to a MCID of 
4.9 units on the scale of UPDRS I-III total scores. This would correspond to a reduction of 20% of the 
expected placebo rate based on a random effects meta-analysis (Fig. 13) of the mean rates of decline in 
UPDRS I-III total scores among de novo PD patients with baseline serum urate levels below 5.9 mg/dL in 
the DATATOP32,34, PRECEPT30, and SURE-PD102 cohorts. Changes in UPDRS I-III total scores were 
analyzed using random-slope mixed models censoring follow-up when dopaminergic therapy was 
Figure 13.  Meta-analysis of the rate of UPDRS 
change in early PD subjects with lower serum 
urate.  Early, largely untreated PD subjects with a serum 
urate of <5.9 mg/dL at baseline from DATATOP (n=155; 
double-placebo only), PRECEPT (n=446) and SURE-PD 
(n=25; placebo only) were followed for up to two years. The 
overall UPDRS rate was obtained by weighting each 
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initiated. The weighted mean estimate was 0.98 points / month or 23.5 points over 2 years with 
substantial heterogeneity in the estimate among studies (see Fig. 13). 
10.3.2   Sample Size 
Power for the primary outcome of rate of change in MDS-UPDRS I-III total score is based on a random 
slopes model with shared baseline. The model will include fixed effects of time, treatment x time, gender, 
gender x time, an indicator of baseline MAO-B inhibitor use, and baseline MAO-B inhibitor use x time 
and random site- and subject-specific intercepts and slopes, each with unstructured covariance. MDS-
UPDRS assessments completed after a subject has initiated dopaminergic therapy will be censored.  
 
Based on applying the same primary analysis model to data from SURE-PD, the following variance 
components were estimated for UPDRS I-III total scores: site-level variance (intercept = 9.75, slope = 
0.0123 / month, covariance = -0.346), subject-level variance (intercept = 77.4, slope = 0.230 / month, 
covariance =2.87), and residual variance = 13.9. We assume that 70% of subjects will initiate 
dopaminergic therapy based on experience in SURE-PD plus up to 8% additional lost to follow-up prior 
to initiating dopaminergic therapy. With the planned schedule for MDS-UPDRS assessments (screening, 
baseline, 3 weeks, 6 weeks, 12 weeks, and then quarterly through 24 months), the variance and censoring 
estimates above imply an effective standard deviation for UPDRS I-III total score slopes of 0.587 units / 
month or 0.758 units / month on the scale of MDS-UPDRS I-III total scores.210 
 
Given a standard deviation of 0.76 units / month, a final two-sided test at alpha = 0.046 allowing 
conservatively for two interim analyses at alpha = 0.001 each, the study would have 80% power with n = 
270 subjects randomized 1:1 to placebo or urate elevation if the true effect of treatment were to reduce the 
rate of increase in MDS-UPDRS I-III total score by 6.3 points over 2 years. 
 
This estimate of power is robust to variable gender-specific enrollment rates and treatment efficacy as 
long as the average effect of treatment across genders in the ratio enrolled is 6.3 points over 2 years (Fig. 
14A). If urate elevation reduces the average rate of progression by 6.3 points over 2 years only among 
male or female participants and the other gender experiences less benefit, power would be lower (Fig. 
14B). This is unavoidable if a large proportion of the enrolled population accrues less benefit from the 
intervention. Conversely, power would be greater than 80% if one gender experiences a benefit greater 
than 6.3 points over 2 years and the other gender experiences at least that large a benefit. 
 
 
 
 
Figure 14. (A) Power for the primary aim across a range of gender-specific treatment responses, all cases with the 
average treatment response across genders equal to the MCID of 6.3 points over 2 years. Note that equal prevalence 
of male (M) and female (F) participants is plotted, but the power curve for other prevalence ratios are so similar as 
A 
B 


 
 
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to be indistinguishable at this scale. (B) Power for the primary aim when the effect of treatment on one gender is 
equal to the MCID and the effect on the alternate gender varies from 50% to 150% of MCID for a range of different 
prevalence ratios. 
10.3.3   Secondary Outcomes 
The trial will have an 80% probability of observing at least one instance of any class of adverse event 
expected to occur in at least 1.2% of individuals receiving inosine. The trial will have 80% power to 
detect increased risk of any class of adverse event among subjects receiving inosine if the true risk is two-
fold higher and the expected proportion among placebo subjects is at least 14% or if the true risk if four-
fold higher and the expected proportion among placebo subjects is at least 3.4%. The trial has 80% 
probability of declaring serum urate elevation tolerable if the true proportion tolerant under the definition 
given in Sec. 10.2.2.2 at 12 weeks and 24 months is at least 62%. 
 
The estimated SE for symptomatic effects on UPDRS I-III total scores during wash-in between the 
moderate elevation and placebo arms in the SURE-PD trial was 0.53 units / month. With n = 25 subjects 
per treatment group in SURE-PD, the expected SE for estimating symptomatic effects in this trial will be 
roughly sqrt (25/135) * 0.53 = 0.23 units / month. With that SE, the trial would have 80% power to detect 
symptomatic effects on the order of a difference in slopes during wash-in or wash-out of 0.65 
units/month.  
 
The Kaplan-Meier product-limit estimate from the SURE-PD trial of the proportion of placebo subjects 
requiring dopaminergic therapy by 24 months was 62%. Assuming constant hazard at the same rate 
among placebo subjects in this trial during period 1 (0 to 24 months) and 8% loss to follow-up prior to 
determining need for dopaminergic therapy, the trial will have 80% power to detect a hazard ratio of 0.62. 
Extrapolating to 27 months, we expect a total of 67% of placebo arm subjects to have disability 
warranting dopaminergic therapy at the end of period 2 (24 to 27 months). The study would have 80% 
power to detect a difference in the proportion of subjects with disability warranting dopaminergic therapy 
if 50% or fewer of active arm subjects have progressed by the end of the trial.  
 
Given preliminary data from SURE-PD on the variance components from random-slope models for 
MoCA after Rasch score conversion and S&E ADL, the effective standard deviations (in points per 
month) for these measures given our planned follow-up schedule are 0.038 and 0.31, respectively. 
Weaver et al.204 report an among-person standard deviation for PDQ-39 at 24 months after deep brain 
stimulation of 14.2 to 15.3. Assuming conservatively no within-person covariance, that would imply a 
standard deviation for 24-month change of approximately 30. Given these estimates, the trial will have 
80% power to detect 2-year treatment differences on these outcomes as small as 0.31, 2.5, and 10.3, 
respectively. 
10.4   Data Monitoring 
In addition to periodic review of accrual and adverse events by an independent DSMB to evaluate 
feasibility and safety, the trial will utilize an information-based group-sequential design with plans for 
two non-binding interim analyses for evaluating efficacy, futility, and sample size requirement. 
10.4.1   Data and Safety Monitoring Board 
An NINDS-appointed independent Data and Safety Monitoring Board (DSMB) has been established to 
monitor the trial. The DSMB is responsible for periodic review of data related to feasibility, safety, and 
efficacy.  A DSMB Charter specifying the composition, responsibilities, frequency, and format of DSMB 
meetings and the content of DSMB reports  has been created and is available to sites.  


 
 
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10.4.2   Feasibility 
Feasibility of completing the trial and adequately addressing the primary aim will be evaluated by the 
DSMB at each meeting. While no hard criteria for declaring the trial infeasible are specified, delays in 
accrual that would preclude adequate enrollment and follow-up within the funding period might be cause 
for the DSMB to recommend termination of the trial.  
10.4.3   Safety 
Safety of serum urate elevation will be evaluated by the DSMB at each meeting and at other times as the 
DSMB may request. Given the diversity of possible adverse event data and the complexities of weighing 
risks and benefits from treatment, no definitive early stopping criteria for safety are specified. As 
described in Sec. 5.1.3a, urolithiasis and gouty arthritis are the safety outcomes of greatest concern. If 
greater than 20% of subjects receiving inosine develop uric acid stones or experience gouty arthritis, then 
the DSMB might recommend termination of the trial.  
10.4.4   Blinded Sample Size Re-Estimation 
The Steering Committee will review updated estimates of nuisance parameters required for sample size 
calculation from blinded interim analyses performed using pseudo-randomizations. Interim analyses for 
possible sample size re-estimation will be performed at the same time as the first planned interim efficacy 
and futility analysis, i.e., after 2000 person-months of period 1 follow-up are completed, roughly one-
third of total anticipated period 1 follow-up. To maintain blinding, pseudo-randomizations stratified by 
site will be generated to assign pseudo-treatment labels to each participant. This yields a slightly 
conservative estimate of variance components given that variance attributable to true treatment 
assignment will remain in the slope and residual terms.  
 
An information-based approach will be used, comparing the square of the observed standard error (SE) 
for the pseudo-treatment x time interaction term from analysis of the interim data to the square of the SE 
expected given the observed distribution of follow-up times and the assumptions used for the initial 
sample size and power calculations. Additional details are provided in the SAP.  
 
A proposal to increase, but not decrease, the sample size will be considered based on the estimated 
sample size required to achieve 80% power. To avoid the administrative burden of small increases that 
negligibly affect power, we would not expect to recommend sample size increases of fewer than 30 
participants. And recognizing practical constraints, we would not expect to recommend sample size 
increases of more than 130 participants. The option to decrease sample size is not needed (and can 
undermine power) because the trial is likely to be stopped early for efficacy or futility if estimates of the 
true treatment x time interaction are more precise than anticipated. Note that this is an information-based 
design updating only the nuisance parameters required for power calculations, not an adaptive design 
updating the planned effect size.  
10.4.5   Efficacy or Futility 
Interim analyses for efficacy or futility will be performed by the unblinded statistician after 2000 and 
5000 person-months of period 1 follow-up are completed, roughly one-third and three-quarters of total 
anticipated period 1 follow-up. Non-binding early stopping for efficacy will be proposed if the active 
treatment group is superior to placebo for the primary efficacy outcome based on a one-sided p-value of 
0.001 or less. Other criteria used in deciding whether to stop early for efficacy will include evaluation of 
safety and secondary efficacy outcomes. We propose stringent early stopping criteria for efficacy in order 
to ensure that evidence for efficacy is unambiguous if the study is stopped early. Non-binding early 
stopping for futility will be proposed based on a beta-spending rule quadratic in information time. If there 
were no benefit from treatment, then the trial would have a 51% probability of early stopping for futility 
based on this rule. As with the efficacy evaluation, the decision to stop early for futility will also include 


 
 
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evaluation of feasibility, safety, and secondary efficacy outcomes. Because the efficacy and futility 
stopping rules are non-binding, we conservatively assume that each look is cumulative for alpha and 
ignore possible findings of futility when calculating the overall type I error.  
10.5    Data Analyses 
The following plans describe proposed analyses of all outcomes. A definitive statistical analysis plan 
(SAP) will be finalized and must be approved by the Steering Committee prior to the final lock of the trial 
data and breaking of the blind. The final approved SAP may differ in detail from analyses described here. 
10.5.1   Primary Analysis 
The primary mITT analysis of rate of change of MDS-UPDRS I-III total scores during period 1 will use a 
random slopes model with shared baseline. The model will include fixed effects of time, treatment x time, 
gender, gender x time, an indicator of baseline MAO-B inhibitor use, and baseline MAO-B inhibitor use x 
time and random site- and subject-specific intercepts and slopes, each with unstructured covariance. Use 
of a shared baseline adjusts for baseline MDS-UPDRS score245,246 in addition to the adjustment for gender 
and baseline MAO-B inhibitor use. Other baseline covariates, including Smart4SURE participation, may 
be included in the final model based on review of blinded data and any revision in our understanding of 
predictors of PD progression prior to finalizing the analysis plan and breaking the blind. Measurements 
made subsequent to initiating dopaminergic therapy will be censored. Inference of benefit from serum 
urate elevation will be made by testing whether the treatment x time interaction term is significantly less 
than zero (i.e., slower progression among subjects randomized to the active arm) using a two-sided test at 
p < 0.046 for a cumulative two-sided alpha = 0.05.  
 
Our estimate of the effect of serum urate elevation on MDS-UPDRS will be unbiased if observed 
trajectories are predictive of MDS-UPDRS assessments that are missing due to loss to follow-up or are 
censored due to initiation of dopaminergic therapy. Data from the SURE-PD trial suggest good 
conformance of UPDRS I-III total score trajectories to the model assumptions. No non-linearity in 
treatment effects on observed UPDRS scores was found and models that included quadratic random 
effects fit worse by Akaike and Bayesian information criteria. Empirical Bayes estimates of 24-month 
UPDRS scores assuming linear trajectories were all within range of the instrument (range 7.4 to 97.4) 
even with 85% of the sample being censored prior to the final 24-month observation (median 12 months). 
Conditional residuals were normally distributed and homoscedastic. Similar assessments and influence 
statistics will be evaluated in judging the adequacy of the proposed primary analysis in this trial.  
10.5.2   Alternative Analyses 
If analysis of the mITT sample does not indicate benefit of randomization to oral inosine, it is still 
possible that (a) inosine supplementation is beneficial if the mITT estimates are affected by non-
compliance or that (b) serum urate elevation itself is protective if achieved. As a key secondary analyses, 
we will analyze the AT sample, censoring follow-up after discontinuation of study drug. This will provide 
an estimate of the effectiveness of inosine among those tolerant of supplementation. We will also analyze 
the AT sample with substitution of mean increase in serum urate from baseline to week 12 in place of 
randomized treatment assignment to estimate method-effectiveness of serum urate elevation. 
 
We will further evaluate robustness of estimates from our primary analysis in a number of other 
secondary analyses, including: (a) alternative models for the mean temporal profile, (b) alternative models 
for handling observations made after loss to follow-up or initiation of dopaminergic therapy, and (c) 
alternative models for handling covariance among repeated observations. To relax the assumption of 
linear change over time, a model with visit and visit x treatment terms in place of the time and time x 
treatment terms will be fit to permit an unstructured temporal profile. Rather than censoring observations 
after initiation of dopaminergic therapy, we will consider several models that include all MDS-UPDRS 


 
 
