Hybrid-FES Exercise to Prevent Cardiovascular Declines in Acute SCI
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: Spaulding Rehabilitation Hospital

Partners Human Research
Partners HealthCare
399 Revolution Drive, Suite 710
Somerville, MA 02145
Tel: 857-282-1900
Fax: 857-282-5693
Official Version Generated from the Partners Human Research System
02/25/2020 12:19
Notification of IRB Review
Protocol #: 2013P000604
Date:
February 25, 2020
To:
Taylor, J., Ph.D
SRH
Partners > SRH > Dept of Physical Med and Rehab 
Baggish, Aaron
MGH
Partners > MGH > Medical Services > Cardiac Unit 
From:
Partners Human Research
399 Revolution Drive, Suite 710
Somerville, MA 02145 
Title of Protocol:
Hybrid-FES Exercise to Prevent Cardiovascular Declines in Acute and 
Chronic SCI
Version/Number:
ASRT_det_pro_V15
Version Date:
09/14/2017
IRB Continuing 
Review #:
8
IRB Review Type:
Expedited
Expedited 
Category/ies:
(8c) Continuing review of research previously approved by the convened IRB 
as follows: where the remaining research activities are limited to data analysis.
IRB Approval Date:
02/25/2020
Approval/Activation 
Date:
02/25/2020
Next Review:
Institutional Review
IRB Expiration Date: 02/25/2021
This project has been reviewed and approved by the PHS IRB. During the review of this project, the IRB 
specifically considered (i) the risks and anticipated benefits, if any, to subjects; (ii) the selection of 
subjects; (iii) the procedures for obtaining and documenting informed consent; (iv) the safety of subjects; 
and (v) the privacy of subjects and confidentiality of the data. 
Please note that if an IRB member had a conflict of interest with regard to the review of this project, 
consistent with IRB policies and procedures, the member was required to recuse him/herself and, if 
applicable, leave the room during the discussion and vote on this project except to provide information 
requested by the IRB. 
Closed to enrollment: Approved for Data Analysis only.  

Partners Human Research
Partners HealthCare
399 Revolution Drive, Suite 710
Somerville, MA 02145
Tel: 857-282-1900
Fax: 857-282-5693
Official Version Generated from the Partners Human Research System
02/25/2020 12:19
 As Principal Investigator, you are responsible for ensuring that this project is conducted in compliance 
with all applicable federal, state and local laws and regulations, institutional policies, and requirements of 
the IRB, which include, but are not limited to, the following: 
1. Submission of any and all proposed changes to this project (e.g., protocol, recruitment 
materials, consent form, status of the study, etc.) to the IRB for review and approval prior 
to initiation of the change(s), except where necessary to eliminate apparent immediate 
hazards to the subject(s). Changes made to eliminate apparent immediate hazards to 
subjects must be reported to the IRB as an unanticipated problem. 
2. Submission of a continuing review submission or institutional status report as required by 
the IRB and/or institution to continue the research, and submission of a final report when 
the project has been closed or completed. 
3. Submission of any and all unanticipated problems, including adverse event(s) in 
accordance with the IRB's policy on reporting unanticipated problems including adverse 
events. 
4. Obtaining informed consent from subjects or their legally authorized representative prior 
to initiation of research procedures when and as required by the IRB and, when 
applicable, documenting informed consent current IRB approved consent form(s) with 
the IRB-approval stamp in the document footer. 
5. Informing all investigators and study staff listed on the project of changes and 
unanticipated problems, including adverse events, involving risks to subjects or others. 
6. When investigator financial disclosure forms are required, submitting updated financial 
disclosure forms for yourself and for informing all site responsible investigators, co-
investigators and any other members of the study staff identified by you as being 
responsible for the design, conduct, or reporting of this research study of their obligation 
to submit updated Investigator Financial Disclosure Forms for this protocol to the IRB if 
(a) they have acquired new financial interests related to the study and/or (b) any of their 
previously reported financial interests related to the study have changed. 
IMPORTANT REMINDER: THE IRB HAS THE AUTHORITY TO TERMINATE PROJECTS 
THAT ARE NOT IN COMPLIANCE WITH THESE REQUIREMENTS.
 
Questions related to this project may be directed to Line Papin | Tel: 857-282-1908 | Email: 
lpapin@partners.org
cc: 
Aaron Baggish, MD, Site Responsible Investigator, Cardiac Unit, Medical Services
J. Taylor, Ph.D, Principal Investigator, Dept of Physical Med and Rehab
Glen Picard, MA, Co-Investigator, SRH Dept of Medicine

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PROTOCOL TITLE:  
Hybrid-FES Exercise to Prevent Cardiovascular Declines in Acute and Chronic SCI 
 
01/09/19 
 
I. BACKGROUND   AND SIGNIFICANCE 
 
 
Each year, 11,000 people suffer a spinal cord injury (SCI) in the U.S. In the first year 
after an SCI, there are profound declines in function, forming an underlying substrate for 
future cardiovascular morbidity and mortality.1 In fact, acquired cardiovascular disease 
(CVD) is an increasingly recognized consequence of SCI and is the leading cause of 
death in this population.1 Almost all risk factors are amplified in those with SCI;2 though 
incompletely understood, the almost 10-fold prevalence of CVD results at least in part 
from profound physiologic >detraining= resulting from motor impairment and immobility. 
Moreover,Aphysical rehabilitation after SCI needs to move beyond the goal of 
maximizing independence to focus on maintenance of optimum health and fitness;@3 
vigorous exercise of the paralyzed limbs may help achieve these objectives as well as 
reduce cardiovascular risk. However, effective interventions preventing acute declines 
that lead to cardiovascular compromise and increased risk in SCI are lacking. 
 
