Clinical trial NCT03824938
Conditions: Multiple Sclerosis
Keywords: exercise aspirin cooling antipyretic
Sponsor: Columbia University
Start date: 2019-04-30; Completion date: 2022-02-28
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study investigates the use of aspirin as an exercise pre-treatment to reduce overheating and exhaustion, which may potentially allow many more people with multiple sclerosis to participate in and benefit from exercise. The design is double-blind, within-subject, with three arms: participants will receive one of three treatments at three separate study visits: aspirin, acetaminophen, and placebo, followed by completion of a maximal exercise test.

Detailed description:
Persons with multiple sclerosis benefit from exercise, but many avoid it because of exhaustion and overheating. This randomized controlled trial (RCT) tests aspirin as a method to increase time to exhaustion for persons with MS, through its antipyretic mechanism. Participants will be seen at our laboratory for maximal exercise tests on three separate days. At each session, they will be given one of three treatments: aspirin, acetaminophen (a drug that is anti-inflammatory but not antipyretic, thereby allowing for isolation of the antipyretic action of aspirin), and placebo. Primary outcome is increased time to exhaustion, secondary outcome is reduced body temperature increase during exercise.

Arms: arm 1: Aspirin 650 mg capsule by mouth, single dose arm 2: Acetaminophen 650 mg capsule by mouth, single dose arm 3: Placebo 650 mg capsule by mouth, single dose
Interventions: intervention 1: Aspirin 650mg Oral Capsule intervention 2: Acetaminophen Tablet 650mg intervention 3: Placebo
Intervention descriptions: intervention 1: A 650mg dose of aspirin is administered in the laboratory one hour before participant completes a maximal exercise test. intervention 2: A 650mg dose of acetaminophen is administered in the laboratory one hour before participant completes a maximal exercise test. intervention 3: A placebo pill is administered in the laboratory one hour before participant completes a maximal exercise test.

Protocol documents:
Prot_SAP_ICF_002.pdf: 
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ASPIRIN FOR EXERCISE IN MULTIPLE
SCLEROSIS (ASPIRE): A DOUBLE-BLIND RCT 
OF ASPIRIN OR ACETAMINOPHEN 
PRETREATMENT TO IMPROVE EXERCISE 
PERFORMANCE IN MS 
Clinical Trial Protocol 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.................................................................................................. 4 
1 
STUDY OBJECTIVES ......................................................................................................... 11 
1.1 
Primary Objectives ......................................................................................................... 11 
1.2 
Secondary Objectives ..................................................................................................... 12 
2 
BACKGROUND .................................................................................................................. 12 
2.1 
Rationale......................................................................................................................... 12 
2.2 
Supporting Data.............................................................................................................. 13 
3 
STUDY DESIGN.................................................................................................................. 15 
3.1 
Scientific Rationale for Study Design ............................................................................ 16 
3.2 
Justification for Dose ..................................................................................................... 16 
3.3 
End of Study Definition ................................................................................................. 16 
4 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................................... 17 
4.1 
Inclusion Criteria ............................................................................................................ 17 
4.2 
Exclusion Criteria ........................................................................................................... 17 
4.3 
Lifestyle Considerations ................................................................................................. 17 
4.4 
Subject Withdrawal Criteria ........................................................................................... 18 
4.5 
Study Enrollment Procedures ......................................................................................... 18 
4.5.1 
Subject Recruitment and Retention ........................................................................ 20 
4.5.2 
Screening Logs........................................................................................................ 21 
4.5.3 
Informed Consent.................................................................................................... 21 
4.5.4 
Assent ..................................................................................................................... n/a 
4.5.5 
Randomization/Treatment Assignment .................................................................. 21 
5 
STUDY INTERVENTIONS/STUDY MEDICATION/STUDY DRUG OR DEVICE ....... 22 
5.1 
Study Medications/Interventions, Administration, and Duration .................................. 22 
5.2 
Device Description and IDE Information [if applicable] .............................................. n/a 
5.3 
Handling of Study Medications/Interventions ............................................................... 22 
5.4 
Concomitant Interventions ............................................................................................ n/a 
5.4.1 
Required Concomitant Medications/Interventions ................................................ n/a 
5.4.2 
Prohibited Medications/Interventions ..................................................................... 22 
5.4.3 
Precautionary Medications/Interventions .............................................................. n/a 
5.5 
Subject compliance ........................................................................................................ 23 
6 
CLINICAL AND LABORATORY EVALUATIONS/STUDY PROCEDURES ............... 23 
6.1 
Schedule of Activities .................................................................................................... 23 
Schedule of Activities ............................................................................................................... 23 
6.2 
Timing of Study Activities ............................................................................................. 23 
6.2.1 
Screening/Pre-Randomization Evaluations/procedures .............................................. 
6.2.2 
On-Study/On-Interventions Evaluations/procedures .............................................. 24 
6.2.3 
Study Medication/Intervention Discontinuation Evaluations/procedures ............. n/a 
6.2.4 
On Study/Off-Intervention Evaluations ................................................................. n/a 
6.2.5 
Final On-Study Evaluations .................................................................................... 25 
6.2.6 
Off-Study Requirements ......................................................................................... 25 
6.2.7 
Pregnancy (Optional) ............................................................................................. n/a 
6.3 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS ................... 26 


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6.3.1 
Informed Consent.................................................................................................... 26 
6.3.2 
Protocol Violations ................................................................................................. 26 
6.3.3 
Documentation of [specify the Disease/Disorder under study] ............................. n/a 
6.3.4 
Medical History ...................................................................................................... 27 
6.3.5 
Treatment History .................................................................................................. n/a 
6.3.6 
Concomitant Medications/Treatments .................................................................... 27 
6.3.7 
Protocol Amendments and Study Termination ....................................................... 27 
6.3.8 
Clinical Assessments .............................................................................................. 27 
6.3.12 Questionnaires......................................................................................................... 27 
6.3.13 Subject Adherence Assessments ............................................................................ n/a 
6.3.14 Additional Evaluations............................................................................................ 28 
7 
MANAGEMENT OF ADVERSE EXPERIENCES ............................................................ 28 
8 
MANAGEMENT OF UNANTICIPATED PROBLEMS .................................................... 28 
10 STATISTICAL CONSIDERATIONS.................................................................................. 29 
10.1 
General Design Issues ................................................................................................ 29 
10.2 
Outcomes .................................................................................................................... 29 
10.2.1 Primary Outcome (including definition) ................................................................. 29 
10.2.2 Secondary Outcome(s) ............................................................................................ 29 
10.3 
Sample Size and Accrual ............................................................................................ 29 
10.4 
Data Monitoring ......................................................................................................... 30 
10.5 
Data Analyses ............................................................................................................. 31 
11 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING ................................................................................................................................ 31 
11.1 
Data Management ....................................................................................................... 31 
11.2 
Role of Data Management .......................................................................................... 31 
11.3 
Quality Assurance....................................................................................................... 32 
11.4 
Adverse Experience Reporting ................................................................................... 32 
11.4.1 Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events ..................................................................................................................... 34 
12 HUMAN SUBJECTS ........................................................................................................... 38 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ............................. 38 
12.2 
Subject Confidentiality ............................................................................................... 38 
12.2.1 Certificate of Confidentiality .................................................................................. 38 
12.3 
Study Modification/Discontinuation .......................................................................... 39 
13 FUTURE USE OF STORE SPECIMENS AND DATA ...................................................... 39 
14 STUDY RECORDS RETENTION ...................................................................................... 39 
15 PUBLICATION OF RESEARCH FINDINGS ........................................................................  
16 CONFLICT OF INTEREST POLICY.................................................................................. 39 
17 REFERENCES ..................................................................................................................... 40 
Appendix A:  Model Informed Consent Form .............................................................................. 41 
 
 


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ASPIRE 
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STATEMENT OF COMPLIANCE  
 
 
(1) [The trial will be carried out in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who 
are responsible for the conduct, management, or oversight of NIH-funded clinical trials 
have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the Institutional Review Board (IRB) for review and approval.  
Approval of both the protocol and the consent form must be obtained before any subject 
is enrolled.  Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study.  In addition, all changes to the consent 
form will be IRB-approved; a determination will be made regarding whether a new 
consent needs to be obtained from subjects who provided consent, using a previously 
approved consent form.] 
 
OR 
 
(2) [The trial will be conducted in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), applicable United States (US) Code of 
Federal Regulations (CFR), and the <specify NIH Institute or Center (IC) > Terms and 
Conditions of Award. The Principal Investigator will assure that no deviation from, or 
changes to the protocol will take place without prior agreement from the Investigational 
New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding agency 
and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial subjects. All personnel 
involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any subject is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented 
to the study.  All changes to the consent form will be IRB approved; a determination will 
be made regarding whether a new consent needs to be obtained from subjects who 
provided consent, using a previously approved consent form.] 
 