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observations. If participants randomized to inosine initiate dopaminergic therapy at a slower rate than 
those on placebo, then lower MDS-UPDRS scores at 24 months irrespective of dopaminergic therapy 
would suggest that the benefit of inosine supplementation carries over after the need for therapy. 
Alternatively, we will include either a simple time-dependent offset for measurements made in the ON 
condition or a time-dependent offset equal to the levodopa equivalent dose prescribed at that time. To 
avoid bias from potentially informative loss to follow-up, we will consider a pattern-mixture model with 
the fixed effects stratified by length of follow-up. The Combined Assessment of Function and Survival 
(CAFS) model211 described in Section 10.5.5 is constructed similarly by comparing pairs of participants 
over equal lengths of follow-up. To relax the assumption of linear random slopes, a model with a full 12 x 
12 unstructured covariance matrix among repeated assessments of MDS-UPDRS (78 covariance terms) 
will be explored. 
10.5.3   Subgroup Analyses 
The potential for differential benefit from serum urate elevation among subgroups of patients will be 
tested by including subgroup, subgroup x time, and subgroup x time x treatment interaction terms into the 
primary random-slopes model. A significant subgroup x time x treatment 3-way interaction in 
combination with significantly slower progression among members of a subgroup randomized to serum 
urate elevation vs. members of the same subgroup randomized to placebo will be taken as evidence of 
differential benefit. The following subgroups will be considered: sex, race (classified as Asian, Black or 
African American, Caucasian, or other, including multiracial; or as Caucasian vs. non-Caucasian if fewer 
than 10% of our sample is non-Caucasian), ethnicity (classified as Hispanic or Latino vs. non-Hispanic), 
use of MAO-B inhibitors at baseline, and age (both categorized as <65 years vs. ≥65 years and 
continuous).  
10.5.4   Disability Warranting Dopaminergic Therapy 
Treatment differences in time to disability warranting dopaminergic therapy during period 1 will be tested 
by a Kaplan-Meier logrank test with a two-sided alpha = 0.05. Subjects lost to follow-up will be censored 
unless available information suggests that a given subject withdrew consent due to increasing disease 
progression or a desire to seek more aggressive care. Note that subjects will continue to be followed even 
if they discontinue study drug. As a sensitivity analysis, subjects lost to follow-up will be classified as 
initiating dopaminergic therapy at the time of their withdrawal.  
10.5.5   Combined Function and Treatment 
A rank-based test of a single outcome combining function as measured by change in MDS-UPDRS I-III 
total scores and time to disability warranting dopaminergic therapy will be constructed paralleling the 
CAFS score methodology developed for ALS.211 MDS-UPDRS I-III total scores will substitute for 
ALSFRS-R total scores and time to disability warranting dopaminergic therapy will substitute for time to 
mortality. The test consists of calculating a rank-sum score for each individual relative to pair-wise 
comparisons with all other subjects. Subjects are ranked according to time to disability warranting 
dopaminergic therapy when that is observed for both members of a pair or when one is censored after the 
observed event time for the other. Pairs that cannot be ranked by time to disability warranting 
dopaminergic therapy are ranked by absolute change from baseline in MDS-UPDRS I-III total score at 
the maximum follow-up time at which both subjects have an observation. Inference is drawn by 
calculating a U-statistic from the rank-sum scores.  
10.5.6   Secondary Efficacy Outcomes 
Most secondary efficacy measures will be analyzed using the same shared-baseline, random-slopes model 
described for analyzing our primary outcome. If analyses of the mITT sample do not indicate significant 
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in inference of the primary outcome are drawn from the alternative models described in Sec. 10.5.2, then 
equivalent models will be explore for our secondary efficacy outcomes.  
10.5.7   Safety and Tolerability Outcomes 
Overall AE and SAE rates will be compared between treatment groups by negative binomial regression. 
Time to first SAE will be compared between treatment groups by Kaplan-Meier logrank test. The 
proportion of subjects experiencing (a) each type of AE, classified by MedDRA preferred term and 
system organ class, (b) clinically-significant abnormal labs, and (c) clinically significant abnormal vital 
signs, including orthostatic hypotension defined as positional dizziness or other clinical symptoms of 
orthostatic hypotension or a drop in systolic and diastolic blood pressures of 20 mm Hg and 10 mg Hg or 
more, respectively, when moving from a supine to a standing position will be compared between 
treatment groups by Fisher’s exact test.  
 
Assuming no administrative censoring, all subjects will be classifiable as tolerant or intolerant, with 
subjects lost to follow-up or withdrawing consent classified as intolerant. Tolerability will then be 
estimated by simple proportions tolerant at 12 weeks and 24 months. Serum urate elevation will be 
declared tolerable at each time point if its exact one-sided lower 95% confidence bound is greater than 
50%. If evaluation of tolerance is censored, then Kaplan-Meier product-limit estimates and their 
complementary log-log confidence bounds will be used. We will explore the relationship between 
tolerance and use of dopaminergic therapy using Cox regression with use of dopaminergic therapy as a 
time-dependent covariate. 
10.5.8   Symptomatic Effects 
The presence of symptomatic effects will be tested using a change-point model constructed as a partial 
linear spline over time with knots at 12 weeks and 24 months. Both fixed and subject-specific random 
terms for intercept, slope from baseline to 12 weeks, slope from 12 weeks to 24 months, and slope from 
24 to 27 months will be included. Unstructured covariance will be assumed among the random effects (10 
terms). The AT sample will be analyzed. Significantly smaller slopes during wash-in or larger slopes 
during wash-out among subjects treated with inosine using one-sided testing at alpha = 0.025 will be 
interpreted as symptomatic effects. If symptomatic effects are not found on that basis, the absence of 
symptomatic effects will be judged based on a non-inferiority test using a non-inferiority bound of 6.3 / 3 
= 2.1 points/month in the direction of a symptomatic effect and using one-sided testing at alpha = 0.05.  
10.5.9   Disease Modification 
A three-part test of time to disability warranting dopaminergic therapy will be used to evaluate whether 
serum urate elevation is disease-modifying247-249. Inference of disease modification would be supported if 
(a) a Kaplan-Meier logrank test of time to disability warranting dopaminergic therapy during period 1 
favors serum urate elevation, (b) the proportion of subjects randomized to serum urate elevation remains 
significantly lower than placebo at the end of period 2 by Chi-square test, and (c) the time-dependent 
hazard ratio for time to disability warranting dopaminergic therapy during period 2 is non-inferior to a 
rate that would lead to equivalence to placebo by 3 months by Cox regression. Inference from each of the 
three component tests will be evaluated sequentially. Difference in time to disability warranting 
dopaminergic therapy will be evaluated first. If significant by logrank test with two-tailed alpha = 0.05, 
then the proportion not yet requiring dopaminergic therapy at the end of period 2 will be tested second. If 
significant by Chi-square test with two-tailed alpha = 0.05, then non-inferiority of the time-dependent 
hazard ratio will be tested by Cox regression based on a one-tailed test at alpha = 0.05.  
10.5.10   Smart4SURE Substudy 
The feasibility of implementing Smart4SURE will be measured by the following metrics among others: 
(a) proportion of eligible participants who consent to Smart4SURE, (b) proportion of randomized 


 
 
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substudy participants who complete a baseline Smart4SURE assessment, and (c) proportion of 
randomized substudy participants who complete at least monthly motor and cognitive assessments and 
quarterly self-report MDS-UPDRS, QoL, and apathy evaluations while on-study in the parent trial.  
 
Correlations between Smart4SURE measures and related clinical assessments will be evaluated both 
cross-sectionally and longitudinally. Cross-sectional associations will be estimated both by correlation of 
baseline data and in mixed models using all contemporaneous assessments. The mixed model will regress 
clinical measures on contemporaneous Smart4SURE measures and will separately estimate within-person 
and among-person associations by recoding the Smart4SURE measures as person-level trends and 
deviations from a given participant's trend. Adequacy of the Smart4SURE measures as proxies for clinical 
assessments requires strong correlation at both within-person and among-person levels. Longitudinal 
associations will be estimated similarly, with direct correlation of the final period 1 assessments and by 
similar mixed models of change-scores calculated as the simple differences from baseline. 
 
Exploratory evaluation of Smart4SURE measures as efficacy outcomes will use the same primary, 
alternative, and subgroup analyses proposed for the primary outcome in Sections 10.5.1-10.5.3 and the 
same analysis of symptomatic effects specified in Section 10.5.8. 
e10.5.11   Serial DAT Scan Substudy 
The primary aim of the serial DAT scan substudy is to determine whether serum urate elevation via oral 
inosine slows the loss of striatal dopamine transporter (DAT) over two years in early PD as measured by a 
reduction in DAT radioligand uptake on serial SPECT brain scans. In pursuit of secondary aims, we will 
determine whether and to what extent change in DAT loss correlates with change in smartphone metrics 
of PD progression as measured in the ‘Smart4SURE’ substudy, and will test whether genetic determinants 
of PD progression (e.g.,variants of SNCA268 or SLC2A9223) or of urate-DAT interaction (e.g., INPP5K 
variants269) identify PD subpopulations in whom inosine alters the DAT loss in SURE-PD3. 
 
Quantitative estimates of striatal binding ratios in the left and right hemispheres of the caudate and 
putamen will be averaged, log-transformed, and modeled in a shared-baseline, repeated measures 
ANOVA with fixed terms for visit (2 levels), post-baseline x treatment interaction (1 term), gender, 
gender x visit interaction, MAO-B inhibitor, MAO-B inhibitor x visit interaction, and unstructured 
covariance between each participant's serial assessments. Back-transformed linear functions of the fixed 
terms will yield estimates of treatment-group specific percent change over 2 years and will be used to test 
for treatment-dependent differences in 2-year change in DAT ligand uptake. This model construction 
increases efficiency by adjusting for baseline, controls for any chance differences in DAT uptake at 
baseline between treatments, and allows inclusion of all participants in the analysis even if some are lost 
to follow-up. Both mITT and AT samples will be analyzed, with the mITT results considered primary. 
Associations between 2-year changes in mean striatal binding ratios and functional measures (e.g., MDS-
UPDRS) will be estimated overall from simple correlations and separately by gender and baseline MAO-
B inhibitor use. We will test for Simpson's paradox (i.e., incongruence between correlations among- vs. 
within-groups). Gender-specific and genotype-specific effects will be considered in secondary analyses 
by including subgroup and subgroup x treatment x post-baseline terms. 
 
 


 
 
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11. 
DATA 
COLLECTION, 
SITE 
MONITORING, 
AND 
ADVERSE 
EXPERIENCE       
REPORTING 
11.1   Records to Be Kept 
11.1.1  Study File and Site Documents 
 
The Site Investigator should have the following study documents accessible to the Study Monitor during 
the study. 
x 
Signed Form FDA 1572 
x 
Curriculum vitae for Site Investigator and staff listed on Form FDA 1572 
x 
The signed IRB/IEC form/letter stating IRB/IEC approval of protocol, consent forms and any 
advertisement notices, documentation of the IRB/IEC composition, and all IRB correspondence 
including notification/approval of protocol amendments, notification of serious SAEs to the 
IRB/IEC, and IRB/IEC notification of study termination 
x 
IRB approved consent form (sample) and any advertisement 
x 
Signed protocol (and amendments, if applicable) 
x 
Signed subject consent forms 
x 
Copies of the completed eCRF worksheets (source), supplemental source notes and subject-
completed medication logs (Study Drug Record sheets) 
x 
Authorization log (Delegation Log - Study Staff and Staff Related Duties) with names, 
signatures, initials and functional role of all persons completing protocol assessments, providing 
back-up to the Site Investigator and Coordinator, if applicable, as well as staff entering data into 
the eRT system. 
x 
Copies of laboratory reports/printouts  
x 
Any source data/records not kept with the subject’s hospital/medical records 
x 
Study Drug Dispensing/Return Log and Dose Management Log  
x 
Signed and dated receipt of supplies 
x 
Record of all monitoring visits made by DCC personnel  
x 
Copies of essential site correspondence to and from CCC and DCC 
x 
Investigator’s Brochure and IND safety letters, as applicable  
x 
Certificate for Human Subject Protection Program for each individual named on the 
Authorization log who has direct subject contact 
x 
Copy of professional licensure/registration, as applicable, for each individual named on the 
Delegation Log, who has direct subject contact ensuring licensure is in the state in which the 
study will be conducted 
x 
A Note to File indicating the assessments that will be considered source documents 
x 
Any other documentation as required by the CCC or PSG (e.g., Conflict-of-Interest/Financial 
Disclosure)  
 
The Site Investigator must also retain all printouts/reports of tests/procedures, as specified in the protocol, 
for each subject.  This documentation, together with the subject’s hospital/medical records, is the 
subject’s SOURCE DATA for the study. 
 
11.1.2  Maintenance and Retention of Records 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the conduct of 
this study and the distribution of investigational drug, including CRFs (if applicable), consent forms, 


 
 
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laboratory test results, and medical inventory records, must be retained by the Site Investigator for two 
years after marketing application approval.  If no application is filed, these records must be kept for two 
years after the investigation is discontinued and the US FDA and the applicable national and local health 
authorities are notified.  The CCC or their representative will notify the Site Investigators of these events. 
The Site Investigators should retain all study documents and records until they are notified in writing by 
the CCC or their representative.  
 
The Site Investigator will be instructed to consult with the CCC before disposal of any study records and 
to notify the CCC of any change in the location, disposition, or custody of the study files. 
11.2   Role of Data Management and Study Monitoring 
11.2.1  Central Data Management  
The Unblinded Biostatistician will be responsible for design of the randomization scheme, creation of 
analytic databases, and the statistical analysis plan. Data management staff at the DCC will be responsible 
for all other data collection procedures.  
 
An Internet-accessible Electronic Data Capture (EDC) system for data management will be utilized for 
this study. This system is protected by 128-bit server certificates and utilizes authenticated, password-
protected accounts for each site. The EDC system is designed to ensure timeliness and accuracy of data as 
well as the prompt reporting of data from the study on an ongoing basis to the study Principal and Co-
Investigators. The system is compliant with relevant FDA regulatory requirements per 21 CFR Part 11.  
 
Sites will enter subject information and data into an electronic case report form (eCRF) in the EDC 
application via computer stations connected remotely through an Internet browser to a central server at 
the DCC.  Authorized study personnel at each site will each be granted access to the electronic data 
capture tool via provision of a unique password-protected user-ID that will limit access to enter and view 
data specifically for subjects enrolled at their site. 
 
It is the Site Investigator’s responsibility to ensure that entries are proper and complete. During entry of 
data, error checks will be performed by the EDC that will flag problematic (i.e., missing, out of range, 
inconsistent) data, allowing for sites to correct the data at that time. Error checks will be implemented in 
the EDC based upon specifications defined in the data management plan.  
 
Once the data are submitted to the EDC system, they are immediately stored in the central study database 
located at the DCC and are accessible for review by data management staff. Data review, coding and 
query processing will be done through interaction with the DCC, site personnel and the Study Monitor. 
Any changes to the data will be fully captured in an electronic audit trail.  The cycle of electronic data 
entry, review, query identification/resolution, and correction occurs over the course of the study period 
until all subjects have completed the study.  Narrative text of AEs and concomitant medications will be 
periodically coded using established coding mechanisms. 
 
Upon completion of a subject’s visit or the study, sites have the option to print the completed eCRFs 
depicting the data that were entered.  At the conclusion of the study, a PDF (portable document format) 
file on electronic media depicting eCRFs for each site will be provided by the CCC for record keeping at 
the site.  
 
Once the Unblinded Biostatistician and the DCC, in conjunction with the Principal Investigator, agree 
that all queries have been adequately resolved and the database has been deemed “clean”, the database 
will be officially signed off and deemed locked. All permissions to make changes (append, delete, modify 
or update) the database are removed at this time.  


 
 
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All site personnel will remain blinded as to treatment assignments until the conclusion of the entire study. 
The treatment assignments are not part of the DCC electronic clinical database. The designated unblinded 
DCC programmer who oversees the dose adjustment algorithm, the drug packaging staff, and unblinded 
statistician at the DCC will have access to the treatment assignments, and these individuals will not 
communicate about treatment-specific results to any other staff involved in the study.  
11.2.2 Site Investigator Responsibilities 
 
This study will be conducted under the supervision and direction of the Site Investigator designated by 
the study Steering Committee as the Site Investigator at the address provided to the CCC.  
 
Clinical supplies will be sent to the address specified to the CCC by the Site Investigator. 
 
The Site Investigator must not conduct the study at any sites other than the one designated by the study 
Steering Committee. 
 
The protocol, informed consent form, and advertisement notices will be approved by the site’s specified 
institutional IRB. 
 
Each Site Investigator is responsible for providing copies of the protocol and all other information relating 
to the preclinical and prior clinical experience, which were furnished to him/her, to all study personnel 
responsible to him/her who participate in this study.  The Site Investigator will discuss this information 
with them to assure that they are adequately informed regarding the study drug and conduct of the study.  
The Site Investigator must assure that all study staff members are qualified by education, experience and 
training to perform their specific responsibilities. 
11.2.3 Case Report Forms 
Sites will enter subject information and data into an electronic case report form (eCRF) in the Electronic 
Data Capture (EDC) application.  The eCRFs are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore the eCRFs must be completed for each subject screened or 
enrolled according to the subject’s source data on a per-visit basis. Authorized study personnel will each 
be granted access to the electronic data capture tool via provision of a unique password-protected user-ID 
that will limit access to enter and view data specifically for subjects enrolled at their site.  Data should be 
entered into the EDC system within 3 business days of a subject’s visit. 
 