An appropriate exercise intervention early after injury could prevent or lessen many of 
the acute declines that predispose those with SCI to a myriad of long-term health risks. 
However, exercise therapy for those with SCI is challenging and when employed, is 
typically limited to upper body activity. Recently, we developed a unique form of 
exercise for those with SCI that specifically mirrors exercise performed by those without 
SCI. Functional Electrical Stimulation Row Training (FES-RT) couples volitional arm and 
electrically controlled leg exercise. In contrast to other forms of exercise (arms only 
exercise, FES leg cycling, or FES leg cycling with arm exercise), FES-RT is unique in 
that the non-innervated legs are integral for the performance of this whole body 
exercise. The full rowing stroke is produced by both the (stimulated) legs and arms, 
increasing the active muscle mass and resulting in a hemodynamic profile that produces 
the beneficial cardiac loading conditions of large muscle mass exercise. As such, FES-
RT may be a safe and effective way to attenuate cardiovascular declines following SCI. 
Our preliminary work in chronic SCI has demonstrated the feasibility of FES-RT and 
suggests important attendant changes in cardiovascular health.4However, it is 
imperative that the positive impact of FES-RT be determined in those with acute SCI, 
because it is at the early stages of injury that future medical complications can be 
prevented. We will also study those with chronic SCI to provide a comparison of the 
magnitude of adaptations across a range of injury duration.  

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II. SPECIFIC AIMS 
 
1) To document changes in body composition (visceral adiposity) and insulin sensitivity 
(homeostatic model assessment) resulting from FES-RT in comparison to a time (wait-
list) control and to arms-only row training (arms-only-RT) 
 
We hypothesize FES-RT will mitigate against increased visceral adiposity and reduced 
insulin sensitivity occurring with acute SCI and that FES-RT will be more effective than 
arms-only-RT.   
 
2) To quantify changes in key indices of cardiovascular health (serum lipids) and control 
(arterial baroreflex gain) with FES-RT in comparison to a time control and to arms-only-
RT 
 
We hypothesize FES-RT will prevent the worsening lipid profile and compromised 
baroreflex function occurring with acute SCI and that FES-RT will be more effective than 
arms-only-RT.  
 
3)To characterize changes in myocardial structure (left ventricular wall thickness) and 
function (left ventricular diastolic velocity) with FES-RT in comparison to a time control 
and to arms-only-RT 
 
We hypothesize FES-RT will counter the ventricular wall thickening and declining 
ventricular function occurring with acute SCI and that FES-RT will be more effective 
than arms-only-RT.  
 
4) To compare the body composition, insulin sensitivity, cardiovascular health and 
control, and myocardial structure and function and the magnitude of adaptations to 
FES-RT across a range of injury duration from acute to chronic SCI. 
 
We hypothesize that cross-sectional declines in all variables will relate directly to injury 
duration and that therefore the magnitude of adaptations will be greater with longer 
injury duration. 
 
III. SUBJECT SELECTION   
 
We will enroll 60 individuals within twelve months post SCI to obtain data on 50 
individuals.  One-half of the subjects (N=25) will be randomized to immediately enroll in 
6 months of FES-RT. One third (N=18) will be randomized to a wait-list to provide time 
control data from baseline to 6 months. A wait-list control group is routine in exercise 
studies because most volunteers are interested in participating in an exercise program. 
Hence, time controls are difficult to capture since many of those randomized to receive 

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no exercise either drop from the study entirely, or end up pursuing some form of 
exercise on their own. Therefore, a vehicle for enrollment of a time control group that is 
acceptable to most volunteers is a wait-list. A six month time control will provide data on 
expected declines. One-third (N=17) of subjects will be randomized to six months of 
arms-only-RT. This will provide data on a comparator that represents a form of arms-
only exercise that would be available to those with SCI. These subjects will undergo six 
months of FES-RT after completing arms-only-RT. This will enhance subject retention 
and provide data for secondary analysis.  
 
To enhance subject recruitment we may enroll subjects into the study before they are 3-
months post injury, most likely while they are still in-patients at Spaulding Rehabilitation 
Hospital. This will help subjects to schedule and plan for transportation for study 
assessments and training to begin when they reach 3-months post injury. No study 
assessments will be scheduled before 3-months from time of their SCI. Study 
participation will not interfere with scheduling of any normal inpatient therapy, nor will 
study participation take place during normal therapy. In-patients will need to be cleared 
to participate by their treating physician. 
 
 
 
 
In addition we will enroll another 25 individuals with chronic SCI to serve as a 
comparator to the acute FES-RT group. Neither a wait-list nor arms-only-RT are 
required for this population. Time control data from baseline to 6 months are not needed 
since expected declines would be minimal over this time period after the acute phase of 
injury. In addition, the fourth aim is solely focused on responses to FES-RT and so a 
comparator that represents a form of arms-only exercise available to those with SCI is 
not necessary. Subjects in the chronic group will be at least 1 year post spinal cord 
injury with adult onset of SCI(SCI occurrence after 18 years of age).  
 
 
All volunteers will continue with regular physical rehabilitation except for modalities that 
overlap study interventions (e.g., FES-cycling). 
 
All Subjects will be 18-40 years of age with spinal cord injury (American Spinal Injury 
Association A, B, C) at the neurological level of C5-T12. Subjects will be medically 
stable (no treatment for DVT, no orthostasis, no spinal precautions or weight-bearing 
precautions associated with a healing long-bone fracture) and be able to tolerate the 
stimulation without dysreflexia. Dysreflexia in some participants is expected in the initial 
FES sessions, but only those in whom dysreflexia abates with repeat exposures will be 
included.  
 