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LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS  
 
AE 
 
 
Adverse Event 
APAP  
 
Acetaminophen 
ASA  
 
Aspirin 
CCC  
 
Clinical Coordination Center 
CDE  
 
Common Data Elements 
CFR 
 
 
Code of Federal Regulations 
CIRB   
 
Central Institutional Review Board (reference to CUMC IRB) 
CRF 
 
 
Case report form 
CS 
 
 
Clinically Significant 
CUMC 
 
Columbia University Medical Center 
DCC  
 
Data Coordination Center 
DM 
 
 
Data Management 
DSMB  
 
Data Safety Monitoring Board 
eCRF  
 
Electronic Case Report Form 
EDC  
 
Electronic data capture 
FDA     
 
Food and Drug Administration 
GCP  
 
Good Clinical Practice 
HIPAA 
 
Health Insurance Portability and Accountability Act 
ICH 
 
 
International Conference on Harmonization  
IMM  
 
Independent Medical Monitor 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MS 
 
 
Multiple Sclerosis 
NINDS 
 
National Institute of Neurological Disorders and Stroke 
PPI/PI  
 
Protocol Principal Investigator 
PSC 
 
 
Protocol Steering Committee 
PwMS  
 
Persons with Multiple Sclerosis  
RRMS  
 
Relapsing Remitting Multiple Sclerosis 
SAE 
 
 
Serious adverse event 
SOA   
 
Schedule of Activities 
 


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SYNOPSIS  
 
Study Title: AAAS2529 (M01Y01): Aspirin for Exercise in Multiple Sclerosis (ASPIRE): A 
Double-Blind RCT of Aspirin or Acetaminophen Pretreatment to Improve Exercise Performance 
in MS 
 
Objectives: The overarching objective of this clinical trial is treatment of exercise-induced 
overheating in persons with RRMS.  
 
Primary Outcome Measure: 
Time-to-exhaustion   [Time Frame: from start of exercise test until self-reported exhaustion, up to 
30 minutes] 
• Duration of time exercising before reaching peak exertion, defined as cadence drop below 40 
RPM for >/= 5 seconds, or patient reaches volitional exhaustion in accordance with American 
Thoracic Society standard test termination criteria. 
 
Secondary Outcome Measures: 
Exercise-induced body temperature increase   [Time Frame: from start of exercise test until self-
reported exhaustion, up to 30 minutes] 
• Change in body temperature from pre- to post- maximal exercise test 
 
1. Aim 1a. Hypothesis: Compared to placebo, Aspiring (ASA) will result in longer Time to 
Exhaustion (TTE). 
2. Aim 1b. Hypothesis: Compared to placebo, ASA will result in reduced exercise-induced 
body temperature increase.  
3. Aim 2a. Hypothesis: Compared to placebo, Acetaminophen (APAP) will result in longer 
TTE.  
4. Aim 2b. Hypothesis: Compared to placebo, APAP will result in reduced exercise-induced 
body temperature increase 
 
Design and Outcomes: 
This study is a prospective, single-center, blinded, within-subject effectiveness study in patients 
diagnosed with RRMS. The study will enroll at least 60 patients. The study will entail 3 study 
visits, separated by no less than 7 days.  
 
The study design consists of: 
• Within-subject crossover placebo-controlled experiment with 3 arms. Participants will be 
randomized to treatment schedule by study biostatistician who will remain double-blind until 
data collection ceases. Each subject serves as her/his own control.  
• This is a Phase 3 study.  
 
The study outcomes are listed as follows: 
• Aim 1 uses a two-armed crossover trial to assess differences in outcomes between ASA and 
placebo; unpaired t-tests will be used to test within-subject differences in outcomes between 
session 1 and session 2.  


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• Aim 2 uses a two-armed crossover trial to assess differences in outcomes between APAP and 
placebo; analytic approach is identical to Aim 1.  
• A sub-analysis of Aim 2 uses an ANOVA to assess difference in outcomes among three 
treatments (ASA, APAP, placebo). All variables will be inspected for outliers or inconsistent 
values. Variables that display an extremely right skewed distribution with outliers will be 
transformed using log transformation. Any remaining outlier values will be winsorized, i.e. 
extreme values will be censored down to the nearest non-outlier value. 
 
 
Interventions and Duration 
• This study will utilize a crossover assignment.   
• This study has a 24-month timeline beginning when the study opens enrollment through 
the completion of data analyses.  
• Each subject will be on study for anywhere between 3 and 12 weeks, depending on the 
scheduling of each exercise session.  
• Enrollment is expected to remain open throughout the course of the study until the target 
goal of 60 completed participants has been reached. 
• Interventions in this study include a 650 mg dose of aspirin, acetaminophen, and placebo 
to be taken orally one hour prior to each exercise session. 
 
 
 
Sample Size and Population 
 
• 60 persons randomized 
• Persons with current diagnosis of RRMS (2010 McDonald criteria) 
o Pilot trial findings of elevated body temperature in MS were limited to RRMS; 
Patients with progressive MS may experience exercise-induced exhaustion for 
different reasons (e.g., increased physical disability); This study limits recruitment 
to RRMS where pilot findings and a priori hypothesis suggest greatest benefits. 
• Persons aged 18 to 65 years 
o Consistent with observations that 75% of relapse-onset MS patients are diagnosed 
between ages 20 and 50, with a mean onset at 30 years, these limits ensure that our 
sample is representative of the relapse-onset MS population; Upper limit is set to 
reduce effects of age-related activity-level decreases. 
• Self-reported heat-sensitivity to exercise 
• Expanded Disability Status Scale (EDSS) total score ≤ 6.0 
o Patients with higher EDSS scores may experience exercise-induced exhaustion for 
different reasons (e.g., increased physical disability) 
• Exacerbation-free (and no use of corticosteroids) for 6 weeks prior to enrollment 
o To avoid any transitory changes in disability related to current disease activity 
• BMI ≤ 35 
o To reduce health-related confounds of obesity. 
 
 


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• When indicating how many subjects will be included in the study, the number of subjects 
to be enrolled should be the number of subjects who are expected to be consented. The 
number of subjects to be randomized should only include the number of subjects who are 
expected to receive either the study intervention or placebo (if applicable).   
 
Please note that the Central IRB defines “enrolled” as “consented,” and therefore they may 
issue a ReqMod if the terms “enrolled,” “consented,” and “randomized” are used 
interchangeably. 
 
Additionally, if the number of anticipated enrollments is higher than the number of 
anticipated randomizations due to anticipated screen failures, please state this explicitly. 
 


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STUDY OBJECTIVES 
1.1 
Primary Objectives 
Objectives 
Corresponding Endpoints 
Primary Objective: 
 
• To evaluate the effectiveness of ASA and APAP 
(compared to placebo) in reducing exercise-induced 
overheating in PwMS  
• Aural body temperature 
 
• To evaluate the effectiveness of ASA and APAP 
(compared to placebo) in reducing exercise-induced 
exhaustion in PwMS 
• Self-reported exhaustion 
• Time to exhaustion 
• Global Fatigue Change 
• Fatigue Severity Scale 
 
• Aim 1 uses a two-armed crossover trial to assess differences in outcomes between ASA 
and placebo; unpaired t-tests will be used to test within-subject differences in outcomes 
between session 1 and session 2.  
• Aim 2 uses a two-armed crossover trial to assess differences in outcomes between APAP 
and placebo.; analytic approach is identical to Aim 1.  
• A sub-analysis of Aim 2 uses a ANOVA to assess differences in outcomes among three 
treatments (ASA, APAP, placebo).  
• All variables will be inspected for outliers or inconsistent values. Variables that display 
an extremely right skewed distribution with outliers will be transformed using log 
transformation. Any remaining outlier values will be winsorized, i.e. extreme values will 
be censored down to the nearest non-outlier value. 
• The primary objective should always be to address a specific hypothesis. 
• State the hypothesis in quantifiable terms: e.g., “the experimental treatment will result 
in 12 months of additional survival compared to the control treatment.” 
• For statistical purposes, it may be worthwhile to state both the null and the alternative 
hypotheses 
• This primary objective must match the one used in section 9, Statistical Design 
 


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1.2 
Secondary Objectives 
Objectives 
Corresponding Endpoints 
Secondary Objective(s): 
 
• To evaluate the impact of ASA and APAP (compared 
to placebo) on mood 
• HADS 
• BDI-II 
• VAS Mood 
 
• To evaluate the impact of ASA and APAP (compared 
to placebo) on fatigue 
• Global Fatigue Change 
• Fatigue Severity Scale 
• VAS Fatigue 
• Hand dynamometer 
 