Sites will be supplied with a set of source document worksheets that correspond to the electronic case 
report form (eCRF).  The worksheets will serve as source documents and are required to be used to enter 
data into the eCRFs.  Sites will initially enter all data into the subject’s medical chart and/or onto source 
documentation worksheets prior to entering data into the eCRFs via computer stations connected remotely 
to the central server through an Internet browser.   
11.2.4 Electronic Signatures 
An electronic signature from the Site Investigator is required on the following eCRFs: 
 
x 
Signature Form (for each visit) 
x 
Adverse Event Form (at the conclusion of the study) 
 
 


 
 
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The data entered from the eCRFs will be securely transmitted to a central database stored on a secure 
server located at the DCC. Sites must print the completed eCRFs depicting the data that were entered, but 
have the option to do so upon completion of either a subject’s visit or the study. 
 
At the conclusion of the study, the site will be provided with a PDF (portable document format) file on 
electronic media depicting eCRFs for their site.  The PDF file should be printed for each subject 
participating in the study and filed in the subject’s binder. 
11.2.5 Primary Source Documents 
The Site Investigator must maintain primary source documents supporting significant data for each 
subject in the subject’s medical notes.  These documents, which are considered ‘source data’, should 
include documentation of: 
x 
Demographic information 
x 
Evidence supporting the diagnosis/condition for which the subject is being studied 
x 
General information supporting the subject’s consent to participate in the study 
x 
General history and physical findings 
x 
Hospitalization or Emergency Room records (if applicable) 
x 
Each study visit by date, including any relevant findings/notes by the Site Investigator(s), 
occurrence (or lack) of adverse events, and changes in medication usage including the date 
the study drug commenced and completed 
x 
Any additional visits during the study 
x 
Any relevant telephone conversations with the subject regarding the study or possible adverse 
experiences 
x 
Original, signed informed consent forms for study participation 
 
The Site Investigator must also retain all subject specific printouts/reports of tests/procedures performed 
as a requirement of the study (e.g., laboratory and ECG reports).  Laboratory reports from the central 
laboratory must be signed and dated by the Site Investigator in a timely fashion following review and 
filed with the subject’s source documents. This documentation, together with the subject’s hospital/site 
medical records, is the subject’s ‘source data’ for the study.  During monitoring visits the Study Monitor 
will need to verify data in the eCRFs against these source data. 
11.2.6 CRF Worksheets 
Sites will be supplied with a set of worksheets that correspond to the electronic case report form (eCRF) 
for this study.  The worksheets will serve as source documents for study observations and assessments and 
should be used to enter data into the eCRF. Additional source documentation for information not 
specifically included on the source document may be recorded on a separate document. 
11.2.7 Study Monitoring 
All aspects of the study will be monitored by authorized individuals in compliance with GCP and 
applicable regulations.  The Study Site Monitors will review, on a regular basis, the progress of the study 
with the Site Investigator and other site personnel. 


 
 
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11.2.8 Monitoring Visits 
To ensure compliance with GCP and other applicable regulatory requirements, the Study Monitor or 
representative is responsible for monitoring that sites conduct the study according to the protocol, 
standard operating procedures, and other written instructions and regulatory guidelines. 
 
 
Monitoring visits by a Study Monitor will be arranged in advance, at a mutually acceptable time, with site 
personnel.  The site personnel must allow sufficient time for the Study Monitor to review CRFs and 
relevant source documents and queries. The site Coordinator and/or Site Investigator(s) should be available 
to answer questions or resolve data clarifications. As part of the supervision of the study progress, the CCC 
and DCC personnel, or Steering Committee members may, on request, accompany the Study Monitor on 
visits to study sites. 
11.2.9 Closeout Visit 
Following the completion of the study, Study Monitor(s) may conduct an on-site closeout visit or a 
telephone closeout visit to ensure that all data queries have been resolved, any protocol deviations are 
documented appropriately, all relevant study data has been retrieved, that study drug and clinical supplies 
have been/will be properly returned and that the Site Investigator has copies of all study-related 
data/information on file and archive responsibilities have been reviewed. 
11.2.10    Study Committees 
11.2.10.1    Steering Committee 
The Steering Committee (SC) is composed of the Principal and Co-Principal Investigators of the study 
(serving as SC Chair and Co-Chair), blinded biostatisticians, independent Investigator members of the 
Parkinson Study Group, investigators with expertise in PD and study-related medical (e.g., renal and 
cardiac) conditions and priorities (trial recruitment and drug supply), and representatives of the CCC, 
DCC, NINDS and patient advocacy community.  The SC is responsible, along with the Study Principal 
Investigator, for the design of the study protocol and analysis plan, and oversees the clinical trial from 
protocol development to study analysis and publication. 
11.2.10.2    Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) has been appointed and is responsible for 
periodic review of the data related to adverse events throughout the trial.  In addition, its responsibilities 
are to review of the research protocol and ongoing study activities, including review of adequacy of subject 
recruitment and retention, data quality and completeness, and fidelity to the study protocol. The DSMB 
will make recommendations to the NINDS and the study PI concerning trial continuation, modification, or 
conclusion. A DSMB Charter specifying the composition, responsibilities, frequency, and format of DSMB 
meetings and the content of DSMB reports has been created and is available to sites.  
11.3 
Quality Assurance 
11.3.1  QA Audits/Site Visits 
During the course of the study and after it has been completed it is likely that one or more study site visits 
will be undertaken by authorized representatives of the DCC. 
 
The purpose of the audit is to determine whether or not the study is being, or has been, conducted and 
monitored in compliance with the protocol as well as recognized GCP guidelines and regulations.  These 
audits will also increase the likelihood that the study data and all other study documentation can withstand 
a subsequent regulatory authority inspection. 
 


 
 
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If such audits occur, they will be arranged for a reasonable and agreed time.  Site staff will receive 
feedback after these visits have taken place.  Action items noted in this correspondence should be attended 
to within 1 week of receipt of the correspondence. 
11.3.2  Regulatory Inspections 
The study may be inspected by regulatory agencies, such as the Food and Drug Administration (FDA).  
These inspections may take place at any time during or after the study and are based on the local 
regulations as well as ICH guidelines. 
 
12.       HUMAN SUBJECTS  
12.1 
Compliance Statement  
This study will be conducted in accordance with the Good Clinical Practice (GCP) guidelines 
promulgated by the International Conference on Harmonization (ICH) and the Food and Drug 
Administration (FDA), and any applicable national and local regulations including FDA regulations under 
21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, 312 and 314. 
 
All procedures not described in this protocol will be performed according to the study Operations Manual 
unless otherwise stated.  Laboratory tests/evaluations described in this protocol will be conducted in 
accordance with quality laboratory standards as described in the central laboratory manual unless otherwise 
stated. 
12.2   Informed Consent 
This study will be conducted in accordance with the provisions of 21 CFR Part 50.  The CCC must be 
given an opportunity to review the site-specific consent form prior to site IRB submission and before it is 
used in the study. 
 
In accordance with relevant regulations, an informed consent agreement explaining the procedures and 
requirements of the study, together with any potential hazards/risks must be read and/or explained to each 
subject.  Each subject will sign such an informed consent form or give oral consent/proxy.  The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation.  A copy of the signed consent form will be given to the subject, and this fact will be 
documented in the subject’s record. The subject must be assured of the freedom to withdraw from 
participation in the study at any time. 
 
It is the Site Investigator’s responsibility to make sure that the subject understands what she/he is agreeing 
to and that written informed consent is obtained before the subject is involved in any protocol-defined 
procedures including screening procedures.  It is also the Site Investigator’s responsibility to retain the 
original signed consent form and provide each subject with a copy of the signed consent form. 
12.3   Institutional Review Board/Independent Ethics Committee 
The CCC will supply all necessary information to the Site Investigator for submission of the protocol and 
consent form to the IRB/IEC for review and approval.  The Site Investigator agrees to provide the 
IRB/IEC all appropriate material.  The trial will not begin until the Site Investigator has obtained 
appropriate IRB/IEC approval.  A copy of the approval letter and approved consent form must be 
submitted to the CCC. 
 
The Site Investigator will request from the IRB/IEC a composition of the IRB members reviewing the 
protocol and informed consent.  Appropriate reports on the progress of this study by the Site Investigator 


 
 
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will be made to the IRB/IEC and the CCC in accordance with institutional and government regulations.  
The CCC will notify the site when the IRB/IEC may be notified of study completion. It is the Site 
Investigator’s responsibility to notify the IRB when the study ends.  This includes study discontinuation, 
whether it is permanent or temporary. A copy of the site IRB/IEC’s acknowledgement of study 
completion must be submitted to the CCC. 
 
The Site Investigator will discuss any proposed protocol changes with the CCC and no modifications will 
be made without prior written approval by CCC, except where clinical judgment requires an immediate 
change for reasons of subject welfare.  The IRB will be informed of any amendments to the protocol or 
consent form, and approval, where and when appropriate, will be obtained before implementation. 
12.4   Protocol Amendments 
Changes to the protocol should only be made via an approved protocol amendment.  Protocol amendments 
must be approved by the PI, the study’s Steering Committee and each respective site’s IRB/IEC prior to 
implementation, except when necessary to eliminate hazards and/or to protect the safety, rights or welfare 
of subjects.  
12.5   Subject Confidentiality 
Clinical information will not be released without written permission of the subject, except as necessary 
for monitoring by IRB, the FDA, the NINDS, the OHRP, the Sponsor, or the Sponsor’s designee. 
 
The Site Investigator must assure that the privacy of subjects, including their personal identity and 
personal medical information, will be maintained at all times.  U.S. sites have additional privacy 
obligations to study subjects under the Health Insurance Portability and Accountability Act (HIPAA).  
Subjects will be identified by code numbers on case report forms and other documents submitted to the 
DCC and CCC. 
 
After a subject signs an informed consent, it is required that the Site Investigator permit the Study 
Monitor, independent auditor or regulatory agency personnel to review the signed informed consent(s) 
and that portion of the subject’s medical record that is directly related to the study including electronic 
medical records.  This shall include all study relevant documentation including subject medical history to 
verify eligibility, laboratory test result reports, admission/discharge summaries for hospital admissions 
occurring while the subject is in the study, and autopsy reports for deaths occurring during the study 
(when available).   
 
The subject’s Authorization allows the CCC and DCC to receive and review the subjects’ protected health 
information that may be re-disclosed to any authorized representative of the PI, CCC or central laboratory 
facility for review of subject medical records in the context of the study. 
12.6   Study Modification/Discontinuation 
The study as represented by this protocol may be modified or discontinued for reasonable cause at any 
time, with approval of IRB as warranted, by the Sponsor, Steering Committee, NINDS, OHRP, FDA, or 
other government agencies as part of their duties to ensure that research subjects are protected. 
 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the Site 
Investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and provided 
the reason(s) for the termination or suspension by the Sponsor or by the Site Investigator/institution, as 
specified by the applicable regulatory requirement(s).  Through timely notification of Site Investigators, 


 
 
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the Sponsor will encourage prompt notification of research subjects with instructions for study drug 
discontinuation and activities completion to ensure their health and well-being. 
 
 
13. 
PUBLICATION OF RESEARCH FINDINGS 
Timely publication of the results of this trial is considered a high priority as part of a non-commercial 
inosine development program for PD. Publication will be governed by the policies and procedures 
developed by the Steering Committee and guided by publications policy and conflict-of-interest 
guidelines of the PSG. Results will also be made public through the NIH clinical trials registration 
website ClinicalTrials.gov. Any presentation, abstract, or manuscript on the primary results will be made 
available for review by NINDS prior to their initial submission for publication. 
 
 
 
 


 
 
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IND # 100896 
Sponsor-Investigator: M. A. Schwarzschild 
Protocol # INO-PD-P3-2014 
 
FDA Annual Report 2014-2015 
 
Page 1 of 1 
 
 
Protocol Change Summary 
 
 
Below is a summary of the changes that were incorporated into version 2.0 to improve the 
protocol, prompted primarily by recommendations made by the National Institutes of Health 
(NIH)/National Institute of Neurological Disorders and Stroke (NINDS) in their scientific review 
of our funding application for the trial. 
 
All listed changes are included in the protocol version 2.0 and are dated December 1, 2015. 
 
• 
[pg 1] Addition of Dr. David Oakes as the senior biostatistician of a senior statistician 
directing the Data Coordination Center for the trial 
 
• 
[pgs 11, 58] Addition of an additional ‘quality of life’ outcome measure (Neuro-QOL)  
 
• 
[pgs 40, 78] Minor modification of the low urine pH criteria that trigger urine 
alkalinization in the placebo group — in order ensure better matching of alkalinization 
rates in the placebo and active study drug groups, and so doing to reduce the risk of 
unblinding by differential rates of alkalinization between the two treatment arms 
 
• 
[pgs 44-47] Additional recruitment & retention enhancement initiatives, including 
IRB-approved health care network database-searching methods. 
 
• 
[pgs 59-60] Addition of several exploratory outcome measures with brief self-
administered patient-reported responses (on REM Behavior Disorder, PD risk factors, 
and study expectations). 
 
• 
[pg 60] Addition of an optional biomarker blood collection, in which subjects may 
provide blood samples (in addition to those drawn for serial urate measurement and 
other safety labs) for DNA extraction and storage serial frozen plasma storage for 
future research 
 
• 
[pgs 86-94] Minor refinements of the statistical analysis plan, such as more detailed 
descriptions of power analyses and of baseline covariates to be incorporated into the 
primary analysis.   
 
• 
Other minor administrative changes and corrections were made that do not affect 
content. 
 
 
Attached is the full copy of the revised protocol. 
 


Summary and Justification of SURE-PD3 protocol revisions from version 2.0 to 3.0 (12-06-2016) 
# 
Proposed Change 
Section 
Purpose 
1 Smart4SURE substudy addition 
6.2.15, 
10.5.10 
primarily to validate smartphone metrics as 
outcome measures for future PD trials; to 
provide secondary outcome measures. 
2 Addition of an exclusion criterion: 
history of nephrectomy 
4.2 
additional safety measure to avoid 
increased risk of a potential kidney stone in 
a subject with a single kidney, per Medical 
Safety Monitor recommendation 
3 
Addition of sections that reintroduce 
language from the phase 2 protocol 
specifying procedures related to 
unplanned changes in study drug 
doses (e.g., missed doses, dose 
reductions, dose suspensions and 
dose rechallenges. 
5.1.2.4-
5.1.2.7 
To clarify these procedures for these 
occasional study drug adjustment scenarios 
in phase 3. 
4 
added that sites should refer to MOP 
for clarification regarding specifics of 
disallowed medications 
5.3.2.2 
To avoid confusion over specific types of 
medications (e.g., non-prescription 
antioxidants and vitamins) 
5 
The time window between screening 
visit 1 and the baseline visit has 
been extended to 60 days from 45 
days.   
6.3 
(SoA), 
7.1.8 
This was extended due to logistical issues 
related to scheduling screening visits and 
receiving results within 45 days prior to the 
baseline visit. 
6 
Replaced Medwatch Form 3500A as 
the source document used for sites 
to report SAEs, with the SURE-PD3 
SAE Form.   
8.3 
Due to the fact the Medwatchform 3500A 
cannot be typed into and saved, and to 
streamline reporting processes, we are 
replacing use of the Medwatch Form 3500A 
as the source document used for sites to 
report SAEs, with the SURE-PD3 SAE Form. 
7 
Time of follow-up for Adverse Events 
has been updated so that it reflects 
that site’s do not need to follow 
subjects with active adverse events 
post the 27 month visit unless it is 
requested by the Medical Safety 
Monitor or the Principal 
Investigator. 
8.6 
To avoid unnecessary subject and site staff 
burden when not warranted. 
8 Minor revisions. 
through
-out 
To improve clarity. 
 
