Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS Inosine Uric acid Urate Glutathione Biomarker Oxidative stress Oxidative damage
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

Brief summary:
This is a multi-center, 20-week study of inosine treatment.

Study Objectives and Endpoints The primary objective of the study is to determine the safety and tolerability of oral administration of inosine (administered daily) dosed to moderately elevate serum urate over 20 weeks.

The primary outcome measures will be

1. Safety, as measured by adverse events
2. Tolerability, defined as the ability of subjects to complete the entire 20-week study.

As an exploratory objective, we will test the feasibility and utility of a smartphone application for monitoring symptoms and disease progression in patients with amyotrophic lateral sclerosis (ALS).

Detailed description:
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease for which there is no cure. Multiple lines of evidence have implicated oxidative stress in the pathophysiology of ALS. Urate (uric acid) is an endogenous antioxidant system, and urate may serve as a major defense against oxidative stress. Urate has emerged as a promising neuro-protectant and therapeutic target based on convergent epidemiological, laboratory, and clinical data in multiple neurodegenerative diseases, most notably Parkinson's disease (PD). In PD, urate elevation has been pursued as a potential therapy by administration of inosine, a urate precursor that is available as an over-the-counter supplement. Administration of inosine results in a predictable elevation of urate levels and has been shown to be safe and well tolerated in PD.

Analysis of ALS databases revealed that higher urate levels are an independent predictor of slower progression and prolonged survival in ALS. However, whether elevating urate in people with ALS would result in better outcomes is unknown.

The Principal Investigator has recently concluded a Pilot Study of Inosine in ALS, which was a short, open label, single center study involving 25 subjects \[NCT02288091\]. The study assessed safety and feasibility of urate elevation in patients with ALS. The Principal Investigator is now pursuing a multi-center Phase II trial to assess the findings of the open label study with longer exposure time.

Arms:
arm 1: Subjects will be administered oral inosine daily. The dose of inosine will be titrated to obtain serum urate levels of 7 - 8 mg/dL. arm 2: Subjects will be administered oral placebo daily. The dose of placebo will be titrated to obtain serum urate levels of 7 - 8 mg/dL.

Interventions: intervention 1: Inosine intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL. intervention 2: Subjects on placebo will receive 1-6 capsules a day of 500 mg placebo (sugar pill) titrated to target urate levels of 7 - 8 mg/dL.

Protocol document:
Prot_SAP_000.pdf: 
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Safety of Urate Elevation in ALS – Phase II (SURE-ALS2) 
 
Regulatory Sponsor: 
Sabrina Paganoni, MD, PhD 
Massachusetts General Hospital  
Neurological Clinical Research Institute (NCRI) 
165 Cambridge St, Suite 600 
Boston, MA 02114 
 
Funding Sponsor: 
 
 
The Salah Foundation 
MGH cure ALS Fund 
Study Product: 
Inosine 
Draft or Version Number: 
V3.0 
 
 
July 1, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.  
 


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SITE INVESTIGATOR AGREEMENT 
Protocol #: Version 3.0 
July 1, 2019 
IND #124,653 
 
Title: Safety of Urate Elevation in ALS – Phase II (SURE-ALS2) 
 
 
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 subjects 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.  
 
Print Site Name:   ______________________________________________________ 
 
Print Site Investigator Name: ____________________________________________ 
 
Site Investigator Signature:   _____________________________ Date: __________ 
 
 
 


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TABLE OF CONTENTS 
SITE INVESTIGATOR AGREEMENT ······················································································ 
2 
LIST OF ABBREVIATIONS ···································································································· 
6 
PROTOCOL SUMMARY ······································································································· 
8 
SCHEDULE OF ACTIVITES ·································································································
 10 
STUDY WORKFLOW ········································································································· 
12 
1 
ETHICS/PROTECTION OF HUMAN SUBJECTS ······························································· 
13 
1.1 
INSTITUTIONAL REVIEW BOARD (IRB) ....................................................................................................... 13 
1.2 
ETHICAL CONDUCT OF STUDY ..................................................................................................................... 13 
1.3 
SUBJECT INFORMATION AND CONSENT ....................................................................................................... 13 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ·············· 
14 
2.1 
BACKGROUND INFORMATION ...................................................................................................................... 14 
2.1.1 
Clinical Features and Epidemiology of ALS ········································································ 
14 
2.1.2 
Role of oxidative stress in ALS Pathogenesis ······································································· 
14 
2.2 
RATIONALE FOR CHOOSING INOSINE FOR ALS ........................................................................................... 15 
2.2.1  Urate as neuroprotective agent: epidemiological evidence ··························································· 
16 
2.2.2 Urate as neuroprotective agent: biological evidence ··································································· 
17 
2.2.3 Urate as neuroprotective agent: early clinical trial evidence ························································· 
18 
2.2.4 Biomarkers of oxidative stress and damage ·············································································· 
19 
2.3 
INOSINE ......................................................................................................................................................... 20 
2.3.1 
Potential Risks and Benefits ···························································································· 
20 
3 
OBJECTIVES ············································································································· 
24 
3.1 
STUDY OBJECTIVES ...................................................................................................................................... 24 
3.2 
STUDY OUTCOME MEASURES ...................................................................................................................... 24 
4 
STUDY DESIGN ·········································································································· 
25 
4.1 
OVERALL STUDY DESIGN AND PLAN ........................................................................................................... 25 
4.2 
STUDY CENTERS ........................................................................................................................................... 25 
4.3 
STUDY DURATION ......................................................................................................................................... 25 
4.4 
PROTOCOL ADHERENCE .............................................................................................................................. 25 
5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION ············································ 
26 
5.1 
NUMBER OF STUDY SUBJECTS...................................................................................................................... 26 
5.2 
INCLUSION AND EXCLUSION CRITERIA ....................................................................................................... 26 
5.2.1 
Inclusion Criteria ········································································································· 
26 
5.2.2 
Subject Exclusion Criteria······························································································ 
27 
5.3 
WITHDRAWAL .............................................................................................................................................. 27 
5.3.1 
Handling of Withdrawals ······························································································· 
27 
5.3.2 
Termination of Study ···································································································· 
28 
6 
TREATMENTS ADMINISTERED ··················································································· 
29 


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6.1 
TREATMENTS ................................................................................................................................................ 29 
6.1.1 
Study Product Description ····························································································· 
29 
6.1.2 
Treatments administered ······························································································· 
29 
6.2 
RECEIVING, STORAGE, DISPENSING ............................................................................................................ 30 
6.2.1 
Receipt of Drug Supply ································································································· 
30 
6.2.2 
Storage ······················································································································ 
31 
6.3 
MODIFICATION OF STUDY INTERVENTION/INVESTIGATIONAL PRODUCT FOR A SUBJECT ....................... 31 
6.3.1 Precautionary suspensions ··································································································· 
31 
6.3.2. 
Dosage Discontinuation ································································································· 
31 
6.4 
ACCOUNTABILITY PROCEDURES ................................................................................................................. 32 
6.5 
PRIOR AND CONCOMITANT THERAPY ......................................................................................................... 32 
6.5.1 
Prohibited Medications and Contraindications ···································································· 
32 
7 
STUDY SCHEDULE ····································································································· 
33 
7.1 
SCREENING VISIT ......................................................................................................................................... 33 
7.1.1 
Screen Failures ············································································································ 
33 
7.2 
BASELINE VISIT ............................................................................................................................................ 34 
7.3 
PHONE CALLS ............................................................................................................................................... 34 
7.4 
WEEK 12 VISIT ............................................................................................................................................. 35 
7.5 
WEEK 20 VISIT ............................................................................................................................................. 35 
7.6 
WEEK 24 PHONE CALL ................................................................................................................................ 35 
7.7 
FINAL SAFETY VISIT..................................................................................................................................... 36 
7.8 
PROTOCOL DEVIATIONS............................................................................................................................... 36 
7.8.1 
Missed Visits and Procedures ·························································································· 
36 
7.9 
RECORDING DEATHS .................................................................................................................................... 37 
8 
CLINICAL ASSESSMENTS AND OUTCOME MEASURES ·················································· 
38 
8.1 
CLINICAL VARIABLES .................................................................................................................................. 38 
8.1.1 
Vital Signs, Height & Weight ·························································································· 
38 
8.1.2 
Clinical Laboratory Assessments ····················································································· 
38 
8.1.3 
Physical Examination ···································································································· 
39 
8.1.4 
Neurological Examination ······························································································ 
39 
8.1.5 
Adverse Events ············································································································ 
39 
8.1.6 
ALSFRS-R ················································································································· 
39 
8.1.7 
Pulmonary Function Testing ··························································································· 
39 
8.1.8  
C-SSRS ····················································································································· 
40 
9 
SAFETY AND ADVERSE EVENTS ················································································· 
41 
9.1 
DEFINITIONS OF AES, SUSPECTED ADVERSE DRUG REACTIONS & SAES ................................................. 41 
9.1.1 
Adverse Event and Suspected Adverse Drug Reactions ·························································· 
41 
9.1.2 
Serious Adverse Events ································································································· 
42 
9.2 
ASSESSMENT AND RECORDING OF ADVERSE EVENTS................................................................................. 43 
9.2.1 
Assessment of Adverse Events ························································································· 
43 
9.2.2 
Relatedness of Adverse Event to Investigational Product························································ 
44 
9.2.3 
Recording of Adverse Events ·························································································· 
44 
9.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS - REPORTABLE EVENTS ............................................ 45 
9.4  KNOWN ADVERSE EVENT/ EXPERIENCE PROPHYLAXIS PLAN ................................................................... 45 
9.4.1   Alkalinization Protocol······································································································ 
46 
9.4.2   Lab Monitoring during Alkalinization Protocol ······································································· 
48 


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10 
SAFETY MONITORING AND STATISTICAL ANALYSIS PLAN ·········································· 
50 
10.1 SAFETY MONITORING .................................................................................................................................. 50 
10.2 STATISTICAL CONSIDERATIONS ................................................................................................................... 50 
10.2.1 Analysis Samples ············································································································· 
50 
10.2.2 Outcomes ······················································································································ 
51 
10.2.2.1 Safety outcomes ············································································································ 
51 
10.2.2.2 Tolerability ·················································································································· 
51 
10.2.2.3 Efficacy and target engagement ························································································ 
51 
10.2.2. Operational endpoints ······································································································ 
51 
10.2.2.5 Power Calculations ········································································································ 
52 
11 
DATA COLLECTION ··································································································· 
53 
11.1 ROLE OF DATA MANAGEMENT .................................................................................................................... 53 
11.1.1 
Data Entry and Checks ································································································· 
53 
11.1.2 
Data Lock Process ········································································································ 
53 
11.1.3 
Quality Assurance ········································································································ 
53 
11.1.3 
Data handling and record keeping ···················································································· 
54 
11.2 CONFIDENTIALITY ........................................................................................................................................ 54 
11.3 STUDY DISCONTINUATION ........................................................................................................................... 54 
11.4 RETENTION OF RECORDS ............................................................................................................................. 55 
11.5 PUBLICATIONS .............................................................................................................................................. 55 
12 
LITERATURE REFERENCES························································································ 
56 
13 
APPENDICES ············································································································· 
60 
13.1 APPENDIX I: EL ESCORIAL WORLD FEDERATION OF NEUROLOGY CRITERIA FOR THE DIAGNOSIS OF ALS
 
60 
13.2 APPENDIX II: ALS FUNCTIONAL RATING SCALE – REVISED (ALSFRS-R) ................................................ 62 
13.3 APPENDIX III: COLUMBIA-SUICIDE SEVERITY RATING SCALE - BASELINE ............................................... 65 
13.4 APPENDIX IV: COLUMBIA-SUICIDE SEVERITY RATING SCALE – SINCE LAST VISIT .................................. 69 
13.5 APPENDIX X: SMARTPHONE USAGE QUESTIONNAIRE .................................................................................. 73 
13.6 APPENDIX XI EXIT QUESTIONNAIRE: STUDY PARTICIPANT .......................................................................... 74 
13.7 APPENDIX XII EXIT QUESTIONNAIRE: SITE INVESTIGATOR ........................................................................ 75 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised 
CFR 
Code of Federal Regulations 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
Diastolic Blood Pressure 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FRAP 
Ferric Reducing Antioxidant Power 
FWA 
Federal-wide Assurance 
GCP 
Good Clinical Practice 
GSH 
Glutathione 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
KO 
Knockout 
MOP 
Manual of Procedures 
MS 
Multiple Sclerosis 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
Nrf2 
Nuclear factor erythroid 2–related factor 2 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PD 
Parkinson’s disease 
PHI 
Protected Health Information 
PI 
Principal Investigator 


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QA 
Quality Assurance 
QC 
Quality Control 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SBP 
Systolic Blood Pressure 
SI 
Site Investigator 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
UOx 
Urate Oxidase 
US 
United States 
VC 
Vital Capacity 
WOCBP 
Women of Childbearing Potential 


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PROTOCOL SUMMARY 
Study Title 
SAFETY OF URATE ELEVATION IN ALS – PHASE II (SURE-ALS2) 
 
Version Number 
3.0 
 
Study Indication 
Amyotrophic Lateral Sclerosis (ALS) 
 
Phase of Development 
2 
 
Rationale for the Study 
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease for which there is no cure.  
Multiple lines of evidence have implicated oxidative stress in the pathophysiology of ALS.  Urate 
(uric acid) is an endogenous antioxidant system, and urate may serve as a major defense against 
oxidative stress.  Urate has emerged as a promising neuro-protectant and therapeutic target based on 
convergent epidemiological, laboratory, and clinical data in multiple neurodegenerative diseases, 
most notably Parkinson’s disease (PD).  In PD, urate elevation has been pursued as a potential 
therapy by administration of inosine, a urate precursor that is available as an over-the-counter 
supplement.  Administration of inosine results in a predictable elevation of urate levels and has been 
shown to be safe and well tolerated in PD.   
 
Analysis of ALS databases revealed that higher urate levels are an independent predictor of slower 
progression and prolonged survival in ALS.  However, whether elevating urate in people with ALS 
would result in better outcomes is unknown.   
 
We have recently concluded a Pilot Study of Inosine in ALS, which was a short, open label, single 
center study involving 25 subjects. The study showed safety and feasibility of urate elevation in 
patients with ALS. We are now pursuing a multi-center Phase II trial to confirm these findings with 
longer exposure time.  
 
Study Design 
This is a multi-center, 20-week study of inosine treatment. 
 
 


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Study Objectives and Endpoints  
The primary objective of the study is to determine the safety and tolerability of oral administration of 
inosine (administered daily) dosed to moderately elevate serum urate over 20 weeks.  
 
The primary outcome measures will be  
1- safety, as measured by adverse events 
2- tolerability, defined as the ability of subjects to complete the entire 20-week study. 
 
As an exploratory objective, we will test the feasibility and utility of a smartphone application for 
monitoring symptoms and disease progression in patients with ALS.  
 
Study Location 
Up to Three (3) Northeast ALS Consortium (NEALS) Centers in the United States 
 
Number of Planned Subjects 
It is expected that approximately 60 subjects will be consented and 30 subjects will be treated in the 
study. 
 
Study Population 
This study will be conducted in subjects who meet the El Escorial criteria of possible, laboratory-
supported probable, probable, or definite criteria for a diagnosis of ALS.  At screening, eligible 
subjects must be at least 18 years old and must provide written informed consent prior to screening. 
Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at 
screening are eligible for inclusion as long as they meet specific protocol requirements.  Detailed 
criteria are described in the body of the protocol. 
 
Treatment Plan 
Subjects will be administered oral inosine daily.  The dose of inosine will be titrated to obtain serum 
urate levels of 7 - 8 mg/dL.   
 
Duration of Treatment and Follow-up 
Subjects will remain on treatment until the Week 20 visit.  Each subject will also have a Week 
24 Follow-up Telephone Interview to assess for adverse events (AEs), changes in concomitant 
medications and to administer the ALSFRS-R.


 
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SCHEDULE OF ACTIVITES  
Activity 
Screening 
Visit1 
Baseline  
Week 3, 6 and 
9 
Phone Call and 
Urate Test 
Week 12 
Week 16 
Phone Call and 
Urate Test 
Week 20 
 
Week 24 
Phone Call 
Final Safety Visit (for 
early study drug 
discontinuation only) 
Visit Names 
Visit 1 
Visit 2 
Visits 3, 4, and 
5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
 
Visit Window 
-21 days from Day 0 
Day 0 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
X 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
ALS Diagnosis History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
Neurological Exam 
X 
 
 
 
 
 
 
 
Vital Signs2/ Height & Weight3 
X 
 
 
X 
 
X 
 
X 
Screening Labs4 
X 
 
 
 
 
 
 
 
C-SSRS 
 
X 
 
X 
 
X 
 
X 
Uric acid level5 
 
X 
X 
X 
X 
X 
 
X 
Urine alkalinization protocol (if needed per protocol) 
 
X 
 
X 
 
 
 
 
Urinalysis6  
 
X 
 
X 
 
X 
 
X 
Basic Metabolic Panel 
X 
 
 
 
 
 
 
 
Safety Labs7 
 
X 
 
X 
 
X 
 
X 
ALSFRS-R8 
 
X 
 
X 
 
X 
X 
X 
Pulmonary Function Testing8 
X 
 
 
X 
 
X 
 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Review 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study Drug 
 
X 
 
X 
 
 
 
 
Drug Accountability 
 
 
 
X 
 
X 
 
X 
Exit Questionnaire 
 
 
 
 
 
X 
 
X 
Mobile app installation10 
 
X 
 
 
 
 
 
 
Mobile app un-installation10 
 
 
 
 
 
X 
 
X 
1 Screening procedures must be completed within 21 days prior to Baseline Visit. 
2 Vital signs include systolic and diastolic pressure in mmHg, respiratory rate/minute, heart rate/minute and temperature.   
3 Height measured at Screening Visit only. 
4 Screening labs include uric acid, urinalysis and Serum pregnancy test (WOCBP) and will be performed at local institution.  