2 
BACKGROUND  
 
2.1 
Rationale 
Multiple sclerosis (MS) is a prevalent and chronic neurologic disease that impacts 
individuals on many levels. Exercise holds a multitude of benefits for persons with MS (PwMS), 
including improved physical function, reduced fatigue, improved mood, and improved cognition. 
There is now evidence from pre-clinical models for neural-level benefits of exercise including 
increased BDNF, and reduced myelin and axonal damage. But exercise only works if people do 
it, and many PwMS are deterred from exercising by overheating, exhaustion, and symptom 
worsening: “Uhthoff’s phenomenon.” Our group extended Uhthoff’s observation by providing 
the first-ever report of elevated resting body temperature and its link to worse fatigue in persons 
with MS; that is, even before exercise, PwMS are already “heated up.” This R21 will support a 
trial of aspirin as a pretreatment for exercise: our pilot data collected in 12 participants show 
improved exercise performance and reduced exercise-induced body temperature increase after 
aspirin. For the proposed study, sixty MS patients will be enrolled in a double-blind RCT with 
three arms: placebo, aspirin, and acetaminophen (APAP). Design is crossover: each participant 
will complete three exercise sessions separated by 1-week intervals. At each session, body 
temperature will be measured before administration of a standard adult dose (one 650-mg 
capsule) of aspirin, APAP, or placebo. One hour later (time to reach peak serum level) 
participants will complete a progressive ramped maximal exercise test on a lower body cycle 
ergometer. Body temperature and biophysical/behavioral variables (VO2max, total watts 
achieved, blood pressure, anaerobic threshold, ratings of perceived exertion) will be recorded 
throughout the test at regular intervals. Past research in MS has found cooling treatments 


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(cooling garments, vacuum hand-cooling chambers) effective for improving exercise 
performance. However, their widespread adoption for research / clinical use is limited by 
practicality and lack of standardization. Aspirin is a simple, readily available, cost-effective 
treatment that does not require FDA approval. If successful, this R21 grant may motivate change 
in clinical care and adoption of ASA therapy for enhancing exercise performance in PwMS. 
Positive findings from this study will facilitate future research to test whether ASA use improves 
exercise adherence, increases everyday physical activity levels, and improves overall QOL for 
persons with MS. 
 
ASA was selected as the agent for use in the current study because: a) it was safe and 
effective in our pilot study; b) prior (non-exercise) studies in MS have shown efficacy of aspirin 
to reduce fatigue, and c) prior work in MS supports its favorable safety profile.[6, 8, 9] In those 3 
RCTs, no adverse events were reported, and side effects were minimal (i.e., did not differ 
appreciably from those reported by the placebo group in each study). Importantly, the daily 
dosage of ASA in those studies (1300 mg/day, for 6 weeks) was much higher than the dosage we 
will use here (650 mg/1 time administration). In the long term, adoption of ASA as a pre-
treatment for exercise would only require the use of aspirin on an as-needed (PRN) basis, thereby 
minimizing the potential impact of aspirin’s side effects. The safety profile for acetaminophen 
(APAP) is similarly favorable, and patients with any contraindication to APAP use (e.g., severe 
active hepatic disease, Hepatitis C Virus) will be excluded from the study. 
 
2.2 
Supporting Data 
Past research in MS has found cooling treatments (cooling garments, vacuum hand-cooling 
chambers) effective for improving exercise performance. However, their widespread adoption 
for research / clinical use is limited by practicality and lack of standardization. Aspirin is a 
simple, readily available, cost-effective treatment that does not require FDA approval. If 
successful, this R21 grant may motivate change in clinical care and adoption of ASA therapy for 
enhancing exercise performance in PwMS. Positive findings from this study will facilitate future 
research to test whether ASA use improves exercise adherence, increases everyday physical 
activity levels, and improves overall QOL for persons with MS. 
2.3 
Risk/Benefit Assessment 
Risks:  
The risks posed by the methods used in this study are minimal. Three doses of 650mg aspirin in 
RRMS has been conducted previously, with no adverse events noted. In addition, physicians 
serving as investigators on this study will work closely during recruitment to ensure that there 
are no counter indications to one-time aspirin use for any participants. Additionally, a study 


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physician will be available during all exercise sessions and will review all stress tests for any 
evidence of cardiovascular disease/ischemic changes.  
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver 
transplant and death. Most cases of liver injury are associated with the use of acetaminophen 
doses that exceed the recommended maximum daily limits, and often involve more than one 
acetaminophen-containing product. The most common adverse reactions in patients treated with 
acetaminophen been associated with cases of acute liver failure, at times resulting in liver were 
nausea, vomiting, headache, and insomnia in adult patients and nausea, transplant and death. 
Most of the cases of liver injury are associated with vomiting, constipation, pruritus, agitation, 
and atelectasis in pediatric patients.  
 
The minimal risks in the study are related to a) ASA/APAP use (which will be minimized by 
screening for any counter indications of ASA use, and the dosage is a single-dose administration 
of the standard adult dose (650mg), and prior ASA trials in MS using this dose twice daily for 6 
weeks reported no adverse events and found minimal side effects that did not differ from the 
placebo condition), and b) discomforts of exercise-induced overheating and exhaustion (which 
will be minimal, as the exercise test is only about 9 minutes in duration, and we anticipate will be 
ameliorated in the ASA/APAP conditions). These minimal risks are easily managed, and will be 
closely monitored; as such, the risk/benefit ratio is very favorable. 
 
A certified exercise physiologist will conduct all exercise tests after subjects have been carefully 
screened (in consultation with Co-I Dr. Riley, MD, and in consultation with Co-I Dr. Stein, MD) 
to ensure no counter indications to ASA use or to participating in a supervised exercise session 
involving stationery cycling. All exercise tests are conducted by an experienced ACLS/BCLS 
certified exercise physiologist, (Nancy Lee, MS) at Columbia University Medical Center in the 
presence of a physician. Subjects will be briefed in detail about what they will experience during 
the exercise sessions. 
 
 
Benefits: 
 
While participants may not benefit directly, participation in research may benefit the community, 
specifically the MS community. Participants will receive $100 at the completion of their 3rd 
exercise session. 
 
This study seeks to test aspirin as an effective pretreatment for exercise to improve exercise 
performance and minimize discomfort related to exhaustion and overheating that serve as 
deterrents to exercise for many persons with RRMS. Positive findings from this study will 
potentially provide an effective, inexpensive, readily available, unobtrusive treatment that will 
avail more persons with RRMS the benefits of exercise. As such, there are potentially far 


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reaching benefits to the MS population associated with the successful completion of this R21 
project. A potential immediate benefit for research participants is if they decide that they want to 
safely incorporate aspirin use into their regular exercise regimen, if they benefit from making 
that change. 
 
The long-term benefits of exercise for persons with MS are well established. Additionally, new 
data are now suggesting that sedentary lifestyle is a risk factor for greater disability. Taken 
together, there is growing motivation to find ways to involve more MS patients in exercise. This 
study aims to provide a treatment that will reduce the extent of exercise-induced overheating and 
exhaustion which serve as serious deterrents to exercise for many with MS. The overarching goal 
of this line of research is to determine whether aspirin use will lead to increased exercise 
adherence, increased physical activity levels, and improved quality of life. These questions 
remain to be answered by future research that will only be possible with the initial level of 
evidence to be provided by this R21 project.     
 
 
 
3 
STUDY DESIGN 
• Design is a within-subject crossover placebo-controlled experiment; subjects will be 
randomized to one of six sequences (see figure) by study biostatistician who will remain 
double-blind until data collection ceases. Each participant will attend three exercise 
sessions scheduled on separate days separated by ≥one-week intervals. Exercise sessions 
will be scheduled at the same time of day (±1 hour), and between the hours of 10 am-5 
pm to reduce the influence of circadian rhythm variability 
• Design is crossover: each participant will complete three exercise sessions separated by 
1-week intervals. At each session, body temperature will be measured before 
administration of a standard adult dose (one 650-mg capsule) of aspirin, APAP, or 
placebo. One hour later (time to reach peak serum level) participants will complete a 
progressive ramped maximal exercise test on a lower body cycle ergometer. Body 
temperature and biophysical/behavioral variables (VO2max, total watts achieved, blood 
pressure, anaerobic threshold, ratings of perceived exertion) will be recorded throughout 
the test at regular intervals. 
 


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3.1 
Scientific Rationale for Study Design 
 
Rationale for study design is based on pilot trial upon which the design of this large-scale trial 
was based (Leavitt et al, 2017). 
3.2 
Justification for Dose 
ASA dose was selected on the basis of prior successful RCTs of ASA to reduce fatigue in non-
exercising PwMS.  
Whereas past studies gave 650mg twice daily for 6 weeks with no adverse events, this study 
gives a one-time, single 650mg dose. 
3.3 
End of Study Definition  
 
The End of Study is defined as follows: 
 
• When 60 participants complete the entirety of the study. A subject is considered to have 
completed the study if he or she has completed all phases of the study including the last visit 
or the last scheduled procedure shown in the Schedule of Activities (SoA).  