 


Summary and Justification of SURE-PD3 protocol revisions from version 3.0 to 4.0 (11/28/17) 
# 
Proposed Change 
Section 
Purpose 
1 
Addition of an optional serial DAT scan sub-
study which involves a second DAT scan one 
to two months following a subject’s two-year 
study visit 
6.2.11.2, 7.1.8 
– 7.2.12, 
7.3.1, 10.5.11 
To allow for comparative analysis 
between pre- and post-study drug 
DAT scan measurements 
2 
Clarifying language concerning the DAT scan 
eligibility read process 
6.2.11.1 
To clarify the process used by the 
imaging core in determining 
eligibility 
3 
Clarifying that the projected enrollment 
number of 270 is an approximation (where 
not already indicated) 
Synopsis, 3.1, 
4.0 
To unify the description of the 
study enrollment goal 
4 
Reduction in number of consecutive urine pH 
values ≤5.5 needed to initiate alkalinization 
therapy from 4 to 3 
8.4.2 
To lower the threshold for 
initiating alkalinization treatment 
to reduce the risk of uric acid 
kidney stones in those most at risk  
5 
Expansion of Smart4SURE sub-study 
enrollment 
7.1.8 – 7.2.11 
To allow subjects who have passed 
their baseline visit to enroll in the 
sub-study 
6 
Updating Schedule of Activities chart to 
include above-mentioned changes as well as 
unplanned visits 
7.7 
To improve clarity 
8 
Minor revisions 
Throughout 
To improve clarity 
 

SAP_000.pdf: 
NCT02642393


SURE-PD3: Statistical Analysis Plan 
Version 1.0, 05 Sep 2019 
 
Page 2 of 34 
 
SAP REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
05 Sep 2019 Initial version 
 
 
 
 


SURE-PD3: Statistical Analysis Plan 
Version 1.0, 05 Sep 2019 
 
Page 3 of 34 
 
Table of Contents 
1. 
Introduction ........................................................................................................................... 5 
2. 
Study Design .......................................................................................................................... 5 
2.1 
Overview ......................................................................................................................................................... 5 
2.2 
Study Objectives ............................................................................................................................................. 5 
2.3 
Study Population ............................................................................................................................................. 6 
2.4 
Participant Flow .............................................................................................................................................. 6 
2.5 
Treatment Allocation ....................................................................................................................................... 7 
2.6 
Treatment Administration ............................................................................................................................... 7 
2.7 
Allocation Concealment .................................................................................................................................. 7 
2.8 
Schedule of Assessments................................................................................................................................. 8 
3. 
Statistical Design ................................................................................................................... 9 
3.1 
Primary Outcome ............................................................................................................................................ 9 
3.2 
Efficacy Outcomes .......................................................................................................................................... 9 
3.3 
Safety Outcomes ............................................................................................................................................. 9 
3.4 
Tolerability .................................................................................................................................................... 10 
3.5 
Symptomatic Effects ..................................................................................................................................... 10 
3.6 
Two-period Evaluations ................................................................................................................................ 10 
3.7 
Effect Size for Primary Outcome .................................................................................................................. 10 
3.8 
Sample Size ................................................................................................................................................... 11 
3.9 
Power for Secondary Outcomes .................................................................................................................... 12 
4. 
Baseline Characteristics, Study Endpoints, and Final Disposition ................................ 13 
4.1 
Baseline Characteristics ................................................................................................................................ 13 
4.2 
Expectancy and Treatment Preference .......................................................................................................... 13 
4.3 
Efficacy Endpoints ........................................................................................................................................ 13 
4.4 
Intervention and Pharmacodynamic Endpoints ............................................................................................. 14 
4.5 
Safety Endpoints ........................................................................................................................................... 14 
4.6 
Tolerability Endpoint .................................................................................................................................... 15 
4.7 
Blinding ......................................................................................................................................................... 15 
4.8 
Final Disposition ........................................................................................................................................... 15 
5. 
Measurement Definitions ................................................................................................... 15 
5.1 
Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) ..................................................... 15 
5.2 
Modified Schwab & England Activities of Daily Living Scale .................................................................... 16 
5.3 
Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) scale .......................................................... 17 
5.4 
Modified Hoehn and Yahr Scale ................................................................................................................... 17 
5.5 
Assess Need for Dopaminergic Therapy ....................................................................................................... 17 
5.6 
Mini-Mental State Examination (MMSE) ..................................................................................................... 17 
5.7 
Montreal Cognitive Assessment (MoCA) ..................................................................................................... 18 
5.8 
Quality of Life in Neurological Disorders (Neuro-QOL) .............................................................................. 18 
5.9 
Initiation of Dopaminergic Therapy .............................................................................................................. 19 
5.10 
Primary Diagnosis Assessment................................................................................................................. 19 
5.11 
Diagnostic Features Assessment............................................................................................................... 19 
5.12 
Dopamine Transporter (DAT) Neuroimaging .......................................................................................... 19 
5.13 
Orthostasis ................................................................................................................................................ 20 
5.14 
Levodopa Equivalent Daily Dosage ......................................................................................................... 20 
5.15 
Blindedness Evaluation ............................................................................................................................ 21 
5.16 
Genetics .................................................................................................................................................... 22 
5.17 
Exploratory Assessments .......................................................................................................................... 22 
6. 
Statistical Methodology ...................................................................................................... 23 
6.1 
General Considerations ................................................................................................................................. 23 
6.1.1 
Statistical Software .............................................................................................................................. 23 
6.1.2 
Summary Statistics .............................................................................................................................. 23 
6.1.3 
Precision .............................................................................................................................................. 23 
6.1.4 
Administration ..................................................................................................................................... 23 
6.2 
Analysis Samples .......................................................................................................................................... 23 


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6.3 
Baseline Comparison ..................................................................................................................................... 24 
6.4 
Sample Size Review ...................................................................................................................................... 24 
6.5 
Interim Analysis ............................................................................................................................................ 24 
6.6 
Efficacy Analysis .......................................................................................................................................... 25 
6.6.1 
Primary Analysis of the Primary Efficacy Endpoint ............................................................................ 25 
6.6.2 
Secondary Analyses of the Primary Efficacy Endpoint ....................................................................... 25 
6.6.3 
Secondary Efficacy Endpoints ............................................................................................................. 26 
6.6.4 
Disability Warranting Dopaminergic Therapy..................................................................................... 26 
6.6.5 
Combined Function and Treatment ..................................................................................................... 26 
6.6.6 
Subgroup Analyses .............................................................................................................................. 27 
6.6.7 
Pharmacogenetics ................................................................................................................................ 27 
6.6.8 
Symptomatic Effects ............................................................................................................................ 27 
6.6.9 
Disease Modification ........................................................................................................................... 28 
6.6.10 
Multiplicity Adjustments ..................................................................................................................... 28 
6.6.11 
Missing Data ........................................................................................................................................ 28 
6.7 
Safety and Tolerability Analysis ................................................................................................................... 28 
6.7.1 
Treatment-emergent Adverse Events ................................................................................................... 28 
6.7.2 
Safety Labs .......................................................................................................................................... 29 
6.7.3 
Vital Signs ........................................................................................................................................... 29 
6.7.4 
Additional Continuous Safety Outcomes ............................................................................................. 29 
6.7.5 
Tolerability .......................................................................................................................................... 29 
6.7.6 
Alkalinization and Nephrolithiasis ...................................................................................................... 29 
6.8 
Other Analyses .............................................................................................................................................. 30 
6.8.1 
Participant Disposition ......................................................................................................................... 30 
6.8.2 
Study Drug Exposure ........................................................................................................................... 30 
6.8.3 
Prior and Concomitant Medication Use ............................................................................................... 30 
6.8.4 
Determinants of change in MDS-UPDRS ........................................................................................... 30 
6.8.5 
Determinants of Early Disability Warranting Dopaminergic Therapy ................................................ 31 
6.8.6 
Placebo Response ................................................................................................................................ 31 
6.8.7 
Blindedness .......................................................................................................................................... 32 
7. 
References ............................................................................................................................ 32 


SURE-PD3: Statistical Analysis Plan 
Version 1.0, 05 Sep 2019 
 
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1. Introduction 
This statistical analysis plan (SAP) defines the outcome measures and analysis samples and 
specifies the planned analyses of data for the SURE-PD3 trial. The SAP supplements the clinical 
protocol. Please refer to the clinical protocol for details on the rationale for the intervention, 
eligibility criteria, conduct of the trial, clinical assessments and the timing of their use in the trial, 
definitions and reporting of adverse events, data management conventions, and regulatory 
oversight and compliance procedures. In case of discrepancies between the SAP and the clinical 
protocol concerning matters of data analysis, the SAP is authoritative. On all other matters, the 
clinical protocol is authoritative. 
This SAP specifies data and planned analyses for the main trial. Specification of data and 
analyses for ancillary studies will be detailed in ancillary SAPs if not covered here. 
2. Study Design 
2.1 
Overview 
This is a phase 3, randomized, two-arm, parallel-group, placebo-controlled, triple-blind, two-
period, multicenter clinical trial of oral inosine titrated to elevate trough serum urate to 7.1 to 8.0 
mg/dL over 24 months with a 3-month wash-out among early Parkinson disease (PD) patients 
exclusive of those with scans without evidence of dopaminergic deficit (SWEDD). The primary 
aim is to test the effectiveness of oral inosine dosed to elevate serum urate in slowing or delaying 
PD progression over 24 months based on rate of change in the Movement Disorders Society 
Uniform Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III total score while 
participants are not receiving dopaminergic therapy (except possibly a stable dosage of a 
monoamine oxidase-B [MAO-B] inhibitor at baseline). Randomizations are stratified by site to 
avoid chance confounding between site characteristics and treatment. The trial is registered at 
Clinicaltrials.gov as study NCT02642393 (see https://clinicaltrials.gov/ct2/show/NCT02642393). 
The randomized, two-arm, parallel-group design provides an unbiased estimate of effectiveness 
of oral inosine dosed to elevate serum urate in slowing or delaying PD progression over 24 
months during period 1. Tracking symptoms during randomized wash-in and during the non-
randomized 3-month wash-out of period 2 will allow estimation of symptomatic effects of serum 
urate elevation and thereby better evaluate whether any observed effects on PD progression 
reflect a disease-modifying effect. Note that although suspension of study drug during the wash-
out will be unmasked, subjects and staff will remain blinded as to whether this represents a 
transition off of active treatment or of placebo treatment, and thus treatment comparison of 
changes during the 3-month wash-out should remain unbiased. The difference in the proportion 
of subjects requiring dopaminergic therapy after the 3-month wash-out among all those 
randomized will provide an estimate of disease-modification by serum urate elevation free of any 
symptomatic effects of study drug. 
2.2 
Study Objectives 
The primary objective of the trial is to determine whether oral inosine dosed to elevate serum 
urate is effective in slowing or delaying PD progression over 24 months. Secondary objectives 
include evaluating the safety and tolerability of serum urate elevation, determining whether 
serum urate elevation causes short-term, reversible effects on clinical symptoms, and whether 


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serum urate elevation is effective in delaying time to need for or initiation of dopaminergic 
therapy or in slowing worsening of cognitive function, mood, autonomic function, quality of life, 
or functional disability. 
2.3 
Study Population 
Individuals eligible for trial participation are men or women age 30 years or older with early 
idiopathic PD, serum urate ≤5.7 mg/dL, with evidence of dopamine deficit by dopamine 
transporter brain scan, and free of risk factors for potential urate-related adverse events (AEs). 
Early PD requires a modified Hoehn and Yahr Scale stage less than 3, diagnosis within 3 years 
of screening, and without current or imminent disability requiring dopaminergic therapy other 
than a stable dosage of an MAO-B inhibitor. Detailed inclusion and exclusion criteria are 
specified in the clinical protocol. Participants will be recruited from approximately 60 clinical 
sites located through the US. 
2.4 
Participant Flow 
After providing informed consent, participants will complete a sequence of three screening visits. 
At Screening Visit 1 (SC1), participants will be screening for serum urate levels and urine pH to 
evaluate the highest yield eligibility criteria (serum urate ≤5.7 mg/dL) and evaluate risk of serum 
urate elevation (urine pH ≤5.0 or history of gout, ). For those subjects who pass SC1, most of the 
remaining screening procedures are conducted on a longer second screening visit (SC2). If 
participants are still eligible, then a dopamine transporter (DAT) ligand binding brain scan will 
be acquired at a local neuroimaging center and read centrally to exclude participants classified as 
having a scan without evidence of dopaminergic deficit (SWEDD). 
Eligible participants will be randomized, complete a baseline visit, and initiate study drug. 
Participants will be seen in-clinic at 3, 6, and 12 weeks and then quarterly to 24 months for study 
visits and collection of blood samples to measure trough serum urate. Following study drug 
discontinuation, participants will be followed during a 3-month wash-out period with monthly 
telephone calls and a final in-clinic study visit 27 months after baseline. 
Detailed descriptions of study procedures and timing are specified in the clinical protocol. A 
schematic of participant flow is given below. 
 


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2.5 
Treatment Allocation 
Prior to the baseline visit, eligible participants will be randomly allocated in equal proportions to 
one of two treatment groups, oral inosine titrated to achieve trough serum urate in the range 7.1 
to 8.0 mg/dL or placebo, according to a permuted-block randomization schedule, stratified by 
site. The randomization schedule was prepared by computer program by the unblinded study 
statisticians. 
2.6 
Treatment Administration 
Study drug will be orally self-administered in capsules containing 500 mg of inosine (active 
drug) or lactose (placebo). Participants will take up to two capsules three times per day (i.e., up 
to 3.0 gm/day) based on individualized titration that aims to achieve trough serum urate in the 
range 7.1 to 8.0 mg/dL in the active arm and equivalent dosage adjustments in the placebo arm. 
Details of the titration algorithm are specified in the clinical protocol. Note, the maximum study 
drug dosage was reduced from 3.0 to 2.0 gm/day beginning 24 Jan 2018 based on safety 
concerns over a higher than expected rate of kidney stones with greatest incidence among 
participants on study drug dosages greater than 2.0 gm/day. 
2.7 
Allocation Concealment 
The randomization schedule is known only by the unblinded study statisticians who generated 
the schedule and implement the titration algorithm and a calibrated urine alkalinization process 
and by the study drug distributor. Concealment of the true treatment allocation of specific 
participants is achieved by use of matched active and placebo capsules, matched titration 
schedules, and matched urine alkalinization rates. Clinical members of the Steering Committee, 
site investigators and other site staff, clinical coordination and data management staff, the 
medical monitor, and all participants are blinded to participant treatment allocations. The Data 
and Safety Monitoring Board (DSMB) members are provided treatment-specific information in 
order to monitor the trial but such information is masked by use of coded values to identify the 
treatment groups. The DSMB may request the true treatment identities. 


