The Effect of an Adaptive Exercise Program on Chronic Inflammation in Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injuries
Sponsor: HealthPartners Institute

 
 
The Effect of an Adaptive Exercise Program on Chronic 
Inflammation in Spinal Cord Injury.  
Protocol Number: Version 5 
National Clinical Trial (NCT) Identified Number: NCT05376449 
Principal Investigators: Amanda A. Herrmann, PhD & Steven D. Jackson, MD, 
MBA 
Site/Sponsor: HealthPartners Neuroscience Center/HealthPartners Institute 
Institutional Review Board Number: A21-006 
Funded by: Minnesota Office of Higher Education 
Date: August 14th, 2023 
 

 
CONFIDENTIALITY STATEMENT 
 
This document is confidential communication. Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be published or disclosed without prior 
approval of the Principal Investigator or other participating study leadership and as consistent with the 
terms of the award. 
 

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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................................................... 1 
INVESTIGATOR’S SIGNATURE ........................................................................................................................ 2 
1 
PROTOCOL SUMMARY ....................................................................................................................... 3 
1.1 
Synopsis ................................................................................................................................... 3 
1.2 
Schema..................................................................................................................................... 3 
1.3 
Schedule of activities ............................................................................................................... 5 
2 
INTRODUCTION ................................................................................................................................. 7 
2.1 
Background & Study Rationale ................................................................................................ 7 
2.2 
Risk/Benefit Assessment.......................................................................................................... 8 
2.2.1 
Known Potential Risks ............................................................................................ 8 
2.2.2 
Known Potential Benefits ...................................................................................... 9 
2.2.3 
Assessment of Potential Risks and Benefits .......................................................... 9 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 9 
4 
STUDY DESIGN ................................................................................................................................... 9 
4.1 
Overall Design .......................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design ..................................................................................... 10 
4.3 
Justification for Intervention ................................................................................................. 10 
4.4 
End-of-Study Definition ......................................................................................................... 10 
5 
STUDY POPULATION ........................................................................................................................ 10 
5.1 
Inclusion Criteria .................................................................................................................... 10 
5.2 
Exclusion Criteria ................................................................................................................... 11 
5.3 
Lifestyle Considerations ......................................................................................................... 11 
5.4 
Screen Failures ....................................................................................................................... 11 
5.5 
Strategies for Recruitment and Retention............................................................................. 12 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .................................................. 12 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration ............................... 12 
6.1.1 
Study Intervention or Experimental Manipulation Description .......................... 12 
6.1.2 
Administration and/or Dosing ............................................................................. 12 
6.2 
Fidelity ................................................................................................................................... 15 
6.2.1 
Interventionist Training and Tracking .................................................................. 15 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 15 
6.4 
Study Intervention/Experimental Manipulation Adherence ................................................. 15 
6.5 
Concomitant Therapy ............................................................................................................ 15 
6.5.1 
Rescue Therapy .................................................................................................... 15 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................................ 16 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ..................................... 16 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 16 
7.3 
Lost to Follow-Up ................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 17 
8.1 
Endpoint and Other Non-Safety Assessments ....................................................................... 17 
8.2 
Safety Assessments ................................................................................................................ 17 

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8.3 
Adverse Events and Serious Adverse Events ......................................................................... 18 
8.3.1 
Definition of Adverse Events ............................................................................... 18 
8.3.2 
Definition of Serious Adverse Events ................................................................... 18 
8.3.3 
Classification of an Adverse Event ....................................................................... 18 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 19 
8.3.5 
Adverse Event Reporting ..................................................................................... 20 
8.3.6 
Serious Adverse Event Reporting......................................................................... 20 
8.3.7 
Reporting Events to Participants ......................................................................... 20 
8.3.8 
Events of Special Interest ..................................................................................... 20 
8.3.9 
Reporting of Pregnancy ....................................................................................... 20 
8.4 
Unanticipated Problems ........................................................................................................ 20 
8.4.1 
Definition of Unanticipated Problems ................................................................. 20 
8.4.2 
Unanticipated Problems Reporting ..................................................................... 21 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 21 
9 
STATISTICAL CONSIDERATIONS ............................................................................................... 21 
9.1 
Statistical Hypotheses ............................................................................................................ 21 
9.2 
Sample Size Determination.................................................................................................... 22 
9.3 
Populations for Analyses ....................................................................................................... 22 
9.4 
Statistical Analyses................................................................................................................. 22 
9.4.1 
General Approach ................................................................................................ 23 
9.4.2 
Analysis of the Primary Endpoint(s) ..................................................................... 23 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 23 
9.4.4 
Analysis of the Tertiary Endpoint(s) ..................................................................... 24 
9.4.5 
Safety Analyses .................................................................................................... 24 
9.4.6 
Baseline Descriptive Statistics ............................................................................. 24 
9.4.7 
Planned Interim Analyses .................................................................................... 24 
9.4.8 
Sub-Group Analyses ............................................................................................. 24 
9.4.9 
Tabulation of Individual Participant Data ............................................................ 24 
9.4.10 
Exploratory Analyses ............................................................................................ 24 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..................... 25 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 25 
10.1.1 
Informed Consent Process ................................................................................... 25 
10.1.2 
Study Discontinuation and Closure ...................................................................... 25 
10.1.3 
Confidentiality and Privacy .................................................................................. 26 
10.1.4 
Future Use of Stored Specimens and Data .......................................................... 27 
10.1.5 
Key Roles and Study Governance ........................................................................ 27 
10.1.6 
Safety Oversight ................................................................................................... 27 
10.1.7 
Clinical Monitoring ............................................................................................... 27 
10.1.8 
Quality Assurance and Quality Control ................................................................ 27 
10.1.9 
Data Handling and Record Keeping ..................................................................... 28 
10.1.10 
Protocol Deviations .............................................................................................. 28 
10.1.11 
Publication and Data Sharing Policy .................................................................... 28 

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10.1.12 
Conflict of Interest Policy ..................................................................................... 28 
10.2 
Additional Considerations ..................................................................................................... 29 
10.3 
Abbreviations and Special Terms ........................................................................................... 29 
10.4 
Protocol Amendment History ................................................................................................ 30 
11 
REFERENCES..................................................................................................................................... 31 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Council 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).  
 