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4 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 
Inclusion Criteria 
 
1. Current diagnosis of Relapsing-Remitting Multiple Sclerosis (2010 McDonald criteria) 
2. Age 18-65, inclusive 
3. Self-reported heat-sensitivity to exercise 
4. Expanded Disability Status Scale (EDSS) total score ≤ 6.0 
5. Exacerbation-free (and no use of corticosteroids) for 6 weeks prior to enrollment 
6. BMI ≤ 40 
 
4.2 
Exclusion Criteria 
 
1. Prior history of significant head injury, stroke, or other neurological disease/disorder 
2. Current daily use of antipyretics or pain medication 
3. Presence of diagnosed major depressive disorder or other diagnosed psychiatric disorders 
(as determined by medical chart review). Patients with previous or current depression or 
anxiety not meeting criteria for MDD will not be excluded 
4. Diagnosed sleep disorder 
5. Vascular disease of the legs, uncontrolled high blood pressure 
6. Uncontrolled diabetes mellitus or problem with blood sugar levels 
7. Contraindications to aspirin use (history of confirmed peptic ulcer, gastrointestinal or 
severe gynecological bleeding) 
8. Tarry stool or known fecal occult blood 
9. Uncontrolled syndrome of asthma, rhinitis, or nasal polyps 
10. Daily APAP use 
11. Contraindications to acetaminophen use  
12. Severe active hepatic disease 
13. Hepatitis C Virus 
14. Pregnant or breastfeeding 
 
4.3 
Lifestyle Considerations  
 
Before testing, participants will be asked to: 
• Refrain from eating and drinking (except water) for 3 hours before the exercise test.  
• Avoid exercising 24 hours prior to testing day.  
• Avoid drinking coffee or caffeine beverages the morning of the test.  
• Drink no more than 2 cups of coffee or caffeine beverages the day before the test.  
• Consume 4-6 fluid ounces of water 2 hours before testing.  
• Avoid supplement consumption other than multivitamins before testing.  
• Abstain from casually smoking cigars, cigarettes, and smoky places for at least 3 hours 
prior to testing.  
• Get their normal amount of sleep the night before testing.  


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• Avoid alcohol consumption prior to testing (No excessive alcohol drinking the night 
before testing; however, participants who always consume a glass of wine or beer with 
dinner are allowed to do so).  
 
4.4 
Subject Withdrawal Criteria 
 
Subjects may be withdrawn from the study by the PI or Sub-Investigator for one of the following 
reasons: 
 
• Adverse event: clinical event that in the medical judgement of the investigator for the 
best interest of the patient are grounds for discontinuation  
• Withdrawal of consent: patient desires to withdraw from further participation in the 
study in the absence of a medical need to withdraw determined by the investigator 
 The reason of consent withdrawal will be documented when available. 
• Suicidal risk evaluated by suicidal risk assessed by the Hospital Anxiety and Depression 
Scale (HADS) 
• Inability to adhere to the study protocol 
 
 
4.5 
Study Enrollment Procedures 
 
Recruitment: 
 
Sixty patients with RRMS will be recruited from the Multiple Sclerosis Clinical Care and 
Research Center at the Columbia University Medical Center (CUMC). This center currently sees 
about forty new MS patients each month, adding to an already large census of MS patients 
treated at the center annually (approximately 900 patients per year, 60% RRMS). Given the rapid 
recruitment for the pilot trial [n=12 patients; total pilot duration (recruitment, enrollment, study 
completion) = 4 months], there is no anticipated difficulty to meet recruitment goals over the 2-
year period of this proposed project. We will screen 100 patients, estimating that 60% of 
screened patients will meet eligibility. Co-I Dr. Riley (Medical Director of the MS Center) and 
the research coordinator will lead patient recruitment and confirm the disease-specific inclusion 
criteria. 
PPI Dr. Leavitt sees patients at the Center weekly in her role as clinical 
neuropsychologist, and therefore has an opportunity to identify potential research subjects who 
will be referred to the study. We do not anticipate any issue with retention, given that the entire 
duration of study participation is 3 study visits spread over about 3 weeks’ time. Enrollment will 
not be closed until all 60 participants have completed all three visits; this will ensure 60 
completed participants are enrolled in this study. 
If the patient's treating physician feels the subject may be a good fit for this study based 
on observations of overheating, fatigue or difficulty with exercising, s/he may discuss the trial 
with the patient to gauge interest. If the patient is interested in the trial, the treating physician 
may have a study coordinator or other study personnel meet with the patient to discuss the trial in 
further detail and answer questions. A screener (attached in Documents) will be reviewed with 


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the potential participant to ensure criteria are met. If the patient meets criteria and wishes to 
participate, study personnel will begin the consenting process.  
Patients will be referred by the patient's treating physician, many from Drs. Leavitt, Riley 
and De Jager, who are investigators on this protocol. All other patients will be referred either by 
colleagues of Dr. Leavitt, all of whom work at the Columbia University Medical Center, or from 
providers outside CUMC whose patients have seen study flyers and have reached out to a study 
team member directly to convey interest in the study. 
Participants may be recruited via person-to-person methods, as well as via flyers and 
handouts. All recruitment methods are IRB approved before implementation. 
 
Procedures for Obtaining Informed Consent: 
 
This study utilizes both in-person consenting and e-consent.  
 
E-consent is done via RedCap, a secure online database. A copy of the e-consent form as a 
Redcap-generated PDF is attached to this protocol to attest to it being identical to the print-
version. We will offer the e-consent to in-person participants as a way to replace the signing of a 
paper-based informed consent as a way to best address the participant's needs or preferences. 
This is optional and a paper copy will always be available. The e-consent will show the same 
pages as the traditional paper consent. The potential research participant will then use this e-
consent to fill out the same signature fields as the traditional paper consent form. Once the 
participant signs the consent and hits submit, a PDF of the completed consent will be generated 
and can be emailed to both the participant and the study coordinator. For both in-person and 
remote e-consenting, study personnel will abide by the guidelines as highlighted in the Columbia 
University Institutional Review Board Guidance on Electronic Informed Consent document. For 
e-consent, study personnel will plan a phone call with each potential participant to discuss the 
consent form and study in detail, allowing for each participant to ask any questions prior to 
signing on the online ICF. Study personnel will confirm the participant's identity by asking for 
the patient's full name and DOB prior to beginning the e-consent process. This process is in 
compliance with the requirements of 21 CFR 11. E-consent will be done via RedCap so that 
study personnel may send interested, potential study participants an email with a link directly to 
the e-consent. The e-consent will appear as a form for the participant to read with a signature line 
at the bottom where participants may type in their names to indicate consent. Study personnel 
will plan a call with any potential study participant who chooses to remotely e-consent. On that 
call, study personnel may consent participants just as they would in person, while also allowing 
for potential participants to ask any questions before choosing to participate. As with in-person 
consenting, the e-consent process may take 20-60 minutes. Our goal in using e-Consent is to 
decrease the wait time and overall study visit length for study participants. Even if previously e-
consented, participants will be required to sign a hard-copy upon their first visit to maintain on 
file. 
 
For in-person consenting, participants will be provided with a signed copy of the ICF in hard 
copy. For e-consent, PDF versions of the signed form may be generated and a copy may be sent 
to both the study coordinator and the participant who has consented. Study coordinators will 
keep a printout copy of this PDF on file throughout the duration of the study. 


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Informed consent with written documentation will be obtained from the research participant or 
appropriate representative. Documentation of informed consent is applicable to the study in its 
entirety. Documentation of participation will be obtained from adult participants. Consent will be 
obtained by one of the study research coordinators, or other study personnel such as Dr. Leavitt. 
A consent form requiring signature will be presented in writing or online via e-consent. 
Regardless of the format of the consent form, a study personnel will verbally review the study 
and consent form with the potential participant - in person or over the phone. All study 
procedures will be thoroughly explained and all questions will be answered prior to any 
participant signing the consent form, either in person or on the online, RedCap e-consent. 
 
Subjects will demonstrate informed consent by signing a consent form approved by the 
Institutional Review Board at CUMC. The consent form will be presented and explained to the 
subject by the research coordinator prior to signature. All questions raised by the subject will be 
answered prior to obtaining the signature. 
 
Once enrolled, patients will be randomized using an electronic algorithm put in place by the 
CUMC Research Pharmacy. Only the Research Pharmacy will have access to the unblinded 
information until the study is completed. PPI and study personnel will be unblinded upon End of 
Study. 
 