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2.8 
Schedule of Assessments 
 


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3. Statistical Design 
3.1 
Primary Outcome 
Our choice of rate of change in MDS-UPDRS I-III total score as our primary efficacy measure is 
based on an interest in an outcome that can be evaluated within 2 years and an interest in a 
patient-reported outcome. Moreover, our preliminary data from the SURE-PD trial (NCT 
NCT00833690) showed dosage-dependent efficacy of serum urate elevation for 24-month 
change in UPDRS I-III total score. Anticipating that recruitment will require 18 months, 
evaluations of the primary outcome needs to be completed in 2 to 2.5 years in order to launch, 
implement, and publish results from the trial within a 5-year grant period.  
Assessing change in MDS-UPDRS or other measures of motor symptoms among initially de 
novo PD patients becomes more complex as subjects begin initiating dopaminergic therapy, with 
roughly two-thirds expected to have initiated dopaminergic therapy by 2 years in the placebo 
group. We feel that assessing motor symptoms when not on dopaminergic therapy best reflects 
the efficacy of the intervention under study, whereas evaluation in the OFF condition after 
dopaminergic therapy has already been initiated is burdensome to subjects and unreliable due to 
incomplete and variable wash-out. Evaluating motor symptoms in the ON condition is prone to 
bias due to adjustment of dopaminergic therapy to achieve a pre-targeted level of symptoms. We 
propose instead to analyze MDS-UPDRS measurements made prior to initiating dopaminergic 
therapy, considering use of such treatments a censoring event that precludes observation of 
future untreated MDS-UPDRS scores. While delaying progression over only 2 years provides 
less benefit to patients than we would ultimately wish to offer, we feel that a demonstration of 
delay over 2 years in the absence of symptomatic effects is an achievable result, one that could 
provide evidence of disease modification early in the clinical course, and may motivate a long-
term trial focused on functional and quality of life endpoints. 
3.2 
Efficacy Outcomes 
Additional efficacy outcomes will include time to disability warranting dopaminergic therapy, 
the prescribed levodopa equivalent dosage (LEDD), motor function as measured by MDS-
UPDRS part III, ambulation subset, and patient-reported sections (IB and II), striatal DAT 
binding by DaTscanTM, cognition as measured by MoCA, mood as measured by Neuro-QOL 
Depression, quality of life as measured by PDQ-39, and functional disability as measured by 
modified Schwab and England. Measures of parkinsonian symptoms assessed by the MDS-
UPDRS will be analyzed in two ways: (a) excluding assessments completed after initiation of 
dopaminergic medication, and (b) adjusting for time-dependent LEDD. 
3.3 
Safety Outcomes 
Safety of oral inosine titrated to achieve trough serum urate in the range 7.1 to 8.0 mg/dL will be 
evaluated by comparing active vs. placebo treatment groups with respect to overall adverse event 
(AE) and serious adverse event (SAE) rate, time to first SAE, and proportions of subjects 
experiencing (a) each type of AE, classified by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term and system organ class, (b) clinically-significant abnormal labs, and 
(c) clinically significant abnormal vital signs, including orthostatic hypotension defined as 
positional dizziness or other clinical symptoms of orthostatic hypotension or a drop in systolic 


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and diastolic blood pressures of 20 mm Hg and 10 mg Hg or more, respectively, when moving 
from a supine to a standing position. 
3.4 
Tolerability 
Tolerance of treatment by an individual participant will be defined as remaining on-study and on 
his/her assigned treatment without one or more AE-associated dosage reductions lasting more 
than 4 weeks cumulative. Tolerability of oral inosine titrated to achieve trough serum urate in the 
range 7.1 to 8.0 mg/dL will be defined as the proportion of all participants in the active arm who 
are tolerant of the treatment at 12 weeks (short-term), 12 months (medium-term), and 24 months 
(long-term). Oral inosine titrated to achieve trough serum urate in the range 7.1 to 8.0 mg/dL will 
be declared tolerable for a given duration of treatment if the proportion who are tolerant is 
significantly greater than 50%. 
3.5 
Symptomatic Effects 
Symptomatic effects will be estimated by changes in motor symptoms (a) during the first 3 
months of wash-in at the start of period 1, and (b) during the 3-month wash-out during period 2 
or at the end of study drug exposure, if earlier. 
3.6 
Two-period Evaluations 
Analysis of the persistence of benefit after the 3-month wash-out of period 2 among subjects 
randomized to active treatment during period 1 permits an evaluation of disease-modifying effect 
of serum urate elevation. Not all measures are amenable to two-period evaluation because of the 
censoring effect of initiation of dopaminergic therapy. In particular, with only one-third of 
subjects expected to have not initiated dopaminergic therapy at the end of period 1, few data on 
uncensored MDS-UPDRS trajectories during wash-out will be available and subjects 
contributing those data are a non-random subset of slow progressors. For LEDD-adjusted 
analysis of MDS-UPDRS and other measures that are equally evaluable at the end of both 
periods, a three-part test of significantly slower worsening during period 1, non-inferior rates of 
worsening during period 2, and a significant net benefit at the end of period 2 would provide 
evidence of disease modification if all three evaluations were favorable. 
3.7 
Effect Size for Primary Outcome 
The effect size for determining power is based on estimates of the minimum clinically important 
difference (MCID) for changes in MDS-UPDRS I-III total scores and on the previously observed 
association between baseline serum urate levels and the rate of change in UPDRS I-III total 
scores in the DATATOP, PRECEPT, and SURE-PD trials. 
Hauser et al.1 report that placebo-treated subjects who reported being minimally worse over 26 
weeks on a global impression of change assessment experienced an average increase in UPDRS 
I-III total scores of 4.9 units. Given our expectation that elevated serum urate will delay 
progression, not improve symptoms, a MCID related to minimal worsening among placebo 
subjects seems most appropriate in this context. Based on estimates by Goetz and colleagues2-5 
for PD patients with mild symptoms (Hoehn and Yahr stage I/II), MDS-UPDRS I-III total scores 
are roughly 30% larger than UPDRS I-III total scores (2.5x for 16 questions in Part 1, 1.1x for 52 
questions in Part II, and 1.2x for 108 questions in Part III, yielding a weighted conversion of 
1.29x), implying a MCID of 6.3 MDS-UPDRS I-III total score units.  


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We expect to enroll subjects with mean baseline serum urate of approximately 4.5 mg/dL based 
on data from SURE-PD and then raise levels in the active arm 3 mg/dL on average at trough 
sampling. A 3 mg/dL difference in baseline serum urate predicted 8.1 and 2.1 unit per year 
differences in UPDRS I-III total score slopes in the DATATOP6 and PRECEPT7 trials. In the 
SURE-PD trial8, subjects randomized to moderate serum urate elevation (7 to 8 mg/dL at random 
sampling) progressed 1.1 unit / year slower than placebo arm subjects with wide confidence 
bounds (95% CI 4.8 units / year slower to 2.8 units / year faster). Note that this estimate from 
SURE-PD (see protocol Fig. 7D) is conservative relative to an alternative model for the effect of 
serum urate elevation (see protocol Fig. 7C). A random-effects meta-analysis of results from the 
three studies yields a weighted estimate of 4.5 units slower progression in UPDRS I-III total 
score over 2 years among patients with higher serum urate levels.  
We propose that 6.3 units over two years or a 
difference in slopes of 3.15 units per year is a 
reasonable minimum clinically important 
difference (MCID) in MDS-UPDRS I-III total 
scores, equal to a MCID of 4.9 units on the scale of 
UPDRS I-III total scores. This would correspond 
to a reduction of 20% of the expected placebo rate 
based on a random effects meta-analysis (Fig. 1 
[from protocol Fig. 13]) of the mean rates of 
decline in UPDRS I-III total scores among de novo 
PD patients with baseline serum urate levels below 
5.9 mg/dL in the DATATOP9,10, PRECEPT11, and 
SURE-PD8 cohorts. Changes in UPDRS I-III total 
scores were analyzed using random-slope mixed 
models censoring follow-up when dopaminergic 
therapy was initiated. The weighted mean estimate 
was 0.98 points / month or 23.5 points over 2 years 
with substantial heterogeneity in the estimate 
among studies (see Fig. 1). 
3.8 
Sample Size 
Power for the primary outcome of rate of change in MDS-UPDRS I-III total score is based on a 
random slopes model with shared baseline. The model will include fixed effects of time, 
treatment x time, sex, sex x time, an indicator of baseline MAO-B inhibitor use, and baseline 
MAO-B inhibitor use x time and random site- and subject-specific intercepts and slopes, each 
with unstructured covariance. MDS-UPDRS assessments completed after a subject has initiated 
dopaminergic therapy will be censored.  
Based on applying the same primary analysis model to data from SURE-PD, the following 
variance components were estimated for UPDRS I-III total scores: site-level variance (intercept 
= 9.75, slope = 0.0123 / month, covariance = -0.346), subject-level variance (intercept = 77.4, 
slope = 0.230 / month, covariance =2.87), and residual variance = 13.9. We assume that 70% of 
subjects will initiate dopaminergic therapy based on experience in SURE-PD plus up to 8% 
additional lost to follow-up prior to initiating dopaminergic therapy. With the planned schedule 
for MDS-UPDRS assessments (screening, baseline, 3 weeks, 6 weeks, 12 weeks, and then 
Figure 1. Meta-analysis of the rate of UPDRS 
change in early PD subjects with lower serum 
urate. Early, largely untreated PD subjects 
with a serum urate of <5.9 mg/dL at baseline 
from DATATOP (n=155; double-placebo 
only), PRECEPT (n=446) and SURE-PD 
(n=25; placebo only) were followed for up to 
two years. The overall UPDRS rate was 
obtained by weighting each estimate by the 
inverse of its standard error. 


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quarterly through 24 months), the variance and censoring estimates above imply an effective 
standard deviation for UPDRS I-III total score slopes of 0.587 units / month or 0.758 units / 
month on the scale of MDS-UPDRS I-III total scores.12 
Given a standard deviation of 0.76 units / month, a final two-sided test at alpha = 0.046 allowing 
conservatively for two interim analyses at alpha = 0.001 each, the study would have 80% power 
with n = 270 subjects randomized 1:1 to placebo or urate elevation if the true effect of treatment 
were to reduce the rate of increase in MDS-UPDRS I-III total score by 6.3 points over 2 years. 
This estimate of power is robust to variable sex-specific enrollment rates and treatment efficacy 
as long as the average effect of treatment across sexes in the ratio enrolled is 6.3 points over 2 
years (Fig. 2A). If urate elevation reduces the average rate of progression by 6.3 points over 2 
years only among male or female participants and the other sex experiences less benefit, power 
would be lower (Fig. 2B). This is unavoidable if a large proportion of the enrolled population 
accrues less benefit from the intervention. Conversely, power would be greater than 80% if one 
sex experiences a benefit greater than 6.3 points over 2 years and the other sex experiences at 
least that large a benefit. 
 
Figure 2. (A) Power for the primary aim across a range of sex-specific treatment responses, all 
cases with the average treatment response across sexes equal to the MCID of 6.3 points over 2 
years. Note that equal prevalence of male (M) and female (F) participants is plotted, but the 
power curve for other prevalence ratios are so similar as to be indistinguishable at this scale. (B) 
Power for the primary aim when the effect of treatment on one sex is equal to the MCID and the 
effect on the alternate sex varies from 50% to 150% of MCID for a range of different prevalence 
ratios. 
3.9 
Power for Secondary Outcomes 
The trial will have an 80% probability of observing at least one instance of any class of adverse 
event expected to occur in at least 1.2% of individuals receiving inosine. The trial will have 80% 
power to detect increased risk of any class of adverse event among subjects receiving inosine if 
the true risk is two-fold higher and the expected proportion among placebo subjects is at least 
14% or if the true risk if four-fold higher and the expected proportion among placebo subjects is 
at least 3.4%. The trial has 80% probability of declaring serum urate elevation tolerable if the 
true proportion tolerant under the definition given in Sec. 3.4 at 12 weeks, 12 months, and 24 
months is at least 62%. 
B 
A 


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The estimated SE for symptomatic effects on UPDRS I-III total scores during wash-in between 
the moderate elevation and placebo arms in the SURE-PD trial was 0.53 units / month. With n = 
25 subjects per treatment group in SURE-PD, the expected SE for estimating symptomatic 
effects in this trial will be roughly sqrt (25/135) * 0.53 = 0.23 units / month. With that SE, the 
trial would have 80% power to detect symptomatic effects on the order of a difference in slopes 
during wash-in or wash-out of 0.65 units/month.  
The Kaplan-Meier product-limit estimate from the SURE-PD trial of the proportion of placebo 
subjects requiring dopaminergic therapy by 24 months was 62%. Assuming constant hazard at 
the same rate among placebo subjects in this trial during period 1 (0 to 24 months) and 8% loss 
to follow-up prior to determining need for dopaminergic therapy, the trial will have 80% power 
to detect a hazard ratio of 0.62. Extrapolating to 27 months, we expect a total of 67% of placebo 
arm subjects to have disability warranting dopaminergic therapy at the end of period 2 (24 to 27 
months). The study would have 80% power to detect a difference in the proportion of subjects 
with disability warranting dopaminergic therapy if 50% or fewer of active arm subjects have 
progressed by the end of the trial.  
Given preliminary data from SURE-PD on the variance components from random-slope models 
for MoCA after Rasch score conversion, GDS-15, and S&E ADL, the effective standard 
deviations (in points per month) for these measures given our planned follow-up schedule are 
0.038, 0.097, and 0.31, respectively. Weaver et al.13 report an among-person standard deviation 
for PDQ-39 at 24 months after deep brain stimulation of 14.2 to 15.3. Assuming conservatively 
no within-person covariance, that would imply a standard deviation for 24-month change of 
approximately 30. Given these estimates, the trial will have 80% power to detect 2-year 
treatment differences on these outcomes as small as 0.31, 0.80, 2.5, and 10.3, respectively. 
4. Baseline Characteristics, Study Endpoints, and Final Disposition 
4.1 
Baseline Characteristics 
Each analysis sample will be summarized overall and by treatment group for the following 
characteristics: randomization site; age, sex, race, ethnicity, time since symptom onset, time 
since PD diagnosis, modified Hoehn and Yahr score, resting tremor, use of an MAO-B inhibitor, 
serum urate, MDS-UPDRS scores, NeuroQoL module scores, years of education, MMSE, 
MOCA score, PDQ-39 score, modified Schwab and England ADL score, smoking history, 
caffeine consumption, sense of smell, RBD history, vigorous physical activity, serum urate, DAT 
ligand uptake, BMI, supine systolic and diastolic blood pressure, and orthostatic hypotension. 
4.2 
Expectancy and Treatment Preference 
Measures of expectancy will be obtained once at baseline by self-report. Participants will be 
asked their expectations of benefit from placebo and oral inosine treatment and their relative 
preference for placebo vs. oral inosine. 
4.3 
Efficacy Endpoints 
The primary outcome of the trial is rate of change in MDS-UPDRS I-III total score over 24 
months estimated in the ITT sample from a shared-baseline, random-slopes mixed model, 
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Secondary efficacy endpoints include the following: 
• MDS-UPDRS scores: Parts I, II, III, IV, ambulation, and patient-reported sections (Parts IB 
and II), 
• Striatal DAT binding by DaTscanTM,  
• Neuro-QOL module scores: Lower Extremity Function, Upper Extremity Function, Anxiety, 
Depression, Positive Affect and Well-being, Cognitive Function, Fatigue, Sleep Disturbance, 
Emotional and Behavioral Dyscontrol, Communication, Ability to Participate in Social Roles 
and Activities, Stigma, and Satisfaction with Social Roles and Activities,  
• Montreal Cognitive Assessment (MoCA) score to assess cognition,  
• Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) score to assess quality of life,  
• Modified Schwab and England ADL score to assess functional disability,  
• Orthostatic vital signs: supine to standing change in systolic blood pressure, diastolic blood 
pressure, and heart rate; orthostatic hypotension, and  
• Medical intervention: levodopa equivalent daily dosage, disability warranting initiation of 
dopaminergic therapy. 
Exploratory efficacy endpoints include: REM sleep behavior disorder (RBD) symptoms and 
symptom severity, quantitative measures derived from tasks completed using the Smart4SURE 
implementation of the mPower smartphone app. 
4.4 
Intervention and Pharmacodynamic Endpoints  
Intervention intensity will be assessed by capsule count. Pharmacodynamic effect of oral inosine 
on serum urate will be assessed by direct measurement. Effects of oral inosine on urate excretion 
will be assessed by comparing measurements of serum urate and 24-hour urine urate excretion.  
4.5 
Safety Endpoints 
The following safety endpoints will be evaluated: 
• 
Overall TEAE and serious TEAE incidence rate,  
• 
Time to first serious TEAE,  
• Proportion of participants experiencing and number of unique events of each type of TEAE 
and serious TEAE classified by MedDRA system organ class and preferred term,  
• Proportion of participants experiencing and number of unique events of each type of TEAE 
within the group of events specified as of special interest,  
• Proportion of participants experiencing and number of unique events of TEAEs classified by 
seriousness, severity, relatedness to study drug, action taken with study drug, and outcome, 
summarized across all MedDRA terms,  
• Mean change from baseline in safety labs: complete blood count, leukocyte differential, 
electrolytes, renal panel, liver function tests, lipid profile, thyroid stimulating hormone, and 
urinalysis of spot and 24-hr samples,  