Investigators and clinical trial site staff who are responsible for the conduct, management, or oversight of 
clinical trials have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol 
and the consent form(s) must be obtained before any participant is consented. 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(s) will be IRB approved; a determination will be made regarding whether 
a new consent needs to be obtained from participants who provided consent, using a previously approved 
consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above. 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name:  Amanda A. Herrmann, PhD 
Title: 
Research Associate 
 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
Name:  Steven D. Jackson, MD, MBA 
Title: 
Physician 
 
Co-Investigator Contact Information 
Affiliation: HealthPartners Neuroscience Center 
Address: 295 Phalen Blvd. 
       St. Paul, MN 55130 
   Mailstop 41200A 
Telephone: (651) 495-6565 
Email: Amanda.A.Herrmann@HealthPartners.com  
Email: Steven.D.Jackson@HealthPartners.com 
 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
The Effect of an Adaptive Exercise Program on Chronic Inflammation in 
Spinal Cord Injury. 
IRB Number: 
A21-006 
Study Description: 
Long lasting inflammation in the body is related to cardiovascular and 
respiratory disease, which are the two most common causes of death in 
people living with spinal cord injury (SCI). Individuals with SCI have been 
reported to have higher levels of inflammation when compared to 
healthy individuals. Exercise is a well-known method to reduce 
inflammation; however, people with SCI are often inactive. The main 
goal of this study is to determine whether a 12-week adaptive exercise 
program can reduce inflammation in people with SCI. Participants will 
be randomized to start exercise immediately or after a 12-week delay. 
Specific Aims: 
 
Specific Aim 1: To examine the effect of a 12-week exercise program on 
inflammation in individuals with SCI. 
Specific Aim 2: To examine the effect of a 12-week exercise program on 
strength and cardiovascular health in individuals with SCI. 
Specific Aim 3: To observe the impact of a 12-week exercise program 
on quality of life (QOL) in individuals with SCI. 
Endpoints: 
Primary Endpoint: Change in inflammatory biomarkers: CRP, IL-6, TNF-α 
Secondary Endpoint: Strength: 1-repitition maximum, Cardiovascular: 
6-minute submaximal exercise test.  
Tertiary Endpoint: Spinal Cord Injury-Quality of Life short forms 
Study Population: 
25 individuals aged 18-70 with a diagnosis of SCI will be recruited for 
this study. 
Description of 
Sites/Facilities Enrolling  
Participants: 
For in-person visits, participants will attend the exercise program at the 
HealthPartners Neuroscience Center, located at 295 Phalen Blvd., St. 
Paul, MN 55130. 
 
Description of Study 
Intervention/Experimental 
Manipulation: 
 
The exercise program will be administered by exercise physiologists 
and physical therapists 3 times per week for a duration of 12 weeks. 
Study Duration: 
The duration of this study is 2 years. 
Participant Duration: 
We anticipate that participants will complete all study-related tasks 
within approximately 6-9 months. 
 
 
 
1.2 
SCHEMA  

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1.3 
SCHEDULE OF ACTIVITIES 
 
 
VISIT SCHEUDULE DESCRIPTION 
 
All in-person visits will take place at: HealthPartners Neuroscience Center, 295 Phalen Boulevard, St. 
Paul, MN, 55130. 
 
1. Pre-screening Phone/Video Call (Groups 1 & 2) 
• 
Duration: Approximately 30 minutes 
• 
Research staff will: 
o Provide potential participants information about the study and ask whether 
they are interested in participating. 
o Determine whether they meet the inclusion/exclusion criteria for the study. 
o Ask participants for permission to communicate through e-mail for the study 
and assist them in setting up an account if they do not have one (e.g. send them 
study documents, QOL survey). 
o Schedule Consent Visit if the person is eligible for the study and e-mail the 
person the Informed Consent, Health Insurance Portability and Accountability 
Act (HIPAA), and HealthPartners non-discrimination forms. 
 
 
Pre-
screening 
Consent  
Pre-
treatment 
1 
Pre-
treatment 
2 
Study 
Intervention 
Post-
treatment 
1 
Post-
treatment 
2 
Early 
Withdrawal 
Visit 
Group 1: 
Immediate 
Start 
Visit 0 
 
 
Visit 1 
Visit 2 
N/A 
Visit 3-38 
Visit 39 
Visit 40 
 
 
 
Group 2: 
Delayed Start 
Visit 3 
Visit 4-39 
Visit 40 
Visit 41 
Review 
Eligibility 
X 
 
 
 
 
 
 
 
Informed 
Consent 
 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
Blood Draw-   
in person 
 
 
X 
X 
 
X 
X 
X 
Strength & 
Cardiovascular 
Testing-             
in person 
 
 
X 
X 
 
X 
X 
X 
SCI-QOL- 
e-mail survey 
 
 
X 
X 
 
X 
X 
X 
Adverse Events 
(AE) Reporting 
 
 
 
 
X 
X 
X 
X 
Treatment 
Adherence 
 
 
 
 
X 
 
 
 

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2. Consent Phone Call (Groups 1 & 2) 
• 
Duration: Approximately 1 hour via phone 
• 
Research staff will:  
o Review the Informed Consent and HIPAA documents with potential participants. 
o Answer any questions of potential participants and ensure they understand the 
expectations of the study.  
o Ask participants to electronically sign the Informed Consent and HIPAA 
documents via REDCap and provide them electronic copies for their records. 
o Complete the Demographics short form in the relevant electronic case report 
forms (eCRFs) in Research Electronic Data Capture (REDCap), a secure web-
based system. 
o Randomize the participant and schedule the Pre-treatment visit(s). 
 
3. Pre-treatment Visit 1 (Groups 1 & 2) 
• 
Duration: Approximately 1 hour in person 
• 
Research staff will:  
o Complete the Medication review in REDCap. 
o Have the laboratory staff obtain a blood sample from the patient. 
o Take the patient to the rehabilitation gym for strength and cardiovascular 
testing (described in detail below) 
• 
Patient will be asked to complete the Spinal Cord Injury-Quality of Life (SCI-QOL) short 
forms via e-mail survey within 3 days (approximately 30 minutes). 
 
4. Pre-treatment Visit 2 (Group 2 only) 
• 
Duration: Approximately 1 hour in person 
• 
Research staff will:  
o Complete the Medication review in REDCap. 
o Have the laboratory staff obtain a blood sample from the patient. 
o Take the patient to the rehabilitation gym for strength and cardiovascular 
testing. 
• 
Patient will be asked to complete the SCI-QOL short forms via e-mail survey within 3 
days (approximately 30 minutes). 
 
5. Study Intervention (Groups 1 & 2) 
• 
Duration: Each visit approximately 1 hour 
• 
The exercise physiologists will:  
o Complete the Adverse Events (AE) Reporting, Medication Review, and 
Treatment Adherence in the relevant eCRFs in REDCap. 
o Provide exercise instruction as described in more detail below. 
 
6. Post-treatment Visit 1 (Groups 1 & 2) 
• 
Duration: Approximately 1 hour in person 
• 
Research staff will:  
o Complete the Medication review in REDCap. 
o Have the laboratory staff obtain a blood sample from the patient. 

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o Take the patient to the rehabilitation gym for strength and cardiovascular 
testing. 
• 
Patient will be asked to complete the SCI-QOL short forms via e-mail survey within 3 
days (approximately 30 minutes). 
 