Patients may be re-screened if they screen fail as a result of the following 
Inclusion/Exclusion Criteria: 
• 
Exacerbation-free (and no use of corticosteroids) for 6 weeks prior to enrollment 
• 
BMI ≤ 40 
• 
Uncontrolled syndrome of asthma, rhinitis, or nasal polyps 
 
If the patient later meets these criteria, they may be re-screened. All screen failures will be 
documented in the Screening Log alongside successful screenings. 
Patients may be re-screened if they are a screen fail as a result of any of the Lifestyle 
Considerations (See Section 4.3). 
 
4.5.1 Subject Recruitment and Retention 
 
Sixty patients with RRMS will be recruited from the Multiple Sclerosis Clinical Care and 
Research Center at CUMC. With approximately 900 patients seen per year, 60% of that 
population has a current RRMS diagnosis. This center additionally sees about 40 new patients 
each month. Therefore, this study does not anticipate difficulty meeting enrollment goals over 
the 2-year period. 100 patients will be screened, estimating that 60% of screened patients will 
meet eligibility.  
 


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As this study is a 3-visit commitment, the study team does not anticipate issues with subject 
retention. Regardless, enrollment will not be closed until all 60 participants have completed all 
three visits; this will ensure 60 completed participants are enrolled in this study. 
 
 
Subject screening will occur as follows: 
 
• If the patient's treating physician feels the subject may be a good fit for this study based 
on observations of overheating, fatigue or difficulty with exercising, s/he may discuss the 
trial with the patient to gauge interest.  
• Patients will be referred by the patient's treating physician, many from Drs. Leavitt, Riley 
and De Jager, who are investigators on this protocol. All other patients will be referred 
either by colleagues of Dr. Leavitt, all of whom work at the Columbia University Medical 
Center, or from providers outside CUMC whose patients have seen study flyers and have 
contacted a member of the study team to express interest. 
• If the patient is interested in the trial, the treating physician may have a study coordinator 
or other member of the study team meet with the patient to discuss the trial in further 
detail and answer questions. A screener (see Documents) will be reviewed with the 
potential participant to ensure criteria are met. If the patient meets criteria and wishes to 
participate, study personnel will begin the consenting process. 
• Participants may be recruited via person-to-person interactions or via flyers and handouts.  
• We do not anticipate recruiting vulnerable subjects, including non-English speaking 
subjects and persons whose capacity to consent may be questionable.  
 
4.5.2 Screening Logs 
 
A screening log to document all successful screenings, leading to enrollment, and all screen 
failures will be maintained and stored centrally at Columbia University Medical Center, in both 
the regulatory binder, as well as in a password-protected Excel spreadsheet.  
 
4.5.3 Informed Consent 
 
Subjects will demonstrate informed consent by signing a consent form actively approved and 
stamped by the Institutional Review Board at CUMC. The consent form will be presented to the 
subject and reviewed with the subject by the research coordinator or another member of the 
study team. Once the consent form has been reviewed and all questions raised by the subject are 
answered, the subject’s signature may be obtained. 
 
4.5.4 Randomization/Treatment Assignment 
 
 


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If unblinding is required, the PPI may request the group assignment information of a specific 
participant or all study participants. This request may be made at the discretion of the PPI.  
 
Accidental unblinding is not predicted. If this occurs, the participant will be removed from the 
study by the PPI. 
 
5 
STUDY INTERVENTIONS/STUDY MEDICATION/STUDY DRUG OR DEVICE 
 
5.1 
Study Medications/Interventions, Administration, and Duration 
 
At each study visit, participants will be administered one 650mg capsule of either 
Acetaminophen or Aspirin, or a Placebo, which they will be instructed to take orally upon their 
arrival to our lab, one hour before the initiation of the exercise test. Each study visit will last 
approximately 1 hour. There will be no changes to this dose. 
 
5.2 
Handling of Study Medications/Interventions 
 
In accordance with local regulatory requirements, the PPI will document the amount of 
investigational product dispensed and/or administered to study subjects, the amount received from 
the central pharmacy, and the amount destroyed upon completion of the study. The PPI is 
responsible for ensuring product accountability records are maintained throughout the course of 
the study. The unblinded pharmacist will maintain these records and provide them to the PPI upon 
request for review. The unblinded pharmacist will maintain the drug inventory and accountability 
logs for study drugs. The inventory will include details of study drug received and dispensed to 
subjects, batch, and ID numbers. All unused pills must be kept until reconciliation of delivery 
records with accountability logs have been reviewed by the PPI. After reviewing the accountability 
logs, the site will be instructed to destroy the remaining study medication. An accounting will be 
made of any drug deliberately or accidentally destroyed. Discrepancies between the amount of 
Aspirin, Acetaminophen, and Placebo received and dispensed drug will be reconciled. 
5.2.1 Prohibited Medications/Interventions 
• Medications (e.g., disease-modifying therapies) will be documented for post hoc 
consideration of any impact on outcomes.  
• Current use of antipyretics pain medication, or APAP are prohibited during study 
participation (See Exclusion Criteria, Section 4.2). 
 
Procedure for handling situation(s) when subject uses prohibited intervention during study 
participation is detailed in section 8: Criteria for Intervention Discontinuation  
 
 


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5.3 
Subject compliance 
 
N/A, as all procedures related to compliance will take place in the exercise physiology laboratory 
during the study visit and under the supervision of the research coordinator. 
 
6 
CLINICAL AND LABORATORY EVALUATIONS/STUDY PROCEDURES 
6.1 
Schedule of Activities 
 
 
6.2 
Timing of Study Activities 
• Each participant will attend 3 exercise sessions scheduled on separate days separated by 
≥one-week intervals (≤ 4 weeks). Exercise sessions will be scheduled at the same time of 
day (±1 hour), and between the hours of 10 am-5 pm to reduce the influence of circadian 
rhythm variability. Each study visit is estimated to take approximately 2 hours total.  
Evaluation 
Screening 
Week 0 
Randomization/Baseline/Visit 1 
Week 1 
+/- 21 days 
Visit 2 
Week 2 
+/- 21 days 
Visit 3 
Week 3  
+/- 21 days 
Written or E- Informed 
Consent 
X 
 
 
 
Inclusion/Exclusion Review 
X 
 
 
 
Documentation of 
Disease/Disorder 
X 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
Vital Signs/Weight/Height 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
Neurological Examination 
X 
 
 
 
Concomitant Medication 
Review  
X 
X 
X 
X 
Exercise Test 
 
X 
X 
X 
Randomization  
 
X 
X 
X 
Dispense Study Drug  
 
X 
X 
X 
Adverse Event Review  
 
X 
X 
X 
Questionnaires 
 
X 
X 
X 


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• If a participant fails to adhere to any of the Lifestyle Considerations (Section 4.3), 
participant’s study visit must be moved to another date within the allotted 1-4 week 
window.  
• For any patients on interferon therapy, exercise sessions will not be scheduled within 48 
hours post-injection, as injection-related flu-like symptoms may compromise exercise 
tolerance. 
• If a patient experiences an MS exacerbation within 4 weeks of her/his scheduled 
enrollment, the study visit will be rescheduled for 4 weeks following resolution of the 
exacerbation (See Inclusion Criteria, Section 4.1). 
 
 
6.2.1 On-Study/On-Interventions Evaluations/procedures 
After a participant has been cleared to participate in the study by his/her physician and study 
personnel, the participant will sign the informed consent form (either a paper copy, in person, or 
an online e-Consent).  
 
Study personnel will then schedule study visits with the participant. Each participant will attend 
three study visits separated by ≥ one-week (≤ 4 weeks). Specific procedures conducted are 
outlined in Section 6.1. 
 
Exercise sessions will be scheduled for the same time of day (±1 hour), between the hours of 10 
am-5 pm to reduce the influence of circadian rhythm variability. Each study visit is estimated to 
take approximately 2 hours total. Participants will refrain from eating for two hours prior to their 
session.  
 
Study drug will be obtained from the Research Pharmacy and will be available to the participant 
upon arrival at Study Visit 1. Body temperature will be measured with a tympanic thermometer 
(right ear; Braun Thermoscan IRT).  
 