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• Mean change from baseline in blood pressure (supine and standing), heart rate (supine and 
standing), orthostasis (change from supine to standing), and body weight,  
• Mean change from baseline in ECG parameters,  
Reported proportions will use as their denominator all participants in the Safety and Tolerability 
sample (see Section 5.2 below). 
4.6 
Tolerability Endpoint 
Tolerance of treatment by an individual participant will be defined as remaining on-study and on 
his/her assigned treatment without one or more AE-associated dosage reductions lasting more 
than 4 weeks cumulative.  Tolerance will only be assessed through 24 Oct 2018, the day before 
clinical sites were notified of early study closeout, as discontinuation of study drug after that date 
may reflect a change in participants' or investigators' equipoise.  Tolerability of oral inosine 
titrated to achieve trough serum urate in the range 7.1 to 8.0 mg/dL will be defined as the 
proportion of all participants in the active arm who are tolerant of the treatment at 12 weeks 
(short-term), 12 months (medium-term), and 24 months (long-term). Oral inosine titrated to 
achieve trough serum urate in the range 7.1 to 8.0 mg/dL will be declared tolerable for a given 
duration of treatment if the proportion who are tolerant is significantly greater than 50%. 
4.7 
Blinding 
The presumed treatment group to which a participant was assigned, a respondent's confidence in 
that presumption, and the reason for that presumption will be collected from participants, site 
investigators, and coordinators at the 6 week visit and at the end of treatment. The proportion 
guessing correctly or incorrectly and the odds ratio of guessing the true treatment vs. the wrong 
treatment will be evaluated for each class of respondent, both overall and among the subset of 
respondents who assert being at least somewhat sure of their guess. 
4.8 
Final Disposition 
The proportion of participants who permanently discontinue study drug, discontinue clinic visits, 
fully withdraw consent, or are lost to follow-up prior to planned study completionwill be 
summarized overall and by treatment group for each period, both overall and stratified by 
occurrence before vs. on or after 25 Oct 2018, when clinical sites were notified of early study 
closeout. The probability that each participant has idiopathic PD based on the site investigator's 
primary diagnostic assessment at the participant's final visit will be summarized overall and by 
treatment group. 
5. Measurement Definitions 
5.1 
Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) 
The MDS-UPDRS138 will serve as the primary outcome variable of the study and will be 
conducted at all standard visits beginning with SC2. The MDS-UPDRS was designed by 
movement disorders experts to address weaknesses of the original UPDRS (e.g., by adding 
questions on constipation and sialorrhea) while preserving its overall format. 
The instrument is divided into four parts:  


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• Part I (non-motor experiences of daily living), comprising 
o Part IA concerning behaviors that are assessed by the Site Investigator with all 
pertinent information from participants and caregivers 
o Part IB that is completed by the participant with or without the aid of the 
caregiver, but independently of the Site Investigator. 
• Part II (motor experiences of daily living), designed to be a self-administered 
questionnaire like Part IB, but similarly can be reviewed by the Site Investigator to 
ensure completeness and clarity. 
• Part III (motor examination) has instructions for the rater to give or demonstrate to the 
participant; it is completed by the clinician rater. 
• Part IV (motor complications) with instructions for the rater and also instructions to be 
read to the participant. This part integrates participant-derived information with the rater's 
clinical observations and judgments and is completed by the rater.  
The full MDS-UPDRS has sixty-five items, each assessed on a 5-point Likert scale ranging from 
0 to 4 with 0=none, 1=slight, 2=mild, 3=moderate, 4=severe. Total scores for Parts I, II, III, and 
IV and for Parts I through III collectively are calculated as simple sums of component items with 
mean imputation by Part if no more than 1, 2, 7, or 0 items is missing for Parts I through IV, 
respectively.16 Two additional summary scores will also be constructed: ambulatory capacity 
(sum of 5 MDS-UPDRS questions: walking and balance [question 2.12], freezing [q. 2.13], gait 
[q. 3.10], freezing of gait [q. 3.11], and postural stability [q. 3.12]) and patient-reported 
symptoms (sum of Parts IB and II). Higher scores imply worse symptoms. 
Participants will self-administer Parts IB and II and will review responses for accuracy and 
clarity with the Site Investigator or Coordinator. Parts IA, III and IV will be conducted by the 
Site Investigator. Parts I, II, and III will be conducted at study visits as indicated on the Schedule 
of Activities (Sec. 2.8). Part IV will be conducted at visits where MDS-UPDRS Parts I-III are 
conducted but only for participants who have started on symptomatic therapy after the Baseline 
visit. 
Use of MDS-UPDRS is responsive to core instrument recommendations for the Quality of Life 
subdomain of the NINDS CDEs for PD and to FDA guidance encouraging use of patient-
reported outcomes (PROs) as a substantial portion of the responses are patient-reported. The 
same Site Investigator should assess all subjects on parts IA and III of the MDS-UPDRS at all 
study visits. 
5.2 
Modified Schwab & England Activities of Daily Living Scale  
The Schwab & England scale181,182 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”. This joint participant/Site Investigator assessment will be 
conducted periodically at the visits indicated in Sec. 2.8. 


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5.3 
Parkinson’s Disease Questionnaire - 39 item version (PDQ-39) scale 
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. The PDQ-39 is the most widely used health 
related-QoL instrument in PD, and is considered to have generally good psychometric properties 
and content validity.183,184 Use of PDQ-39 is responsive to core instrument recommendations for 
the Quality of Life subdomain of the NINDS CDEs for PD, and to FDA guidance encouraging 
use of PROs. This assessment will be collected from subjects periodically at the visits indicated 
in Sec. 2.8. 
5.4 
Modified Hoehn and Yahr Scale 
The Modified Hoehn and Yahr Scale181, 185 is a 6-level PD staging instrument of motor 
manifestations and disability. It is an ordinal scale, scored by the Site Investigator. Scores range 
from 0 to 5 with higher scores associated with more motor symptoms and disability. Stage 0 is 
“no signs of disease”, stage 1 is “unilateral disease’, stage 1.5 is “unilateral disease with axial 
involvement”, stage 2 is “bilateral disease, without balance impairment”, stage 2.5 is “bilateral 
disease, with recovery on the pull test”, stage 3 is “mild to moderate bilateral disease; needs 
assistance to prevent falling on pull test”, stage 4 is “severe disability, but still able to walk or 
stand unassisted” and stage 5 is “wheelchair bound or bedridden unless aided.” This Site 
Investigator assessment will be conducted periodically at the visits indicated in Sec. 2.8. 
5.5 
Assess Need for Dopaminergic Therapy 
At each visit beginning with Baseline Visit, the Site Investigator will assess the subject’s need 
for dopaminergic therapy. (See Sec. 5.3.3.1 for definition of dopaminergic therapy.) A 
questionnaire will be used to facilitate the Site Investigator’s decision. As in the DATATOP9,10 
and PRECEPT11 trials, this will be based on PD disability posing a threat to the subject’s current 
occupational status, current abilities (potential capacities) related to occupational matters, to 
handle routine personal finances and domestic responsibilities, and activities of daily living.  
Subjects who are judged to require dopaminergic therapy at Baseline or are thought likely to 
need therapy within the 3 months after Baseline, will be excluded from participation in this 
study. Subjects who are judged to require dopaminergic therapy after starting study drug will 
continue in the study after anti-parkinsonian therapy is instituted. 
5.6 
Mini-Mental State Examination (MMSE)  
The Mini-Mental State Examination186 is a 30-point ordinal scale that is widely used for the 
evaluation of degenerative dementia in patients with a variety of neurologic and psychiatric 
disorders, and is designated an NINDS CDE for PD. The MMSE includes 11 questions which 
evaluate orientation (10 points), immediate recall (3 points), attention (5 points), delayed recall 
(3 points), naming (2 points), repetition (1 point), 3-stage command (3 points), reading (1 point), 
copying (1 point) and writing (1 point). The test is referred to as “mini” because it focuses only 
on the cognitive aspects of mental functions and does not include questions related to mood, 


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abnormal mental experiences, or the form of thinking. The total score ranges from 0 to 30, with 
higher scores signifying better cognition. A total score of 23 or less is associated with varying 
severities of cognitive impairment.  
Subjects will complete the MMSE at the Screening Visit 2. Participants with an MMSE score 
less than 25 will be excluded from participation in the study.   
5.7 
Montreal Cognitive Assessment (MoCA) 
The MoCA (Nasreddine et al. 2005) consists of 8 clinician-administered cognitive tasks designed 
to screen for mild cognitive impairment. The MoCA assesses attention and concentration, 
executive functions, memory, language, visuoconstructional skills, conceptual thinking, 
calculations, and orientation. The MoCA was developed to be more sensitive than the MMSE to 
patients presenting with mild cognitive complaint and may be less prone to a ceiling effect 
(Zadikoff et al. 2008). One point is awarded for correct completion of each item of the 
visuospatial/executive function task (5 items), naming task (3 items), digit vigilance and tapping 
items of the attention task (3 items), the sentence repetition items of the language task (2 items), 
abstraction task (2 items), delayed recall task (5 items), and orientation task (6 items). One point 
is awarded for naming 11 or more words during the fluency item of the language task. Zero 
(none correct) to 3 (4 or more correct) points are awarded based on the number of correct 
subtractions by 7 starting at 100 in the attention task. One point is awarded if the participant has 
12 years or less of education unless the score is already 30. Scores for each task are summed for 
a total score (range 0 to 30) with higher scores indicating greater cognitive capacity. The MoCA 
will be administered by Site Investigators at Baseline, Week 12, Month 12, Month 24 and Month 
27 or the Discontinuation of In-person Follow-up Visit for subjects unwilling to continue in-
person visits. 
5.8 
Quality of Life in Neurological Disorders (Neuro-QOL) 
Neuro-QOL is a set of patient-reported outcome (PRO) measures that assess health-related 
quality of life (HRQoL) of people with neurological disorders.190,191 It facilitates comparisons 
between diseases and within individual patients over time. Developed through a collaborative 
NINDS-sponsored research initiative, Neuro-QOL is an NINDS CDE and has been validated in 
multiple patient populations including PD.190,192 It comprises 17 domains of HRQL covering 
physical, psychological and social health. It has 13 item banks, 3 item pools and 1 stand-alone 
scale. There are short forms for each item bank which each form containing 8 to 9 items. 
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. In a PD population, Neuro-QoL 
measures including its short forms have demonstrated high internal consistency, with acceptable 
test-retest reliability and support for convergent validity with PD specific measures including 
PDQ-39 and MDS-UPDRS.190 An instrument comprising multiple short form domains will be 
employed before and after the study drug treatment period (at SC2 and SV) while the depression 
domain will be employed on its own at additional visits during the treatment period, as indicated 
in Sec. 6.3. 


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5.9 
Initiation of Dopaminergic Therapy 
For the purposes of this trial, the date at which a participant initiates dopaminergic therapy will 
be calculated as the first day that the participant either (a) initiates use of one of the following 
medications as labeled in the WHO Drug Dictionary: amantadine, pramipexole, ropinirole, 
rotigotine, sinemet, trihexyphenidyl, benztropine, rasagiline, selegiline, safinamide, or levodopa 
at a LEDD greater than 2 mg/day, or (b) increases the LEDD of one of the following medications 
over the dosage taken at baseline by more than 2 mg/day: rasagiline, selegiline, safinamide. 
5.10 Primary Diagnosis Assessment 
The Primary Diagnosis form captures, in the Site Investigator’s opinion, a current percentile 
probability the subject has idiopathic Parkinson disease based on available information. Ranges 
include: 90-100%; 50-89%, 10-49% and 0-9%. In addition the Site Investigator selects the most 
likely primary diagnosis from a listing that includes idiopathic PD, many other neurological 
disorders, and the option of no neurological disorder. To correlate with the MDS-UPDRS, this 
percentile probability and most likely diagnosis will be captured at Month 27 or the 
Discontinuation of In-person Follow-up Visit for subjects unwilling to continue in-person visits. 
5.11 Diagnostic Features Assessment 
The Diagnostic Features form is a companion to the Primary Diagnosis form. It is a review by 
the Site Investigator of factors that do and do not suggest a diagnosis of Parkinson disease. This 
assessment is completed at Month 27 or the Discontinuation of In-person Follow-up Visit for 
subjects unwilling to continue in-person visits. 
5.12 Dopamine Transporter (DAT) Neuroimaging  
A radionuclide-labeled dopamine transporter (DAT) ligand, and specifically DaTscanTM (123I-
ioflupane injection), is approved by the FDA for striatal DAT visualization using single photon 
emission computed tomography (SPECT) brain imaging to assist in the evaluation of adult 
patients with suspected parkinsonian syndromes. DaTscanTM is approved to help differentiate 
essential tremor from tremor due to parkinsonian syndromes (including idiopathic PD, multiple 
system atrophy and progressive supranuclear palsy) and not for the diagnosis of PD among 
parkinsonian syndromes. Nevertheless, DAT brain scans (using any of several radioligands) in 
clinical research have consistently identified a small but substantial (~10%) portion of subjects 
who are enrolled in clinical trials based on an expert clinician diagnosis of probable early PD but 
who turn out to be unlikely to have PD.30,140,143,145-147 
DAT scans will be performed prior to the baseline visit, and will generally be conducted as the 
final screening evaluation (DS1) at a certified neuroimaging center at or near the clinical site. A 
determination of whether DaTscanTM imaging supports a diagnosis of PD and therefore study 
eligibility will be made by the study imaging core. Its experienced nuclear medicine specialists 
(trained in the visual read method appropriate for DaTscanTM) will perform the qualitative 
eligibility assessment. Each scan will be assessed independently by at least two readers as 
described in the Imaging Core Charter.  
An additional follow-up DaTscanTM imaging study (DS2) will be performed one to two months 
following the final study clinic visit (V10, or its equivalent), and before the final safety visit 
(SV), for active SURE-PD3 subjects who have consented to participate in a serial DAT scan 
substudy, who have been on study drug through at least the 1-year visit (V06), and who are not 


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using or expected to use any of the following medications within 90 days prior to DS2: 
modafinil, armodafinil, metoclopramide, alpha-methyldopa, methylphenidate, reserpine, or 
amphetamine derivative.  The substudy will quantify changes in DAT binding between the pre-
study drug exposure and post-study drug exposure timepoints. 
5.13 Orthostasis 
Orthostatic hypotension will be defined as a maximum decrease of 20 mm Hg or greater in 
systolic blood pressure (SBP) or a maximum decrease of 10 mm Hg or greater in diastolic blood 
pressure (DBP) when moving from a supine to a standing position, with measurements 
completed 1 min and 3 min after standing. 
5.14 Levodopa Equivalent Daily Dosage 
The levodopa equivalent daily dosage (LEDD) will be calculated using data from the 
concomitant medications log. The conversion from dopamergic drugs other than carbidopa-
levodopa will follow the recommendations by Tomlinson et al. (2010) with the following 
additions for anti-cholinergic medications and more recently approved drugs. 
• Trihexyphenidyl (Artane™) will be converted at 25 mg levodopa equivalent per mg 
trihexyphenidyl based on equivalent symptomatic effect of 8 mg/day trihexyphenidyl and 
200 mg/day amantadine reported in Parkes et al. (1974); 
• Benztropine (Cogentin™) will be converted at 50 mg levodopa equivalent per mg 
benztropine based on the ratio of the recommended range of total daily dosages for treating 
Parkinson disease patients between benztropine and trihexyphenidyl; 
• Extended release formations of carbidopa-levodopa (Rytary™) will be converted at 60% of 
their levodopa content based on mean post-baseline daily dosages reported in Hauser et al. 
(2013); 
• Extended release formations of ropinorole (RequipXL™) will be converted at 20 mg 
levodopa equivalent per mg ropinirole based on equivalent maximum recommended daily 
dosage; 
• Safinamide (Xadago™) will be converted at 2 mg levodopa equivalent per mg safinamide 
based on a retrospective study by Mancini et al. (2018). 
The full calculation is as follows: 
1. At each time any oral levodopa is taken per day, calculate the immediate release 
levodopa (e.g., Sinemet, Parcopa) dosage (mg) based on the number of tablets taken per 
dose and the dosage of levodopa in each tablet 
2. At each time any oral levodopa is taken per day, calculate the controlled release levodopa 
(e.g., Sinemet CR) dosage (mg) and multiply by 0.75 to account for loss of bioavailability 
3. At each time any oral levodopa is taken per day, calculate the extended release levodopa 
(e.g., Rytary) dosage (mg) and multiply by 0.60 to account for loss of bioavailability 
4. At each time any oral levodopa is taken per day, calculate the total daily oral levodopa 
dosage by summing together the oral levodopa dosage from immediate release, controlled 
release, and extended release formulations (quantities 1 through 3) 