 
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5 Uric acid level will be measured just before the first dose (Baseline visit) or just before scheduled morning dose (trough) (Weeks 3, 6, 9, 12, 16, 20) (Quest Diagnostics) 
6Urinalysis with sediment (Quest Diagnostics) 
7Safety labs include Hematology (CBC with differential), Basic Metabolic Panel, Liver Function Tests and will be performed at local institution.  
8Pulmonary Function Testing includes Slow Vital Capacity (SVC)  
9Adverse events that occur AFTER signing consent form will be recorded. 
10App installation and un-installation procedures include a brief survey about phone use 


 
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STUDY WORKFLOW
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
            
  
 
 
 
 
 
 
 
 
         
 
 
 
 
 
 
 
 
           
 
 
Screening Period 
On Active Treatment 
Washout Period 
~ 60 Screened 
15 Subjects on inosine (administered as 500 mg caps;  
1 to 6 caps a day; dose titrated to target urate levels of  
7 - 8 mg/dL). 
21 Days 
Subjects who discontinue from the study early will be asked to return to the study site for Final Safety assessments, and will be asked to have a final Follow-Up 
Telephone Call 28 days (+5 days) after taking their last dose of study drug. 
 
 
Screening 
Baseline 
Week 3 
Week 6 
Week 9 
Week 16 
Week 20  
Week 12 
Week 24 
15 Subjects on placebo (administered as 500 mg caps;  
1 to 6 caps a day; pseudo-titration will be performed to maintain blinding). 


 
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1 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
1.1 
Institutional Review Board (IRB) 
This study will be conducted in compliance with current Good Clinical Practices (GCP) and 
Title 21 Part 56 of the United States of America Code of Federal Regulations (CFR) relating to 
IRBs.  
1.2 
Ethical Conduct of Study 
The study will be conducted in accordance with GCP defined by the International Conference on 
Harmonization (ICH) and the ethical principles of the Declaration of Helsinki. 
1.3 
Subject Information and Consent 
This study will be conducted in compliance with Title 21 Part 50 of the United States of America 
Code of Federal Regulations (CFR), Federal Regulations and ICH Guidance Documents pertaining 
to informed consent.  At the first visit, prior to initiation of any study-related procedures, subjects 
will be informed about the nature and purpose of the study, participation/termination conditions, and 
risks and benefits. Subjects will be given adequate time to ask questions and become familiar with 
the study prior to providing consent to participate. Subject will give their written consent to 
participate in the study and will be provided with a copy of the fully executed consent form for their 
records. 


 
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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
2.1.1 Clinical Features and Epidemiology of ALS 
Amyotrophic lateral sclerosis (ALS) is a rare degenerative disorder of large motor neurons of the 
cerebral cortex, brain stem and spinal cord that results in progressive wasting and paralysis of 
voluntary muscles1. The incidence of ALS is currently approximately 2/100,0002. The lifetime ALS 
risk is 1 in 600 to 1 in 10002. Even though the incidence of ALS is similar to that of multiple 
sclerosis, the prevalence is only 4- 6/100,000 (about 25,000-30,000 subjects in the United States), 
due to the higher mortality rate. Fifty per-cent of ALS cases die within three years of onset of 
symptoms and 90% die within five years3. The median age of onset is 55 years3. The cause in most 
cases is unknown4. Age and male gender are the only risk factors repeatedly documented in 
epidemiological studies. No treatment prevents, halts or reverses the disease, although the use of 
riluzole (the only FDA-approved therapy for ALS) is associated with a slight prolongation of 
survival5. 
2.1.2 Role of oxidative stress in ALS Pathogenesis 
Despite decades of focused research, a unifying and well-tested theory of ALS disease 
pathophysiology remains enigmatic4. At the same time, the body of knowledge has expanded 
dramatically as research tools have improved. Research increasingly implicates oxidative stress as 
one of the major molecular mechanisms leading to neuronal death in ALS6.  
 
Oxidative stress has been implicated in the pathophysiology of ALS since the discovery that 
mutations in an antioxidant system, the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) 
gene, are associated with 20% of cases of familial ALS7, 8.  Identification of SOD1 as the first gene 
linked to ALS pathophysiology has enabled the development of animal models from which much of 
our understanding of the mechanisms of neurodegeneration in ALS has emerged.  These studies have 
shown that the neurodegenerative processes involved in this disease are diverse and complex 
including not only oxidative stress, but also excitotoxicity, mitochondrial dysfunction, defects in 
RNA processing, inflammation, protein aggregation, disruption of neurofilaments and intracellular 
trafficking along microtubules, as well as involvement of non-neuronal cells in the vicinity of motor 
neurons8, 9.  Nevertheless, oxidative stress, whether as a primary cause of disease or a secondary 
consequence, has been implicated in many of these processes and appears as a central mechanism by 
which motor neuron death occurs7.  


 
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Despite the compelling evidence supporting a pathogenic role of oxidative stress in ALS, the agents 
with antioxidant properties studied to date (such as CoQ10 and Vitamin E)10, 11 in randomized 
placebo-controlled clinical trials have failed to show benefits on disease progression.  This 
observation highlights the fact that it is important to include assessment of measures of target 
engagement in the study design of pilot, proof-of-concept studies of candidate compounds in order to 
demonstrate the intended biological effect in early studies prior to proceeding along the drug 
development process. 
2.2 
Rationale for choosing inosine for ALS 
Inosine is an intermediary metabolite of purine metabolism, is available as 
an over-the-counter oral supplement. Inosine is converted into urate, the 
anionic form of uric acid (Fig. 1).  
 
Urate may be one of our major endogenous defenses against oxidative 
stress.   As an apparent consequence of multiple independent mutations in 
the urate oxidase gene (UOx) during primate evolution12-14, urate 
circulates at high concentrations near the limits of its solubility 
(accounting for our susceptibility to gout) and constitutes the end product 
in the metabolism of purines in humans and apes (Fig. 1).  The 
demonstration that urate possesses antioxidant properties comparable to 
those of ascorbate13, 15 and accounts for most of the antioxidant capacity in 
human plasma16, 17, supports the hypothesis that our ancestors gained 
antioxidant benefits from UOx mutations and the resulting urate 
elevation18, 19.  
 
Interestingly, urate has been gaining momentum as a promising agent for neuroprotection based on 
rapidly accumulating epidemiological observations, laboratory data, and early clinical trial results in 
multiple neurologic diseases, most notably Parkinson disease (PD)20, 21.  These lines of evidence 
(summarized below) demonstrate the potential therapeutic significance of unraveling the molecular 
mechanisms of urate actions in the CNS and have already prompted clinical development of urate-
elevating strategies for PD21 and stroke22.   
 
 
 
 
 
Figure 1.  
Purine metabolism  


 
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2.2.1  Urate as neuroprotective agent: epidemiological evidence 
 
Urate is a strong molecular predictor for both reduced risk and 
favorable progression in PD.  A meta-analysis of prospective 
epidemiological data on urate and PD risk suggested a 20% 
reduction in the pooled rate ratio of PD for each 1.3 mg/dL 
increase in blood urate concentration23.  Further, PD disability 
progressed more slowly among early PD patients with higher 
urate levels at baseline (Fig. 2).  In the PRECEPT clinical 
trial, the risk of PD disability progressing to the need for 
dopaminergic therapy among those in the highest quintile of 
serum urate concentration was half that of the lowest 
quintile24.  Similarly, in the DATATOP clinical trial, risk of 
PD progression was reduced by 18% for each 1.5 mg/dL 
increase in serum urate concentration with a similar inverse 
correlation between cerebrospinal fluid (CSF) urate and 
progression25.   
 
Further epidemiological support to a potential pathogenic 
association between urate and PD is provided by studies 
showing that both dietary and genetic factors that affect urate 
levels modify susceptibility to PD. Thus, a higher dietary urate 
index was associated with a lower risk of PD (top quintile vs. 
bottom: relative risk = 0.47, p-trend = 0.0008), after 
adjustment for potential confounders26 and genetic variability in nine genes known to influence urate 
levels was found to be associated with PD risk27.  Higher urate levels have also been correlated with 
slower clinical progression in Huntington’s disease, multiple system atrophy, and mild cognitive 
impairment28-30 raising the hypothesis of a broad neuroprotective effect of urate in multiple CNS 
neuronal populations.   
 
Based on this convergence of data linking higher urate levels with improved outcomes in multiple 
neurodegenerative diseases, we examined ALS clinical trial data and found that urate levels are an 
independent predictor of progression and survival in ALS, where higher levels are associated with 
improved outcomes31 (Figure 3). In a clinical trial database study of 251 ALS subjects, we found a 
39% reduction in risk of death during the study for men, but not women, with each 1 mg/dL increase 
in urate levels31.   
 
Figure 2. Higher serum urate as a predictor  of 
favorable clinical progression in early PD.  Risk 
of progression is defined as *the hazard ratio of 
reaching disability sufficient to require dopaminergic 
therapy among 1,578 de novo PD subjects of the 
DATATOP and PRECEPT clinical trial cohorts.  Values 
(mean and SD) are shown for increasing quintiles of 
serum urate measured at baseline, and are relative to 
the lowest quintile.  Data are pooled (unpublished data, 
Schwarzschild MA et al.) form our prior publications on 
PRECEPT and DATATOP cohorts. The 1st, 3rd and 5th 
quintiles correspond to serum urate values of <4.1, 4.9-
5.5 and>6.4 mg/dL, respectively. 


 
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Similar results were reported by other groups32-34 and were confirmed and expanded by our recent 
analysis of individuals from PRO-ACT, the largest available ALS clinical trial dataset (Pooled 
Resource Open-Access ALS Clinical Trials database)35.  In PRO-ACT, urate levels at trial entry 
were available for almost 1,800 individuals and were found to be one of the strongest predictors of 
disease progression and survival35.  Thus, higher levels of urate at trial entry were predictive of a 
slower drop in ALS functional rating scale-revised [ALSFRS-R (p=0.01)] and vital capacity [VC 
(p<0.0001)], and longer survival (p=0.02) in both men and women (35 and Paganoni et al., 
unpublished data). 
2.2.2 Urate as neuroprotective agent: biological evidence 
 
Pre-clinical evidence from multiple labs further supports urate as a neuroprotective agent. 
   
In vitro, across a range of PD models, urate has prevented spontaneous degeneration of cultured 
nigral neurons as well as dopaminergic cell death induced by oxidative and mitochondrial toxins36-45. 
Urate protected dopaminergic neurons in cellular models of PD36-38. Interestingly, urate-mediated 
effects required its accumulation in astrocytes, suggesting a non cell-autonomous mechanism for 
urate’s activity38, 39.  Urate confers protection in various cellular models of neurotoxicity beyond that 
of PD.  Urate protected cultured spinal cord neurons from glutamate toxicity39 and from 
peroxynitrite-mediated death40 in models of spinal cord injury and stroke40, 41.   
 
 


 
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Recently, the Schwarzschild lab has also characterized the effect of urate manipulation in vivo in 
animal models of PD.  In mice, administration of urate or a urate precursor does not lead to 
appreciable increase in urate CNS concentration as urate is metabolized peripherally by the enzyme 
urate oxidase (UOx). Therefore, mice with a knockout (KO) of the UOx gene (effectively were 
employed. These mice have increased concentrations of urate in the central nervous system (CNS)36. 
Effects of UOx manipulation were then assessed in a model of hemiparkinsonism induced by 
unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) (Fig. 4).   
 
UOx KO mice exhibited attenuated neurotoxic effects of 6-OHDA on nigral dopaminergic cell 
counts (Fig. 4), striatal dopamine content and rotational behavior36.  These results strengthened the 
evidence supporting a neuroprotective role of endogenous urate in neurodegeneration.   
2.2.3 Urate as neuroprotective agent: early clinical trial evidence 
 
Indeed, based on the strong pre-clinical evidence of a neuroprotective role for urate in the CNS, 
recent clinical trials have begun to examine the feasibility of urate manipulation in a clinical setting 
with promising results21, 22.   
 
The Safety of Urate Elevation in Parkinson Disease (SURE-PD) trial, a phase II randomized, double-
blind, placebo-controlled, dose-ranging trial of oral inosine in PD21 recently demonstrated that 
inosine supplementation leads to a dose-dependent increase in blood and CSF urate levels in patients 
with PD. Inosine is available as an over-the-counter supplement. Although the study was not 
powered to test efficacy, secondary analyses demonstrated non-futility of inosine treatment for 
slowing disability21.  Encouraging clinical results were also recently obtained by the Safety and 
Efficacy of Uric Acid in Patients with Acute Stroke (URICO-ICTUS) study: a randomized, double-
blind trial of intravenous urate administration within a few hours of stroke onset22.   
 
A follow-up. NIH-funded, Phase 3 study of inosine in PD (SURE-PD3) is currently ongoing). 
Figure 4. Evidence for neuroprotective effects 
of urate in an animal model of PD.   
UOx KO mice (bottom panels), which have 
elevated brain urate levels, are resistant to loss of 
nigral tyrosine hydroxylase (TH)-positive 
neurons induced by intrastriatal 6-OHDA (EXP 
panel, bottom left) compared to lesioning in 
wild-type (WT) littermate mice (upper left 
panel).  


 
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While urate is a mature target in PD and experience on inosine pharmacology is rapidly 
accumulating, urate manipulation is a new target for ALS. With this Phase 2 study, we seek to 
confirm the safety of inosine when administered to people with ALS as well as gather data on target 
engagement as measured by neuroimaging biomarkers.  
2.2.4 Biomarkers of oxidative stress and damage 
 
Oxidative stress arises from an imbalance between the production of oxidizing agents (such as 
reactive oxygen species, ROS) and the ability of the system to remove the damage they cause and to 
restore the prevailing reducing environment.  Most ROS arise as by-products of aerobic metabolism 
and central nervous system (CNS) neurons are known to be especially susceptible to oxidative 
damage42.  Oxidative stress and the capacity to manage it can be tested in several ways, ranging from 
direct measurement of the ROS; measurement of the resulting oxidative damage to biomolecules 
(such as nucleic acids, proteins or lipids); and detection of antioxidant levels (e.g., by measuring a 
composite index such as ferric reducing antioxidant power [FRAP], or individual antioxidants such 
as urate, ascorbate or glutathione).  Elevated levels of markers of oxidative damage to different 
biomolecules have been repeatedly demonstrated in postmortem tissue and/or the cerebrospinal fluid 
(CSF) from ALS patients1, including elevated protein carbonyl levels, a marker of oxidized 
proteins43, and increased 3-nitrotyrosine levels, a marker for nitrosative damage44 resulting from 
reactive nitrogen species comparable to ROS.  As demonstrated by Dr. Cudkowicz and colleagues at 
MGH elevated levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a well-established marker of 
oxidized DNA, correlated with disease progression, 
suggesting it may represent a biomarker of disease 
severity45.  Among antioxidant systems, FRAP and 
urate were found to be lower in ALS subjects 
compared to controls34, 46, 47.   
 
More recently, MRS has enabled the measurement 
of various metabolites in vivo and has been utilized 
to show that the levels of glutathione are reduced in 
the motor cortex of ALS patients by about 30%48. 
Altogether, these results suggest that antioxidant 
capacity is reduced in ALS.  
 
The mechanisms of urate-based neuroprotection are 
not completely clear. However, recent evidence from 
the Schwarzschild lab38  and other labs49 suggests a role for nuclear factor erythroid 2–related factor 
2 (Nrf2) signaling pathway in urate-mediated neuroprotection.  In primary astrocytic cultures, urate 


 
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treatment induced expression of key Nrf2 target genes50 including expression of the first enzyme of 
the glutathione (GSH) biosynthetic pathway.  Consistently, urate treatment resulted in up-regulation 
of GSH synthesis and release (Fig. 5).   
 
Further, results from the SURE-PD trial demonstrated that 
inosine supplementation leads to increased plasma 
antioxidant capacity as measured by FRAP (Fig. 6). These 
findings provide evidence of an intended biological effect 
of potential therapeutic relevance and suggest that 
homeostatic mechanisms do not counteract the plasma 
antioxidant effects of urate elevation.  
2.3 
Inosine  
Elevation of urate levels in humans cannot be achieved by 
oral administration of urate, possibly due to its degradation by the activity of uricase expressed by 
the intestinal flora before reaching the circulation51. On the other hand, predictable elevation of urate 
levels can be obtained by administration of the urate precursor inosine. 
 