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Participants will be excluded if they have: 1)Hypertension (blood pressure >140/90 
mmHg), 2) significant arrhythmias, 3) coronary disease, 4) diabetes, 5) renal disease, 6) 
cancer, 7) epilepsy, 8) current use of cardioactive or antidepressant medications, 9) 
family history of significant arrhythmia or sudden cardiac death 10) orthostatic 
hypertension with symptomatic fall in blood pressure > 30 mmHg when upright 11) 
current grade 2 or greater pressure ulcers at relevant contact sites, 12) other 
neurological disease, 13) peripheral nerve compressions or rotator cuff tears that limit 
the ability to row, 14) history of bleeding disorder, 15) regular use of tobacco,  
16) current deep venous thrombosis, 17) severe spasticity (that prevent rowing 
movements), 18) severe autonomic dysreflexia, 19) implanted electronic cardiac device 
(pace maker, cardiac defibrillator), 20) ventilator-dependent condition, 21) sensations 
that prevent the use of the electrical stimulation, 22) other medical contraindications to 
vigorous exercise. 
 
The American College of Sports Medicine’s Guidelines for Exercise Testing and 
Prescription 9th edition will be followed as the standard of care along with the clinical 
specialists’ opinion (Drs. Stephanie Cho and Aaron Baggish) regarding any additional 
pre-participation screening needed prior to beginning this vigorous exercise training 
program. 
 
Pregnant and nursing women are not eligible for this study because of the potential risk 
to the fetus from radiation that goes along with the DXA scan. Women who are able to 
become pregnant must agree to use contraceptive methods while participating in the 
study. Acceptable contraceptive methods are:  a) hormonal methods (birth control pills, 
patches, injections, vaginal ring or implants); b) barrier methods (condom or diaphragm, 
with a foam, cream or gel spermicide); c) intrauterine device (IUD); or d) abstinence (no 
sex).  Women are considered unable to become pregnant if they are menopausal and 
have not had a menstrual period for at least one year or if they have had a 
hysterectomy (surgical removal of your uterus and/or ovaries).  
 
IV. SUBJECT ENROLLMENT  
 
Research study staff will obtain volunteer consent in accordance with guidelines 
established by the Institutional Review Board during the first visit to the Laboratory. 
Participants will be sent the consent form at least 48 hours in advance so they have 
ample time to read and ask questions.  Participants are encouraged to ask questions 
and are reminded that participation is strictly voluntary and will not affect their current or 
future care at Spaulding Rehabilitation Hospital or any of its affiliates.  
 
 
 
 
 

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V. STUDY PROCEDURES 
 
Volunteers who enroll in the study before 3-months from their injury date will have a 
partial screening visit in which informed consent and detailed health history will be 
obtained(all other assessments will be scheduled after they  reach at least 3-month post 
SCI. Once recruited for the study volunteers (that are at least 3-months post injury) will 
visit the laboratory for a health screening session to further determine eligibility.  This 
two may require one or two visits depending on the ability to schedule with the 
physician. It will include obtaining informed consent, detailed health history, PROMIS 57 
questionnaire, a standard physical exam (ASIA exam and Ashworth Scale) performed 
by a physician (if necessary), height and weight measurements, resting blood pressure, 
electrocardiogram (EKG) and FES-device test.  
 
Note: If an ASIA exam and Ashworth Scale have previously been performed by a 
physician and results can be obtained, those medical records may be used and the 
physical exam will not be necessary during screening. 
 
 
Subjects may also be asked to provide additional medical records or may need further 
testing to determine their eligibility and the safety of their participation in this program 
which includes regular vigorous exercise. These additional tests may or may not be 
covered by insurance. The subject will be responsible for obtaining any additional 
testing and providing the program with medical records or results.  
 
Approximately 40% of spinal cord injured women have amenorrhea for an average of 
eight months. Therefore, menstrual status will be tracked and explored as a potential 
covariate. A prospective menstrual diary will be collected for three months prior to each 
data acquisition time-point. For each monthly diary, women will mark the day of the 
month when bleeding occurred and rate the heaviness of blood flow (spotting to heavy). 
If no bleeding occurred during a particular month or the menstrual period, this will be 
indicated. Bleeding patterns will be used to define normal, irregular, or absent menstrual 
cycles. 

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Training Protocols for Each Study Group 
 
1) FES-RT GROUP (Acute and Chronic SCI) 
 