7. Post-treatment Visit 2 (Groups 1 & 2) 
• 
Duration: Approximately 1 hour in person 
• 
Research staff will:  
o Complete the Medication review in REDCap. 
o Have the laboratory staff obtain a blood sample from the patient. 
o Take the patient to the rehabilitation gym for strength and cardiovascular 
testing. 
• 
Patient will be asked to complete the SCI-QOL short forms via e-mail survey within 3 
days (approximately 30 minutes). 
 
8. Early Withdrawal Visit (For patients who begin the intervention and then withdraw from the 
study.) 
• 
Duration: Approximately 1 hour in person 
• 
Research staff will:  
o Complete the Medication review in REDCap. 
o Have the laboratory staff obtain a blood sample from the patient. 
o Take the patient to the rehabilitation gym for strength and cardiovascular 
testing (if medically able). 
• 
Patient will be asked to complete the SCI-QOL short forms via e-mail survey within 3 
days (approximately 30 minutes). 
 
2 
 
INTRODUCTION 
2.1 
BACKGROUND & STUDY RATIONALE 
 
Two of the most common causes of death in people living with spinal cord injury (SCI), cardiovascular and 
respiratory disease, have been linked to chronic low-grade inflammation.1 Inflammation has also been 
linked to obesity, pulmonary issues, diabetes, and poor wound healing.2 Although some levels 
inflammation in the body can be considered “good” (e.g. inflammation occurs during injury repair), 
chronic inflammation can have negative consequences.  Fortunately, chronic inflammation after a SCI 
could likely be reduced through modifiable risk factors, as described below. 
 
Higher levels of inflammatory biomarkers are observed in SCI when compared to healthy individuals. 
Biomarkers are measurable substances from the body (e.g. blood serum). C-reactive protein, which is a 
marker of both inflammation and cardiovascular disease, was reported to be higher in adults with chronic 
SCI.3 Proinflammatory cytokines (signaling molecules that promote inflammation) interleukin 6 (IL-6) and 
tumor necrosis factor alpha (TNF-α), and the IL-1 receptor agonist (IL-1RA) (produced in response to 
infection or inflammation) are also increased.4 Finally, Antiganglioside (anti-GM1) immunoglobulin (IgG), 
which are antibodies that are typically also present in autoimmune diseases (e.g. Guillain–Barré 
syndrome), have also been shown to be elevated.4 Not only are these inflammatory biomarkers elevated 

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in individuals with SCI, they are even more elevated in those with medical complications (e.g. urinary tract 
infection, pressure ulcers).4 
 
A well-known method to reduce inflammation is through exercise; however, due to limitations in mobility, 
individuals with SCI are among the most sedentary and inactive in the world.5 Muscle atrophy, damaged 
muscle innervation, and reduced muscle activation create barriers for individuals with SCI to exercise. In 
addition, exercise conditioning in persons with SCI is complicated, because its benefits can be potentially 
counterbalanced by both ineffective exercise activities and the consequences of imprudent exercise, 
lending to further injury and accelerated musculoskeletal decline. Individuals with SCI also frequently 
encounter challenges and barriers when navigating a typical gym space. Therefore, individuals with SCI 
may be limited in their ability to achieve anti-inflammatory benefits through exercise. 
 
While exercise has been shown to reduce biomarkers of inflammation6,7 and increase the release of anti-
inflammatory proteins7 in healthy individuals, it has not been extensively examined in individuals with SCI. 
In one study, CRP, IL-6, and TNF-α were all reduced in individuals with SCI after participation in a 10 week 
cycling exercise program.8 In another study, CRP and erythrocyte sedimentation rate (ESR; test to detect 
inflammation) were both reduced in individuals with SCI following a 6-week body weight supported 
treadmill training program.9 However, these studies included small sample sizes (18 and 14, respectively), 
did not include a control group, examined biomarkers immediately after the program, and included only 
cardiovascular exercise. In another study that included both individuals with SCI and multiple sclerosis 
(MS), there was a significant decrease in TNF-α after one exercise session.10 However, these results 
included both patients with SCI and MS and only a single exercise session. Thus, the generalization of the 
results, the long-term effects, and the effects of strength training are not yet known. 
 
While there is limited evidence that an exercise program can reduce inflammation in individuals with SCI, 
exercise has been shown to have other important beneficial effects. A recent review found evidence that 
exercise can improve fitness (cardiorespiratory fitness, power output, muscle strength) and 
cardiometabolic health (body composition, cardiovascular risk) of individuals with SCI.11 Another review 
reported evidence that exercise can greatly improve the physical and psychosocial well-being of 
individuals with SCI.12 As the result, if the barriers to exercise participation after a SCI can be overcome, 
individuals may have multiple positive health benefits. For this study, we anticipate that a 12-week 
adaptive exercise program will reduce chronic inflammation and improve overall health in individuals with 
SCI. 
 
2.2 
RISK/BENEFIT ASSESSMENT  
2.2.1 KNOWN POTENTIAL RISKS  
 
Exercise 
Potential risks of exercise in individuals with SCI include autonomic dysreflexia, musculoskeletal injury, 
hypotension, thermal dysregulation,13  pain, fatigue, and skin breakdown. The exercise program will be 
supervised by exercise physiologists to reduce these risks. 
 
Blood Draw 
Potential risks of blood draws include pain, bruising, dizziness, and local infection. 
 
Assessments/Questionnaires (SCI-QOL) 

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The Spinal Cord Injury-Quality of Life short forms are standardized questionnaires that will measure 
personal perception of life. The questions on these assessments may make participants feel 
uncomfortable because some parts may be easy to answer, while some parts may be difficult or tiring. 
Filling out the questionnaires may also cause individuals to feel uncomfortable or upset. 
 
Loss of Confidentiality 
There may be a slight possibility of breach of confidential information that was collected. However, the 
following procedures will be implemented to reduce this risk: 
• 
Data collection and reporting tools will be developed and stored internally. 
• 
Data collected and stored electronically will remain confidential and secure (e.g. secured server 
and password protected files [REDCap]).  
• 
Study binders will be stored in a locked file cabinet within a locked office. 
• 
After the study is closed, all subject identifiers and blood samples will be destroyed. 
 
2.2.2 KNOWN POTENTIAL BENEFITS  
 
Exercise has been shown to reduce inflammation in other populations, but has not been studied much in 
people with SCI. Therefore, exercise may reduce inflammation in the SCI population, however this is not 
guaranteed. In addition, there will be no cost for individuals to participate in the exercise program, while 
enrolled in the study. 
 
2.2.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
We believe the potential risks to the participants in this study are minimal and that the benefit of 
understanding whether exercise can reduce chronic inflammation and improve strength, cardiovascular 
health, and quality of life in patients with SCI outweighs the potential risks. 
 
3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To examine the effect of a 12-week exercise 
program on inflammation in individuals with SCI. 
Change in inflammatory biomarkers:              
CRP, IL-6, TNF-α 
Secondary 
 
To examine the effect of a 12-week exercise 
program on strength and cardiovascular health in 
individuals with SCI. 
Strength: 1-repitition maximum, 
Cardiovascular: 6-minute submaximal 
exercise test. 
Tertiary 
 
To observe the impact of a 12-week exercise 
program on QOL in individuals with SCI. 
SCI-QOL 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
 
Study Design: 

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This study is an unblinded, randomized, 2-arm clinical trial. 
 