Inosine (chemical name: hypoxanthine 9-β-D-ribofuranoside) is an intermediary metabolite of purine 
metabolism (see Fig. 1). Inosine is available as an over-the-counter supplement for oral use.  
2.3.1 Potential Risks and Benefits 
 
Inosine’s reputation as an athletic performance enhancer has led to its widespread marketing and use 
as a nutritional supplement. Potential side effects of inosine relate to the resulting elevated urate 
(uric acid) levels (hyperuricemia). Hyperuricemia has been linked to gout. Gout generally develops 
in people with serum urate concentrations above 8 mg/dL (the upper limit of the normal range). 
Hyperuricemia has also been linked to the formation of urate stones in the kidneys or ureters 
(urolithiasis). Urate urolithiasis account for 5 to 10 percent of urinary tract stones in the United 
States and Europe. In most urate stone formers the primary pathophysiologic defect, however, is an 
excessively acidic urine pH rather than hyperuricemia and hyperuricosuria52. High urate levels have 
also been associated with high blood pressure and increased risk for cardiovascular events.  
However, whether a causal relationship between high urate and cardiovascular disease exists is 
unclear53.   
 
Considerable non-clinical human experience on inosine has been gained from the widespread use of 
inosine as a nutritional supplement and a purported (but unsubstantiated) athletic performance 


 
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enhancer. Although inosine use has been generally considered safe in these contexts, exposures are 
variable in size and poorly documented.  
 
Three exercise physiology studies of oral inosine on athletic performance in humans have been 
published54-56. All three reported that multi-gram doses (up to 10 gm/day) were well tolerated short-
term (up to 10 days), but had no demonstrable benefit on athletic performance. 
 
Of relevance to the proposed study, multi-year clinical trials of oral inosine in multiple sclerosis 
(MS) and Parkinson’s disease (PD) at doses comparable to those planned here have been conducted. 
In these studies, inosine at doses sufficient to chronically elevate urate into the ranges targeted here 
was well tolerated, with the most consistent AE being the rare development of uric acid urolithiasis. 
 
The MS literature includes 4 peer-reviewed published studies on the use of inosine51, 57-59. Inosine 
has been administered in this population for prolonged periods (up to 1 year) at up to 3 gm/day 
(divided into 2 or 3 doses daily). 
 
In the study by Spitsin et al.51, 11 subjects with advanced MS received increasing doses of inosine 
from 1 to 3 gm/day. Urate levels in blood were monitored every 2 weeks and the daily inosine dose 
was increased every other week until serum urate levels reached approximately 8 mg/dl. Thereafter, 
each patient received a daily dose of inosine sufficient to maintain serum urate levels within a range 
of 7 ± 9 mg/dL for up to a year. No patients experienced symptomatic hyperuricemia or gouty 
arthritis, and no urate crystals or other abnormalities were reported in urine. 
 
Gonsette et al57 performed a placebo-controlled trial of inosine in MS. Seventy-nine subjects with 
MS received inosine for 24 months. The treatment regimen consisted of 1 gm of inosine 
administered three times a day (initial total daily dose 3 gm daily). Inosine dose was then adapted by 
the treating neurologist after 1 month and then every 3 months to keep serum urate levels lower than 
9 mg/dl in women and lower than 10 mg/dl in men. Particular attention was paid to side effects 
possibly related to a chronic, asymptomatic hyperuricemia. There were no reports of gout, stroke, or 
coronary heart disease. Symptoms of renal or ureteral stones were reported in three cases in the 
experimental group (3.8%) and one case in the placebo group (1.3%). Spontaneous elimination 
occurred in three cases and one patient had lithotripsy. Of note, in this study there were no efforts to 
reduce the risk of stone formation through screening of low urine pH, a major risk factor in the 
formation of urate urolithiasis52. In addition, subjects with baseline urate up to 7 mg/dL were 
allowed into the study with target urate levels up to 9-10 mg/dL (both entry cut-off and target urate 
levels in the MS study were higher than in the planned study for ALS). 
 
Spitsin, Markowitz and colleagues58, 59 administered inosine to a group of 16 subjects with MS for 
one year. The goal of the study was to investigate the effect of chronically elevated urate levels on 


 
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blood pressure as well as collect MS-related inflammatory and imaging biomarkers. The inosine 
dosage was initiated at 1–2 gm per day, and increased by 0.5 g per day at biweekly intervals until the 
target serum UA levels of 6–9 mg/dL were achieved. For most patients the inosine dose required to 
maintain target UA levels was between 2 and 3 g per day. Inosine treatment did not affect blood 
pressure over a one-year period58. Four subjects (25%) developed kidney stones which were treated 
with conservative measures including termination of inosine administration, improved hydration, 
and pain medication. Exceptionally high serum urate levels were recorded for at least two of these 
subjects (10–15 mg/dL)58. In all patients in whom inosine treatment was stopped, serum UA levels 
returned to pretrial levels within 3–5 days and no re-occurrence of kidney stones was reported. This 
included a subject who resumed inosine treatment 2 months after developing a kidney stone59. In 1 
patient who developed kidney stones, an ultrasound scan revealed the presence of kidney cancer in 
the other kidney, which was successfully treated surgically59. Similar to the study by Gonsette et 
al.57, this study did not exclude subjects with acidic urine at baseline52.  
 
In the recent SURE-PD trial21, a total of 75 subjects with Parkinson’s Disease (mean age, 62 years; 
55% women) were randomized to either placebo or inosine titrated to produce mild (6.1-7 mg/dL) or 
moderate (7.1-8 mg/dL) serum urate elevation and were followed for up to 24 months. Individuals at 
greatest risk of known effects of increased urate (i.e., those with a history of gout or urolithiasis, or 
with urine pH ≤5.0, a major risk factor for uric acid urolithiasis) were excluded from enrolling. 
Treatment was initiated gradually with 1 capsule (500 mg of inosine per capsule) taken 2 times daily 
for 2 weeks. After the 2- and 4-week visits, participants received up to 2 capsules 2 to 3 times daily, 
as algorithmically determined by serum urate concentration and treatment group assignment. Target 
urate levels were achieved between 2 and 4 weeks after initiation of inosine treatment21. Serious 
adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates 
in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine 
developed symptomatic nephrolithiasis (6%); two were determined to be calcium oxalate stones and 
one was believed to be a uric acid stone. Despite the increased frequency of nephrolithiasis while 
receiving inosine, there were no other renal SAEs and renal function measures of glomerular 
filtration rate and serum creatinine remained unchanged from baseline in all groups. Serial vital 
signs, serum assays, and electrocardiograms showed no effect of inosine on blood pressure, body 
mass index, serum glucose and cholesterol levels or electrocardiographic parameters. Treatment was 
tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse 
event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs. placebo, 
and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, 
respectively). Secondary analyses demonstrated non-futility of inosine treatment for slowing 
disability.  
 
The Phase III SURE-PD3 trial is ongoing and the goal is to enroll 270 subjects with Parkinson’s 
Disease by December 2017. 


 
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2.3.2 SAFETY SUMMARY 
 
Inosine is available over-the-counter as an athletic performance enhancer. Considerable non-clinical 
human experience on inosine has been gained from its widespread use as a nutritional supplement. In 
this context, inosine has been considered safe, although exposures are variable in size and poorly 
documented.  
 
Potential side effects of inosine relate to the resulting elevated urate (uric acid) levels 
(hyperuricemia). Hyperuricemia has been linked to gout (which generally develops in people with 
serum urate concentrations above 8 mg/dL) and to the formation of urate stones in the kidneys or 
ureters (urolithiasis). In most uric acid stone formers the primary pathophysiologic defect, however, 
is an excessively acidic urine pH rather than hyperuricemia52. High urate levels have also been 
associated with high blood pressure and increased risk for cardiovascular events.  However, whether 
a causal relationship between high urate and cardiovascular disease exists is unclear53.   
 
The safety profile of chronic inosine administration in a human clinical research setting has been 
well characterized by research studies in MS51, 57-59 and PD21. At doses comparable (or higher) to 
those planned here, inosine was well tolerated up to 2 years. The most consistent AE was the 
development of uric acid urolithiasis. In the PD study21, where people with acidic urine were 
excluded and target urate levels did not exceed 8 mg/dL (as planned here), the prevalence of 
urolithiasis was 6%. There were no reports of gout and no excess cardiovascular events relative to 
placebo in any of these studies.  
 


 
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3 
OBJECTIVES 
3.1 
Study Objectives 
The primary objective of the study is to determine the safety and tolerability of oral administration of 
inosine (administered daily) dosed to moderately elevate serum urate over 20 weeks.  
 
An exploratory objective of the study is to test the feasibility and utility of a smartphone application, 
for monitoring symptoms and disease progression in patients with ALS.  
 
3.2 
Study Outcome Measures 
The primary outcome measures will be: 
1- Safety, as measured by adverse events; 
2- Tolerance will be defined as completion of the 20-week study without permanently 
discontinuing study drug or suspending study drug for greater than 28 days. 
 
Exploratory outcome measures will be: 
1-  feasibility of a smartphone application for monitoring ALSFRS-R in patients with ALS; 
 
 


 
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4 
STUDY DESIGN 
4.1 
Overall Study Design and Plan 
During the enrollment period, approximately 60 subjects will be screened at up to three (3) Northeast 
ALS Consortium (NEALS) Centers in the United States.  Approximately 30 of these subjects are 
expected to be found eligible for study enrollment and will be randomized 2:1 to receive inosine or 
placebo. Per study protocol, the aim is to elevated serum urate levels only in those subjects whose 
baseline urate level falls below the predicted median for this population.  Approximately 30 subjects 
will receive inosine or placebo for 20 weeks (administered in the form of 500 mg capsules, 1 to 6 
capsules a day for a total daily dose of up to 3 gm).  The dose of inosine will be titrated to target 
urate levels of 7-8 mg/dL based on urate level measurement that will occur at the Week 3, Week 6, 
Week 9, Week 12 and Week 16 visits. Clinic visits will occur at Screening, Baseline, Week 12, 
Week 20 and Unscheduled Safety Visits. Telephone visits and remote serum urate testing will occur 
at Week 3, Week 6, Week 9 and Week 16. There will be a window of ± 3 days for each visit. The 
Screening Visit must be completed within 21 days of the Baseline Visit.  All visit windows are 
consecutive calendar days and are calculated from the day the participant starts study treatment (Day 
0, the day of the Baseline Visit).  
4.2 
Study Centers 
This study will be conducted as a multi-center study at up to three (3) Northeast ALS Consortium 
(NEALS) Centers in the United States. 
4.3 
Study Duration 
Subjects will remain on treatment until the Week 20 visit.  Each subject will also have a Week 24 
Follow-up Telephone Interview to assess for adverse events (AEs), changes in concomitant 
medications and to administer the ALSFRS-R. 
4.4 
Protocol Adherence 
The Site Investigators agree to adhere to the protocol detailed in this document and agree that any 
changes to the protocol must be approved by the site Institutional Review Board (IRB).   The Site 
Investigator (SI) will be responsible for enrolling only those study subjects who have met protocol 
eligibility criteria. 


 
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5 
SELECTION AND WITHDRAWAL OF STUDY POPULATION 
5.1 
Number of Study Subjects 
Approximately 60 subjects will be consented for the study. Any subject who signs consent will be 
considered enrolled in the study. Screening study procedures will begin after informed consent. 
 
We expect a 50% screen fail rate based on our goal of elevating serum urate levels only in those 
subjects whose serum urate level falls below the population median. This subpopulation is at greater 
risk of faster disease progression and can also accommodate an increase in serum urate to higher, but 
still normal levels, which are known to be associated with slower disease progression21, 31, 35.  
 
Thirty (30) subjects will receive inosine or placebo for 20 weeks per study protocol and will be 
followed up to Week 24.  
 
If a subject fails screening, at a minimum, the following information will be captured and entered in 
the data capture system: inclusion/exclusion criteria, demographics, screening lab results, reason for 
screen failure. 
5.2 
Inclusion and Exclusion Criteria 
5.2.1 Inclusion Criteria 
Study subjects meeting all of the following criteria will be allowed to enroll in the study:  
1. Age 18-85. 
2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or 
definite as defined by revised El Escorial criteria (Appendix 1).  
3. Slow vital capacity (SVC) ≥ 60% of predicted for age, height, and gender at the Screening 
Visit. 
4. Capable of providing informed consent and following trial procedures. 
5. Serum urate < 5.5 mg/dL at screening (i.e. below the population median serum urate levels). 
6. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile, or 
using adequate birth control methods) for the duration of the study and 3 months after study 
completion. Adequate contraception includes: abstinence, hormonal contraception (oral 
contraception, implanted contraception, injected contraception or other hormonal (patch or 
contraceptive ring, for example) contraception), intrauterine device (IUD) in place for ≥ 3 
months, barrier method in conjunction with spermicide, or another adequate method.  
7. Is able and willing to participate in the Mobile app study procedures. 


 
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5.2.2 Subject Exclusion Criteria  
Study subjects meeting any of the following criteria during screening evaluations will be excluded 
from entry into the study: 
1. History of urolithiasis. 
2. Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid urolithiasis).  
3. History of gout. 
4. History of stroke or myocardial infarction. 
5. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic 
peripheral arterial disease within 1 year prior to Screening. 
6. Symptomatic congestive heart failure with a documented ejection fraction below 45%. 
7. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).  
8. Women who are pregnant or lactating. 
9. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would 
impair ability of the subject to provide informed consent, according to Site Investigator 
judgment, or a history of active substance abuse within the prior year.   
10. Anything that, in the opinion of the Site Investigator, would place the subject at increased 
risk or preclude the subject’s full compliance with or completion of the study. 
11. Use of the following within 30 days prior to Screening: inosine, allopurinol, probenecid, 
more than 300mg vitamin C daily (note that a subject may take a standard multivitamin up to 
one tablet or capsule daily). Use of thiazides is permissible as long as the subject is on a 
stable dose from 1 week prior to Screening.  
12. Known hypersensitivity or intolerability to inosine.  
13. Renal insufficiency as defined by eGFR < 60 mL/min/1.73m2 at Screening. 
 
Participation in other investigational trials for the treatment of patients with ALS is allowed. 
5.3 
Withdrawal 
Study drug will be discontinued if: 
• Any clinical adverse event (AE), laboratory abnormality, concurrent illness, or other medical 
condition or situation occurs such that continued participation in the study would not be in 
the best interest of the subject. 
 
Subjects are free to withdraw from participation in the study at any time upon request. 
 
Subjects who withdraw from the study will not be replaced. 
5.3.1 Handling of Withdrawals 
A subject may choose to discontinue participation in the study at any time.  However, the Site 
Investigator or designee will encourage subjects to continue with follow-up, regardless of their 
compliance with study drug. If a subject who initiated study drug permanently discontinues study 
drug, the SI or designee should still encourage subjects to follow the study protocol under the 


 
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modified intent-to-treat principle (ITT). These subjects will be encouraged to follow the study visits, 
off drug, up to the final visit. Loss to follow-up should be prevented whenever possible. 
 
Any subject who is on study drug and needs to begin the use of any prohibited medication, must 
immediately discontinue use of study drug.  Subjects who permanently discontinue study drug 
should return any unused study drug and complete early study drug discontinuation procedures per 
protocol. 
 
If a subject wishes to withdraw consent, i.e., withdraw his or her participation in future study 
procedures, the subject will be asked to delay consent withdrawal to allow for a final safety visit and 
final safety telephone call. The subject will be asked to return to the study site for a final safety visit 
within 14 days of asking to withdraw consent. The subject will also be asked to have a final 
telephone call 28 days (+ 5 days) after taking their last dose of study drug.  
 
In the event a subject no longer wishes to have their personal health information used for the analysis 
of this study, he or she will notify the site through an authorized letter and his or her data will no 
longer be included as part of the results for this study. 
5.3.2 Termination of Study  
This study may be prematurely terminated if, in the opinion of the Principal Investigator or Medical 
Monitor, there is sufficient reasonable cause.   
 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Enrollment is unsatisfactory. 
• Insufficient adherence to protocol requirements. 
• Data that is not sufficiently complete and/or evaluable.  
 


 
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6 
TREATMENTS ADMINISTERED 
6.1 
Treatments  
6.1.1 Study Product Description 
 
Inosine (chemical name: hypoxanthine 9-β-D-ribofuranoside) is an intermediary metabolite of purine 
metabolism (structure shown below) that is ultimately converted into urate. 
 
Chemical Formula: C10H12N4O5  
Molecular Weight: 268.23 
 
 
 
Inosine is a white powder. It is provided by a commercial vendor as 500 mg capsules for oral 
use.  
6.1.2 Treatments administered 
 
Inosine will be administered as one capsule twice a day for the first 3 weeks of the study. Inosine 
dose will be titrated at Weeks 3, 6, 9, 12 and 16 to target urate levels (7 – 8 mg/dL). Inosine will 
be provided to each subject in individually labeled containers by the site research pharmacy.  
 
The following pre-specified titration algorithm will be used to adjust inosine dose based on urate 
levels measured at Weeks 3, 6, 9, 12 and 16. 


 
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1- Serum urate < 67% increase from most recent level to lower limit of target range (7 
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, then continue at this dose. 
 
2- Serum urate 67-less than 100% increase from most recent level to lower limit of target 
range (7 mg/dL) ==> increase by 1 cap/day, except:  
 
• If subject is already at 6 caps/day, then continue at this dose. 
 