FES-strength training prior to FES-RT 
To be able to FES-row, a certain level of leg muscle strength and endurance is essential; 
therefore, prior to FES-row training, the ability of the subject to perform 30 minutes of FES-
induced leg extension will be evaluated. Electrodes will be placed over the motor points of the 
rectus femoris, vastus medialis, vastus lateralis, biceps femoris and semitendinosos . A four-
channel Odstock stimulator will alternate stimulation between the hamstrings and the 
quadriceps while the subject is seated in their wheelchair or on an exam table. The stimulus 
parameters will be set at 12 second periods with a 6 second on-time per channel without a 
ramp and with a pulse width of 450ms at 50 Hz. The intensity of the stimulus to the quadriceps 
will be set at the level that produces full knee extension.  If the knee does not achieve full 
extension due to fatigue the intensity of the stimulation will be increased. If fatigue does not 
occur prior to 30 minutes, the individual will advance to FES-rowing. If fatigue occurs prior to 
30 minutes and at maximal intensity (approximately 100mA), the subject will engage in two 
weeks (3x/week) of strength training using this same protocol. Previous experience has 
indicated that this protocol is effective in enhancing muscle strength. Following two weeks of 
training, the strength and endurance capacity of the knee-extensor muscles will be evaluated 
and further training will be performed, if necessary, including the additional use of the QAA-
9054 Total Power strength training machine. The QAA-9054 is a unique machine that provides 
the safety of accommodating resistance without the need of eccentric contractions. This type 
of resistance will not only allow the proper resistance to be safely placed on the knee extensors 
but also the knee flexors. Our past experience has shown that the knee flexors may lag behind 
the knee extensors and prevent continuous FES-rowing. The Strength training will continue 
until the subject is able to complete the knee flexion-extension protocol for 30 minutes without 
rest. This may take between 2 and 12 weeks depending on the subject’s response to the FES-
strength training.  Subjects will also be encouraged to begin arms only rowing during the initial 
FES-strength training period. This will be done at the same visits as the FES-strength training 
sessions. Participants will be seated on the rowing machine with the rowing seat locked in a 
fixed position and will perform short intervals of rowing at a moderate intensity using only their 
arms. Intensity will be monitored by heart rate and rating of perceived exertion. Subjects will 
be allowed to take the FES-device home after they have completed the first two weeks of 
training and have shown adequate understanding of how to use the device properly. Subjects 
will perform strength training session at Spaulding Boston or Spaulding Cambridge  as needed 
during home strength training. Subjects will also be given a logbook to track their usage. 
 

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FES-RT 
Subjects will begin with short intervals of FES-RT interspersed with rest intervals and/or arms-
only rowing intervals depending on fitness level and the response to the FES. A maximum 
FES-rowing test will be performed at baseline. This will be repeated after three months of 
training and training intensity will be adjusted to maintain the training stimulus at the same 
relative intensity. The goal is for each volunteer to achieve an exercise intensity of 75-85% 
maintained for a continuous 30 minutes performed three times each week. A maximum FES-
rowing test will be performed at the end of the six months of FES-RT to determine increases 
in fitness. Measurements of force produced at the foot and handle during FES-row training 
sessions will also be used to monitor training and possibly improve rowing technique. 
 
Strength Training during FES-RT 
After the first two weeks of FES-leg strength training (it may take longer depending on the 
subject’s response, see above) and when the subjects have demonstrated the ability to 
properly use the stimulation unit, the stimulation unit will be used at home to continue with 
leg strengthening on non FES-rowing days (~3 days/week, 30-60 minutes/session). This can 
be closely monitored since they will also be exercising 3 times per week at Spaulding Boston 
or  Spaulding Cambridge. 
 
2) ARMS-ONLY-RT GROUP(Acute SCI only) 
 
The arms-only-RT group will commence exercise training upon enrollment. Training sessions 
will be 3 times per week for 26 weeks. To parallel the FES-RT, the initial training sessions will 
also consist of 6 sets of arms-only rowing for five minutes at 60% of VO2peak with a work-to-
rest ratio of 2:1 and progress over the six months to an exercise intensity of 75-85% maintained 
for 30 minutes performed three times each week. The arms-only-RT group will also perform 
the FES-leg strength training protocol as described above during their six months of arms-only 
training. During this time they will not use the FES-device on the rowing ergometer. 
Strengthening the leg muscles during the arms-only period will lessen leg muscle atrophy and 
allow faster progress in FES-row training when they enter that phase of the study. A maximum 
arms-only rowing test will be performed at baseline. This will be repeated after three months 
of training and training intensity will be adjusted to maintain the training stimulus at the same 
relative intensity.  A maximum arms-only rowing test will be performed at the end of the six 
months of training to determine increases in fitness. Subsequently, after the six months of 
arms-only-RT, subjects will begin the FES-RT as described above.  
 
 
 
 
 
3) WAIT-LIST GROUP(Acute SCI only) 
 

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The wait list group will not participate in any row training for 6 months. A maximum 
arms-only rowing test will be performed immediately after enrollment, after initial 
familiarization with arms-only-RT equipment (usually 2-3 sessions) and will be repeated 
after 3 and 6 months (before FES-RT begins). The wait-list group will also perform the 
FES-leg strength training protocol as described above during the six months of the wait-
list period. During this time they will not use the FES-device on the rowing ergometer. 
Strengthening the leg muscles during the wait-list period will lessen leg muscle atrophy 
and allow faster progress in FES-row training when they enter that phase of the study. 
At the end of the 6 month wait period, subjects will begin the FES-RT as described 
above.  
 
Alternate Training Sites: 
 
Community Rowing Inc. as an additional training site 
After subjects have completed screening and initial leg muscle strengthening, and have 
advanced in their training to the point at which they demonstrate sufficient knowledge 
and skill level at performing the FES-RT or arms-only-RT they may begin training at our 
alternate training site, Community Rowing Inc (CRI).There will be a SRH staff member 
on-site at CRI to supervise all FES-row or arms-only row training sessions. Also, only 
subjects who have demonstrated the ability to transfer onto the rower safely with 
minimal assistance will be allowed to perform the FES-RT or arms-only-RT at CRI. 
(There is not a lift system available at CRI.) All Laboratory visits will continue to be 
performed at Spaulding Hospital Cambridge or Spaulding Charlestown. 
 
Home Rowing as an additional training site 
Subjects who own an adapted rowing machine may perform some or all of their row 
training at home. Home rowing will only be allowed after subjects have completed 
screening and have advanced in their FES-RT or arms-only-RT to the point atwhich 
they demonstrate sufficient knowledge and skill in the use of the FES-unit and /or the 
adapted rowing machine and fully understand their individualized exercise program. All 
subjects must also demonstrate transfer competency on and off the rower with use of 
any assistance that they will have available at home. All Laboratory visits will continue 
to be performed at Spaulding Hospital Cambridge or Spaulding Charlestown. 
 