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5. At each time any oral levodopa is taken per day, if entacapone but not tolcapone is taken 
at the same time, either separately or as a combination drug (e.g., Stalevo), then multiply 
the total levodopa dosage at that time (quantity 4) by 0.33 
6. At each time any oral levodopa is taken per day, if tolcapone (e.g., Tasmar) is taken at the 
same time, then multiply the total levodopa dosage at that time (quantity 4) by 0.50 
7. Calculated the COMT-adjusted total daily levodopa equivalent dosage associated with 
oral levodopa as the sum over all time points of quantities 4 through 6 
8. If enteral levodopa is taken without any COMT inhibitor, then multiply the total enteral 
levodopa (e.g., Duopa) daily dosage (mg) by 1.11 
9. If enteral levodopa is taken with entacapone but not tolcapone, then multiply the total 
daily enteral levodopa dosage (mg) by 1.48 
10. If enteral levodopa is taken with tolcapone, then multiply the total daily enteral levodopa 
dosage (mg) by 1.67 
11. If immediate release or modified release pramipexole (e.g., Mirapex) is taken, multiply 
the daily dosage (mg/day of the dihydrochloride monohydrate salt) by 100 
12. If immediate release or extended release ropinirole (e.g., Requip, Requip XL) is taken, 
multiply the dosage (mg/day) by 20 
13. If a rotigotine patch (e.g., Neupro) is used, multiply the dosage (mg/day) by 30 
14. If oral selegiline (e.g., Eldepryl) is taken, multiply the dosage (mg/day) by 10 
15. If sublingual selegiline (e.g., Zelapar) is taken, multiply the dosage (mg/day) by 80 
16. If oral rasagiline (e.g., Azilect) is taken, multiply the dosage (mg/day) by 100 
17. If oral safinamide (e.g., Xadago) is taken, multiply the dosage (mg/day) by 2 
18. If oral amantadine (e.g., Symmetrel) is taken, multiply the dosage (mg/day) by 1 
19. If an injection or infusion of apomorphine (e.g., Apokyn) is taken, multiply the dosage 
(mg/day) by 10 
20. If oral trihexyphenidyl (e.g., Artane) is taken, multiply the dosage (mg/day) by 25 
21. If oral benztropine (e.g., Cogentin) is taken, multiply the dosage (mg/day) by 50 
22. Calculate total LEDD as the sum of quantities 7 through 21. 
5.15 Blindedness Evaluation 
At week 6 and either month 24 (V10), V10-equivalent visit due early study closure, an 
Unscheduled Visit due to study drug discontinuation, or a Discontinuation of In-person Follow-
up Visit (whichever of the 4 visits comes first), the Site Investigator, Coordinator, and subject 
will complete a blindedness evaluation in which each is asked to give his/her independent 
impression of the subject’s treatment assignment and the primary and secondary reasons for this 
opinion. Participants' responses will not be available to the site Investigator or Coordinator when 
they make their assessments. 


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5.16 Genetics  
DNA samples will be sequenced using whole genome sequencing (WGS) supported by the 
NIH’s Accelerating Medicines Partnership for Parkinson’s Disease (AMP-
PD; https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/parkinsons-
disease) based on established methods (e.g, Allen et al. 2016), with variants scored under the 
AMP program 
(e.g, http://www.type2diabetesgenetics.org/variantSearch/variantSearchWF; Butkiewicz et al. 
2018). The following single nucleotide polymorphisms (SNPs) or repeat polymorphisms may be 
investigated amongst emerging genetic variants contributing to progression of PD across motor, 
non-motor and holistic domains (Iwaki et al. 2019), with simple additive, recessive, dominant, 
interactive, haplotypic, polygenic or other models to be determined based on current 
understanding of genetic risk determinants upon availability of WGS expected by early 2020.  
Genetic predictors of PD progression that may be specific for urate-targeting inosine treatment, 
and those that are more likely generalized will be considered: 
• Potential predictors of PD progression, specific to urate/inosine intervention; e.g.: 
o rs1109303 (INPP5K), stratifying for TT vs G carriers (Nazeri et al. 2015) 
o s6855911, rs7442295, rs16890979 (SLC2A9; encoding urate transporter gene 
Glut9), adjusting for and stratifying by a composite score of proportional to the # 
of their minor alleles) (Simon et al. 2014) 
o rs2231142 (ABCG2 encoding urate transporter gene), stratifying for CC vs A 
carriers (Matsuo et al. 2015) 
• Potential predictors of PD progression, generalized; e.g.: 
o rs76904798 (near/5’ to LRRK2) (Iwaki et al. 2019) 
o D4S3481 (SNCA-Rep1; complex repeat polymorphism upstream of SNCA)  (Ritz 
et al. 2012) 
o rs76763715 (GBA N370S; but MAF 0.007) (Davis et al. 2016) 
o rs9298897 and rs17710829, alone and in a modeled interaction (Latourelle et al. 
2017) 
o rs2230288 (GBA), rs17649553 (MAPT), apolipoprotein E4 (APOE4), COMT 
val158met (COMT) and BDNF val66met (BDNF) alone and in additive model for 
cognitive progression outcomes (Iwaki et al. 2019; Caspell-Garcia et al. 2017). 
5.17 Exploratory Assessments  
Three brief, self-administered questionnaires will be included to explore whether readily 
ascertained historical factors modify or otherwise interact with inosine effects.  
• REM Sleep Behavior Disorder (RBD) Single-Question Screen (RBD1Q)– A single 
“yes-no” question on dream-enactment behaviour will be asked at SC1, BL, and 3 mo, 12 
mo, 24 mo, and 27 mo visits. 
• PD Risk Factors Questionnaire – A self-administered questionnaire assessing 
exposures and experiences linked to the risk of PD will be collected at BL. The 
questionnaire was developed by the PSG and derived from NINDS CDEs. 
• PD - Expectancy Questionnaire – A self-administered questionnaire assessing 
expectations of study drug effect will be collected at BL. 


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• Smart4SURE assessments – A set of smartphone metrics of parkinsonian features 
adapted from the mPower app developed as a sub-study of SURE-PD3. 
6. Statistical Methodology 
6.1 
General Considerations 
6.1.1 Statistical Software 
All statistical analyses will be performed using SAS (SAS Institute, NC, USA) or R (R 
Foundation for Statistical Computing, Vienna, Austria).  
6.1.2 Summary Statistics 
Data will be summarized with respect to disposition, demographics, pre-treatment 
characteristics, safety outcomes, tolerability, and efficacy outcomes. Summary statistics for 
continuous variables will include the number of subjects, the mean, median, standard deviation, 
and range. For categorical data, summaries will include counts and percentages. 
6.1.3 Precision 
Results will generally be reported to 3 significant figures. Percentages will generally be reported 
to 0.1 percentage points. P-values will be reported to two digits when greater than or equal to 
0.095, to three digits when greater than or equal to 0.00095 and less than 0.095, and as <0.001 
for all smaller values. 
6.1.4 Administration 
A test set of tables and figures specified in the SAP will be produced prior to breaking the blind 
using a dummy randomization schedule. The SAP will be finalized and must be approved by the 
Steering Committee prior to the final lock of the trial data and breaking of the blind. 
6.2 
Analysis Samples 
The following analysis samples will be used for testing effectiveness, efficacy, safety, and 
tolerability endpoints: 
• 
Intent-to-treat (ITT) Sample: Participants who are randomized, classified according to their 
randomized treatment assignment. Participants determined to have been ineligible prior to 
randomization, participants who never initiate study drug, and observations made after 
premature permanent discontinuation of study drug are included in this sample. 
• 
As-treated (AT) Sample: Participants who are eligible, randomized, and take at least one 
dose of study drug. If a participant permanently discontinues study drug, observations made 
during period 1 will be censored following the first visit after study drug discontinuation. 
Separate analyses will classify participants in the AT sample either according to the actual 
treatment received or according to the average post-baseline serum urate concentration 
achieved. Participants randomized to inosine who report not taking inosine will be 
reclassified as placebo participants. Participants randomized to placebo who report taking 
inosine or whose serum urate during treatment averages 6.5 mg/dL or greater will be 
reclassified as inosine participants. 


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• 
Safety and Tolerability (ST) Sample: Participants who are randomized and take at least one 
dose of study drug, classified according to the actual treatment received. Participants 
determined to have been ineligible prior to randomization and observations made after 
premature permanent discontinuation of study drug are included in this sample. 
The primary efficacy analyses will use the ITT sample to best estimate the expected 
effectiveness of urate-elevating oral inosine supplementation in clinical practice, recognizing that 
compliance in clinical use may differ from compliance in the clinical trial. Secondary analyses of 
efficacy outcomes will use the AT sample to best estimate efficacy of inosine supplementation as 
administered and serum urate elevation as achieved. Analyses of safety and tolerance will use the 
ST sample. 
6.3 
Baseline Comparison 
While recognizing that any difference observed between treatment groups is axiomatically due to 
chance, nominal p-values will be calculated as a measure of the magnitude of difference for each 
baseline characteristic summarized using Fisher's exact tests for nominal variables, exact 
Cochran-Armitage trend tests for ordinal variables, and two-sample t-tests for approximately 
continuous variables. 
6.4 
Sample Size Review 
Estimates of variance components and censoring and drop-out rates required for sample size 
calculation will be reviewed periodically using blinded data. No formal sample size re-estimation 
is proposed. 
6.5 
Interim Analysis 
Interim analyses for efficacy or futility will be performed by the unblinded statistician using an 
information-based group-sequential design. Interim analyses will be performed after approximately 
2000 and 5000 person-months of period 1 follow-up are completed, roughly one-third and three-
quarters of total anticipated period 1 follow-up. Non-binding early stopping for efficacy will be 
proposed if the active treatment group is superior to placebo for the primary efficacy outcome 
based on a one-sided p-value of 0.001 or less. Other criteria used in deciding whether to stop 
early for efficacy will include evaluation of safety and secondary efficacy outcomes. We propose 
stringent early stopping criteria for efficacy in order to ensure that evidence for efficacy is 
unambiguous if the study is stopped early. Non-binding early stopping for futility will be 
proposed based on a beta-spending rule quadratic in information time. If there were no benefit 
from treatment, then the trial would have a 51% probability of early stopping for futility based 
on this rule. As with the efficacy evaluation, the decision to stop early for futility will also 
include evaluation of feasibility, safety, and secondary efficacy outcomes. Because the efficacy 
and futility stopping rules are non-binding, we conservatively assume that each look is 
cumulative for alpha and ignore possible findings of futility when calculating the overall type I 
error. 


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6.6 
Efficacy Analysis 
6.6.1 Primary Analysis of the Primary Efficacy Endpoint 
The primary analysis of the primary efficacy endpoint will estimate the effectiveness to slow PD 
disease progression of oral inosine titrated to achieve serum urate in the range 7.1 to 8.0 mg/dL. 
The analysis will use the ITT sample to estimate of rate of change of MDS-UPDRS I-III total 
scores during period 1 in a random slopes model with shared baseline, censoring observations 
made subsequent to initiation of dopaminergic therapy. The model will include fixed terms for 
time, treatment x time, and sex, baseline MAO-B inhibitor use, baseline Schwab and England 
ADL score, and their interactions with time and random site- and participant-specific intercepts 
and slopes, each with unstructured covariance. Use of a shared baseline adjusts for baseline 
MDS-UPDRS score14,15 in addition to the adjustment for sex, baseline MAO-B inhibitor use, and 
baseline modified Schwab and England ADL score. Inference of benefit from serum urate 
elevation will be made by testing whether the treatment x time interaction term is significantly 
less than zero (i.e., slower progression among subjects randomized to the active arm) using a 
two-sided test at p < 0.046 for a cumulative two-sided alpha = 0.05. 
This estimate of the effectiveness of serum urate elevation on MDS-UPDRS will be unbiased if 
observed trajectories are predictive of MDS-UPDRS assessments that are missing due to loss to 
follow-up or are censored due to initiation of dopaminergic therapy. Data from the SURE-PD 
trial suggest good conformance of UPDRS I-III total score trajectories to the model assumptions. 
No non-linearity in treatment effects on observed UPDRS scores was found and models that 
included quadratic random effects fit worse by Akaike and Bayesian information criteria. 
Empirical Bayes estimates of 24-month UPDRS scores assuming linear trajectories were all 
within range of the instrument (range 7.4 to 97.4) even with 85% of the sample being censored 
prior to the final 24-month observation (median 12 months). Conditional residuals were normally 
distributed and homoscedastic. Similar assessments and influence statistics will be evaluated in 
judging the adequacy of the proposed primary analysis in this trial. 
6.6.2 Secondary Analyses of the Primary Efficacy Endpoint 
Several secondary analyses will be investigated to assess sensitivity of our estimates of treatment 
effect to alternative modeling assumptions. 
• Shared-baseline repeated-measures model: The fixed effects of time and its interactions will 
be replaced by visit-specific fixed effects. The interaction between fixed effects for treatment 
group and visit will be restricted to post-baseline visits by including a numeric indicator 
variable (0 pre-treatment, 1 post-treatment) in the interaction. The participant-specific 
random intercepts and slopes will be replaced with participant-level unstructured covariance 
among repeated measures. 
• AT sample by treatment group: The primary efficacy model and the secondary repeated-
measures model will be applied to the AT sample, replacing the treatment group as 
randomized by the treatment actually received. 
• AT sample by serum urate achieved: The primary efficacy model and the secondary 
repeated-measures model will be applied to the AT sample, replacing the treatment group as 
randomized by the average post-baseline serum urate level achieved. 