3- Serum urate within target range (7-8 mg/dL) ==> no change. 
 
4- Serum urate > upper limit of target range (8.1 mg/dL or higher) but ≤ 9.0 mg/dL ==> 
reduce by 1 cap/day the dose being taken at the most recent visit, except: 
 
• If subject was already down to 1 cap/day, s/he will continue at 1 cap/day.  
 
5- Serum urate > 9.0 mg/dL ==> hold treatment (i.e., take 0 caps/day) x 7 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 7 more days, then resume treatment at 1 cap/day. 
 
6- If a subject returns 3 consecutive serum urate levels > 9.0 mg/dL, then the study drug will 
be permanently discontinued due to “excess sensitivity to study drug” (This will not be 
treated as an adverse event (AE)).    
 
7- If a subject’s baseline level is ≥ 7.0 mg/dL, study drug will be held until the Week 3 labs.  
 
6.2 
Receiving, Storage, Dispensing 
6.2.1 Receipt of Drug Supply 
 
Inosine will be shipped from the central pharmacy to the study research pharmacies.  


 
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6.2.2 Storage 
 
The drug supply will be kept at the site research pharmacies in a locked, safe area at controlled room 
temperature with access limited to those directly involved in the study.  
 
6.2.3 Dispensing of Study Drug 
 
Inosine will be provided to each subject in individually labeled containers by the site research 
pharmacies. Subject compliance will be determined at the end of the study as detailed below.  
6.3 
Modification of Study Intervention/Investigational Product for a Subject 
Any dosage adjustment, including the reason for and dates of adjustment, will be documented in the 
CRF for each subject requiring this manipulation. The Site Investigator (SI) or licensed physician 
Sub-Investigator may reduce the dosage of study drug or discontinue the study drug in its entirety for 
adverse events (AEs) thought to be related to the study drug or for other reason during the trial (the 
reason for, and dates of suspension or dose reduction must be documented).  If the AE is mild or 
moderate, the dosage may be reduced until the event improves.  The SI may then choose to resume 
the higher dosage or maintain the subject at a reduced dosage.  
 
If the event is serious or life threatening, and deemed to be definitely drug related, the study drug 
will be discontinued immediately. Study subjects must remain off the study drug permanently. 
Subjects may not resume study drug.  All AEs will be followed to resolution.  
 
6.3.1 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). 
6.3.2. Dosage Discontinuation 
Reasons for discontinuation of study medication may include an AE, Medical Monitor or Principal 
Investigator recommendation, protocol deviation, loss-to-follow-up, subject request, or death.   
 


 
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Study subjects who discontinue study drug prematurely (early termination from study) will be 
encouraged to return for a Final Safety Visit and participate in a Follow-Up Telephone Call 28 days 
(+ 5 days) after the last dose of study drug.  
6.4 
Accountability Procedures  
At the completion of the study, there will be a final reconciliation of drug consumed and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  
Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction 
of unused study drug.  Drug destroyed on site will be documented in the study files. 
6.5 
Prior and Concomitant Therapy 
Throughout the study, the subject may be prescribed concomitant medications or treatments deemed 
necessary to provide adequate supportive care provided that the medications are licensed in the 
United States. All concomitant medications and/or treatments received by a subject should be 
recorded on the appropriate source document and eCRF. 
6.5.1 Prohibited Medications and Contraindications 
Prohibited Medications 
Throughout the course of the trial, study subjects should not be treated with the following 
medications.  If, for safety or health reasons, or by subject choice, the prohibited medication cannot 
be stopped, then the study medication should be stopped. 
 
Prohibited medications include: 
• Inosine from a different source 
• Allopurinol 
• Probenecid 
• More than 300mg Vitamin C daily (please note that a daily multivitamin containing vitamin 
C is allowed) 
 
Pregnancy & Nursing Mothers 
There are no adequate and well-controlled studies in pregnant women.   Subjects or partners of male 
subjects should not become pregnant during the study or 3 months after stopping study drug.  If a 
female subject becomes pregnant, study treatment must be discontinued immediately.  
 
It is not known whether inosine is excreted in human milk.  Caution should be exercised; therefore, 
no subject should nurse their infant while participating in this study. 
 


 
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7 
STUDY SCHEDULE 
No study procedures should be performed prior to the signing of the informed consent form (ICF). 
All subjects will sign an ICF prior to undergoing any study tests or procedures. The VC should be 
performed first at the visits so as not to fatigue the subject with other testing. 
 
Visit windows are consecutive calendar days and the target visit dates are calculated from the 
Baseline Visit.   
 
Subjects who withdraw consent or early terminate from the study will be asked to come in for a 
Final Safety Visit and will have a Final Telephone Interview 28 days (+5 days) after stopping study 
drug.   
7.1 
Screening Visit 
The following procedures will be performed at an office visit to determine the subject’s eligibility 
for the study: 
o Obtain written informed consent from subject 
o Assess inclusion and exclusion criteria 
o Obtain medical history and demographics 
o Obtain ALS diagnosis history 
o Perform Pulmonary Function Tests (SVC) 
o Perform physical examination 
o Perform neurological examination 
o Measure vital signs including height and weight 
o Collect blood for screening labs 
o Review and document concomitant medications and therapies 
o Assess and document adverse events (AEs) that occur after subject signs informed consent 
form (ICF) 
7.1.1 Screen Failures 
Any subject who signs consent will be considered enrolled in the study.  If a subject fails screening, 
at a minimum, the following information should be captured and entered in the Electronic Data 
Capture (EDC) System if it performed/completed: 
o Demographics 
o Inclusion and Exclusion criteria 
o Reason for screen failure 
o Screening labs results 


 
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7.2 
Baseline Visit 
This visit will take place within 21 days of the Screening Visit.  The following procedures will be 
performed: 
o Review inclusion and exclusion criteria  
o Review and document concomitant medications and therapies 
o Assess and document AEs 
o Collect blood samples for clinical laboratory assessments (urate level, safety labs)  
o Collect urine for urinalysis 
o Administer ALSFRS-R questionnaire  
o Perform Pulmonary Function Tests (SVC) 
o Columbia Suicide Severity Rating Scale (C-SSRS) – Baseline 
o Administer first dose of study drug.  The subject should be observed at the site for 15 
minutes by an appropriate healthcare staff member according to the site’s institutional/state 
regulations to assess medical status and any immediate reaction to the study drug. 
o Dispense study medication and dosing diary 
o Subjects will be given a written schedule of the Week 3, Week 6, Week 9 and Week 16 
phone calls. They will also be provided with laboratory requisition forms for blood draws at 
a Quest Diagnostics laboratory.  They will be instructed to have the blood draw performed 
on specific days prior to each phone call as detailed below.  Subjects will also be provided 
with written address and contact information of the Quest Diagnostics laboratory that is 
closest to their place of residence.  
o Mobile app installation. 
7.3 
Phone Calls  
Subjects will be called sometime after the Baseline Visit to remind them to go to a Quest Diagnostics 
laboratory to have blood draw for urate level assessment per written schedule that they were given at 
the Baseline Visit. Subjects should have blood drawn in the morning just prior to scheduled dose 
(trough level). 
 
Week 3 blood draw to monitor urate level will occur 21 ± 3 days after the Baseline Visit. 
 
Week 6 blood draw to monitor urate level will occur 42 ± 3 days after the Baseline Visit. 
 
Week 9 blood draw to monitor urate level will occur 63 ± 3 days after the Baseline Visit. 
 
Week 16 blood draw to monitor urate level will occur 112 days ± 3 days after the Baseline Visit. 
 
The Phone Calls will take place approximately one-seven days after each blood draw and the 
following procedures will be performed: 
o Review results of the urate level test  


 
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o Instruct subject to continue the same dose of inosine or modify dose to target urate levels   
o Review and document concomitant medications and therapies 
o Assess and document AEs 
7.4 
Week 12 Visit  
This visit will take place 84 ± 3 days after the Baseline Visit. This visit should occur in the morning 
and subjects should hold their morning dose to obtain uric acid trough level. The following will be 
performed: 
o Measure vital signs, including weight 
o Collect blood samples for clinical laboratory assessments (urate level, safety labs) 
o Collect urine for urinalysis 
o Administer ALSFRS-R questionnaire 
o Perform Pulmonary Function Tests (SVC) 
o Columbia Suicide Severity Rating Scale (C-SSRS) – Since Last Visit 
o Review and document concomitant medications and therapies 
o Assess and document AEs 
o Dispense study medication and dosing diary 
o Perform study drug accountability and collect all unused study drug and empty containers 
 
7.5 
Week 20 Visit  
This visit will take place 140 ± 7 days after the Baseline Visit. This visit should occur in the morning 
and subjects should hold their morning dose to obtain uric acid trough level. The following will be 
performed: 
o Measure vital signs, including weight 
o Collect blood samples for clinical laboratory assessments (urate level, safety labs) 
o Collect urine for urinalysis 
o Administer ALSFRS-R questionnaire 
o Perform Pulmonary Function Tests (SVC) 
o Columbia Suicide Severity Rating Scale (C-SSRS) – Since Last Visit 
o Review and document concomitant medications and therapies 
o Assess and document AEs 
o Collect study drug and dosing diary 
o Perform study drug accountability and collect all unused study drug and empty containers 
o Uninstall mobile app 
 
7.6 
Week 24 Phone Call 
A follow-up phone call will take place 28 + 5 days after the subject’s last dose of study drug. The 
following will be performed: 


 
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o Complete ALSFRS-R Questionnaire 
o Review and document concomitant medications and therapies 
o Assess and document AEs 
7.7 
Final Safety Visit 
Subjects who early terminate from the study and do not wish to be followed per protocol off study 
drug will be asked to come in for a Final Safety Visit and will be asked to have a final Follow-Up 
Telephone Call (+ 5 days, but no earlier than 28 days, after subject’s last dose of study drug). 
 
The following will be performed at the Final Safety Visit: 
o Measure vital signs, including weight 
o Collect blood samples for clinical laboratory assessments (urate level, safety labs) 
o Administer ALSFRS-R questionnaire 
o Perform Pulmonary Function Tests (SVC) 
o Columbia Suicide Severity Rating Scale (C-SSRS) – Since Last Visit 
o Review and document concomitant medications and therapies 
o Assess and document AEs 
o Collect study drug and dosing diary 
o Perform study drug accountability and collect all unused study drug and empty containers 
o Uninstall mobile app. 
 
 
The following procedures will be performed via telephone 28 + 5 days after the Final Safety Visit: 
o Administer ALSFRS-R questionnaire 
o Review and document concomitant medications and therapies 
o Assess and document AEs 
 
 
7.8 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol.  The noncompliance may 
be either on the part of the subject, the Site Investigator, or the study site staff.  As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly. 
 
 
All deviations from the protocol must be addressed in the subject’s source documents.  All major 
protocol deviations will be entered in the Protocol Deviations Log in the Electronic Data Capture 
(EDC) System and should be submitted to the site’s local IRB per institutional guidelines.  
7.8.1 Missed Visits and Procedures  
Missed visits and any procedures not performed (not attempted) for reasons other than screen failure, 
illness, injury or progressive disability (i.e. subject is physically unable to perform test) will be 
reported as protocol deviations.   
 


 
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Procedures or visits not performed due to screen failure, illness, injury or disability, including 
procedures that were attempted but failed (i.e. blood samples unable to be drawn after multiple 
attempts, or weight unable to be obtained due to subject immobility) will not be reported as protocol 
deviations.   
 
Details and specific instructions regarding protocol deviations, including any exceptions to this 
standard procedure, are found in the Site Manual of Procedures. 
 
7.9 
Recording Deaths 
Information on whether a subject has died may be obtained by the subject’s family, clinic notes, or 
utilizing public means such as a reliable internet source such as the Centers for Disease Control and 
Prevention (CDC) National Death Index (http://www.cdc.gov/nchs/ndi.htm) or the Social Security 
Death Index (http://ssdmf.info/). 
 


 
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8 
CLINICAL ASSESSMENTS AND OUTCOME MEASURES 
8.1 
Clinical Variables 
Assessments will be performed at designated time-points throughout the study for clinical 
evaluation.  In addition to the assessments evaluated below, subjects will provide information on 
their demographics, past medical history, including ALS, as well as concomitant medication usage. 
8.1.1 Vital Signs, Height & Weight 
Vital signs will be obtained after the subject has been in a seated position for several minutes.  Vital 
signs, including systolic and diastolic blood pressure, pulse rate (radial artery)/minute, respiratory 
rate/minute, temperature and weight will be assessed at specified visits.  Height will be measured 
and recorded at the Screening Visit only.   
8.1.2 Clinical Laboratory Assessments 
 
The following laboratory tests will be performed during the study: 
 
o Serum urate level (Screening, Baseline, Weeks 3, 6, 9, 12, 16 and 20) 
o Urinalysis: albumin, bilirubin, blood, clarity, color, glucose, ketones, nitrate, pH, protein, 
specific gravity, urobilinogen and WBC screen (Screening, Baseline, Week 12 and Week 20 
visits). Urine sediment analysis will be also performed at the Baseline, Week 12 and Week 
20 visits. 
o Serum human chorionic gonadotrophin (hCG) for women of childbearing potential 
(WOCBP) (Screening ONLY) 
o Hematology with differential panel: complete blood count with differential (hematocrit, 
hemoglobin, platelet count, RBC indices, Total RBC, Total WBC, and WBC & differential) 
(Baseline, Week 12 and Week 20) 
o Blood chemistry panel/Liver function tests (LFTs): alanine aminotransferase (ALT (SGPT)), 
aspartate aminotransferase (AST (SGOT)), albumin, alkaline phosphatase, bicarbonate, 
blood urea nitrogen, calcium, chloride, creatinine, glucose, magnesium, phosphate, 
potassium, sodium, total bilirubin and total protein (Screening, Baseline, Week 12 and Week 
20) 
 
Additional testing, may be ordered if needed, to further assess an adverse event (AE), or if there is 
any suspicion that a subject may be pregnant, throughout the course of the study. 


 
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8.1.3 Physical Examination 
A physical examination will be performed and recorded.  The following systems will be examined: 
head/neck, eyes, ears, nose/throat, cardiovascular, lungs, abdomen, musculoskeletal, central nervous 
system, extremities, and skin.   
8.1.4 Neurological Examination 
A neurological examination will be performed and recorded.   
8.1.5 Adverse Events 
Adverse events (AEs) will be documented at each study visit, including the Screening Visit once the 
informed consent form has been signed by the subject, and at all study visits, including the final 
telephone call 28 days after the last dose of study drug.  Information on adverse effects of study 
medication and on inter-current events will be determined at each visit by direct questioning of the 
subjects and review of concomitant medications.  
8.1.6 ALSFRS-R 
The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to 
determine subjects' assessment of their capability and independence in 12 functional activities.  All 
12 activities are relevant in ALS. Initial validity was established by documenting that in ALS 
patients, change in ALSFRS-R scores correlated with change in strength over time, was closely 
associated with quality of life measures, and predicted survival. The test-retest reliability is greater 
than 0.88 for all test items. The advantages of the ALSFRS-R are that the categories are relevant to 
ALS, it is a sensitive and reliable tool for assessing activities of daily living function in those with 
ALS, and it is quickly administered.  With appropriate training the ALSFRS-R can be administered 
with high inter-rater reliability and test-retest reliability.  The ALSFRS-R can be administered by 
phone with good inter-rater and test-retest reliability.  The equivalency of phone versus in-person 
testing, and the equivalency of study subject versus caregiver responses have also recently been 
established.  Therefore, if necessary, the ALSFRS-R may be given to the study subject over the 
phone.  All ALSFRS-R evaluators must be NEALS certified. 
8.1.7 Pulmonary Function Testing 
Pulmonary Function Testing includes Slow Vital Capacity (SVC). 
 
Slow Vital Capacity (SVC): The vital capacity (VC) (percent of predicted normal) will be 
determined, using the upright slow VC method. The VC can be measured using conventional 
spirometers that have had a calibration check prior to subject testing.  A printout from the spirometer 
of all VC trials will be retained.  Three VC trials are required for each testing session, however up to 
5 trials may be performed if the variability between the highest and second highest VC is 10% or 
greater for the first 3 trials. Only the 3 best trials are recorded on the CRF.  


 
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8.1.8  C-SSRS 
The US FDA recommends the use of a suicidality assessment instrument that maps to the Columbia 
Classification Algorithm for Suicide Assessment (C-CASA)62. The C-CASA was developed to assist 
the FDA in coding suicidality data accumulated during the conduct of clinical trials of antidepressant 
drugs. One such assessment instrument is the Columbia Suicide Severity Rating Scale (C-SSRS)63. 
The C-SSRS involves a series of probing questions to inquire about possible suicidal thinking and 
behavior. 
Only investigators who have been fully trained in the administration of the C-SSRS will assess 
subject suicidality. As part of training, investigators are prepared to respond to and manage instances 
in which patients express suicidal ideation or exhibit suicidal behavior. 
At the Baseline Visit, the C-SSRS Baseline version will be administered. This version is used to 
assess suicidality over the subject’s lifetime and specifically for the previous 6 month time period. 
At the Week 12 and the Final Safety visit, as applicable, the Since Last Visit version of the C-SSRS 
will be administered. This version of the scale assesses suicidality since the subject’s last visit. 
Information obtained from: http://www.cssrs.columbia.edu/ 
8.1.9 Mobile App Study 
The objective of the proposed study is to test the feasibility and utility of a novel smartphone 
application (‘app’) for monitoring disease progression in patients with Amyotrophic Lateral 
Sclerosis (ALS). The cell phone app will collect two broad categories of data: 
1) 
“Actively collected data,” wherein the subject is instructed to complete selected 
activities, and data about these activities is recorded, and  
2) 
“Passively collected data,” wherein data is recorded as the subject performs everyday 
activities naturally using existing cell phone sensors 
 
Data will be collected from the subjects’ smartphones over the course of the study (20 weeks), and 
only pre-specified forms of data will be accessed and collected by the app. In addition, the subject 
will be asked about their general smartphone usage. 
 