 
Notes: There is no limit or specific requirement for training sessions that must be 
attended to continue participating in this protocol. Subjects, in all training groups, will be 
encouraged by study staff to attend three training sessions per week. Un-reported 
missed training session will be followed up with a phone call to document why the 
training session was missed and to encourage prompt return to training sessions as 
soon as possible.   
 
Subjects who enroll before 3-months from their date of SCI will be given the opportunity 

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to participate in the FES-strength training during the period before study assessments 
begin after they reach 3-months post SCI. This will lessen leg muscle atrophy and allow 
faster progress in FES-row training when they enter that phase of the study. 
 
 
 
 
Study Assessments  
Most Assessments will be performed at baseline and after 3 and 6 months for each study 
group.  The DXA measurements and the AO-VO2max test (for the FES-RT group only) 
will only be performed at baseline and after 6 months. The Arms-only-RT and Wait-list 
groups will immediately enter baseline FES-RT protocol after completing all study 
procedures required in their initial group. Their six month lab visit and DXA scan data will 
also be used as their baseline FES-RT measures. Subjects may be asked to repeat any 
of the study assessments if there is difficulty obtaining results that meet our quality 
standards or there are equipment issues that arise.  
 
Subjects that take longer than eight weeks to progress to performing their baseline FES-
VO2max test will perform an extra assessment around the time of their baseline FES-
VO2max test to account for changes that may occur over that time period. This extra 
study session will consist of: height, weight and circumference measures, blood samples, 
health questionnaires, pulmonary function tests, resting cardiovascular hemodynamics 
and neck suction-barorefex testing. This extra testing session will take about 2-hours and 
can be done on a normal training day. 
 
Study Procedure Time Line:  
 
 
Baseline 
3-Month 
6-Month 
Baseline-RT 
3-Month-
RT 
6- Month-RT 
FES-RT 
Acute and 
Chronic 
FES-VO2max 
AO-VO2max 
Lab Visit 
DXA Scan 
FES-
VO2max 
Lab Visit 
FES-VO2max 
AO-VO2max 
Lab Visit 
DXA Scan 
N/A 
N/A 
N/A 
AO-RT 
Acute 
AO-VO2max 
Lab Visit 
DXA Scan 
AO-VO2max 
Lab Visit 
AO-VO2max 
Lab Visit 
DXA Scan 
FES-VO2max 
 
FES-
VO2max 
Lab Visit 
FES-VO2max 
Lab Visit 
DXA Scan 
Wait list 
Acute 
AO-Vo2max 
Lab Visit 
DXA Scan 
AO-VO2max 
Lab Visit 
AO-VO2max 
Lab Visit 
DXA Scan 
FES-VO2max 
 
FES-
VO2max 
Lab Visit 
FES-VO2max 
Lab Visit 
DXA Scan 
 
 
Measurements and Testing Protocols: 
 
VO2max Testing 
For subjects in the arms-only-RT and FES-RT groups VO2max testing will be 

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performed on a day scheduled for regular training.   On-line computer-assisted 
open circuit spirometry will be used to determine O2 consumption, CO2 production, 
and respiratory exchange ratio. Expired O2 and CO2 gas fractions will be measured 
with a paramagnetic O2 and infrared CO2 analyzers. Ventilation will be measured 
via a Hans Rudolph 3813 pneumotachograph. Subjects will perform FES-rowing 
or arms-only-rowing while increasing power output every 1 to 2 minutes until 
volitional exhaustion. Immediately after FES-rowing or arms-only-rowing has 
stopped at the end of the VO2max test, subjects will have a finger tip pricked with 
a safety lancet in order to get a drop of blood that will be used  to measure peak 
lactate levels in whole blood. Peak lactate levels will be used to evaluate exercise 
intensity as well as to monitor training status. To ensure attainment of maximal 
exercise capacity, at least 3 of the following criteria will be met: 1) O2 consumption 
plateaus despite increasing workload, 2) respiratory exchange ratio equals or 
exceeds 1.10 at end exercise, 3) 85% age-predicted maximal heart rate is 
achieved, and 4) perceived exertion is rated at least 17 on the Borg scale of 6-20.  
 
Lab Visit(s) 
All lab studies will be performed in the morning. All subjects will be instructed to 
abstain from vigorous exercise for 2 days prior to each study to avoid autonomic 
and neuroendocrine effects of exercise. In addition, subjects will refrain from 
caffeine and alcohol for the previous 24 hrs, and be studied after a 12 hr fast.  
 
 
Neck Suction- Baroreflex Testing:  
We will rely on neck pressure and neck suction to evaluate carotid sinus 
baroreceptor function at rest and during a variety of conditions. This technique 
has been employed to safely study cardiovascular physiology in human since the 
1950’s. The subject’s neck is sealed by a neck collar connected to a computer-
controlled bellows (pressure/vacuum pump). The neck collar is cushioned with an 
airtight silicon rubber bladder that is independently sealed and positioned against 
the contour of the anterior lateral neck. The bellows is used to increase or 
decrease pressure inside the neck collar, effectively compressing or distending 
the carotid sinus in the neck and causing reflex changes in heart rate and muscle 
sympathetic activity. However, these responses are evanescent since aortic 
baroreceptors are not affected; therefore heart rate and sympathetic activity (and 
sometimes blood pressure) are changed for only a few beats with any level of 
stimulus. Carotid baroreceptor reflex responses will be elicited during held 
expiration by application of an external neck pressure and suction sequence. 
Subjects will hold a normal end-expiratory volume, which triggers an external 
neck pressure increase of +40 mmHg for 4 heart beats and subsequent, serial R-
wave triggered reductions of 15 mmHg to a pressure of -65 mmHg. This 
sequence results in stepwise initial carotid sinus compression followed by 
distension, evoking stepwise reflex changes in heart rate and sympathetic 

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activity. For each baroreflex testing, this procedure is repeated seven times to 
provide an averaged reproducible carotid baroreceptor reflex response relation. 
 