Hypotheses: 
Primary Hypothesis: We hypothesize that exercise will reduce inflammatory biomarkers. 
Secondary Hypothesis: We hypothesize that exercise will improve strength and cardiovascular health. 
Tertiary Hypothesis: We hypothesize that exercise will improve QOL. 
 
Randomization: 
At the consent visit, participants will be randomized into one of two treatment groups. Randomization is 
explained in Section 6.3. 
 
Treatment Groups: 
Group 1: 10 participants will begin the exercise program immediately (3x per week for 12 weeks 
= 36 total). 
Group 2: After a 12-week delay, 10 participants will begin the exercise program (3x per week for 
12 weeks = 36 total). 
 
 
Study Intervention: 
Exercise sessions will last approximately 1 hour and will be lead by exercise physiologists and therapists. 
Additional details are discussed in Section 6.1. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Justification for an unblinded study: Because it will be clear to both study personnel and participants who 
will have a delayed start and who will start immediately, neither will be blinded in this study. This will be 
reported as a limitation of the study. 
 
Justification for an uncontrolled study with no control group: N/A 
 
4.3 
JUSTIFICATION FOR INTERVENTION 
 
Exercise is well known to have positive health effects, such as reducing inflammation and improving fitness 
and cardiometabolic health. For this study, we anticipate that a 3-month adaptive exercise program will 
reduce chronic inflammation and improve overall health in individuals with SCI. 
 
4.4 
END-OF-STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed study treatment visits 
and assessments. The end of the study is defined as completion of the last post-treatment visit for each 
group. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 

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In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Ability to provide and provision of signed and dated informed consent form 
• 
Age 18-70 
• 
Diagnosis of SCI and post injury ≥ 6 months 
• 
Able to achieve adequate active range of motion at the elbow and wrist (flexion/extension) and 
able to achieve at least 90° active shoulder flexion, in order to complete study activities 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Non-English speaking 
• 
Exercise program participation ≤1 month from study enrollment or any other exercise 
participation during the duration of the study 
• 
Patients with significant cognitive impairment of any etiology that prevents them from being able 
to participate 
• 
Patients that were given sternal or spinal precautions that would prevent excessive twisting, 
bending, overhead reaching and lifting over 10 pounds 
• 
Patients with a history heart failure, chronic lung disease, angina or any other condition that 
causes unreasonable shortness of breath on exertion 
• 
Has been diagnosed with autonomic dysreflexia that is severe, unstable, and uncontrolled 
• 
Requires ventilator support 
• 
Spasms that limit the ability of the subjects to participate in the study training as determined by 
the Investigator 
• 
Pregnant, planning to become pregnant 
• 
Any other medical conditions that could affect their ability to participate in the exercise program 
(as determined by study investigators) 
• 
Active participation or past participation ≤3 months in any other interventional study. 
• 
Unwilling to participate in all study related activities 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A 
 
5.4 
SCREEN FAILURES 
 
Pre-screening Phone Call: 
All potential participants will undergo a pre-screening phone call to determine whether they meet the 
inclusion/exclusion criteria. Patients will be considered ineligible if they do not meet one or more of the 
inclusion/exclusion criteria during pre-screening. We will collect information on why participants are 
ineligible or decide not to move forward with the trial. 
 
Pre-treatment Visit: 
Screen failures are defined as participants who are considered eligible during the pre-screening phone 
call, but it was subsequently determined that they do not meet one or more of the inclusion/exclusion 
criteria at or after the Pre-treatment (baseline) visit. We will collect information on why participants 
screen fail or decide not to move forward with the trial.  

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Rescreening Patients: 
Individuals who do not meet the criteria for participation in this trial (ineligible or screen failure) because 
of meeting one or more exclusion criteria that are likely to change over time may be rescreened up to one 
time. Examples include: patient no longer has sternal or spinal precautions; exercise program participation 
≤ 1 month from study enrollment; or participation in an interventional study ≥3 months prior. Rescreened 
participants will be assigned a new participant number. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment: Individuals with SCI will be recruited by physician and therapist referrals from 
HealthPartners’ clinics. We will also advertise our research study by distributing flyers to HealthPartners’ 
physicians and throughout HealthPartners’ and Park Nicollet clinics. Recruitment flyers will also be 
provided to our community partners, for example, the Minnesota Spinal Cord Injury Association and the 
Get Up Stand Up to Cure Paralysis Foundation. If we encounter difficulties with recruitment, we plan to 
submit an amendment to the IRB to contact HealthPartners patients and members and invite them to 
participate. To reach our target enrollment, we anticipate that we will need to screen 60 people, of those 
25 individuals will sign the informed consent and will be randomized to treatment groups. 
 
Remuneration: Participants will be provided gift cards totaling $20 per person for completing certain time 
points of the research study. Group 1: Will receive a $20 gift card at each of the pre- and post-treatment 
visits (3 visits x $20 = $60 total). Group 2: Will receive a $20 gift card at each of the pre- and post-treatment 
visits (4 visits x $20 = $80 total). 
 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
 
The study intervention for both groups is an adaptive exercise program. The exercise program is described 
next in more detail. 
6.1.2 ADMINISTRATION AND/OR DOSING 
 
Exercise Program:  
Twenty individuals with a SCI will participate in a 12-week strength and endurance adaptive exercise 
program. They will be enrolled into our already existing NeuroWell program, which is an exercise program 
geared toward individuals with neurological disorders or injuries run by the Regions Hospital 
Rehabilitation department at the HealthPartners Neuroscience Center. Prior to participating in the 
exercise program, the prospective participant will provide a medical clearance by their physician. Certified 
Clinical Exercise Physiologists will supervise the program. Therapists will also assist with the program as 
needed. The exercise programming will be designed by the exercise physiologists and adapted to 
individuals’ abilities. Exercise prescriptions will be designed based on established guidelines, level and 
completeness of injury, individual functional ability, individual goals, and baseline exercise assessments. 
 