Participants will receive one of three treatments at each session prior to the exercise test. Order 
of treatment will be randomized and counter-balanced, with each participant serving as his/her 
own control. Treatment will be administered as one capsule containing 650mg (i.e., standard 
adult dose for ASA and APAP) of ASA, APAP, or placebo; time of administration will be 
recorded. Exercise will not begin until 1 hour after the participant has taken the study drug in 
order to allow peak serum level to be reached. During this 1-hour waiting period, participants 
will complete the Hospital Anxiety and Depression Scale (HADS) and Fatigue Severity Scale 
(FSS) to characterize the sample; the Paffenbarger Physical Activity Scale for post-hoc 
evaluation of physical activity levels; and the following: day of last menstrual cycle (if female), 
number of hours slept prior night, any physical/outdoor activities engaged in today, presence of 
illness in self or family members today; and visual analog scales (VAS) of pain, fatigue, and 
sadness. Participants will be familiarized with Borg’s ratings of perceived exertion (RPE) CR10 
scale for breathing (RPEbr) and legs (RPEleg), consistent with Collett et al and the thermal 
sensation scale (ASHRAE scale) to be completed by participants at 60-second intervals 
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The exercise session portion of each study visit will use the following tools: 
 
Exercise tests will be conducted by the study team certified exercise physiologist who will be 
accompanied by a physician to ensure safety. All exercise testing equipment is current and 
certified for use with human subjects. Cardiopulmonary exercise testing is performed using 
Vmax Encore Metabolic Cart (CareFusion Corp, San Diego, CA). Echocardiogram (ECG) 
monitoring is done with a twelve-lead system attached to the Vmax Encore Metabolic Cart with 
cardiosoft software (CareFusion Corp). Maximum aerobic fitness (VO2max) will be measured 
by graded maximal exercise test on a VIAsprint 150P electronic-braked cycle ergometer 
(CareFusion Corp). Each subject will have peak ventilatory capacity (Maximum Voluntary 
Ventilation, MVV) determined before exercise test via Vmax Encore System (CareFusion Corp). 
Flow sensor and gas analyzer will be calibrated against known medical grade gases before each 
test. VO2max will be determined from peak 20-second average of breath-by-breath measurement 
of VO2. Anaerobic threshold will be determined for each subject using the V-slope technique 
 
The exercise session portion of each study visit will occur as follows: 
 
Each subject will complete a 5-minute resting phase followed by a 3-minute warm up and then a 
progressive ramped exercise test until achieving volitional fatigue. An individualized ramping 
protocol will be determined by a certified exercise physiologist based on subject’s weight and 
exercise profile. This ramping protocol will be identical between study visits within subjects. 
Patients will maintain a cadence of 50-60 revolutions per minute (RPM) for test duration. The 
test is terminated when cadence drops below 40 RPM for ≥ 5 seconds, or when participant 
reaches volitional exhaustion in accordance with American Thoracic Society (ATS) standard test 
termination criteria. Throughout the test, RPE and HR will be recorded every 60 sec. Blood 
pressure (BP) and ear temperature will be recorded every 2 minutes. At termination, RPE, BP, 
and ear temperature will be recorded, as well as minute ventilation, expired oxygen (O2), carbon 
dioxide (CO2), watts, RER, and total time. VAS of fatigue and Global Fatigue Change (GFC) 
will be recorded.  
 
To test effectiveness of blinding, participants will be asked which condition they think they were 
in at the end of each session. 
 
 
6.2.2 Final On-Study Evaluations 
 
The subject’s final visit on study is Study Visit 3. This study visit will be identical to the 
previous two study visits.  
 
6.2.3 Off-Study Requirements 
 
There are no off-study requirements for this clinical trial.  


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6.3 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS 
 
6.3.1 Informed Consent 
E-Consent 
We will be utilizing both in-person consenting and e-consent. E-consent will be done via 
RedCap, a secure online database. A copy of the e-consent form as a Redcap-generated PDF is 
attached to this protocol to attest to it being identical to the print-version. We will offer the e-
consent to in-person participants as a way to replace the signing of a paper-based informed 
consent to best address the participant's needs or preferences. This is optional and a paper copy 
will always be available. The e-consent will show the same pages as the traditional paper 
consent. The potential research participant will then use this e-consent to fill out the same 
signature fields as the traditional paper consent form. Once the participant signs the consent and 
hits submit, a PDF of the completed consent will be generated and can be emailed to both the 
participant and the study coordinator. For both in-person and remote e-consenting, study 
personnel will abide by the guidelines as highlighted in the Columbia University Institutional 
Review Board Guidance on Electronic Informed Consent document. For e-consent, study 
personnel will plan a phone call with each potential participant to discuss the consent form and 
study in detail, allowing for each participant to ask any questions prior to signing on the online 
ICF. Study personnel will confirm the participant's identity by asking for the patient's full name 
and DOB prior to beginning the e-consent process. This process is in compliance with the 
requirements of 21 CFR 11. E-consent will be done via RedCap so that study personnel may 
send interested, potential study participants an email with a link directly to the e-consent. The e-
consent will appear as a form for the participant to read with a signature line at the bottom where 
participants may type in their names to indicate consent. Study personnel will plan a call with 
any potential study participant who chooses to remotely e-consent. On that call, study personnel 
may consent participants just as they would in person, while also allowing for potential 
participants to ask any questions before choosing to participate. As with in-person consenting, 
the e-consent process may take 20-60 minutes. For in-person consenting, participants will be 
provided with a signed copy of the ICF in hard copy. For e-consent, PDF versions of the signed 
form may be generated and a copy may be sent to both the study coordinator and the participant 
who has consented. Study coordinators will keep a printout copy of this PDF on file throughout 
the duration of the study. 
The Research Pharmacy requires at least 2 hours to prepare the study medication. With e-
consenting, preparation of study drug may be hastened, allowing for shorter study visits and 
increasing likelihood of participation and subject retention.  
6.3.2 Protocol Violations 
Protocol Violations are defined by the study site’s local IRB. These include, but are not limited 
to: 
 


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• 
Using unstamped documents 
• 
Enrolling unqualified participants 
 
6.3.3 Medical History 
 
Participant’s medical history will be documented. Medical history includes, but is not limited to: 
 
1. Multiple Sclerosis history 
2. Psychiatric history 
3. Diseases resulting in exclusion from the study 
 
 
6.3.4 Concomitant Medications/Treatments 
 
The only concomitant medications that may be documented for this study are: 
 
4. APAP or ASA 
5. Multiple Sclerosis treatment 
6. Psychiatric medications 
7. Pain medications 
6.3.5 Protocol Amendments and Study Termination 
 
All revisions and/or amendments to this protocol must be approved in writing by the PPI and the 
CIRB. The Investigator will not make any changes to the conduct of the study or the protocol 
without first obtaining written approval from CIRB, except where necessary to eliminate an 
apparent immediate hazard to a study subject. 
 
6.3.6 Clinical Assessments 
 
All clinical assessments will be documented on CRFs and maintained in individual participant’s 
study folder. See Section 6.1 and 6.2 for details on study activities. 
 
6.3.7 Questionnaires 
 
Participants will complete the Hospital Anxiety and Depression Scale (HADS) and Fatigue 
Severity Scale (FSS) to characterize the sample; the Paffenbarger Physical Activity Scale for 
post-hoc evaluation of physical activity levels; and the following: day of last menstrual cycle (if 
female), number of hours slept prior night, any physical/outdoor activities engaged in today, 


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presence of illness in self or family members today; and visual analog scales (VAS) of pain, 
fatigue, and sadness. 
 
 
6.3.8 Additional Evaluations 
 
7 
MANAGEMENT OF ADVERSE EXPERIENCES 
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.  FDA, Office of Human Research Protection (OHRP), and Columbia University Medical 
Center IRB requirements for reporting AEs will be followed. Subjects will be monitored for AEs 
from the time they sign consent until 30 days following permanent discontinuation of study drug. 
At that point, all ongoing AEs will be followed to resolution, but no new AEs will be recorded. 
The IMM/DSMB will review cumulative AEs; the frequency of this review will be determined by 
the IMM/DSMB in conjunction with the Protocol PI. 
 
8 
 
MANAGEMENT OF UNANTICIPATED PROBLEMS  
 
An Unanticipated Problem (UP), per the Columbia University Medical Center IRB, is defined as: 
“any incident, experience or outcome involving risk to subjects or others in any human subjects 
research that meets all of the following criteria: 
A. 
unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) 
the characteristics of the subject population being studied; 
B. 
related or possibly related to participation in such research (i.e., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the 
procedures involved in such research); and 
C. 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or 
recognized.” 
 
Per CIRB reporting guidelines, UPs will be reported if they require changes to the protocol due 
to added risk to participants. All participants will be notified of any protocol changes and will be 
reconsented as appropriate. If an UP does not pose additional risk to participants and does not 
require changes made to the protocol, the UP may be reported as an Adverse Event.  
 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
General Design Issues 
Statistical methods recommended for the proper analysis of crossover trial data will be used (for 
details, see Wellek and Blettner). Our primary outcomes evaluate differences between treatment 
condition (ASA, APAP and placebo) with respect to (a) TTE (that is, length of time spent 
exercising) and (b) increase in exercise-induced body temperature (°F). Differences between 
pretreatment conditions (ASA, APAP, placebo) will be analysed separately by sequence group to 
account for possible order effects (ie, stepwise assessment of outcome differences across six 
possible sequences). Although significant differences in outcome variables between ASA and 
APAP are not anticipated, we are interested in seeing how they compare in the full analyses. A 
mixed-effects linear model will be used to account for repeated measurements of each outcome, 
period effect, sequence effect and carryover effect. Using mixed-effects linear model will enable 
us to model differences in outcomes both within and between patients (intrapatient and interpatient 
variability). If assumptions for mixed-effects linear model are not met and log transformation is 
not appropriate, non-linear mixed-effects models will be used. Moreover, exploratory analyses 
will examine potential pretreatment differences for additional outcome measures, such as 
physiological indices (eg, HR, BP) and behavioural self-reports (eg, RPEs, fatigue, pain). 
 