Echocardiography. We will use a portable, commercially available system (Vivid-I, 
GE Healthcare, Milwaukee, Wis.), for cardiac characterization.  Images will be 
obtained after 20 minutes of rest. Conventional 2-dimensional, Doppler, and color 
tissue-Doppler imaging from standard parasternal, apical, and subcostal positions 
will be performed. All data will be stored digitally for post-study off-line data 
analysis (EchoPac, Version 6.5, GE Healthcare). Left ventricular and atrial cardiac 
chamber volumes will be calculated using the modified Simpson=s technique. LV 
mass will be calculated using the area-length method. Relative wall thickness, an 
index of LV geometry, will be defined as: [interventricular septal thickness (mm) + 
posterior wall thickness (mm)] / LV internal end-diastolic diameter (mm). 
Myocardial tissue velocities (diastolic function) will be measured off-line from 2D 
color-coded tissue Doppler images and reported as the average of 3 consecutive 
cardiac cycles. Strain, strain rate, and LV rotational (systolic function) assessment 
will be performed by speckled tracking analysis. Peak global strain will be 
calculated as the average strain in the basal, mid, and apical LV as measured in 
the apical 4-chamber view. Atrial volumes will be calculated using the bi-plane 
area-length method. Right ventricular diastolic area, systolic area, fractional area 
change, tissue velocities will be measured. Measurements will be indexed for body 
surface area when appropriate. 
 
Note: Subjects may also have their echocardiogram test performed at the Heart 
Center at Massachusetts General Hospital (MGH) if the cardiologist can be 
scheduled for a more convenient time for them at MGH than at Spaulding 
Cambridge. We will pay for parking if they choose to go to MGH for their 
echocardiogram. 
 
Note: As of 1/1/19 we will no longer be able to measure any further 
echocardiogram tests in this protocol. 
 
 
Resting Cardiovascular Hemodynamics: Heart rate and blood pressures will be 
measured after a 15-minute period of quiet supine rest. Heart rate will be measured 
by a standard 12-lead ECG and blood pressure by an automated 
sphygmomanometer. There will be a short period of time paced breathing in which 
subjects follow an audio cue to breath at a rate of 15 breaths per minute. 
 
Pulmonary Function Tests: Spirometry will be used to measure lung function, 
specifically the measurement of the amount (volume) and/or speed (flow) of air 
that can be inhaled and exhaled. Specifically, Forced Volume Vital Capacity 

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(FVC) and Maximum Voluntary Ventilation (MVV) tests will be administered.  
 
 
Height, Weight, and Circumferences:  Weight will be measured on a scale. Height 
will be measured in the supine position with a tape measure. Circumferences of 
the waist, hip, abdomen, and thigh will be measured with a tape measure in the 
supine position.  
 
Blood Samples: 70 ml of blood via venipuncture will be taken. Standard assays will 
include measures of insulin sensitivity and serum lipids. The homeostasis model 
assessment (HOMA) of insulin resistance, the quantitative insulin check index 
(QUICKI) and the serum insulin-like growth factor binding protein-1 (IGFBP-1) will 
be assessed. Plasma total cholesterol, low density cholesterol, high density APOa 
lipids, and triglycerides will also be measured. Other assays will include: total 
testosterone, calculated free testosterone, CBC, high sensitivity (hs) C-reactive 
protein, hemoglobin AIC, prealbumin and zinc. Blood work will be sent to Quest 
Diagnostics for analysis. 
 
ASIA and Ashworth exams: Standard physical exams will be performed by a 
physician to categorize injury level and degree of spasticity. 
Note: The ASIA and Ashworth exams will only be performed at Screening Visit 1 
and 6-month and 12-month time points. 
 
 
PROMIS 57 Questionnaire: The PROMIS 57 questionnaire will be used to 
assess changes in subject’s views on their physical, psychological, and social 
well-being. The PROMIS 57 scales include eight items from seven primary 
PROMIS domains: depression, anxiety, physical function, pain interference (and 
one pain intensity item), fatigue, sleep disturbance and satisfaction with social 
roles. 
 
PROMIS Cognition Short Form: a brief well validated self-report measure to 
assess perceived cognitive functioning. 
 
The Patient Health Questionnaire (PHQ-9): a brief, well validated depression 
screening test that is widely used in medical research. 
 
NIH Toolbox Meaning and Purpose Short Form: is a 7 item questionnaire that 
measures a person’s sense of meaning and purpose in life over the past 7 days. 
 
Craig Handicap Assessment and Reporting Technique Short Form (CHART-SF): 
is valid, reliable, and widely used in rehabilitation research to measure various 
community integration in people with various neurological conditions. We will be 

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collecting data on the Physical Independence, Mobility, Occupation, and Social 
Integration subscales.  
 
SCI Exercise Self- Efficacy Scale (ESES): is a reliable and valid measurement of 
self-efficacy, or belief and confidence in one's skill and ability, to engage in 
physical activity.  
 