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The American College of Sports Medicine recommends that those with an SCI participate in 2-3 exercise 
sessions per week consisting of moderate intensity (40-59% Heart Rate Reserve) aerobic exercise, light to 
moderate intensity (20 RM to 10 RM) resistance training, and daily flexibility training. Therefore, 
participants will exercise 3 times a week during the 12-week program, following these guidelines. Each 
session will consist of 20-30 minutes of endurance exercise, 20 minutes of resistance training, and 10 
minutes of flexibility, core exercises, and seated balance training. Types of exercise and equipment utilized 
are described in Table 1. The program will allow individuals who have suffered a SCI to access an exercise 
program that is adaptive to their current function and tailored to their individual fitness goals. 
Endurance/Aerobic 
Strength/Resistance 
Flexibility, Core, Balance 
FES Cycle 
(Restorative 
Therapies, Inc) 
(Figure 1a) 
IncludeStrength 
(IncludeHealth) 
(Figure 1d) 
Passive 
Upper Body 
Ergometer 
(SCIFIT) 
(Figure 1b) 
Resistance Machines (leg 
press, chest press, lat 
pulldown, rowing machine, 
CanDo Rickshaw) 
Active 
Wheelchair Ergometer 
(Wheelers’ Paramill) 
(Figure 1c) 
Resistance Bands 
(Theraband) 
Active-Assisted 
Ankle/wrist cuff weights 
Functional Activities (e.g. 
mat exercises) 
 
Improvements in fitness and health outcomes will be optimized through the utilization of adaptive 
equipment and expert exercise programming. Novel, adaptive equipment and technology is integrated 
into the exercise program to accommodate varying levels of abilities. The RT300 Functional Electrical 
Stimulation (FES) Leg | Core cycle (Figure 1a; Restorative Therapies, Inc) transmits electrical pulses 
through surface electrodes, which allows individuals with little or no lower limb voluntary movement to 
pedal. The Pro1 upper body ergometer (Figure 1b; SCIFIT) is a versatile arm exerciser that includes a 
removable seat and wheelchair platform for easy wheelchair access. The wheelchair ergometer (Figure 
1c; Wheelers’ Paramill) is a treadmill designed to fit all manual wheelchairs and allows for backward and 
forward motion. The IncludeStrength (Figure 1d; IncludeHealth, Inc) machine includes movable seating 
for wheelchair access, the ability to secure a wheelchair, and dexterity-free handles. Finally, the exercise 
program will have access to specialty equipment to offer further adaptive support such as gripping aids 
(Active Hands) and leg stabilizers (NuStep, Inc). 
 
Table 1. Exercise Session Components 

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Biomarker Quantification (Aim 1): The primary outcome for Aim 1 will be change in inflammatory 
biomarkers: CRP, IL-6, TNF-α, as these were the primary biomarkers shown to be higher in individuals with 
SCI compared to healthy individuals in previous studies. Patients in Group 1 will undergo 3 blood draws 
and patients in Group 2 will undergo 4 blood draws. Patients will give approximately 2.5 teaspoons of 
blood for each blood draw. Blood samples will be collected by the HealthPartners Neuroscience Center 
laboratory staff. CRP will be analyzed through Regions Hospital Central Laboratory.  IL-6 and TNF-α will be 
analyzed using the MAGPIX® by Millipore Sigma™, a multiplex ELISA, allowing the quantification of 
multiple analytes from a single sample by combining magnetic and fluorescent technology. After 
collection, blood will be allowed to clot for at least 30 minutes before centrifuging for 10 minutes at 
1000xg. Serum will be removed, aliquoted and stored in sterile cryo-preservation tubes in -80°C freezers 
onsite in a secured location with temperature tracking until time of analysis. At the time of analysis 
samples will be thawed and diluted 1:2 in Assay Buffer provided by a custom Milliplex® kit: HCTYA-60K-
03 (IL6, TNFa, IL1RA). The beads provided by the kit will also be added and the plate will be incubated on 
a plate shaker following the kit protocol. After incubation the plate will be placed on a magnet and 
washed, then incubated with a secondary antibody provided by the kit. Once the secondary incubation is 
completed the plate will be again placed on a magnet and washed before being run by the MAGPIX®. Data 
quantification will be acquired using the xPonent® software provided by Millipore Sigma™.  
 
Strength and Cardiovascular Health (Aim 2): Participants will undergo a strength and cardiovascular test 
during the pre-treatment and first post-treatment visits. The strength test will consist of a 1-repetition 
maximum chest press test. This test quantifies the amount of weight that participants can possibly lift 
during the one repetition. The cardiovascular test will consist of a 6-minute submaximal exercise test using 
an arm ergometer following previously published methods.14 Heart rate (HR) and blood pressure will be 
Figure 1. Adaptive Equipment 

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measured before and after the test. Rate of perceived exertion (RPE), a measure of physical activity 
intensity, will be measured after the test. 
 
Spinal Cord Injury-Quality of Life (Aim 3): Participants will be asked to complete the Spinal Cord Injury-
Quality of Life (SCI-QOL) short forms at the pre-treatment and post-treatment visits. The SCI-QOL includes 
the following domains: basic mobility, fine motor, manual/power wheelchair, self-care, ability to 
participate in social roles and activities, anxiety, bladder complications, bladder/bowel management 
difficulties, depression, grief/loss, independence, pain behavior, pain interference, positive affect and 
well-being, pressure ulcer, resilience, satisfaction with social roles and activities, self-esteem, stigma, and 
trauma. The SCI-QOL has strong reliability and validity.15 
 
6.2 
FIDELITY 
 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 
 
Training and Tracking: 
The PI will train research staff on data collection using REDCap. All training will be documented on a 
training log. This will include dates and times of the trainings, and printed names and signatures of the 
trainees and PI. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization:  
Randomization will be performed with a 1:1 allocation ratio. Balanced treatment assignments will be 
achieved using permuted block randomization with random block sizes. The study biostatistician will 
generate a randomization schedule using the SURVERYSELECT procedure in SAS. Assignments will not be 
seen by other study personnel in advance and will not be changed after randomization. 
 
Blinding:  
Study personnel will be unblinded to the randomization, as it will be clear the number of participants who 
have a 12-week delay and those who do not. In addition, it will be clear to participants which treatment 
group they are in and it will be impossible to blind them from this information. 
 
6.4 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
 
Participants will be asked to adhere to study visits and to complete study assessments. Participants will 
remain active unless withdrawn from the study (see Section 7). We will track participants’ adherence to 
study visits, as well as completion of the assessments. These will be documented in the relevant eCRF. 
 
6.5 
CONCOMITANT THERAPY 
 
Participants may use over-the-counter medications, dietary supplements, and prescribed medications. 
Medications will be assessed at each study visit and documented in the relevant eCRF. 
 
6.5.1 RESCUE THERAPY 

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7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
When a participant who signed the consent form chooses to discontinue participation in the study after 
beginning the study intervention, or if the principal investigators (PIs) and co-investigators determine that 
a participant should discontinue participation, they will be withdrawn from the study. A withdrawal will 
either be defined as ‘Patient Withdrawal’ or ‘PI Withdrawal’. The participant will be asked to complete an 
early withdrawal visit within 14 days from the date the intervention was discontinued. The purpose of the 
visit will be to obtain study outcome data and to record any AEs or serious adverse events (SAEs) that may 
have occurred after the discontinuation of the intervention. Research staff will attempt to call the 
participant up to 3 times to set up an in person visit. 
 