9.2 
Outcomes 
 
9.2.1 Primary Outcome 
Primary outcomes are total time to exhaustion (TTE) measured at exercise cessation and change 
in temperature from baseline (pre-exercise) to exercise cessation. 
9.2.2 Secondary Outcomes 
Secondary outcomes included patient-reported outcomes: Borg’s ratings of perceived exertion 
scale (RPE) for breathing (RPEbr) and muscle fatigue (RPEleg) collected every 2 minutes 
throughout the exercise test; 10-point visual analog scales (VAS) of pain (VAS-P) and fatigue 
(VAS-F) measured pre- and post-exercise test; and physiological measures: heart rate (HR), 
systolic and diastolic blood pressure (SBP, DBP), expO2, peak minute ventilation, maximum 
watts, and RER. 
 
 
 
9.3 
Sample Size and Accrual 
In a pilot trial with 12 participants, effect sizes for both outcomes (time to exhaustion/TTE and 
body temperature) were very large (Cohen’s d=1.45). Here, we conservatively estimated medium-
sized effects (0.5) to calculate a power estimate for the proposed trial. With significance set at 
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detect differences between interventions. Our plan to enroll 60 participants allows for 10% 
attrition, which accounts for both participant drop-out as well as exclusion due to relapses. 
9.4 
Data Monitoring 
All aspects of the study will be monitored by qualified individuals designated by the sponsor.  
Monitoring will be conducted according to Good Clinical Practice and applicable government 
regulations.  The investigator agrees to allow monitors access to the clinical supplies, dispensing 
and storage areas, and to the clinical files of the study subjects, and, if requested, agrees to assist 
the monitors. 
 
Safety monitoring will include careful assessment and appropriate reporting of adverse events.  
Medical monitoring will include contemporaneous assessment of serious adverse events. 
 
The monitoring of subject safety and data quality will follow the NINDS Guidelines for Data and 
Safety Monitoring in Clinical Trials.  A Data and Safety Monitoring Board (DSMB) appointed by 
the NIH/NINDS will meet at six-month intervals (or as determined by the NINDS) to review 
partially unblinded study data provided by the study statistician.  This committee will monitor rates 
of adverse events and endpoints in the trial and will monitor the performance of the trial. The 
frequency and format of DSMB meetings, reports, and guidelines for interim analysis will be 
agreed upon prior to study subject enrollment. 
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.  FDA, Office of Human Research Protection (OHRP), and Columbia University Medical 
Center IRB requirements for reporting AEs will be followed. Subjects will be monitored for AEs 
from the time they sign consent until 30 days following permanent discontinuation of study drug. 
At that point, all ongoing AEs will be followed to resolution, but no new AEs will be recorded. 
The IMM/DSMB will review cumulative AEs; the frequency of this review will be determined by 
the IMM/DSMB in conjunction with the Protocol PI. 
The PPI and research team are responsible for identifying and reporting AEs and determining the 
relationship of the event to the study drug/study procedures.  Aggregate reports blinded by 
treatment group, detailed by severity, attribution (expected or unexpected), and relationship to 
the study drug/study procedures, will be available from the DCC for review. 
 
Because the potential risks are low and the trial is limited to 3 study visits (where ASA, APAP or 
placebo are administered in a controlled setting) that occur within a ~3 week period (i.e., there is 
no at-home requirement, no daily use of study drug), PI Leavitt will hold primary responsibility 
for monitoring the overall safety of all participants enrolled in the trial. She will work in close 
consultation with Co-I Stein, who will oversee the certified exercise physiologist who conducts 
all exercise tests, and Co-I Riley, who will ensure the suitability of all potential participants for 
the study. Should any of the following specific events occur, a participant would be precluded 
from continuing the intervention: adverse reaction to exercise test, adverse reaction to any 
treatment condition (ASA, APAP, placebo), patient desire to discontinue participation for any 
reason. If any medication-related issues are noted during the study (e.g., allergic reactions or 


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other adverse reaction, which is unlikely considering most of our participants will likely have 
used aspirin and acetaminophen already), Dr. Riley will be consulted, patient will be treated as 
needed, and participation in the trial will cease. 
 
9.5 
Data Analyses 
  
All data analyses will be conducted by the study biostatistician, Dr. Amelia Boehme, who will be 
blinded to treatment condition until the primary analysis has been completed. 
 
 
10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING 
10.1 Data Management 
Site personnel will collect, transcribe, correct, and transmit the data onto source documents, CRFs, 
and other forms used to report, track and record clinical research data.  The DCC will monitor 
clinical sites to ensure compliance with data management requirements and Good Clinical 
Practices. The DCC is responsible for developing, testing, and managing clinical data management 
activities, as required, at the study sites, the CCC, and at the DCC. 
 
The general NINDS Common Data Elements (CDE) will be used to construct data collection 
forms. All study data will be collected via systems created in collaboration with the DCC and will 
comply with all applicable guidelines regarding patient confidentiality and data integrity. 
 
10.2 Role of Data Management 
 
Data Management (DM) is the development, execution and supervision of plans, policies, 
programs, and practices that control, protect, deliver, and enhance the value of data and 
information assets. The PPI and study coordinators will be responsible for DM and will act as the 
DCC for this trial. 
 
All data will be managed in compliance with applicable regulatory requirements. 
 
The DCC is responsible for all aspects of clinical data management, and for properly instructing 
key study personnel on how to collect, transcribe, correct and transmit the data onto CRFs or other 
data collection forms and logs. 
 
The DCC is responsible for establishing procedures to ensure that clinical data management 
activities occur as required at the CCC, the CSS, and at the DCC. 
 
All precautions to ensure patient privacy will be taken. All discussions and screening activities 
will be held in a private area or will be conducted by phone, with the coordinator seated in a quiet 


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office with only the study's coordinators being present. All patient data will be coded and all 
patients will be given a unique study ID number. All manipulations of samples and data will be 
performed using this unique number, which is separated from any subject identifier. 
 
 
10.3 Quality Assurance 
By signing this protocol, the Investigator agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written standard operating 
procedures (SOPs) to ensure that studies are conducted and data are generated, documented, and 
reported in compliance with the protocol, accepted standards of GCP, and all applicable federal, 
state, and local laws, rules and regulations relating to the conduct of the clinical study. 
 
 
10.4 Adverse Experience Reporting 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with 
all applicable United States Food and Drug Administration (FDA) regulations and International 
Conference on Harmonization (ICH) guidelines.  The Site 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 important to report all AEs, especially those that result 
in permanent discontinuation of the investigational product being studied, whether serious or non-
serious. 
Any adverse events (AE), serious adverse events, or unanticipated problems involving risks to 
subjects or others occurring during the exercise test will be immediately reported by Dr. Leavitt to 
the NIH program officer according to the following timetable: deaths related to study participation 
(though not anticipated) will be reported no later than within 5 business days of Dr. Leavitt first 
learning of the death. Unexpected serious adverse events (SAEs) will be reported by Dr. Leavitt 
to her program officer within 10 business days of the study team becoming aware of the SAE. All 
AEs and SAEs that are deemed expected and/or unrelated to the study will be submitted in a 
summary to NIH program officer with the annual progress report. Any protocol violations that 
occur will be submitted with the annual progress report. All documentation submitted to the NIH 
PO will be prepared in accordance with NIH guidelines for documentation of Reportable Events. 
In the event of any adverse events, Dr. Leavitt will work closely with Drs. Stein and Riley to ensure 
appropriate clinical management of the participant. Dr. Leavitt will provide written 
documentation, conduct a complete investigation, and follow-up on any/all possible study-related 
AEs. Any AEs will be reported by Dr. Leavitt to the Institutional Review Board and 
clinicaltrials.gov. Dr. Leavitt will be responsible for describing and adhering to the procedures for 
identifying, monitoring, and reporting reportable events as outlined in the Protection of Human 
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Specific plan and timeframe for reporting IRB and/or ISM/DSMB actions (e.g., protocol 
violations, non-compliance, suspensions, terminations): Any suspension or termination of 
approval will include a statement of the reason(s) for the action and will be reported promptly by 
Dr. Leavitt to the NIH program officer within 3 business days of receipt. 
 
An adverse event is defined as: “…an unfavorable and unintended sign, symptom, or disease 
associated with a subject’s participation in this research trial.” 
 