8.1.11 Exit Questionnaire 
An Exit questionnaire will be collected at Week 20 and will include a trial satisfaction survey and a 
blindedness questionnaire. 


 
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9 
SAFETY AND ADVERSE EVENTS 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with 
all applicable regulations and International Conference on Harmonization (ICH) guidelines.  The 
Principal Investigator will carefully monitor each subject throughout the study for possible adverse 
events.  All AEs will be documented on CRFs designed specifically for this purpose.  It is also 
important to report all AEs, especially those that result in permanent discontinuation of the 
investigational product being studied, whether serious or non-serious. 
9.1 
Definitions of AEs, Suspected Adverse Drug Reactions & SAEs 
9.1.1 Adverse Event and Suspected Adverse Drug Reactions 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a study, 
use of a drug product or device whether or not considered related to the drug product or device.  
 
Adverse drug reactions (ADR) are all noxious and unintended responses to a medicinal product 
related to any dose.  The phrase “responses to a medicinal product” means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out.  Therefore, a subset of AEs can be classified as suspected ADRs, if 
there is a causal relationship to the medicinal product. 
 
Examples of adverse events include: new conditions, worsening of pre-existing conditions, clinically 
significant abnormal physical examination signs (i.e. skin rash, peripheral edema, etc), or clinically 
significant abnormal test results (i.e. lab values or vital signs), with the exception of outcome 
measure results, which are not being recorded as adverse events in this trial (they are being collected, 
but analyzed separately). Stable chronic conditions (i.e., diabetes, arthritis) that are present prior to 
the start of the study and do not worsen during the trial are NOT considered adverse events.  Chronic 
conditions that occur more frequently (for intermittent conditions) or with greater severity, would be 
considered as worsened and therefore would be recorded as adverse events. 
 
Adverse events are generally detected in two ways: 
 
 
Clinical  symptoms reported by the subject or signs detected on examination. 
 


 
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Ancillary Tests  abnormalities of vital signs, laboratory tests, and other diagnostic 
procedures (other than the outcome measures, the results of which are not being captured as 
AEs). 
 
For the purposes of this study, symptoms of progression/worsening of ALS, including ‘normal’ 
progression, will be recorded as adverse events.     
 
The following measures of disease progression will not be recorded as adverse events even if they 
worsen (they are being recorded and analyzed separately): vital capacity results and ALSFRS-R 
results.  
 
If discernible at the time of completing the AE log, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Site Investigator and recorded 
on the AE log.  However, if an observed or reported sign, symptom, or clinically significant 
laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease 
or syndrome, then it should be recorded as a separate AE on the AE log.  Clinically significant 
laboratory abnormalities, such as those that require intervention, are those that are identified as such 
by the Site Investigator. 
 
Subjects will be monitored for adverse events from the time they sign consent until completion of 
their participation in the study (defined as death, consent withdrawal, loss to follow up, early study 
termination for other reasons or following completion of the entire study).   
 
The following will be considered Adverse Events of Special Interest regardless of severity: 
nephrolithiasis, urolithiasis, and gouty arthritis. 
9.1.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following 
criteria: 
1. Results in death. 
2. Is life threatening: that is, poses an immediate risk of death as the event occurred. 
a. This serious criterion applies if the study subject, in the view of the Site Investigator 
or Sponsor, is at immediate risk of death from the AE as it occurs.  It does not apply 
if an AE hypothetically might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
a. Hospitalization for an elective procedure (including elective PEG tube/g-tube/feeding 
tube placement) or a routinely scheduled treatment is not an SAE by this criterion 
because an elective or scheduled “procedure” or a “treatment” is not an untoward 
medical occurrence. 


 
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4. Results in persistent or significant disability or incapacity. 
a. This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subject’s ability to carry out normal life functions. 
5. Results in congenital anomaly or birth defect in the offspring of the subject (whether the 
subject is male or female).   
6. Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 
7. Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered SAEs 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 blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for "seriousness" but is not an adverse experience, and will 
therefore, not be considered an SAE.  An example of this would include a social admission (subject 
admitted for other reasons than medical, e.g., lives far from the hospital, has no place to sleep). 
 
The Site Investigator is responsible for classifying adverse events as serious or non-serious. 
9.2 
Assessment and Recording of Adverse Events 
The Site Investigator will carefully monitor each subject throughout the study for possible AEs.  All 
AEs will be documented on CRFs designed specifically for this purpose.  All AEs will be collected 
and reported in the electronic data capture (EDC) system and compiled into reports for periodic 
reviewing by the Medical Monitor. The Medical Monitor shall promptly review all information 
relevant to the safety of the investigational product, including all serious adverse events (SAEs).  
Special attention will be paid to those that result in permanent discontinuation of the investigational 
product being studied, whether serious or non-serious. 
9.2.1 Assessment of Adverse Events 
At each visit (including telephone interviews), the subject will be asked if they have had any 
problems or symptoms since their last visit in order to determine the occurrence of adverse events.   
If the subject reports an adverse event, the Investigator will probe further to determine: 
1. Type of event 
2. Date of onset and resolution (duration) 
3. Severity (mild, moderate, severe) 
4. Seriousness (does the event meet the above definition for an SAE) 


 
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5. Causality, relation to investigational product and disease 
6. Action taken regarding investigational product 
7. Outcome 
9.2.2 Relatedness of Adverse Event to Investigational Product 
The relationship of the AE to the investigational product should be specified by the Site Investigator, 
using the following definitions: 
 
1.  Not Related:           
Concomitant illness, accident or event with no reasonable association 
with treatment. 
 
2.  Unlikely:  
 
The reaction has little or no temporal sequence from administration of 
the investigational product, and/or a more likely alternative etiology 
exists. 
 
3.  Possibly Related:  
The reaction follows a reasonably temporal sequence from 
administration of the investigational product and follows a known 
response pattern to the suspected investigational product; the reaction 
could have been produced by the investigational product or could 
have been produced by the subject’s clinical state or by other modes 
of therapy administered to the subject. (Suspected ADR) 
 
4.  Probably Related:  
The reaction follows a reasonably temporal sequence from 
administration of investigational product; is confirmed by 
discontinuation of the investigational product or by re-challenge; and 
cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. (Suspected ADR) 
 
5.  Definitely Related:  
The reaction follows a reasonable temporal sequence from 
administration of investigational product; that follows a known or 
expected response pattern to the investigational product; and that is 
confirmed by improvement on stopping or reducing the dosage of the 
investigational product, and reappearance of the reaction on repeated 
exposure. (Suspected ADR) 
9.2.3 Recording of Adverse Events 
All clinical adverse events are recorded in the Adverse Event (AE) Log in the subject’s study binder. 
The site should fill out the AE Log and enter the AE information into the Electronic Data Capture 


 
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(EDC) system within 48 hours of the site learning of a new AE or receiving an update on an existing 
AE.   
 
Please Note: Serious Adverse Events (SAEs) must be reported to the Medical Monitor and 
Coordination Center within 24 hours of the site learning of the SAE.  
 
Entries on the AE Log (and into the EDC) will include the following: name and severity of the event, 
the date of onset, the date of resolution, relationship to investigational product, action taken, and 
primary outcome of event.   
 
9.3 
Adverse Events and Serious Adverse Events - Reportable Events 
The following are considered reportable events and must be reported to the Medical Monitor and 
Coordination Center within 24 hours of the site being notified of the event.  
 
o All events that meet the above criteria for Serious Adverse Events (SAEs) 
 
o Dosage Changes (Dose Management) 
o Investigational Product Suspension, Reduction or Re-challenge 
o Investigational Product Discontinuation 
 
o Key Study Events: 
o Subject Final Disposition 
o Feeding Tube Placement 
o Permanent Assisted Ventilation (PAV)* 
o Tracheostomy 
o Mortality 
o Pregnancy 
o Diaphragm Pacing System (DPS) device implantation 
o Emergency or Accidental Unblinding Events 
 
* Permanent Assisted Ventilation (PAV) is defined as more than 22 hours daily of non-invasive 
mechanical ventilation for more than one week (7 days).  The date of onset of PAV is the first day of 
the seven days. 
 
9.4  
Known Adverse Event/ Experience Prophylaxis Plan 
Acidic urine is a major risk factor for uric acid urolithiasis, which form from uric acid crystals. 
Accordingly, urine samples will be collected at in-person site visits for urinalysis to determine 
pH. A pre-specified algorithm will be followed for triggering urine alkalinization therapy for uric 
acid stone prophylaxis, starting at the Baseline visit. Because urate-elevating inosine treatment 
does not have an appreciable effect on urine pH as demonstrated in SURE-PD, the rate of 


 
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alkalinization due to low urine pH will be similar in placebo- and inosine-assigned subjects, 
mitigating any unblinding effect. 
9.4.1   Alkalinization Protocol 
Site staff will receive notification from the Coordination Center of the need to initiate alkalinization 
within a few days of the urinalysis that triggers the protocol. The following steps should then be 
taken: 
 
1- Site staff will prescribe “lower-dose” potassium citrate, which depends on subject weight (as 
recorded most recently on a study visit): 
•   Less than 70 kg:  10 mEq, in tablet form, po tid (with meals) 
•   70 kg or greater:  10 mEq, in tablet form, po qid (with meals and at bedtime) 
 
2- Staff will phone the subject to review the purpose, administration, potential adverse effects 
of potassium citrate, and plan rechecking urine pH and labs (CBC and BMP) in two weeks. 
In addition, staff will review recommendations for adequate hydration. The prescriber should 
review with the subject:  
• 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) 
then site staff may work with the Medical Safety Monitor to employ an 
alternative dosing schedule or an alternative alkalinizing agent such as 
sodium bicarbonate. 
• 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.  
• The possibility of abnormal results of blood lab test that will be monitored regularly 
on subsequent visits. 
• The importance of taking each dose faithfully, 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. 
 
3- Site staff will order urine pH and labs (CBC and BMP) to be collected two weeks after the 
initiation of urine alkalinization and will follow the algorithm in the figure to adjust 


 
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alkalinization therapy. Urine pH and labs (CBC and BMP) will be collected every two weeks 
as needed per algorithm illustrated in the figure. 
• 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: 
i. less than 70 kg:   20 mEq, in tablet form, po tid (with meals) 
ii. 70 kg or greater:   20 mEq, in tablet form, po qid (with meals and at bedtime) 
4- For any deviations from compliance with the medication site staff will contact the CCC who 
may engage the Medical Safety Monitor to obtain guidance.  
5- 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 Week 20 visit 
will be discontinued immediately after that visit (or at the time of study drug discontinuation 
if occurring earlier) irrespective of urine pH results at the visit.   
 
 


 
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9.4.2   Lab Monitoring during Alkalinization Protocol 
Current full prescribing information for potassium citrate indicates that laboratory tests should be 
checked every 4 months for: 
• Electrolytes (to monitor for potassium elevation) 
• Creatinine (to monitor for renal disease, a risk factor for hyperkalemic complications) 
• 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). 
 


 
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Under the study protocol labs will be monitored even more frequently as per algorithm above. 
 
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 above 5. If 
hyperkalemia remains, the potassium citrate will be discontinued.  An alternative, non-potassium-
based alkalinization measure 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 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. 
 


 
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10 
SAFETY MONITORING AND STATISTICAL ANALYSIS PLAN 
10.1 
Safety Monitoring  
An independent Medical Safety Monitor (MSM) will review receive a quarterly report of all AEs 
and safety laboratory tests. Recommendations for modification or termination of the trial based on 
safety data will be made by the MSM to the PI and the DSMB.   
 
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.  
 
Unanticipated problems involving risks to subjects or others including adverse events will be 
reported to the local site IRB in accordance with institutional guidelines for reporting unanticipated 
problems including adverse events. 
 
If serum urate is found to be above target range (i.e. 8.1 mg/dL or higher), inosine dose will be 
reduced or treatment will be stopped following the pre-specified titration algorithm described in 
Section 6.  
10.2 
Statistical Considerations 
10.2.1 Analysis Samples 
The As-treated (AT) sample will include all subjects who receive at least one dose of study drug 
classified according to the actual treatment received. An intention-to-treat (ITT) sample will include 
all randomized subjects classified according to their randomized treatment assignment without 
regard to compliance with their assigned treatment. The AT sample will be used as the primary 
sample for analyzing safety, tolerability, efficacy, and target engagement outcomes. Secondary 
analyses of safety outcomes will look at the AT sample with events censored after discontinuation of 
inosine among participants initiated on inosine and after initiation of inosine among participants 
initiated on placebo should any off-label use be detected. Secondary analysis of the ITT sample will 
be used to estimate efficacy in preparation for future phase 3 trials. 
 


 
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10.2.2 Outcomes  
10.2.2.1 Safety outcomes 
The proportion of subjects experiencing one or more adverse events (AE) prior to treatment, one or 
more treatment-emergent (TE, defined as occurring any time after first dose of study drug) AEs, one 
or more severe TE AEs, one or more serious TE AEs (SAE), one or more TE AEs of special interest 
(AESI, including gout, gouty arthritis, and kidney stones), and one or more AEs classified by 
MedDRA system organ class, higher level term, and preferred term over 24 weeks in the inosine 
group will be compared to the placebo group using one-tailed Fisher's exact tests at alpha = 0.05. 
The proportion of subjects experiencing one or more TE clinically significant abnormal labs for each 
safety assay performed or clinically significant abnormal vital signs for each vital sign monitored 
over 24 weeks in the inosine group will be compared to the placebo group using Fisher's exact tests. 
As a sensitivity analysis, we will also analyze event rates using negative binomial models for each 
type of event, adjusting for each participant's length of follow-up. 
10.2.2.2 Tolerability 
Tolerance will be defined as completion of the 20-week study without permanently discontinuing 
study drug or suspending study drug for greater than 28 days. Tolerability of inosine vs. placebo will 
be based on the proportion determined tolerant at week 20 and compared by Fisher's exact test from 
the AT sample. Serum urate elevation via oral inosine as titrated in this study will be judged 
tolerable if the lower one-sided 95% confidence bound on the proportion tolerant is greater than 
50%. 
10.2.2.3 Efficacy and target engagement 
Effects of treatment on ALSFRS-R, will be analyzed in shared-baseline generalized least squares 
models with among-person effects of visit and the interaction of treatment group x post-baseline visit 
and within-person unstructured covariance among repeated measurements. Shared-baseline random-
slopes linear mixed models will be used to analyze high-frequency smartphone metrics with fixed 
effects of time and treatment x post-baseline time and random participant-specific intercepts and 
slopes with unstructured covariance.  Baseline characteristics will be compared by masked treatment 
groups prior to finalizing analysis of efficacy outcomes to select covariates to include the models to 
avoid chance confounding.  Two-tailed tests at alpha = 0.05 will be used. 
10.2.2. Operational endpoints 
Accuracy of serum urate titration will be evaluated relative to the average levels from the week 12 
visit onward and relative to the proportion of samples that are within the target range.  Inosine 
dosage associated with accurate titration will be summarized.  Urine pH trajectories and the 
frequency of alkalinization will be summarized. 


 
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10.2.2.5 Power Calculations 
Assuming that 50%, 20%, and 10% of participants in the placebo group are expected to experience 
an AE or a given type of AE, we will have 80% power to declare a significant treatment-dependent 
increase in the proportion experiencing an AE if at least 95%, 71%, and 59% of participants in the 
inosine group are expected to experience an AE, respectively. We will have 80% power to observing 
at least one instance of any inosine-associated AE with a true probability of occurrence of at least 
8%. For tolerability, we will have 80% power to declare inosine tolerable if the true proportion 
tolerant is at least 71%. Variance component estimates for calculating power for effects of treatment 
on ALSFRS-R are from a single arm pilot study of 25 participants on inosine for 20 weeks. Based on 
the follow-up schedule for this trial and assuming a random-slopes model, the estimated effective SD 
for ALSFRS-R slope per month is 1.4. Given this estimate, we will have 80% power to detect a 
difference in ALSFRS-R slopes between the inosine and placebo groups of 1.05 units per month.  
We will have 12% power for a difference in slopes of 0.3 units per month. 
 


 
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11 
DATA COLLECTION 
11.1 
Role of Data Management 
Data Management (DM) is responsible for the development, execution and supervision of plans, 
policies, programs, and practices that control, protect, deliver, and enhance the value of data and 
information assets. 
 