The data that will be collected at the time of study withdrawal will include the following: 
• 
The reason(s) for discontinuation of the study intervention 
 
The data that will be collected during the early withdrawal visit will include the following: 
• 
Blood sample 
• 
Strength and cardiovascular testing (if medically able) 
• 
Medication review 
• 
AEs or SAEs that occurred since the time of withdrawal 
• 
SCI-QOL via e-mail survey 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue a participant from the study for the following reasons: 
 
1. Participant has not completed a intervention treatment session for > 10 days, unless a participant 
has an illness, such as COVID-19. In this case, additional time may be allowed, as determined by 
the investigator. 
2. Significant study intervention non-compliance during exercise sessions 
3. Lost-to-follow up; unable to contact subject (see Section 7.3, Lost to Follow-Up) 
4. Any event or medical condition or situation occurs such that continued collection of follow-up  
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study 
5. The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the relevant 
eCRF. Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced. Subjects who sign the informed consent form, and are randomized and 

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receive the study intervention, and subsequently withdraw, or are discontinued from the study, will not 
be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to attend any scheduled study visit and 
study staff are unable to contact the participant after at least 5 attempts, while maintaining the 10 day 
maximum between visits. 
 
The following actions must be taken if a participant fails to attend any required study visit: 
 
• 
Study staff will attempt to contact the participant, reschedule the missed visit, counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, telephone calls or e-mail – if no 
answer leave a voicemail on the first and last attempt). These contact attempts will be 
documented. 
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
 
Demographics: Demographic information will be collected, including: gender, age, race, ethnicity, 
language, height, zipcode, weight, marital status, employment status, medical history, and medications. 
 
Injury, Illness, & Life Events: At all pre- and post-treatment visits, patients will be asked over the last 7 
days whether they have had any injuries, illnesses, or major life events to report. This information will be 
tracked as it may likely impact inflammatory biomarkers. 
 
Treatment Adherence: The participant’s treatment adherence will be measured to determine tolerability 
of the intervention. We will record the number of attended sessions. We will also record participants’ 
ability to complete the entire session. 
 
Quality of Life: Participants will be asked to complete the SCI-QOL short forms, which include questions 
regarding quality of life, such as mobility, self-care, pain, and independence. 
 
8.2 
SAFETY ASSESSMENTS 
 
Assessment of Adverse and Serious Adverse Events: 
AEs and SAEs will be monitored by study staff throughout the study. Staff will immediately notify the PIs 
and utilize the eCRF to record any AEs or SAEs. The PIs will review and categorize all AEs or SAEs and report 
them accordingly, as discussed below. 
 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS 
 
This protocol uses the definition of AE from 21 CFR 312.32 (a): any untoward medical occurrence 
associated with the use of an intervention in humans, whether or not considered intervention-related. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
 
This protocol uses the definition of SAE from 21 CFR 312.32 (a): An AE or suspected adverse reaction is 
considered "serious" if, in the view of either the investigator or study clinician, it results in any of the 
following outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
 
1. Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
2. Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
3. Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 
  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
 
All AEs will have their relationship to study procedures, including the intervention, assessed by an 
appropriately-trained clinician based on temporal relationship and his/her clinical judgment. The degree 
of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study procedures administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study procedures should be clinically plausible. The event must be pharmacologically or 
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• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study procedures, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study procedures). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study procedures administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
procedures) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
8.3.3.3 EXPECTEDNESS  
 
The physician PI will be responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study procedures. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant. 
 
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate eCRF. Information 
to be collected includes event description, time of onset, clinician’s assessment of severity, relationship 
to study procedures (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study will be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Documentation of onset and duration of each episode will be 
maintained for AEs characterized as intermittent. 
 
Study staff will record AE/SAEs with start dates occurring any time after the first intervention treatment 
session until the last post-treatment visit for each group. All reported events will be monitored until the 

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last post-treatment visit for each group. Any reported event that is definitely or probably related to the 
intervention will be followed until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
In consultation with the PIs, a trained member of the study team will be responsible for conducting an 
evaluation of an AE and shall report the results of such evaluation to the reviewing IRB either at the time 
of continuing review or within 10 working days of becoming aware of the event if the event is considered 
to be serious or meets the definition of an unanticipated problem involving risks to study subjects or 
others. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
In consultation with the PI and the study clinician, a trained member of the study team will be responsible 
for conducting an evaluation of a SAE and shall report the results of such evaluation to the reviewing IRB 
as soon as possible, but in no event later than 10 working days after the investigator first learns of the 
event. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Following IRB review of any AEs or SAEs, the PI will follow the IRB’s recommended actions. This may 
include, but is not limited to, modifying the informed consent document or process, re-consenting current 
participants, providing information to past or current participants (e.g. whenever the information may 
relate to the participant’s willingness to continue participants), and modifications to the 
protocol/research plan. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
Women who are currently pregnant or planning to become pregnant during the study are excluded from 
this study. This is because it would be considered a high-risk pregnancy. If any participant who is 
undergoing exercise expectedly or unexpectedly becomes pregnant while active in the trial, the 
participant will be withdrawn from the study by the PI. The participant will be asked to complete an early 
withdrawal phone call in 7-14 days from the date the intervention was discontinued for safety follow-up. 
 
If any participant who has completed all exercise sessions expectedly or unexpectedly becomes pregnant, 
the participant may remain in the study until study completion. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS 
 

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This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP). OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 UNANTICIPATED PROBLEMS REPORTING  
 
The PIs will report unanticipated problems (UPs) to the reviewing IRB. The UP report will include the 
following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number 
• 
A detailed description of the event, incident, experience, or outcome  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs will be reported to the IRB as soon as possible, but no later than 10 working days after the 
investigator first learns of the event 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Following IRB review of any unanticipated problems, the PI will follow the IRB’s recommended actions. 
This may include, but is not limited to, modifying the informed consent document or process, re-
consenting current participants, providing information to past or current participants (e.g. whenever the 
information may relate to the participant’s willingness to continue participants), and modifications to the 
protocol/research plan. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary: 
We hypothesize that exercise will reduce inflammatory biomarkers. 

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• 
Secondary: 
We hypothesize that exercise will improve strength and cardiovascular health. 
 
• 
Tertiary: 
We hypothesize that exercise will improve QOL. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
The primary analysis is an superiority test of means on data from a parallel-group design. Assuming a 
standard deviation of 2.0 units for CRP, 1.0 units for IL-6, and 0.5 units for TNF-α,8 and a true difference 
between means of 0, 10 subjects in each study group achieves 80% power at a 5% significance level to 
detect a 1.3 SD difference in mean change in inflammatory biomarkers between groups (PASS 2019 
software). No interim analysis is planned. The potential effect on our power if our estimates for the effect 
size are displayed on the table below.  
 