 
DXA Scan(s) 
 A licensed radiology technician will perform all DXA scans. We will use a 5th 
generation GE Healthcare iDXA dual x-ray absorptiometry (DXA) scanner with 
enCore configuration version 12.3. For regional fat measurements, the DXA 
software can be used to define standard regions that will allow comparability of 
measurements throughout the study. DXA-derived visceral adipose tissue will be 
measured from a 5 cm slice placed across the entire abdomen above the iliac 
crest at the 4th lumbar vertebrae. Although DXA measures both visceral and 
subcutaneous fat, on each side of the abdominal cavity DXA can directly 
measure subcutaneous fat. The location of the abdominal cavity is detected by 
the gray scale change as the tissue contains lesser fat due to abdominal wall 
muscles. Subcutaneous fat over the visceral cavity is estimated from the DXA 
measurement of subcutaneous fat on each side of the abdominal cavity. The 
total estimated subcutaneous fat is subtracted from the total abdominal fat for 
DXA-derived visceral adipose tissue. This approach has been shown to 
performed as well as a clinical read from a CT scan. The precision of regional fat 
measures is ±1%.  
 
Note: If a DXA scan has recently been performed at Spaulding Rehabilitation 
Hospital and the results can be obtained, those medical records may be used 
and the baseline DXA scan will not be necessary. 
 
 
VI. BIOSTATISTICAL ANALYSIS 
Power analysis: Based on longitudinal exercise capacity data from our lab, extensive 
sets of power analyses were performed. For the main analysis (acute subjects only), 
there will be 3 groups of subjects (FES-RT, wait-list and arms-only-RT) and measures 
at baseline, 3 months, 6 months, except for visceral adiposity (only at baseline and 6 
months). The primary analysis (below) will include the three groups and will have as 
predictors two indicator (dummy) variables for two of the groups, and indicators for the 3 
month and 6 month time points and interactions between the time points and the group 
indicator variables; this will be estimated as a linear mixed model. The only random 
effect will be for subject. In addition, for the fourth aim, the analysis will only include 
those entered into into FES-RT at the outset, i.e., the FES-RT with acute SCI and all 

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volunteers with chronic SCI. The main analysis will consist of comparisons across time 
with injury duration as a covariate. 
 
Given logistical constraints, we began with the assumption that data on 50 acute SCI 
subjects (out of 60 recruited - a ~15% dropout rate) would be advantageous if that 
sample size allowed us to find differences that are substantively meaningful. This group 
would be allocated (randomly; see below) as 40% to FES-RT and 30% to each of wait-
list and arms-only-RT. We also checked other total sample sizes and allocation rules 
(e.g., data from 20 in each group, data from 25 in FES and 15 in each of the other two 
groups). In addition, 25 individuals with chronic SCI would provide sufficient power to 
detect meaningful (e.g., >15%) differences between acute and chronic SCI at the same 
power outlined below.  
 
These calculations were performed assuming an alpha of 0.05 and a correlation 
between baseline and 6 month measure of about 0.7; unless the correlation was very 
different from 0.7 (e.g., 0.25), there was little difference in the results. This shows that 
we will have sufficient power under this plan with a sample size of 50 acute SCI 
subjects and allocation of 20/15/15. Subjects will be randomized at the ratio of 1.33:1:1 
to each of the three groups by a randomization plan constructed by the project 
statistician. The investigator will have no knowledge of group assignment until the time 
of subject enrollment. During the study, there can be no blinding of the subject or the 
investigator, however all measures will be obtained by an individual blind to subject 
group assignment. 
 
Primary data analysis: The primary analysis will test whether the FES-RT has ‘better’ 
values of the outcome variables at 6 months post-baseline. A general linear mixed 
model with a random effect for subjects will be used to conduct an intent-to-treat 
analysis. The main predictors will be indicator variables for group with the FES-RT 
group as the reference group and indicators for each of the other two groups, the time 
at which the outcomes were measured and treatment group by time interactions; 
menstrual status (with men coded the same as women who are not menstruating) will 
be included as a dummy variable; for the insulin resistance measure, body weight/fat 
changes will be included as a predictor. In a secondary analysis, we will include 
interactions terms between the group indicators and the 3 month indicator. In addition, 
similar models to the above will be estimated for secondary outcomes. 
  
Checking and Sensitivity Analyses: It is important to ensure that data idiosyncrasies do 
not impact the results and that the results are generalizable. We will check for 
systematic differences between the model and the data using graphs, such as 
comparisons of predicted and observed values of the outcome variable, and other 
standard diagnostics. An extension of this idea is to simulate new sets of data based on 
our model and use the simulated data as a reference test group by comparing this to 
the observed data; we do this to look for situations in which the data appear different 

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from what we would expect by using the model to predict the data. We will also check 
whether any important predictors have been left out of the model, for example, gender 
or severity of SCI or level of SCI. These will be tested by including them in revised 
versions of the model and testing whether the model is substantively improved. It is also 
important to explore the ‘missingness’ of data. The model we plan to use assumes that 
missing data are “missing at random.” This can be checked in several ways including 
comparing the characteristics of observations with and without missing values. More 
importantly, we can check whether our results would change if the data is “missing not 
at random” in several ways. For certain outcome variables, it may be the case that 
subjects who are either at the high end or the low end are more likely to be missing. For 
example, people at baseline who are very fat or very lean may be more likely to drop 
out. This can be checked by using constrained multiple imputation where we constrain 
our imputations to one end of the adiposity range. Comparing the results based on the 
constrained imputation to the unimputed results gives us a sensitivity analysis. 
 