All data will be managed in compliance with applicable Sponsor (or their designee) policies and 
regulatory requirements. Site personnel will collect, transcribe, correct, and transmit the data onto 
source documents, Case Report Forms (CRFs), and/or other forms used to report, track and record 
clinical research data.  Clinical sites will be monitored to ensure compliance with data management 
requirements and Good Clinical Practices.  DM is responsible for developing, testing, and managing 
clinical data management activities. 
11.1.1 Data Entry and Checks 
The site personnel are instructed to enter information into the Electronic Data Capture (EDC) 
System within 5 days of a visit.  Please Note: Serious Adverse Events (SAEs) must be reported to 
the Coordination Center within 24 hours of the site learning of the SAE.  Data collection is the 
responsibility of the staff at the site under the supervision of the Site Investigator (SI).  During the 
study, the SI must maintain complete and accurate documentation for the study. 
 
The EDC includes password protection.  An edit checking and data clarification process will be put 
in place to ensure accuracy and completeness of the database.  Logic and range checks as well as 
more sophisticated rules may be built into the eCRFs to provide immediate error checking of the 
data entered.  The system has the capability to automatically create electronic queries for forms that 
contain data that are out of range, out of window, missing or not calculated correctly.  The site will 
only have access to the queries concerning their subjects.   
11.1.2 Data Lock Process 
The application will have the ability to lock the database to prevent any modification of data once 
the study is closed.  Once this option is activated, every user will have Read-Only access to the data. 
The database can only be locked after each Site Investigator (SI) has signed off on their subjects and 
all queries have been resolved.   
11.1.3 Quality Assurance 
Protocol procedures are reviewed with the Site Investigator (SI) and associated personnel prior to the 
study to ensure the accuracy and reliability of data. Each SI must adhere to the protocol detailed in 


 
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this document and agree that any changes to the protocol must be approved by the Coordination 
Center prior to seeking approval from the central IRB.  Each Site Investigator will be responsible for 
enrolling only those study subjects who have met protocol eligibility criteria. 
11.1.3 Data handling and record keeping 
The Site Investigator (SI) is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible manner 
to ensure accurate interpretation of data. Dark ink is required to ensure clarity of reproduced copies.  
When making changes or corrections, cross out the original entry with a single line, and initial and 
date the change. Do not erase, overwrite, or use correction fluid or tape on the original.  
 
Source document templates (SDTs) will be provided for use and maintained for recording data for 
each subject enrolled in the study. Data reported in the eCRF derived from source documents should 
be consistent with the source documents and discrepancies should be explained.  The Coordination 
Center will provide guidance to SIs on making corrections to the source documents and eCRFs. 
11.2 
Confidentiality 
Study subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited. Upon the subject’s permission, medical 
information may be given to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare. All local and federal guidelines and regulations regarding 
maintaining study subject confidentiality of data will be adhered to. 
 
Data generated by this study must be available for inspection by representatives of the US FDA, by 
the Office for Human Research Protections (OHRP), the Sponsor, all pertinent national and local 
health and regulatory authorities, the Coordination Center or their representative, and the sites local 
IRB. 
11.3 
Study Discontinuation  
The study can be terminated at any time by the Sponsor, DSMB, or FDA.  Reasons for terminating 
the study may include the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
study subjects. 
• Study subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
• Sponsor withdraws funding. 


 
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11.4 
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, laboratory test results, and medical inventory records, must be retained by the Site 
Investigator (SI) 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 Coordination Center 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 Sponsor or their 
representative.  
11.5 
Publications 
The Principal Investigator, Sabrina Paganoni, MD, will be responsible for publications of results 
from this trial. Responsibilities will include the following: 
• Analyze and interpret data gathered in this study, and write publications from these data. 
• Submit manuscripts to selected journals and address peer reviewers’ comments. 
• Submit abstracts to selected meetings and present data at the meetings. 
• Determine authorship on the basis of the Uniform Requirements for Manuscripts. 
 


 
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12 
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uric acid concentration and risk of Parkinson's disease. Mov Disord 2013;28:1737-1740. 
28. 
Auinger P, Kieburtz K, McDermott MP. The relationship between uric acid levels and 
Huntington's disease progression. Mov Disord 2010;25:224-228. 
29. 
Irizarry MC, Raman R, Schwarzschild MA, et al. Plasma urate and progression of mild 
cognitive impairment. Neurodegener Dis 2009;6:23-28. 
30. 
Lee JE, Song SK, Sohn YH, Lee PH. Uric acid as a potential disease modifier in patients 
with multiple system atrophy. Mov Disord 2011;26:1533-1536. 
31. 
Paganoni S, Zhang M, Quiroz Zarate A, et al. Uric acid levels predict survival in men with 
amyotrophic lateral sclerosis. J Neurol 2012;259:1923-1928. 
32. 
Abraham A, Drory VE. Influence of serum uric acid levels on prognosis and survival in 
amyotrophic lateral sclerosis: a meta-analysis. J Neurol 2014. 
33. 
Ikeda K, Hirayama T, Takazawa T, Kawabe K, Iwasaki Y. Relationships between disease 
progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with 
amyotrophic lateral sclerosis: a cross-sectional study. Intern Med 2012;51:1501-1508. 
34. 
Keizman D, Ish-Shalom M, Berliner S, et al. Low uric acid levels in serum of patients with 
ALS: further evidence for oxidative stress? J Neurol Sci 2009;285:95-99. 
35. 
Nazem Atassi JB, Amy Shui, Neta Zach, Alexander Sherman, Ervin Sinani, Jason Walker, 
Igor Katsovskiy, David Schoenfeld, Merit Cudkowicz, Melanie Leitner The PRO-ACT 
Database: Design, Initial Analyses, and Predictive Features. Neurology In press. 
36. 
Chen X, Burdett TC, Desjardins CA, et al. Disrupted and transgenic urate oxidase alter urate 
and dopaminergic neurodegeneration. Proc Natl Acad Sci U S A 2013;110:300-305. 
37. 
Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA. Urate and its 
transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson's 
disease. PLoS One 2012;7:e37331. 
38. 
Cipriani S, Desjardins CA, Burdett TC, Xu Y, Xu K, Schwarzschild MA. Protection of 
dopaminergic cells by urate requires its accumulation in astrocytes. J Neurochem 
2012;123:172-181. 
39. 
Du Y, Chen CP, Tseng CY, Eisenberg Y, Firestein BL. Astroglia-mediated effects of uric 
acid to protect spinal cord neurons from glutamate toxicity. Glia 2007;55:463-472. 


 
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40. 
Scott GS, Cuzzocrea S, Genovese T, Koprowski H, Hooper DC. Uric acid protects against 
secondary damage after spinal cord injury. Proc Natl Acad Sci U S A 2005;102:3483-3488. 
41. 
Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against 
excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in 
vivo. J Neurosci Res 1998;53:613-625. 
42. 
D'Amico E, Factor-Litvak P, Santella RM, Mitsumoto H. Clinical perspective on oxidative 
stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 2013;65:509-527. 
43. 
Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both 
sporadic and familial amyotrophic lateral sclerosis. J Neurochem 1997;69:2064-2074. 
44. 
Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH, Jr. Increased 3-
nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 
1997;42:644-654. 
45. 
Bogdanov M, Brown RH, Matson W, et al. Increased oxidative damage to DNA in ALS 
patients. Free Radic Biol Med 2000;29:652-658. 
46. 
Siciliano G, Piazza S, Carlesi C, et al. Antioxidant capacity and protein oxidation in 
cerebrospinal fluid of amyotrophic lateral sclerosis. J Neurol 2007;254:575-580. 
47. 
Lawton KA, Brown MV, Alexander D, et al. Plasma metabolomic biomarker panel to 
distinguish patients with amyotrophic lateral sclerosis from disease mimics. Amyotroph 
Lateral Scler Frontotemporal Degener 2014:1-9. 
48. 
Weiduschat N, Mao X, Hupf J, et al. Motor cortex glutathione deficit in ALS measured in 
vivo with the J-editing technique. Neurosci Lett 2014;570:102-107. 
49. 
Zhang N, Shu HY, Huang T, et al. Nrf2 Signaling Contributes to the Neuroprotective Effects 
of Urate against 6-OHDA Toxicity. PLoS One 2014;9:e100286. 
50. 
Bakshi R MM, Logan R, Chen X, Schwarzschild M. Astroglia-dependent protective 
mechanisms of urate in a cellular model of Parkinson's disease. Society for Neuroscience, 
Annual Meeting, 2013 2013. 
51. 
Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of 
peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest 
possible approaches to therapy of the disease. Mult Scler 2001;7:313-319. 
52. 
Cameron MA, Sakhaee K. Uric acid nephrolithiasis. Urol Clin North Am 2007;34:335-346. 
53. 
Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible 
relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol 2013;14:164. 
54. 
McNaughton L, Dalton B, Tarr J. Inosine supplementation has no effect on aerobic or 
anaerobic cycling performance. Int J Sport Nutr 1999;9:333-344. 
55. 
Starling RD, Trappe TA, Short KR, et al. Effect of inosine supplementation on aerobic and 
anaerobic cycling performance. Med Sci Sports Exerc 1996;28:1193-1198. 
56. 
Williams MH, Kreider RB, Hunter DW, et al. Effect of inosine supplementation on 3-mile 
treadmill run performance and VO2 peak. Med Sci Sports Exerc 1990;22:517-522. 
57. 
Gonsette RE, Sindic C, D'Hooghe M B, et al. Boosting endogenous neuroprotection in 
multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting 
Multiple Sclerosis (ASIIMS) trial. Mult Scler 2010;16:455-462. 
58. 
Spitsin S, Markowitz CE, Zimmerman V, Koprowski H, Hooper DC. Modulation of serum 
uric acid levels by inosine in patients with multiple sclerosis does not affect blood pressure. J 
Hum Hypertens 2010;24:359-362. 


 
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59. 
Markowitz CE, Spitsin S, Zimmerman V, et al. The treatment of multiple sclerosis with 
inosine. J Altern Complement Med 2009;15:619-625. 
60. 
Bogner W, Hess AT, Gagoski B, et al. Real-time motion- and B-correction for LASER-
localized spiral-accelerated 3D-MRSI of the brain at 3T. Neuroimage 2013;88C:22-31. 
61. 
Bhattacharyya S BR, Logan R, Ascherio A, Macklin E, Schwarzschild M. Oral inosine 
persistently elevates plasma antioxidant capacity in early Parkinson's disease. AAN Annual 
Meeting 2014. 
62. 
Posner K, (et.al), Columbia Classification Algorithm of Suicide Assessment (C-CASA): 
Classification of Suicidal Events in the FDA’s Pediatric Suicidal Risk Analysis of Anti-
depressants, Am J Psychiatry, 2007, 164:1035-1043. 
63. 
September 2010 US FDA Draft Guidance for Industry Suicidality: Prospective Assessment 
of Occurrence in Clinical Trials 
 
 
 


 
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13 
APPENDICES 
13.1 APPENDIX I: EL ESCORIAL WORLD FEDERATION OF NEUROLOGY CRITERIA 
FOR THE DIAGNOSIS OF ALS 
 
Information obtained from the web site: www.wfnals.org. 
 
The diagnosis of Amyotrophic Lateral Sclerosis [ALS] requires:  
A - The presence of: 
 
(A:1) evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiology cal 
or  
neuropathologic examination,  
 
(A:2)  evidence of upper motor neuron (UMN) degeneration by clinical examination, and  
 
(A:3) progressive spread of symptoms or signs within a region or to other regions, as 
determined  
by history or examination, together with 
B - The absence of: 
 
(B:1) electrophysiological and pathological evidence of other disease processes that might  
 
explain the signs of LMN and/or UMN degeneration, and  
 
(B:2) neuroimaging evidence of other disease processes that might explain the observed 
 
clinical and electrophysiological signs.  
 
CLINICAL STUDIES IN THE DIAGNOSIS OF ALS 
A careful history, physical and neurological examination must search for clinical evidence of UMN 
and LMN signs in four regions [brainstem, cervical, thoracic, or lumbosacral spinal cord] (see Table 
1) of the central nervous system [CNS]. Ancillary tests should be reasonably applied, as clinically 
indicated, to exclude other disease processes. These should include electrodiagnostic, 
neurophysiological, neuroimaging and clinical laboratory studies.  Clinical evidence of LMN and 
UMN degeneration is required for the diagnosis of ALS.  The clinical diagnosis of ALS, without 
pathological confirmation, may be categorized into various levels of certainty by clinical assessment 
alone depending on the presence of UMN and LMN signs together in the same topographical 
anatomic region in either the brainstem [bulbar cranial motor neurons], cervical, thoracic, or 
lumbosacral spinal cord [anterior horn motor neurons]. The terms Clinical Definite ALS and 
Clinically Probable ALS are used to describe these categories of clinical diagnostic certainty on 
clinical criteria alone: 
 
A. Clinically Definite ALS is defined on clinical evidence alone by the presence of UMN, as well as 
LMN signs, in three regions.  


 
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B. Clinically Probable ALS is defined on clinical evidence alone by UMN and LMN signs in at least 
two regions with some UMN signs necessarily rostral to (above) the LMN signs. 
 
C. Clinically Probable ALS - Laboratory-supported is defined when clinical signs of UMN and LMN 
dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN 
signs defined by EMG criteria are present in at least two limbs, with proper application of 
neuroimaging and clinical laboratory protocols to exclude other causes. 
 
D. Clinically Possible ALS is defined when clinical signs of UMN and LMN dysfunction are found 
together in only one region or UMN signs are found alone in two or more regions; or LMN signs are 
found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported ALS 
cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, 
neurophysiologic, neuroimaging or clinical laboratory studies. Other diagnoses must have been 
excluded to accept a diagnosis of Clinically Possible ALS. 
 
 
Table 1 
 
Brainstem  
Cervical  
Thoracic  
Lumbosacral  
Lower motor 
neuron signs 
weakness, 
atrophy, 
fasciculations  
jaw, face, 
palate, 
tongue, larynx  
neck, arm, hand, 
diaphragm  
back, 
abdomen  
back, abdomen, leg, 
foot  
Upper motor 
neuron signs 
pathologic spread 
of reflexes, clonus, 
etc.  
clonic jaw 
gag reflex 
exaggerated 
snout reflex 
pseudobulbar 
features 
forced yawning 
pathologic 
DTRs 
spastic tone  
clonic DTRs  
Hoffman reflex 
pathologic 
DTRs 
spastic tone 
 
preserved reflex 
in weak wasted 
limb  
loss of 
superficial 
abdominal 
reflexes 
pathologic 
DTRs 
spastic tone  
clonic DTRs - 
extensor plantar 
response 
pathologic DTRs 
spastic tone 
 
preserved reflex in 
weak wasted limb  
 


 
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13.2 APPENDIX II: ALS FUNCTIONAL RATING SCALE – REVISED (ALSFRS-R) 
ALSFRS-R 
 
QUESTIONS:  
 
 
 
 
 
 
SCORE: 
    
1. Speech 
4 = Normal speech processes 
3 = Detectable speech disturbances 
2 = Intelligible with repeating 
1 = Speech combined with nonvocal communication 
0 = Loss of useful speech 
 
2. Salivation 
4 = Normal 
3 = Slight but definite excess of saliva in mouth; may have nighttime drooling 
2 = Moderately excessive saliva; may have minimal drooling 
1 = Marked excess of saliva with some drooling 
0 = Marked drooling; requires constant tissue or handkerchief 
 
3. Swallowing 
4 = Normal eating habits 
3 = Early eating problems – occasional choking 
2 = Dietary consistency changes 
1 = Needs supplemental tube feeding 
0 = NPO (exclusively parenteral or enteral feeding) 
 
4. Handwriting 
4 = Normal 
3 = Slow or sloppy; all words are legible 
2 = Not all words are legible 
1 = No words are legible but can still grip a pen  
0 = Unable to grip pen 
 
5a. Cutting Food and Handling Utensils (patients without gastrostomy) 
 
 
 
4 = Normal 
3 = Somewhat slow and clumsy, but no help needed 
2 = Can cut most foods, although clumsy and slow; some help needed 
1 = Food must be cut by someone, but can still feed slowly 
0 = Needs to be fed 
 


 
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5b. Cutting Food and Handling Utensils (alternate scale for patients with gastrostomy) 
4 = Normal 
3 = Clumsy, but able to perform all manipulations independently 
2 = Some help needed with closures and fasteners 
1 = Provides minimal assistance to caregivers 
0 = Unable to perform any aspect of task 
 
6. Dressing and Hygiene 
4 = Normal function 
3 = Independent, can complete self-care with effort or decreased efficiency 
2 = Intermittent assistance or substitute methods 
1 = Needs attendant for self-care 
0 = Total dependence 
 
7. Turning in Bed and Adjusting Bed Clothes 
4 = Normal function 
3 = Somewhat slow and clumsy, but no help needed 
2 = Can turn alone, or adjust sheets, but with great difficulty 
1 = Can initiate, but not turn or adjust sheets alone 
0 = Helpless 
 
8. Walking 
4 = Normal 
3 = Early ambulation difficulties 
2 = Walks with assistance 
1 = Nonambulatory functional movement only 
0 = No purposeful leg movement 
 
9. Climbing Stairs 
4 = Normal 
3 = Slow 
2 = Mild unsteadiness or fatigue 
1 = Needs assistance 
0 = Cannot do 
 


 
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R-1. Dyspnea  
 
 
 
4 = None 
3 = Occurs when walking 
2 = Occurs with one or more of the following: eating, bathing, dressing 
1 = Occurs at rest, difficulty breathing when either sitting or lying 
0 = Significant difficulty, considering using mechanical respiratory support 
 
R-2 Orthopnea 
 
 
 
4 = None 
3 = Some difficulty sleeping at night due to shortness of breath, does not routinely use more than 
two pillows 
2 = Needs extra pillow in order to sleep (more than two) 
1 = Can only sleep sitting up 
0 = Unable to sleep without mechanical assistance 
 
R-3 Respiratory Insufficiency 
 
4 = None 
3 = Intermittent use of BiPAP 
2 = Continuous use of BiPAP during the night 
1 = Continuous use of BiPAP during the night and day 
0 = Invasive mechanical ventilation by intubation or tracheostomy 
  
Evaluator’s Initials: _____ _____ ______ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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13.3 APPENDIX III: COLUMBIA-SUICIDE SEVERITY RATING SCALE - BASELINE 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
Version 1/14/09 
 
 Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, 
P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in the Columbia-Suicide Severity Rating 
Scale are suggested probes. Ultimately, the determination of the presence of suicidal ideation or behavior depends on the judgment of the individual administering 
the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, developed by John Mann, MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 
10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries and 
training requirements contact posnerk@nyspi.columbia.edu  
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
 


 
 
 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” 
section below. 
 