Power for N = 20 (10/arm) 
ɑ = 0.05 
CRP (σ=2.0) 
Δ 
δ/σ 
Power 
2.3 
1.2 
0.70 
2.6 
1.3 
0.80 
3.1 
1.5 
0.90 
IL-6 (σ = 1.0) 
Δ 
δ/σ 
Power 
1.2 
1.2 
0.70 
1.3 
1.3 
0.80 
1.5 
1.5 
0.90 
TNF-α (σ=0.5) 
Δ 
δ/σ 
Power 
0.6 
1.2 
0.70 
0.7 
1.3 
0.80 
0.8 
1.5 
0.90 
 
Based on preliminary estimates, we do not anticipate difficulty recruiting 25 participants. Physical 
Medicine and Rehabilitation physicians see approximately 25 individuals with SCI per month at the 
Neuroscience Center. Therefore we will need a 10% enrollment rate to reach our recruitment goal in the 
allotted time frame. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All analyses will be performed on an intention-to-treat basis. If poor attendance is observed and/or 
patients choose to withdraw early, we will perform a per-protocol analysis as a sensitivity analysis.  
 
9.4 
STATISTICAL ANALYSES 

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9.4.1 GENERAL APPROACH 
 
Discrete variables will be summarized using frequencies and percentages, while continuous variables will 
be summarized by means and standard deviations. If the continuous variables are found to be skewed, 
we will instead report medians and interquartile ranges. Statistical significance will be determined using 
p-values less than 0.05 and 95% confidence intervals, unless otherwise indicated. All inferential tests will 
be two-sided. For descriptive statistics (means, SDs, proportions) where no inferential statistics were 
conducted, we will refrain from making confirmative statements. All covariates will be pre-specified in 
the sections below. Any additional analyses will be described as post-hoc and exploratory. 
 
Distribution of the outcome variables will be assessed prior to conduct of our analyses to determine if 
the planned tests are appropriate and to identify outliers. If variables are found to be non-normally 
distributed and/or outliers are present we will explore the use of log-transformations or non-parametric 
tests such as the Kruskal-Wallis test.  
 
Patients who do not complete all assessments required for a given analysis will be excluded from the 
model/test and described separately. If missingness > 10% within the full analytic dataset, a comparison 
of participants with and without missing values will be performed and used to inform possible next steps 
(imputation, feasibility assessment of program, etc.). Reports of injury, illness, and life events occuring 
during the data collection period will be summarized and compared between arms. These summaries will 
be used to inform possible sensitivity analysis as described in section 9.4.10. All analysis will be performed 
in SAS 9.4 using two-sided alphas of 0.05 to determine significance. 
 
 
9.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
 
The primary outcome, change in inflammatory biomarker (CRP, IL-6, TNF-α), will be measured using a 
series of blood draws as described in Section 6.1.  For our primary analysis, we are interested in the change 
over the course of the first 3 months, during which group 1 completes the exercise program and group 2 
acts as a control. The change in inflammatory biomarker will be calculated by measuring the difference 
between the first and second measurement for each pariticipant. We will then present the mean change 
by group with corresponding standard deviations. Analysis of covariance (ANCOVA) will be used to 
compare the change in each of the 3 inflammatory biomarkers between groups: An unadjusted model will 
account for a participant’s baseline biomarker measurement while an adjusted model will include the set 
of covariates identified in Section 9.4.6. If these analyses identify a significant difference in change of 
inflammatory biomarkers associated with participation in the exercise program, next steps will assess if 
this change is still present three months after completing the exercise program. Using data from both 
groups in aggregate, paired t-tests will be used to compare the inflammatory marker level directly after 
participation in the exercise program and inflammatory marker levels three months afterward.  
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Similarly structured ANCOVA models will be used to evaluate the change in secondary outcome measures 
(HR, RPE, and maximal weight) associated with participation in the intervention. Data from the first 3 
months from both groups will be compared in both unadjusted and adjusted analyses. This maintains the 

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benefits of including control data when estimating the intervention effect on strength  and cardiovascular 
health. If there is a significant change in secondary outcome measures after participation in the 
intervention, participants’ measurements directly post-exercise program will be compared to those taken 
12-weeks later to determine if the effect persists. These measurements will be compared using paired t-
test or Wilcoxon signed rank tests, as appropriate, with no group comparisons. 
 
9.4.4 ANALYSIS OF THE TERTIARY ENDPOINT(S) 
 
To evalulate the effect of the exercise program on QOL, SCI-QOL scores will be analyzed similarly to the 
primary and secondary endpoints.This includes exploration of any observed effects on QOL in the 12-
weeks after program completion.  
 
9.4.5 SAFETY ANALYSES 
 
AE/SAEs will be reported as described in Section 8.3 of this document. They will be classified by severity, 
relationship to study procedures, and expectedness. No other formal safety analyses will be conducted.  
 
9.4.6 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline variables will be compared between groups to ensure randomization achieved balanced 
treatment assignments. This will include demographics (e.g. gender, age, race).  All such variables are 
listed in Section 8.1 of this document. Variables will be summarized using descriptive statistics (e.g. mean 
and SD, or frequency and proportion) and compared inferentially. Continuous variables will be compared 
using two-sample t-tests or Wilcoxon rank tests and discrete variables will be compared using chi-square 
tests for independence or Fisher’s exact tests. Variables that are unbalanced between the groups, as 
identified with p<0.1 due to small sample size, will be included as covariates in adjusted analysis.  
 
9.4.7 PLANNED INTERIM ANALYSES  
 
N/A 
 
9.4.8 SUB-GROUP ANALYSES 
 
Both primary and secondary outcomes will be descriptively summarized based on gender. Our sample size 
is unlikely to allow for other meaningful sub-group analyses.  
 
9.4.9 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
 
9.4.10 EXPLORATORY ANALYSES 
 
Exploratory outcomes (e.g. treatment adherence) will be compared between groups with Student’s t-test, 
Chi-square test, and Mann-Whitney-U test and mixed-model ANOVAs, as appropriate. 
 

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Planned sensitively analysis includes per-protocol analyses to accompany the main intent-to-treat results. 
Patients who choose to withdraw early and complete the early withdrawal assessment will analyzed 
separately from those who complete the intervention as planned. If the results from the per-protocol 
analysis demonstrate inconsistent findings from the main intent-to-treat analysis, the interpretation of 
any observed intervention effects will be qualified in all future presentation of the results. If necessary, 
we will conduct a sensitivity analysis in which we exclude participants that had protocol deviations (e.g. 
large delays between treatments) and those that report any injury, illness, or life events during the data 
collection period.   
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and documentation of informed consent will be completed prior to starting the study 
intervention.  The following consent materials are submitted with this protocol: 
 