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• AT sample by change in serum urate: The primary efficacy model and the secondary 
repeated-measures model will be applied to the AT sample, replacing the treatment group as 
randomized by the change from average pre-treatment to average post-baseline serum urate 
level achieved. 
• AT sample by average daily inosine capsule count: The primary efficacy model and the 
secondary repeated-measures model will be applied to the AT sample, replacing the 
treatment group as randomized by the daily inosine treatment actually received. 
• AT sample excluding participants who initiated dopaminergic therapy by their 12-week 
(V03) visit: The primary efficacy model and the secondary repeated-measures model will be 
applied to the subset of the AT sample who initiated dopaminergic therapy by their 12-week 
visit (V03). 
• LEDD-adjusted analysis: The primary efficacy model, the secondary repeated-measures 
model, and the secondary analyses of the AT sample listed above will be augmented by 
including observations after initiation of dopaminergic medication and adjusting for time-
dependent LEDD. 
6.6.3 Secondary Efficacy Endpoints 
Continuous secondary efficacy endpoints will all be analyzed using the ITT and AT samples and 
the primary and secondary efficacy analysis described above. Variables that are strongly right-
skewed will be log-transformed prior to analysis, and estimates will be back-transformed for 
reporting. 
The binary indicator of orthostatic hypotension will be analyzed in an equivalent generalized 
mixed model treating the indicator variable as a Bernoulli random variable with logit link. 
6.6.4 Disability Warranting Dopaminergic Therapy 
Treatment differences in time to disability warranting dopaminergic therapy during period 1 will 
be tested by a Kaplan-Meier logrank test with a two-sided alpha = 0.05. Participants lost to 
follow-up will be censored. Note that subjects will continue to be followed even if they 
discontinue study drug. 
The following secondary analyses of time to disability warranting dopaminergic therapy will be 
pursued: 
• Subjects lost to follow-up will be classified as initiating dopaminergic therapy at the time 
of their withdrawal. 
• Cox regression will be used to compare treatments with adjustment for baseline modified 
Schwab and England ADL score. 
6.6.5 Combined Function and Treatment 
A rank-based test of a single outcome combining function as measured by change in MDS-
UPDRS I-III total scores and time to disability warranting dopaminergic therapy will be 
constructed paralleling the Combined Assessment of Function and Survival (CAFS) score 
methodology developed for ALS.17 MDS-UPDRS I-III total scores will substitute for ALSFRS-R 
total scores and time to disability warranting dopaminergic therapy will substitute for time to 
mortality. The test consists of calculating a rank-sum score for each individual relative to pair-


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wise comparisons with all other subjects. Subjects are ranked according to time to disability 
warranting dopaminergic therapy when that is observed for both members of a pair or when one 
is censored after the observed event time for the other. Pairs that cannot be ranked by time to 
disability warranting dopaminergic therapy are ranked by absolute change from baseline in 
MDS-UPDRS I-III total score at the maximum follow-up time at which both subjects have an 
observation. Inference is drawn by calculating a U-statistic from the rank-sum scores.  
6.6.6 Subgroup Analyses 
The following subgroups will be considered: sex, race (classified as Asian, Black or African 
American, Caucasian, or other, including multiracial; or as Caucasian vs. non-Caucasian if fewer 
than 10% of our sample is non-Caucasian), ethnicity (classified as Hispanic or Latino vs. non-
Hispanic), use of MAO-B inhibitors at baseline, and age (both categorized as <65 years vs. ≥65 
years and continuous). For each subgroup, the potential for differential benefit from serum urate 
elevation will be tested by including subgroup, subgroup x time, and subgroup x time x treatment 
interaction terms into the primary random-slopes model. A significant subgroup x time x 
treatment 3-way interaction in combination with significantly slower progression among 
members of a subgroup randomized to serum urate elevation vs. members of the same subgroup 
randomized to placebo will be taken as evidence of differential benefit. For sex, we will also test 
for sex-specific effects in selected secondary analyses of efficacy, disability warranting 
dopaminergic therapy, and symptomatic effects and in safety analyses related to kidney stone 
risk. For safety analyses, we will also summarize and compare eligible vs. the few ineligible 
participants in the ST sample. 
6.6.7 Pharmacogenetics 
The above listed and any subsequently designated genetic variants will be tested as potential 
modifiers of treatment effect. For each genetic variant, the potential for differential benefit from 
serum urate elevation will be tested by including genotype, genotype x time, and genotype x time 
x treatment interaction terms into the primary random-slopes model. A significant genotype x 
time x treatment 3-way interaction in combination with significantly slower progression among 
members of a genotype randomized to serum urate elevation vs. participants with the same 
genotype randomized to placebo will be taken as evidence of differential benefit. 
6.6.8 Symptomatic Effects 
The presence of symptomatic effects will be tested using a change-point model constructed as a 
partial linear spline over time with knots at 12 weeks and 24 months. Both fixed and subject-
specific random terms for intercept, slope from baseline to 12 weeks, slope from 12 weeks to 24 
months, and slope from 24 to 27 months (or from V10-equivalent visit on study drug to SV) will 
be included. Unstructured covariance will be assumed among the random effects (10 terms). The 
AT sample will be analyzed. Significantly smaller slopes during wash-in or larger slopes during 
wash-out among subjects treated with inosine using one-sided testing at alpha = 0.025 will be 
interpreted as symptomatic effects. If symptomatic effects are not found on that basis, the 
absence of symptomatic effects will be judged based on a non-inferiority test using a non-
inferiority bound of 6.3 / 3 = 2.1 points/month in the direction of a symptomatic effect and using 
one-sided testing at alpha = 0.05.  


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6.6.9 Disease Modification 
A three-part test of time to disability warranting dopaminergic therapy will be used to evaluate 
whether serum urate elevation is disease-modifying18-20. Inference of disease modification would 
be supported if (a) a Kaplan-Meier logrank test of time to disability warranting dopaminergic 
therapy during period 1 favors serum urate elevation, (b) the proportion of subjects who 
developed disability warranting dopaminergic therapy remains significantly lower among those 
randomized to serum urate elevation vs. placebo at the end of period 2 by Chi-square test, and (c) 
the time-dependent hazard ratio for time to disability warranting dopaminergic therapy during 
period 2 is non-inferior to a rate that would lead to equivalence to placebo by 3 months by Cox 
regression. Inference from each of the three component tests will be evaluated sequentially. 
Difference in time to disability warranting dopaminergic therapy will be evaluated first. If 
significant by logrank test with two-tailed alpha = 0.05, then the proportion not yet requiring 
dopaminergic therapy at the end of period 2 will be tested second. If significant by Chi-square 
test with two-tailed alpha = 0.05, then non-inferiority of the time-dependent hazard ratio will be 
tested by Cox regression based on a one-tailed test at alpha = 0.05.  
6.6.10 Multiplicity Adjustments 
With two interim efficacy analyses each testing for benefit of serum urate elevation at a one-
sided p < 0.001, the final primary analysis tested using a two-sided p < 0.046 ensures that the 
overall type I error rate is under 5%. Results from analysis of secondary efficacy endpoints and 
subgroup analyses will report nominal, comparison-wise p-values, recognizing that the totality of 
results will be evaluated in judging the potential efficacy of serum urate elevation. 
6.6.11 Missing Data 
Baseline values for efficacy endpoints will be determined from the last non-missing data 
collected prior to the first dose of study medication. The planned mixed model yields estimates 
that are unbiased conditional on the observed scores under a missing at random assumption. In 
addition, a secondary analysis of the primary endpoint will use placebo-based multiple 
imputation of missing data. Additional sensitivity analyses may be pursued to impute missing 
values or otherwise construct models for unobserved outcomes if more than 20% of participants 
are missing follow-up data for any reason. 
6.7 
Safety and Tolerability Analysis 
6.7.1 Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by the number of events of a given classification 
experienced by participants in each treatment group and by the number and proportion of 
participants experiencing such an event in each treatment group in the ST sample. TEAEs will be 
summarized in aggregate across all MedDRA terms and separately by MedDRA system organ 
class and preferred term. 
Aggregate summaries of TEAE grade will include characteristics of: (a) seriousness, (b) severity, 
(c) relatedness to study drug, (d) action taken with study drug, (e) action taken with study 
procedure, and (f) outcome. For each level of a given TEAE characteristic, summaries will 
include the number of events of a given classification and by the number and proportion of 
participants for which that level of a characteristic was the worst they experienced (treating any 
unknown characteristic as not worst).  


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6.7.2 Safety Labs 
The absolute level and the absolute change from baseline for each safety laboratory assay will be 
summarized as means, standard deviations, medians, and ranges at each visit by treatment group. 
The proportion of participants with safety lab levels below the lower limit of normal or above the 
upper limit of normal will be summarized by treatment group by visit and at any post-baseline 
visit. 
6.7.3 Vital Signs 
The absolute level and the absolute change from baseline for vital signs will be summarized as 
means, standard deviations, medians, and ranges at each visit by treatment group. 
6.7.4 Additional Continuous Safety Outcomes 
The additional continuous safety outcomes of weight, ECG parameters, and their absolute 
change from baseline will be summarized as means, standard deviations, medians, and ranges at 
each visit by treatment group and tested for group differences in linear mixed models. 
6.7.5 Tolerability 
Participants will be classified as tolerant, intolerant, or censored with subjects lost to follow-up 
or withdrawing consent prior to administrative termination classified as intolerant. Tolerability 
will then be estimated from Kaplan-Meier product-limit methods with complementary log-log 
confidence bounds at 12 weeks, 12 months, and 24 months. Serum urate elevation will be 
declared tolerable at each time point if its one-sided lower 95% confidence bound is greater than 
50%. We will explore the relationship between tolerance and use of dopaminergic therapy using 
Cox regression with use of dopaminergic therapy as a time-dependent covariate. 
6.7.6 Alkalinization and Nephrolithiasis 
The frequency of persistent acidic urine will be summarized by treatment group and tested by 
Fisher's exact test in the ST sample. The efficacy of the alkalinization protocol to increase urine 
pH will be summarized overall in the ST sample. The frequency of nephrolithiasis and the 
absolute rate of nephrolithiasis per time exposed to study drug will be summarized by treatment 
group. Risk factors for nephrolithiasis will be tested in a binary generalized linear model with log 
link and with log time on study drug as an offset. The following risk factors will be tested in a 
multivariable model:  
• age,  
• sex,  
• treatment,  
• uric acid excretion fraction at baseline estimated from serum urate and 24-hr urine urate,  
• uric acid crystals/hpf prior to first nephrolithiasis 
o in most recent urinalysis,  
o average in post-randomization urinalyses,  
o maximum in any urinalysis,  
• urine specific gravity prior to first nephrolithiasis 
o in most recent urinalysis,  
o average in all urinalyses,  
o maximum in any urinalysis,  
• urine pH prior to first nephrolithiasis 


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o in most recent urinalysis,  
o average in all urinalyses, and  
o minimum in any urinalysis. 
6.8 
Other Analyses 
6.8.1 Participant Disposition 
The number of participants who were screened, randomized, completed scheduled follow up, and 
prematurely withdrew study participation will be summarized overall and by treatment group. 
Reasons for screen failure and for withdrawal from study will be presented. 
6.8.2 Study Drug Exposure 
The number of capsules of study drug prescribed will be summarized by visit and treatment 
group. Total study drug exposure will be calculated and will be summarized by treatment group. 
Compliance with study drug will be calculated as the number of doses taken divided by the 
scheduled number of doses taken prior to permanent discontinuation, expressed as a percentage. 
6.8.3 Prior and Concomitant Medication Use 
Concomitant medications taken during the study period will be listed for each participant, coded 
using the World Health Organization Drug Dictionary Enhanced. The percentage of participants 
taking each class of medication will be summarized overall and by treatment group. 
6.8.4 Determinants of change in MDS-UPDRS 
Potential determinants of change in MDS-UPDRS will be tested to assess their relationship to 
PD progression independent of serum urate elevation. This may motivate further adjustment of 
the primary model as additional secondary analyses and may also assist in the design of future 
trial. In addition to those noted above in 6.6.1, we will test the following: 
• Prodromal PD features, either individually or as an index 
o Positive RBD screen at SC1 or BL 
 RBD characterization: At SC1, do those who are RBD-positive vs 
negative (2 vs. 1 on Q1 of RBD Sleep Question) have higher age- and sex-
adjusted serum urate? 
o Positive hyposmia screen: Response of 1 on Q9a of the PD Risk Factor 
Questionnaire 
 Hyposmia characterization: Do hyposmics (1 on Q9a vs. 0 on Q9) have 
lower age- and sex- adjusted BMI at SC2? 
o Positive constipation screen: Response of >2 on Q1.11 of MDS-UPDRS at SC2 or 
daily (non-prn) laxative use on concomitant medication log at SC2 
 Constipation characterization: Do those who are positive by this 
moderately stringent criterion have a: 
• Lower current, vigorous physical activity score (Q3 on PD Risk 
Factor Questionnaire; among those selecting response 1-4)? 


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• Lower caffeine intake (Q3-4 on Smoking, Alcohol and Caffeine 
Status) 
o SURE-PD3 prodromal PD Index (range 0, 1, 2 or 3) with simple sum values for 
presence (= 1) for each of above three features.  
6.8.5 Determinants of Early Disability Warranting Dopaminergic Therapy 
An earlier, mid-study effort to identify determinants of need for dopaminergic therapy occurring 
prematurely (by the 12-week visit) was prompted by a higher than expected rate of these events 
and a concern that it would reduce study power to meet its primary analysis objective.  Modified 
Schwab and England ADL score at screening was identified as a significant predictor, and site 
staff were advised to keep in mind that a Modified Schwab and England ADL score below 90% 
was predictive of premature need for dopaminergic therapy, the expectation of which is an 
exclusionary criterion. Because this clinical eligibility criterion is common in PD trials of 
candidate neuroprotectants, a fuller assessment of predictors would be valuable.  
The following potential determinants of Early Disability Warranting Dopaminergic Therapy will 
be tested: Modified Schwab and England ADL score, time between symptom onset or diagnosis 
and baseline visit, having taken dopaminergic medication (other than an MAO-B inhibitor) prior 
to screening, being on a stable dosage of an MAO-B inhibitor at baseline, baseline MDS-UPDRS 
Part I-III total score, DaTscanTM SBR, expectation of improvement on inosine (on Expectancy 
Questionnaire), baseline Neuro-QOL Depression score, and baseline MoCA score. 
6.8.6 Placebo Response 
The frequency of a placebo-associated improvement in activities of daily living (ADL) and 
motor symptoms as measured by the MDS-UPDRS Parts IB and II and Part III, respectively, will 
be summarized among all placebo arm participants, by visit, and by site. Following Goetz et al. 
2000, we will define placebo-associated improvement as a reduction in the ADL or motor score 
of at least 50% or an improvement from baseline of two or more points on at least two different 
items of the respective MDS-UPDRS scale. Stability of the rates of placebo-associated 
improvements will be tested across visits using mixed model logistic regression with fixed 
effects of visit and random participant-specific intercepts. The following predictors of placebo-
associated improvement at any visit will be tested by logistic regression:  
• age at baseline (less than 65 years versus greater or equal to 65 years),  
• disease duration at baseline (less than 2 years vs. greater or equal to 2 years),  
• disease severity at baseline (modified Hoehn and Yahr Stages 1 and 1.5 vs. 2 and 2.5), 
• number of years education (Q1 on Socio-Economics form) 
• daily caffeine intake: lower vs higher (Q3 + 0.3xQ4 from Smoking, Alcohol and Caffeine 
form)  
• expectation of inosine: “A lot better” vs “Somewhat better” vs “No change” or worse (Q2 
on PD-Expectancy questionnaire) 
• expectation of inosine-placebo difference:  >/=2 vs <2 units more favorable for inosine 
(Q2 - Q1 on PD-Expectancy questionnaire) 
• preference for inosine: “strong” vs other (Q3 on PD-Expectancy questionnaire) 
• treatment belief: placebo vs inosine (Q2 on Blindedness Questionnaire). 
 


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6.8.7 Blindedness 
Descriptive stats will be summarized for responses on the early and late administrations of the 
Blindedness Questionnaire and the change between them. The following predictors of treatment 
assignment belief reported on the Blindedness Questionnaire will be tested by logistic regression. 
For belief of inosine assignment (stratified by correct and incorrect): 
• age at baseline (categorized as <65 years vs. ≥65 years) 
• sex 
• treatment assignment 
• MDS-UPDRS I-III censored change at wash-in (per 6.6.8) for response at the 6-week 
(V02) administration 
• MDS-UPDRS I-III censored change to ~24-mo/V10 for response at the ~24-mo/V10 
administration 
• history of preceding nephro-lithiasis TEAE 
• history of preceding gout, gout-like or other arthritic TEAE 
• average preceding daily number study drug capsules 
• expectation of inosine: “A lot better” vs “Somewhat better” vs “No change” or worse (Q2 
on PD-Expectancy questionnaire), 
• expectation of inosine-placebo difference:  >/=2 vs <2 units more favorable for inosine 
(Q2 - Q1 on PD-Expectancy questionnaire) 
• preference for inosine: “strong” vs other (Q3 on PD-Expectancy questionnaire). 
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