Lifetime:  
Time He/She 
Felt Most 
Suicidal 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
 
Yes       No 
□    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways 
to kill oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 
Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 
Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?                                        
                                
If yes, describe: 
 
 
Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or 
acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop 
the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to 
get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                        living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 


 
 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth 
but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling 
trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down 
from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a 
gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 


 
 
 
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Answer for Actual Attempts Only 
Most Recent  
Attempt 
Date: 
Most Lethal      
     
Attempt 
Date: 
Initial/First  
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., 
comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can 
recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without 
reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major 
damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Enter Code 
 
 
 
______ 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so 
no medical damage; laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
                  C-SSRS—Baseline (Version 1/14/09)    
 
 
                                        
        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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13.4 APPENDIX IV: COLUMBIA-SUICIDE SEVERITY RATING SCALE – SINCE LAST VISIT 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, 
P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in the Columbia-Suicide Severity Rating 
Scale are suggested probes. Ultimately, the determination of the presence of suicidal ideation or behavior depends on the judgment of the individual administering 
the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, developed by John Mann, MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 
10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries and 
training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


 
 
 
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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” 
section below. 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways 
to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never 
go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts 
but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?                                           
                             
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the 
least severe and 5 being the most severe).  
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or 
acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop 
the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to 
get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 


 
 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is 
in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling 
trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down 
from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before 
you actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting 
a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 


 
 
 
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Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding 
of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-
degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 
20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very 
serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train 
but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                                        
                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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13.5 APPENDIX X: SMARTPHONE USAGE QUESTIONNAIRE  
 
 
1. How do you use your phone?   
              Independently  
              With help for some functions 
              Someone else uses my phone on my behalf 
              I don’t use a phone. I am participating with a tablet.  
 
2. How often is your phone with you?   
  Almost all the time when I am awake.  
  Most of the time 
  Some of the time 
  Very little 
 
3. How do you carry your phone most of the time? 
In your pocket 
Purse/Bag 
On a wheelchair 
Other 
Someone else carries my phone.  
 
4. What do you do with your phone when you are at home?  
I carry my phone with me most of the time.  
I leave it on a surface most of the time.  
  
5. When do you first use your phone in the morning?   
Immediately after I wake up 
Within one hour after I wake up 
2+ hours after I wake up 
 
6. When do you last use your phone at night?   
Just before going to bed 
About an hour before going to bed  
More than 2 hours before going to bed  
 
7. What do you do with your phone when you sleep? 
I keep the phone with me in bed.  
I leave it on a surface in my room.  
I leave it on a surface in another room.  
 
8. Do you use your phone as an alarm clock? 
Yes 
Sometimes 
No 
 


 
 
 
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13.6 APPENDIX XI EXIT QUESTIONNAIRE: STUDY PARTICIPANT 
Status:  Done 
 
 Not Done 
 
1. 
Which treatment do you believe you were assigned to during this study? 
 Active Treatment  
 Placebo 
 
2. 
How sure are you of this answer? 
 Just guessing, not sure at all 
 Somewhat sure 
 Very sure 
 
3. 
If somewhat sure or very sure, provide the primary reason for your treatment guess:  
 Improvement in symptoms of disease under study 
 Lack of improvement in symptoms of disease under study 
 Adverse effects of study medication  
 Lack of adverse effects of study medication 
 Appearance, taste or odor or other physical characteristics of the study medication 
 Other reasons  
 
4. 
If somewhat sure or very sure, provide the secondary reason for your treatment guess:  
 Improvement in symptoms of disease under study 
 Lack of improvement in symptoms of disease under study 
 Adverse effects of study medication  
 Lack of adverse effects of study medication 
 Appearance, taste or odor or other physical characteristics of the study medication  
 Other reasons  
 
5. 
How did you take the study drug? 
 By mouth 
 By feeding tube  
 Both 
 
How easy/challenging did you find administration of the study drug? Any comments on the study drug’s 
consistency? Anything you would like to see changed or different?  
 
6. 
Do you have any general comments or suggestions that you would like to share with the study team?  


 
 
 
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13.7 APPENDIX XII EXIT QUESTIONNAIRE: SITE INVESTIGATOR 
 
Status:  Done  
 Not Done 
 
1. 
Which treatment do you believe the subject was assigned to during this study? 
 Active Treatment 
 
 Placebo 
 
2. 
How sure are you of this answer? 
 Just guessing, not sure at all  
 Somewhat sure 
 Very sure 
 
3. If somewhat sure or very sure, provide the primary reason for your treatment guess:  
 Improvement in symptoms of disease under study 
 Lack of improvement in symptoms of disease under study 
 Adverse effects of study medication  
 Lack of adverse effects of study medication 
 Appearance, taste or odor or other physical characteristics of the study medication  
 Other reasons  
 
4. 
If somewhat sure or very sure, provide the secondary reason for your treatment guess:  
 Improvement in symptoms of disease under study 
 Lack of improvement in symptoms of disease under study 
 Adverse effects of study medication  
 Lack of adverse effects of study medication 
 Appearance, taste or odor or other physical characteristics of the study medication 
 Other reasons  
 

ICF_001.pdf: 
Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
Page 1 of 22 
 
Subject Identification 
Protocol Title: Study of Urate Elevation in ALS – Phase II (SURE-ALS2) 
 
Principal Investigator: Sabrina Paganoni, MD, PhD 
 
Site Investigator:       
 
NEALS study site:       
 
Description of Subject Population: Amyotrophic Lateral Sclerosis (ALS) 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
[Name of site] is [description of site]. This research is being conducted at academic centers that 
are part of the Northeast ALS (NEALS) Consortium.  
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
We are doing this research study to find out if inosine is safe to take without causing too many 
side effects in people with amyotrophic lateral sclerosis (ALS).   
 
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of the nerves controlling 
movement (“motor neurons”). ALS causes muscles to become weak and thin, which leads to 
paralysis (the loss of the ability to move). Oxidative damage to the motor neurons, similar to rust 
destroying the molecular machinery that runs them, is one of the proposed mechanisms (ways) 
that causes their degeneration (worsening) and resulting paralysis in ALS. It is possible that 
drugs that reduce oxidative stress may be beneficial in ALS.   
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 2 of 22 
 
Subject Identification 
Inosine is as an over-the-counter supplement. Taking inosine causes an increase in the blood 
levels of urate (uric acid). Urate is a natural antioxidant present in the body that may help 
counteract (cancel out) oxidative stress.  The U.S. Food and Drug Administration (FDA) has not 
approved inosine to treat ALS. 
 
We are asking you to take part in this research study because you have ALS. About 60 subjects 
with ALS will take part in this research study at 3 Northeast ALS Centers in the United States.  
About [INSERT NUMBER] subjects with ALS will take part in the study at [INSERT SITE 
NAME]. 
 
The study is being paid for by the Salah Foundation and the MGH cure ALS Fund. 
 
Study Information Included in Your Electronic Medical Record 
A notation that you are taking part in this research study may be made in your electronic medical 
record.  Information from the research that relates to your general medical care may be included 
in the record (for example, list of allergies, results of standard blood tests done at the hospital 
labs). 
 
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record. 
 
How long will I take part in this research study? 
 
It will take you about 27 weeks to complete this research study.   
 
During this time, we will ask you to make at least 4 in-person study visits. We will call you 
approximately 15 times during the study to remind you of your schedule and to let you know 
what your urate (uric acid) levels are. We may adjust the dose of inosine/placebo based on the 
urate (uric acid) levels. Each phone call will last about 15 minutes. 
 
What will happen in this research study? 
 
This is a double-blind, placebo controlled study where the subjects are selected by chance (like 
tossing a coin) to be in 1 of 2 groups – this is called ‘randomization’.  “Double-blind” means that 
neither you, the study doctor, nor any of the study staff will know which drug you are receiving, 
although your study doctor can find out in case of an emergency.  The placebo looks and tastes 
exactly like the study drug, but contains no study drug.   
 
You have a 2 in 3 chance of being assigned to the treatment group and a 1 in 3 chance of 
being assigned to the placebo group.   
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 3 of 22 
 
Subject Identification 
• Group 1- Inosine (study drug) 
 
• Group 2 – Placebo  
 
You will take your study drug (capsule) orally (by mouth) twice a day, once in the morning and 
once at night for the first 2 weeks. Your study drug dose will then be adjusted based on your 
urate (uric acid levels) during the rest of the study. 
 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. 
 
MOBILE APPLICATION 
This study will utilize a mobile application to collect information on tasks that you perform 
while using your smartphone.  You will be required to have and use a smartphone to participate 
in this study. 
 
The mobile application will primarily collect two different types of data - active data and 
background data. Active data is information that will be collected when you complete certain 
tasks using the smartphone app like answering surveys, recording your voice, and completing 
exercises using your finger. Background data is information that is collected from your 
smartphone when you are not using the app like how often and with what speed do you type, 
how long and frequent are phone calls made, when your phone is off or on, etc. We will not be 
collecting data about the actual content of your phone call conversations, multimedia messages, 
text messages, contacts, web activity or emails. 
 
Data that is collected is automatically secured and encrypted before it is transmitted to an online 
HIPAA-compliant Amazon Data Storage account. Once your data reaches the online storage 
account, it is further secured by another layer of security. The Amazon S3 Data Storage is where 
encrypted information relayed from your smartphone will be stored and accessed by research 
teams. Your encrypted information will only be accessed after your participation in the study has 
ended. The data is sent only through a Wi-Fi connection and not through your smartphone’s data 
plan. 
 
Passive Data Collection – refers to data that is collected when you are not using the app. 
 
Accelerometer - The app records information about your phone’s movement when the phone is 
on. This information can be used to estimate how long you sat still, when you were walking, how 
many steps you took while walking, and other general activity levels. 
 
GPS – The app records information regarding your smartphone’s location and the accuracy of 
such information. The GPS data will be used to calculate movement based on the relative 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 4 of 22 
 
Subject Identification 
differences between coordinates. GPS coordinates are recorded, but not on a map. It cannot 
identify how you travelled. This data will only be transmitted when you are connected to Wi-Fi. 
We will not track your location in real time. It is not possible to completely remove information 
about where and when you have travelled. The app does not record GPS continuously, only 
intermittently. 
 
Phone/Screen Usage – The app records when you turn on or off your smartphone’s screen, when 
you turn off or reboot your smartphone, and when you plug in or unplug your smartphone. 
Tracking when the screen is on provides some information for when you are using your 
smartphone. 
 
Nearby Wi-Fi Routers – The app records a list of all Wi-Fi routers with which your smartphone 
can communicate, and the signal strength of each of those routers. This serves to provide 
information regarding your relative location. When your smartphone has a very strong, clear 
signal from a Wi-Fi router, it is probably in the same room as that router. 
 
 
 
Phone Call Log – The app records specific data on all incoming, outgoing, and missed calls to 
and from your smartphone. It does not record the audio or content of the calls. It also does not 
record the identity or actual phone number of the person called. It records the time of each call 
and the length of the call. 
 
Text Message Log – The app records specific information on the text messages sent from and 
received by your phone. It does not record the content of text messages, and does not record the 
phone number of the person called. It records the time each message was sent or received and the 
length of the message (in number of characters). 
 
Active Data Collection – refers to data that is collected when you are using the app. 
 
The app will remind you to take a questionnaire, voice recording, or virtual slider exercise by 
making a notification appear on your smartphone’s screen. The app will record how long it takes 
to answer questions and how long it takes to complete each of the following items: 
 
Survey Data – the app will ask you to fill out weekly surveys. Each survey appears with a 
notification on your smartphone.  
 
ALSFRS-R Questionnaire – the app asks you to fill out a weekly 12-question 
questionnaire. 
Each 
questionnaire 
appears 
with 
a 
notification. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 5 of 22 
 
Subject Identification 
Voice Recordings –Once a week, the app may ask you to make voice recordings. Your 
voice will be saved as an audio file so that researchers can analyze it. 
 
 
 
 
SCREENING VISIT 
At this visit, we will do some tests and procedures to see if you qualify to take part in this 
research study.  The study doctor will review the results of these tests and procedures.  If you 
don’t qualify, the study doctor will tell you why.   
 
Length of time = about 1 hour   
 
At this visit, we will: 
• Obtain written informed consent  
• Review eligibility criteria 
• Review your medical history and demographic information (for example, your race and 
gender) 
• Review your ALS diagnosis history  
• Perform the Slow Vital Capacity (SVC) 
• Perform physical examination, including height, weight and vital signs 
• Perform neurological examination 
• Collect blood for screening labs and check the level of urate (uric acid) in your body 
(approximately 3 tablespoons) 
• Ask about medications and supplements you are currently taking and/or any therapies 
you are receiving 
• Review side effects and changes in your health after signing the consent form 
 
NOTE: The study doctor or study coordinator will call you about 1-5 days after this visit to tell 
you if you are eligible for this study. If you are eligible, you will be asked to return for a Baseline 
Visit within 21 days of the Screening Visit.  
BASELINE VISIT  
Length of time = about 2 hours  
 
At this visit, we will: 
• Review eligibility criteria 
• Review the medications and supplements you are currently taking and/or any new 
therapies you are receiving 
• Ask you to complete the ALSFRS-R questionnaire 
• Complete the suicide questionnaire (a questionnaire about suicidal thinking and behavior) 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 6 of 22 
 
Subject Identification 
• Collect a urine sample for urinalysis 
• Draw blood samples for routine safety lab test and to check the level of urate (uric acid) 
in your body   
• Ask you about changes in your health condition since your last visit 
• Give you the first dose of study drug/placebo in the office. We will observe you for 10 
minutes after you take the drug to monitor for immediate drug reaction. 
• Download, install and briefly orient you to the mobile application  
 
NOTE: You may receive a phone call within 5 days of this visit and you may be asked to take 
alkalinization therapy (with Potassium Citrate) if the results of the urinalysis test show that you 
have acidic urine. The alkalinization therapy will help to make your urine less acidic, reducing 
your risk of kidney stones. If your urinalysis test comes back normal, you will not be asked to 
take alkalinization therapy. 
 
Taking the Study Drug 
We will give you a supply of study drug/placebo to take home with you at the Baseline Visit to 
last until Week 12. We will make sure you know how to take the study drug.  
 
You will take the study drug/placebo by mouth with or without food for the entire study. Study 
staff will give you specific instructions on how many capsules of study drug/placebo to take 
from the time of your screening visit to your next visit. 
 
From Week 3 to Week 20, the dose of study drug/placebo will be adjusted based on the results of 
the blood tests that will be performed at Week 3, Week 6, Week 9, Week 12 and Week 16. You 
will receive a phone call within 5 business days of your appointment and may be instructed to 
increase (take more), decrease (take less) or maintain (keep the same) the dose of study 
drug/placebo. 
 
It is important for you to follow our instructions about how to take the study drug.  Bring any 
unused study drug and empty bottles with you to the Week 12 and Week 20 study visits.  
 
Your Study Drug Diary 
We will give you a study diary to fill out at home each day.  You will write down the date and 
time you take the study drug/placebo and how much study drug/placebo you take.  Bring this 
diary with you to the Week 12 and Week 20 visits. 
 