• 
Study Participant Informed Consent Form 
• 
Study Participant HIPAA Authorziation Form 
• 
Recruitment Brochure 
• 
Recruitment Flyer 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
At the end of the Pre-screening phone call, all eligible patients will be provided a copy of the consent and 
HIPAA forms via e-mail. Patients will also be provided an electronic copy of HealthPartners’ statement of 
non-discrimination form.  During the Consent phone call, research staff will review the consent and HIPAA 
forms with the patients. Patients will be allowed time to review all documents and ask any questions prior 
to signing electronically. Research staff will confirm that the patients understand the information in the 
forms and answer any questions. To obtain signature, the e-consent framework in REDCap will be utilized. 
This framework allows the patient initials, date, time to be stamped in the footer as extra identity as to 
who is completing the consent and HIPAA documents. Following the consent conversation, the staff 
member will sign and e-mail the consent and HIPAA electronically to the patient. The patient will 
electronically sign, certify, and submit the consent and HIPAA in REDCap.  A fully executed PDF copy of 
the consent and HIPAA will be provided electronically to the patient for their records as well as saved via 
the auto-archiver function in REDCap. Research staff will complete this process during the Consent phone 
call, to ensure completion and assist if there are any questions.  
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 

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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigators, the funding agency, the IRB 
and regulatory authorities. If the study is prematurely terminated or suspended, the PIs will promptly 
inform study participants, the IRB, and the funding agency and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of changes 
to the study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
1. Determination of unexpected, significant, or unacceptable risk to participants 
2. Demonstration of efficacy that would warrant stopping    
3. Insufficient compliance of study staff to the protocol (ie, significant protocol violations) 
4. Data that are not sufficiently complete and/or evaluable 
5. Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, IRB, or other relevant regulatory or oversight bodies. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written approval 
of the sponsor/funding agency.  
 
All research activities will be conducted in as private a setting as possible. 
 
All study regulatory binders will be stored in a locked file cabinet within a secure office. The internal study 
monitor, representatives of the IRB, or regulatory agencies, may inspect all documents and records 
required to be maintained by the investigators, for the participants in this study. The clinical study site will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency 
requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be password-protected and stored on REDCap, a secure web-based system. Only research study staff will 
have access to the data. Individual participants and their research data will be assigned a unique study 
identification number. While the study is active, subject identifiers (e.g. name, MRN) will be stored in 
REDCap, however, after the study is closed all subject identifiers will be removed. 
 
The PIs will ensure all mechanisms used to share data will include proper plans and safeguards for the 
protection of privacy, confidentiality, and security for data dissemination and reuse (e.g., all data will be 

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thoroughly de-identified and will not be traceable to a specific study participant). Plans for archiving and 
long-term preservation of the data will be implemented, as appropriate.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
After the study is completed, any stored blood samples will be destroyed and the de-identified data will 
be stored in REDCap for use in future research. Permission to keep the de-identified data will be included 
in the informed consent. 
  
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Co-Principal Investigator 
Co-Principal Investigator 
Amanda A. Herrmann, PhD 
Steven D. Jackson, MD, MBA 
HealthPartners Neuroscience Center 
HealthPartners Neuroscience Center 
295 Phalen Blvd. St. Paul, MN 55130 
295 Phalen Blvd. St. Paul, MN 55130 
(651) 495-6356 
(651) 495-6412 
Amanda.A.Herrmann@HealthPartners.com 
Steven.D.Jackson@HealthPartners.com 
 
10.1.6 SAFETY OVERSIGHT 
 
There is no Data Safety Monitoring Board for this study, as exercise has been previously shown to be safe 
and have minimal risks. During team meetings, the PI and study will regularly review a rolling report of 
adverse events and report them appropriately. 
 
10.1.7 CLINICAL MONITORING 
 
N/A, refer to next section. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study staff will perform internal quality management of study conduct, data collection, documentation 
and completion. 
 
Quality control (QC) procedures will be implemented as follows: 
 
Informed consent --- Study staff will review both the documentation of the consenting process and 10% 
of the completed consent documents. Feedback will be provided to study staff to ensure proper 
consenting procedures are followed. 
 
Source documents and the electronic data --- The majority of data will be directly entered into eCRFs in 
REDCap. To ensure accuracy for data not directly entered in REDCap, study staff will compare a 
representative sample of source data against the database, targeting key data points in that review. 
 
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study. Procedures for ensuring fidelity of intervention delivery are described in 
Section 6.2.1, Interventionist Training and Tracking. 
 

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Protocol Deviations – The study team will review documented protocol deviations on an ongoing basis 
and will implement corrective actions when the quantity or nature of deviations are deemed to be at a 
level of concern. 
 
Should independent monitoring become necessary, the PIs will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection will be the responsibility of the research study staff under the supervision of the PIs. The 
PIs will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All data will be entered directly into eCRFs in REDCap. The data system includes password protection and 
internal quality checks by study staff to identify data that appear inconsistent, incomplete, or inaccurate. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Investigator records will be retained in accordance with regulatory, organizational and sponsor or grantor 
requirements, but no less than 6 years following the completion of the research.  All records will be 
maintained securely with limited access. Disposal of investigator records will be done in such a manner 
that no identifying information can be linked to research data. 
 
10.1.10 PROTOCOL DEVIATIONS   
 
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol. The 
noncompliance may be either on the part of the participant, the investigators, or the study site staff. As a 
result of deviations, corrective actions will be developed by the site and implemented promptly.  
 
It will be the responsibility of the PIs to use continuous vigilance to identify, document, and report 
deviations as soon as possible, but no later than 10 working days after identification of the protocol 
deviation. Minor deviations, which do not impact participant safety, compromise the integrity of study 
data and/or affect the participant’s willingness to participate in the research are to be reported at the 
time of continuing review. Protocol deviations will be addressed in study source documents and sent to 
the reviewing IRB per their policies. The PIs will be responsible for knowing and adhering to the reviewing 
IRB requirements. 
10.1.11 PUBLICATION AND DATA SHARING POLICY  
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. 
 
10.1.12 CONFLICT OF INTEREST POLICY 
 

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The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, 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 HealthPartners Institute 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. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
COVID-19: This study will align with the HealthPartners’ policies regarding COVID-19 for in-person visits. 
This will be done to ensure the safety of patients and study staff. Appropriate COVID-19 screening 
procedures and personal protective equipment (PPE) will be utilized for all in person visits. Participants 
will be screened for COVID-19 on the day of each clinic visit. If a patient screens positive for COVID-19, 
study visits will be postponed for the appropriate amount of time per current guidance, and we will follow 
the current clinic site process for COVID-19 positive screens, as defined by the medical group. 
 
10.3 ABBREVIATIONS AND SPECIAL TERMS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability 
ICH 
International Council on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QOL 
Quality of Life 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SCI 
Spinal Cord Injury 
UP 
Unanticipated Problem 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
03/02/22 
Response to RRC & IRB Review 
 
3.0 
06/30/22 
Expand window for pre-tx visit 
Scheduling conflicts 
4.0 
08/03/22 
Update blood amount for accuracy 
Due to protocol deviation for 
amount of blood that was 
drawn, wanted to make it clear 
to patients. 
5.0 
08/14/23 
Increase enrollment to 25 
Replace participants who 
withdrew prior to intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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