A second type of sensitivity analysis was originally suggested by Rubin and has been 
extended by Carpenter, Kenward and White who suggest weighting each imputed result 
(rather than Rubin's standard “rules” of averaging the results), where the weight 
depends on the assumed departure from the MAR assumption. This technique relies on 
the imputations covering a fairly wide range of values (we would use 100 imputations) 
but this can be checked and additional data sets imputed if the range is too narrow. 
Carpenter, et al., provide a graphic method of checking whether the range is wide 
enough. Finally, if dropouts are much more common that missing an occasion and then 
returning, we will estimate a pattern-mixture model. However, if there are many people 
who miss the 3 month measure, but not the 6 month measure, we will not pursue this 
strategy. A fourth issue deals with the variance structure of the model. Our prime model 
assumes that the variances are the same across groups. This will be tested by 
estimating a model with heterogeneous variance structures by group (this is available in 
some statistical packages, including Stata or SAS). 
 
 
 
 

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VII. RISKS AND DISCOMFORTS 
Moderate risks are associated with exercise testing and exercise training. Some 
discomfort and feeling of fatigue will be experienced during these tests. There are other 
risks associated with these tests including abnormal blood pressure responses, fainting, 
irregular, fast or slow heart rhythm, and in rare instances, heart attack, stroke, or death. 
Wearing the mouthpiece during the VO2max testing may cause feelings of 
claustrophobia. Exercise training may induce some muscle or joint discomfort when 
beginning an exercise program and could result in tendonitis and/or musculoskeletal 
overuse injuries over time. The electrical stimulation unit can cause tingling, pins and 
needles sensations on the skin, skin irritation, increased muscle spasticity and autonomic 
dysreflexia (signs include: headache, nausea, rise in blood pressure, sweating, and 
goosebumps). There is some discomfort with venipuncture and the lancet used on the 
finger for lactate measurement and there is the possibility of swelling and bruising at the 
site(s), there is also a slight chance that individuals become dizzy and even faint. The 
neck suction/pressure collar may cause some discomfort and a mild choking feeling which 
resolves quickly when pressure or suction is turned off. 
 
The risk of DXA scanning is minimal. Participants in this study will be exposed to radiation 
from two or three DXA scans of the whole body depending on study group. The total 
amount of radiation that will be received from participation in this study is equal to a whole 
body exposure of less than 0.26 milliSierverts (mSv). For comparison, the average person 
in the United States receives a radiation exposure of 3.6 mSv per year from natural 
background sources (the earth and the sky). The dose from participation in this research 
study is about the same as what a person would normally receive in less than one month 
from these natural sources. Scientists disagree on whether radiation doses at these low 
levels are harmful. A possible effect that could occur at doses associated with this study 
is a slight increase in the risk of developing cancer later in life. Women of childbearing 
potential will be given a urine or serum pregnancy test before any DXA scan and not 
scanned if they are pregnant.  
 
There are no known risks associated with the EKG or the echocardiogram.  A subject 
must remove his or her shirt and have sticky patches applied to the hest for the 
electrocardiogram (EKG) and have gel applied for the echocardiogram. In some cases, 
chest hair may have to be shaved where the EKG patches are placed. If a structural 
abnormality is identified on an EKG  or echo, the subject would be given this information 
and referred to his or her own doctor for further evaluation. Subjects may feel lightheaded 
or short of breath during the pulmonary function tests, there is also a slight chance that 
individuals become dizzy and even faint. 
 
 

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VIII. POTENTIAL BENEFITS 
Volunteers will have the opportunity to participate in a supervised exercise program, 
which may improve their overall cardiovascular fitness and endurance during activities 
of daily living as well as decrease risk of chronic disease. 
 
IX. MONITORING AND QUALITY ASSURANCE 
The program director will be responsible for monitoring the completeness of all data and 
source documents. The Principal Investigator will monitor the informed consent 
procedures in accordance with the Informed Consent Compliance Checklist of Partners 
HealthCare Systems HRQIP. The subjects data/protocol adherence will be monitored 
by the research coordinator at each step in the study including. Checklists and note 
pages are used to note any deviations or omissions from the protocols. All spinal cord 
injured participants will be asked the “Pre-Study Screening” questions before every visit. 
The Cardiovascular Research Laboratory Medical Emergency Safety Plan will be 
followed in the case of an adverse medical event. Any clinical/health related issues 
would be immediately presented to the subject (i.e. abnormal EKG, blood chemistries, 
etc) to determine appropriate notification (ie. current physician or appropriate specialist) 
Based on the seriousness of the situation  Dr. Schwartz may be contacted to provide 
clinical guidance on the appropriate course of action. 
 
Serious adverse events will be reported to the IRB via phone, email, or fax. The 
principal investigator will follow this with a full written report using the PHRC Adverse 
Event Form within 10 working days. If a mild or moderate adverse event occurs that is 
definitely, probably, or possibly related to the study, a written report will be sent to the 
IRB within 20 working days. All other events will be summarized in a progress report at 
continuing review. 
 
X. REFERENCES  
Reference List 
 
 (1)  Myers J, Lee M, Kiratli J. Cardiovascular disease in spinal cord injury: an overview 
of prevalence, risk, evaluation, and management. Am J Phys Med Rehabil 
2007;86:142-152. 
 (2)  Cragg JJ, Stone JA, Krassioukov AV. Management of cardiovascular disease risk 
factors in individuals with chronic spinal cord injury: an evidence-based review. J 
Neurotrauma 2012;29:1999-2012. 
 (3)  Galea MP. Spinal cord injury and physical activity: preservation of the body. Spinal 
Cord 2012;50:344-351. 

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 (4)  Taylor JA, Picard G, Widrick JJ. Aerobic capacity with hybrid FES rowing in spinal 
cord injury: comparison with arms-only exercise and preliminary findings with 
regular training. PM R 2011;3:817-824.