WEEK 3, 6, 9 AND 16 VISITS  
Length of time = about 15 minutes 
 
In between the study visits, we will ask you to go to a local Quest Diagnostics Laboratory for 
blood draws. You will receive a written schedule that will tell you exactly when to go to the lab 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
 
 
 
 
 
Page 7 of 22 
 
Subject Identification 
for blood draws. These blood draws will allow us to monitor the levels of urate (uric acid) in 
your blood. We need to do so because taking inosine results in elevated urate (uric acid) levels 
and we want to make sure that the dose of inosine is the right one for you and results in the right 
levels of urate (uric acid). We will give you the exact address and phone number of the closest 
Quest facility where your blood draw will be performed. 
TELEPHONE CALLS 
Length of time = 15 minutes 
We will call you within 5 days of your blood draw to discuss the following: 
• Review results of the urate (uric acid) level test 
• Tell you to increase (take more), decrease (take less) or maintain (keep the same) your 
dose of study drug/placebo 
• Review the medications and supplements you are currently taking and/or any new 
therapies you are receiving 
• 
Ask you about changes in your health condition since your last visit 
• 
Discuss initiation of alkalinization therapy (if applicable) 
• 
Review your study diary 
WEEK 12 Visit  
Length of time = about 2 hours 
 
At this visit, we will: 
• Ask you about changes in your health condition since your last visit 
• Review the medications you are currently taking and/or any new therapies you are 
receiving 
• Ask you to complete the ALSFRS-R questionnaire 
• Complete the suicide questionnaire (a questionnaire about suicidal thinking and behavior) 
• Collect weight and vital signs 
• Perform the Slow Vital Capacity (SVC) 
• Collect a urine sample for urinalysis 
• Draw blood samples for routine safety lab test and to check the level of urate (uric acid) 
in your body (about 3 tablespoons) 
• Review your study diary  
• Perform study drug accountability and collect all unused study drug and empty containers 
• Dispense enough study drug/placebo to last until Week 20 
 
NOTE: You will receive a phone call within 5 days of this visit with instructions to increase 
(take more), decrease (take less) or maintain (keep the same) your study drug/placebo dose. In 
addition, you may be asked to take alkalinization therapy (with Potassium Citrate) if the results 
of the urinalysis test show that you have acidic urine. The alkalinization therapy will help to 


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Subject Identification 
make your urine less acidic, reducing your risk of kidney stones. If your urinalysis test comes 
back normal, you will not be asked to take alkalinization therapy. 
 
 
 
WEEK 20 VISIT 
Length of time = about 2 hours 
 
At this visit, we will: 
• Ask you about changes in your health condition since your last visit 
• Review the medications you are currently taking and/or any new therapies you are 
receiving 
• Ask you to complete the ALSFRS-R questionnaire 
• Complete the suicide questionnaire (a questionnaire about suicidal thinking and behavior) 
• Perform a physical exam, including weight and vital signs 
• Perform a neurological examination 
• Perform the Slow Vital Capacity (SVC) 
• Collect a urine sample for urinalysis 
• Draw blood samples for routine safety lab test and to check the level of urate (uric acid) 
in your body (about 3 tablespoons) 
• Review your study diary  
• Perform study drug accountability and collect all unused study drug and empty containers 
• Assist you with the uninstallation and removal of the mobile application 
 
TELEPHONE CALL AT WEEK 24  
Length of time = about 15 minutes  
 
During this call we will: 
• Ask you about changes in your health condition since your last visit 
• Review the medications you are currently taking and/or any new therapies you are 
receiving 
• Ask you to complete the ALSFRS-R questionnaire 
 
After You Complete the Study 
After you complete the study, we will refer you back to your own doctor for your ongoing 
medical care.  
 
IF YOU WANT TO STOP STUDY DRUG 
If you wish to stop the study drug, you should tell Dr. [INSERT SITE INVESTIGATOR 
NAME] so that [he/she] may plan for your continued medical care.  [INSERT SITE 
INVESTIGATOR NAME] may decide to stop your study drug or participation in the study, 


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Subject Identification 
without your permission if [he/she] feels that you cannot follow the study plan or if your health 
is in question.  Side effects from the study drug are an example of a reason for the study doctor 
to stop the study drug.   
 
Also, the study doctor may take you out of the study without your permission.  This may happen 
because: 
• The study doctor thinks it is best for you to stop taking the study drug 
• You can’t make the required study visits 
• The Sponsor decides to stop the study 
• We stop doing the study for other reasons 
 
If this happens, the study doctor will explain why you need to stop taking part in the study.  We 
will ask you to come in for a final study visit as described above. 
 
IF YOU STOP THE STUDY EARLY 
If you stop study drug early or stop participating in the study before the end of the study, you 
will be asked to come in for a final safety visit and receive a phone call about 28 days after your 
last dose of study drug. If you stop using the mobile application, we will ask you that you follow 
certain procedures to un-install it. 
 
FINAL SAFETY VISIT 
Length of time = 2 hours 
 
At this visit, we will: 
• Ask you about changes in your health condition since your last visit 
• Review the medications you are currently taking and/or any new therapies you are 
receiving 
• Ask you to complete the ALSFRS-R questionnaire 
• Complete the suicide questionnaire (a questionnaire about suicidal thinking and behavior) 
• Perform a physical exam, including weight and vital signs 
• Perform a neurological examination 
• Perform the Slow Vital Capacity (SVC) 
• Collect a urine sample for urinalysis 
• Draw blood samples for routine safety lab test and to check the level of urate (uric acid) 
in your body (about 3 tablespoons) 
• Review your study diary  
• Perform study drug accountability and collect all unused study drug and empty containers 
• Assist you with the un-installation of the mobile application 
 
FINAL TELEPHONE CALL 
Length of time = 15 minutes 


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Subject Identification 
 
We will discuss the following: 
• Ask you about changes in your health condition since your last visit 
• Review the medications you are currently taking and/or any new therapies you are 
receiving 
• Ask you to complete the ALSFRS-R questionnaire 
 
What are the risks and possible discomforts from being in this research 
study? 
Risks of Taking Inosine 
Taking inosine may cause you to have one or more of the side effects listed below. These side 
effects are due to high urate (uric acid) levels that occur as a result of taking inosine. 
 
Serious side effects: 
• Gout (pain and swelling in some joints) 
• Kidney stones (pain in the back or belly, pain on urination, red or brown 
urine) 
 
Acidic urine can increase the risk of uric acid kidney stone formation. For this reason, we will 
check the acidity of your urine prior to taking initial dose of study drug at Baseline and at Week 
12.  If urine tests show that you have acidic urine, we will encourage you to drink lots of water 
and will prescribe the medication potassium citrate, which has an antacid effect. 
 
High urate (uric acid) levels have also been found in people with high blood pressure and history 
of heart attack and stroke. However, we don’t know if high urate (uric acid) caused these 
problems. There may be other risks that are currently unknown. 
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing.  If you think you are having an 
allergic reaction, call the study doctor right away.  If you are having trouble breathing, call 911 
immediately.  
 
Risk of Potassium Citrate [Alkalinization Therapy] 
Potassium citrate will only be prescribed if you have acid urine. It may help to reduce your risk 
of developing uric acid kidney stone. If you do not have acidic urine, you will not be asked to 
take potassium citrate. 
 


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Subject Identification 
Possible side effects of potassium citrate include nausea, vomiting, diarrhea, stomach pain or 
upset and rarely gastrointestinal bleeding. Call a doctor at once if tarry (black colored) stools or 
other signs of gastrointestinal bleeding are noticed. 
Potassium citrate is available over-the-counter and works by raising urinary pH. In the unlikely 
event that you are allergic to or unable to take potassium citrate, another alkalinizing medication 
will be prescribed based on your individual needs. The risks of this medication would be 
discussed with you in detail if it were prescribed.  
If you are started on potassium citrate you will have extra blood and urine tests. These blood 
tests will help us check for too much potassium in your blood, for any signs of kidney disease, 
and for too few red blood cells (anemia). The urine tests will tell us how acidic your urine is, and 
we may ask you to perform some of these extra urine tests at your own home.  
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
The effect of inosine on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are: 
• Pregnant 
• Trying to become pregnant  
• Breastfeeding 
 
If you are a menopausal woman and have not had a menstrual period for the past 12 months or 
more, you will not need to have a pregnancy test.  Also, if you have had any well-documented 
method of surgical sterilization, you will not need to have a pregnancy test.  Methods of surgical 
sterilization include having had a hysterectomy (removal of the uterus), bilateral oophorectomy 
(removal of both ovaries), a tubal ligation (having your tubes tied), and transvaginal occlusion 
(plugging the opening of the tubes with a coil).  All other female subjects must have a negative 
pregnancy test before starting the study drug. 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.  You must use birth control for the entire study and for at least 3 
months after your last dose of study drug.  
 
Acceptable birth control methods for use in this study are: 
• hormonal methods, such as birth control pills, patches, injections, vaginal 
rings, or implants 
• barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
• intrauterine device (IUD) 
• abstinence (no sex) 


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Subject Identification 
 
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.  The study doctor may ask for your permission to collect information 
about the outcome of your pregnancy and the condition of your newborn.  
 
If you are sexually active and able to father a child, you must agree to use one of the birth control 
methods listed below.  You must use birth control for the entire study and for at least 3 months 
after your last dose of study drug.  
 
Acceptable birth control methods that you can use in this study are: 
• condoms with spermicide (a foam, cream, or gel that kills sperm) 
• abstinence (no sex) 
 
Acceptable birth control methods that your partner(s) should use are: 
• hormonal methods, such as birth control pills, patches, injections, vaginal 
ring, or implants 
• barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
• intrauterine device (IUD) 
 
If your female partner becomes pregnant, the study doctor would like to follow the outcome of 
the pregnancy. You should notify us immediately if your partner becomes pregnant. She may be 
asked to sign a release of medical information form that gives her doctors permission to provide 
information to the study doctor.  You will not have to stop taking the study drug or stop taking 
part in the study if your partner becomes pregnant.  
Risks of Taking Inosine with Other Medications 
Do not take inosine from other sources, allopurinol, probenecid while you are in the study.  Do 
not take more than 300mg vitamin C daily (you may take a standard multivitamin containing 
vitamin C up to one tablet or capsule daily). Taking these drugs and inosine together may cause 
serious side effects. 
 
For your safety during this study, call your study doctor BEFORE you take any: 
• new medications prescribed by your own doctor 
• other medications sold over-the-counter without a prescription 
• dietary or herbal supplements 
Risks of Blood Draws 
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There 
is also a small risk of infection, lightheadedness, and/or fainting. 


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Subject Identification 
 
Acute Kidney Damage as a result of Dehydration  
If you become dehydrated for any reason, there is a possibility you will be at risk of kidney 
damage. It is possible that elevating uric acid levels could contribute to kidney damage due to 
dehydration. To avoid the risk of dehydration you should drink lots of water when taking study 
drug and if you have initiated the alkalinization therapy. If you are restricted to a limited water 
intake due to reasons such as a medical precaution or due to religious fasting, please let the study 
staff know immediately. 
 
Study Questionnaires and Health Questions  
The daily activity questionnaire (ALSFRS-R) and reviewing health information may cause you 
to feel sad or upset about how ALS has changed how well you can perform daily activities, and 
how it has affected your quality of life, or may make you uncomfortable. Although we would 
like you to answer all the questions, you may skip over any questions that you do not wish to 
answer.  You may stop a health interview at any time. 
 
Mobile Application 
The mobile application questionnaires may cause you to feel sad or upset about how ALS has 
changed how well you can perform daily activities, and how it has affected your quality of life. 
You may get tired or bored when we are asking you questions or you are completing 
questionnaires. You do not have to answer any question you do not want to answer. 
 
Slow Vital Capacity 
The risks and discomforts associated with the Slow Vital Capacity testing include feeling tired, 
light-headed or short of breath. These symptoms will disappear with rest. 
 
Confidentiality Risks 
Every possible effort will be made to keep the research information strictly confidential, but we 
cannot provide an absolute guarantee that unintentional disclosure may not occur. 
 
For this research project, some identifiable information may be collected and stored in the data 
repository, which is collect via the mobile application. This might include information like your 
date of birth or the date your symptoms began. At the end of this project, all data will be de-
identified (all identifying information including dates will be removed). The de-identified dataset 
combined with information from other projects will then become available for sharing with other 
researchers. 
 
Other Risks 
Reviewing health related information might be stressful or make you feel uncomfortable.  You 
do not have to answer any questions you do not want to, and you may stop the interview at any 
time if it is too uncomfortable.   There may be other risks to taking the drug used in this study 


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Subject Identification 
that are not known yet.  It is possible that the study drug may make your symptoms of ALS 
worse, or make your ALS progress faster, although this is not expected. 
 
Unknown Risks 
There may be additional risks that we don’t know about at this time. 
 
 
 
 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this research study.  If you receive inosine, it is possible 
that your ALS symptoms will improve while you are taking it.  Others with ALS may benefit in 
the future from what we learn in this study.  
 
What other treatments or procedures are available for my condition? 
 
You do not have to participate in this study to receive care for ALS.  There may be other clinical 
research studies available to you.  The study doctor can discuss with you other studies open for 
enrollment at this time.   
 
Riluzole (Rilutek®) and Edaravone (Radicava®) are two drugs that are FDA approved for the 
treatment of ALS.  You are allowed to take Riluzole and/or Edaravone during this study if you 
wish to do so. 
 
Please be sure to let the study doctor know if you are taking either of these drugs, and/or if you 
change the dose you are taking during the study.  
Will I be paid to take part in this research study? 
 
You will not be paid to take part in this research study. We will pay for parking in the hospital 
garage during study visits. 
 
We may use your samples and information to develop a new product or medical test to be sold.   
The Sponsor, hospital, and researchers may benefit if this happens.  There are no plans to pay 
you if your samples are used for this purpose.   
 
What will I have to pay for if I take part in this research study? 
 


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Subject Identification 
Study funds will pay for the study drug (inosine), study-related procedures, study visits that are 
done only for research and the mobile application. You/your health insurer will be responsible 
for the costs of other treatments, including care for your ALS, because this would be needed for 
your care even if you are not in the study. 
 
Study funds will pay for certain study-related items and services.  We may bill your health 
insurer for, among other things, routine items and services you would have received even if you 
did not take part in the research.  You will be responsible for payment of any deductibles and co-
payments required by your insurer for this routine care or other billed care.  If you have any 
questions about costs to you that may result from taking part in the research, please speak with 
the study doctors and study staff.  If necessary, we will arrange for you to speak with someone in 
Patient Financial Services about these costs. 
 
 


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Subject Identification 
Can I still get medical care within [SITE NAME] if I don’t take part in 
this research study, or if I stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within [Site Name] now or in the 
future.  There will be no penalty, and you won’t lose any benefits you receive now or have a 
right to receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
The decision to withdraw from the study will not affect in any way your current or future 
medical care or any other benefits to which you are otherwise entitled.  
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 


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Subject Identification 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
 
[Insert name and academic degrees] is the person in charge of this research study.  You can call 
him/her at [Insert phone number] [insert when person is available M-F 9-5 or 24/7].  You can 
also call [Insert name(s)] at [Insert phone number(s)] [insert when each person is available M-F 
9-5 or 24/7] with questions about this research study. 
 
If you have questions about the scheduling of appointments or study visits, call [Insert name(s)] 
at [Insert phone number(s)].
 
If you want to speak with someone not directly involved in this research study, please contact 
the [Insert name of local IRB].  You can call them at [Insert phone number of local IRB]. 
 
You can talk to them about: 
• Your rights as a research subject 
• Your concerns about the research 
• A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so. 
 
INSTRUCTIONS: Below in RED is Partners Approved IRB HIPAA authorization language.  
Sites can use this language, or use their own language, or use a separate authorization form. 
 
In this study, we may collect health information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 


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Subject Identification 
 
Who may see, use, and share your identifiable health information and why they may need 
to do so: 
• Research staff involved in this study 
• Non-research staff within the institution who need this information to do their jobs (such 
as for treatment, payment (billing), or health care operations) 
• The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 
• Other researchers and medical centers that are part of this NEALS clinical study and their 
ethics boards 
• Other researchers and medical centers that are not part of this NEALS clinical study but 
are part of the NEALS Consortium   
• MGH NCRI (the NEALS Coordinating Center and Data Coordinating Center) 
• A group that oversees the data (study information) and safety of this research 
• People from organizations that provide independent accreditation and oversight of 
hospitals and research 
• People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
• Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research)  
• Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
• Representatives of the MGH Biostatistics Department (the academic group responsible 
for the data analysis for the study) 
• Individuals at the local lab where your blood is processed will have access to limited 
identifiable information, specifically your gender and date of birth, in order to properly 
run their tests 
• Individuals working with the mobile applications, including Dr. Jukka-Pekka Onnela and 
Dr. Jordan Green and their research teams 
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 


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Subject Identification 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.    
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished.  


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Subject Identification 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 
 
 
 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 


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Subject Identification 
 
 
Consent of Non-English Speaking Subjects Using the “Short Form” in the 
Subject’s Spoken Language 
 
Statement of Hospital Medical Interpreter 
 
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
Hospital Medical Interpreter 
Date 
Time (optional) 
 
OR 
 
Statement of Other Individual (Non-Interpreter) 
 
As someone who understands both English and the language spoken by the subject, I represent 
that the English version of the consent form was presented orally to the subject in the subject’s 
own language, and that the subject was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
Name 
Date 
Time (optional) 
 
 


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Subject Identification 
Witness to Consent of Subjects Who Cannot Read or Write or are Physically 
Unable to Talk or Write 
 
Statement of Witness 
 
I represent that the consent form was presented orally to the subject in the subject’s own 
language, that the subject was given the opportunity to ask questions, and that the subject has 
indicated his/her consent and authorization for participation by (check one box as applicable): 
 Making his/her mark above 
 Other means ________________________________________________________________ 
(Fill in above) 
 
 
 
 
 
 
 
 
Witness 
Date 
Time (optional) 
 
 
 
 
 
Consent Form Version/Date:  v2.0 / 01 July2019