Serious adverse events include those events that:  “result in death; are life-threatening; require 
inpatient hospitalization or prolongation of existing hospitalization; create persistent or significant 
disability/incapacity, or a congenital anomaly/birth defects.”  
 
Unexpected adverse event is defined as any adverse experience…the specificity or severity of 
which is not consistent with the risks described in the protocol.  
 
Expected adverse events are those that are known to be associated with or have the potential to 
arise as a consequence of participation in the study. 
 
 
On-line Adverse Event Reporting System  
 
 
• Within 24 hours (of learning of the event), investigators must report any Serious Adverse Event 
(SAE) Investigators must report all other AEs within 5 working days/7 calendar days (of 
learning of the event). 
 
Serious adverse events: The site investigator determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. The IMM 
will review the SAE report.  The IMM may request further information if necessary.  The Online 
Adverse Event Reporting System maintains audit trails and stores data (and data updated) and 
communication related to any adverse event in the study.  The IMM may determine that the Serious 
Adverse Event requires expedited reporting to the FDA.  The DCC will prepare a Medwatch safety 
report for submission to the FDA.  If warranted, the IMM will notify the DSMB chair.  The DSMB 
may suggest changes to the protocol or consent form to the Study Chair as a consequence of 
adverse events.  
 
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the DCC in a timely fashion 
(within 5 working days). The events will be presented in tabular form and given to the IMM on a 
quarterly basis or as requested. Local site investigators are also required to fulfill all reporting 
requirements of their local institutions. 
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious, 
expected/unexpected and relationship to study drug) for review. A separate report detailing 


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protocol compliance will also be available from the DCC for DSMB and/or site review monthly 
or as requested. The research team will then evaluate whether the protocol or informed consent 
document requires revision based on the reports.  
 
10.4.1 Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events 
10.4.1.1 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. 
 
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). 
 
 
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 
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An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with the current Investigators Brochure or package insert or described in the protocol.  
An unexpected, suspected adverse drug reaction is any unexpected adverse event that, in the 
opinion of the Investigator, there is a reasonable possibility that the investigational product caused 
the event. 
 
10.4.1.2 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. 
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, 
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). 
 
A serious, suspected adverse drug reaction is an SAE that, in the opinion of the Site Investigator 
or Sponsor, suggests a reasonable possibility that the investigational product caused the event. 
 
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10.4.1.3 Assessment and Recording of Adverse Events 
 
This study will utilize the CTCAE version 4.0 coding system for adverse event recording.  Adverse 
events reported using CTCAE will be recoded into the CRF. 
 
Assessment of Adverse Events 
At each visit (including telephone interviews), the subject will be asked “Have you had any 
problems or symptoms since your last visit?” in order to determine the occurrence of adverse 
events. If the subject reports an adverse event, the Investigator will 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) 
5. Causality, relation to investigational product and disease 
6. Action taken regarding investigational product 
7. Outcome 
 
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) 
 


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Recording of Adverse Events 
 
All clinical adverse events are recorded in the Adverse Event (AE) Log in the subject’s study 
binder.  
 
Please Note: Serious Adverse Events (SAEs) must be reported to the CUMC IRB within 24 hours 
of learning of the SAE.  
 
Entries on the AE Log (and into the online Adverse Event Reporting System) 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. 
 
Adverse Events and Serious Adverse Events - Reportable Events 
 
The following are considered reportable events and must be reported to the CUMC IRB within 24 
hours of the site being notified of the event.  
 
• All events that meet the above criteria for Serious Adverse Events (SAEs) 
 
 
All occurrences of Serious Adverse Events (SAEs) must be reported within 24 hours of discovery 
of the event.   All other Adverse Events (AEs) must be reported within 5-10 business days (of 
discovery of the event). 
 
Adverse Event Data Management System (AEDAMS) 
 
Upon entry of a serious adverse event by a clinical site, the DCC Online Adverse Event Reporting 
System will immediately notify the IMM. If warranted, the IMM will notify the DSMB chair.  
 
Serious adverse events: The investigator determines causality (definitely not related, probably not 
related, possibly related, probably related, definitely related) of the adverse event. The PPI will 
review the SAE report and may request further information if necessary.  The DSMB may suggest 
changes to the protocol or consent form to the Project PI as a consequence of adverse events. The  
 
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the IRB within 5 working days. 
The events will be presented in tabular form and given to the PI on a monthly basis or as requested.  
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious and expected, 
unexpected) for review. 
 


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11 HUMAN SUBJECTS 
Documented approval from the CUMC IRB will be obtained for all participating centers prior to 
clinical trial start, according to ICH GCP, local laws, regulations and organization. When 
necessary, an extension, amendment or renewal of the CIRB approval must be obtained. 
Evidence of training in responsible conduct of research shall be on file for the PI and co-
investigators. 
 
11.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document (Appendix A) and any subsequent modifications 
will be reviewed and approved by the CUMC IRB responsible for oversight of the study.  A signed 
consent form, approved by the CUMC IRB, will be obtained from the subject.   For subjects who 
cannot provide consent for themselves, such as those below the legal age, a parent, legal guardian, 
or person with power of attorney, must sign the consent form; additionally, the subject's assent 
must also be obtained if he or she is able to understand the nature, significance, and risks associated 
with the study.  The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.  A copy of the consent form will be given to 
the subject, and this fact will be documented in the subject’s record. 
 
11.2 Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave 
the clinical study site will be identified only by the study specific Subject Identification Number 
(SID) to maintain subject confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done using study specific SIDs only.  Clinical 
information will not be released without written permission of the subject, except as necessary for 
monitoring by CIRB, the FDA, the NINDS, the OHRP, and the investigator. 
 
11.2.1  Certificate of Confidentiality  
 
To further protect the privacy of study subjects, a Certificate of Confidentiality will be issued by 
the National Institutes of Health (NIH).  This certificate protects identifiable research information 
from forced disclosure. It allows the investigator and others who have access to research records 
to refuse to disclose identifying information on research participation in any civil, criminal, 
administrative, legislative, or other proceeding, whether at the federal, state, or local level. By 
protecting researchers and institutions from being compelled to disclose information that would 
identify research subjects, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to subjects. 
 
 


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11.3 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the CIRB, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected. If the 
study is terminated or suspended, the PI will promptly inform study subjects, and the IRB and 
provide the reason(s) for the termination or temporary suspension. 
 
 
12  FUTURE USE OF STORED SPECIMENS AND DATA  
• Data is anticipated for future research use. Some of all data, as applicable, will be 
retained by Columbia researchers for future use. Current PI will retain the materials and 
there is no intent to create a repository or share with other CU researchers.  
• Note: Information provided in original consent forms will be considered when an 
addition of future uses is submitted via modification. Data may be examined 
retrospectively in the future, however any/all future analyses to be conducted will 
be specific to the research analyses and aims outlined under this protocol 
• Data will be labeled during storage for future uses in the same manner as during 
collection (e.g., with direct identifiers, coded, de-identified, anonymous).  
• Data will be physically stored in the same manner as during collection.  
• Data may be released to the NIH. All data shared will be coded with no identifiers; no 
PHI will be released. All data will be shared via a secure file transfer or encrypted format 
• The Principal Investigator and study coordinator will have access to the stored data. 
Other study personnel may request access to stored data from the study coordinator or PI. 
Some or all data/specimens will be released to a non-Columbia entity for future use and 
Columbia researchers will not have direct control. 
 
13 STUDY RECORDS RETENTION  
As per NIH guidelines, records will be retained for a period of three years from the date of 
Federal Financial Report (FFR) submission.  
 
14 CONFLICT OF INTEREST POLICY  
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who 
have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the National Institute of Child Health and Development has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest. 


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15 PUBLICATION OF RESEARCH FINDINGS 
Research findings will be published in peer-reviewed journals in a timely manner after the trial 
has been completed. 
 
16 REFERENCES  
Leavitt VM, Blanchard AR, Guo CY, Gelernt E, Sumowski JF, Stein J. Aspirin is an effective 
pretreatment for exercise in multiple sclerosis: A double-blind randomized controlled pilot trial. 
Mult Scler. 2018 Oct;24(11):1511-1513. doi: 10.1177/1352458517739138. Epub 2017 Oct 27. 
PMID: 29076760. 
 
Kever A, Nelson KE, Aguerre IM, Riley CS, Boehme A, Lee NW, Strauss Farber R, Levin SN, 
Stein J, Leavitt VM. ASPIRE trial: study protocol for a double-blind randomised controlled trial 
of aspirin for overheating during exercise in multiple sclerosis. BMJ Open. 2020 Nov 
14;10(11):e039691. doi: 10.1136/bmjopen-2020-039691. PMID: 33191260; PMCID: 
PMC7668379. 
 
 
 
 
 
 
 
 


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Appendix A:  Model Informed Consent Form 


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