Higher-Than-Replacement Testosterone Plus Finasteride Treatment After SCI
Phase: PHASE2
Conditions: Spinal Cord Injury, Spinal Cord Injuries, Trauma, Nervous System, Wounds and Injuries, Central Nervous System Diseases, Nervous System Diseases, Spinal Cord Diseases, Gonadal Disorders, Endocrine System Diseases, Hypogonadism, Genital Diseases, Male
Sponsor: VA Office of Research and Development

 
 
 
 
 
 
 
 
 
Testosterone Plus Finasteride Treatment After Spinal Cord Injury 
Application #: 1I01RX00-1449-01A1 
Funding Agency: VA RR&D 
Principal Investigator/Study Chair: Joshua Yarrow, MS, PhD 
10/03/2022 
 
 
 
 

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Abstract 
 
 
The Institute of Medicine has indicated that short-term, small scale randomized clinical trials 
(RCTs) should be conducted to establish the efficacy of testosterone replacement therapy (TRT) 
as a strategy to enhance muscular strength and reduce disability in clinical populations of 
hypogonadal men. Men with spinal cord injury (SCI) experience a high prevalence of 
hypogonadism which influences the neural, muscular, skeletal, and body composition deficits that 
occur after injury. A single retrospective analysis has reported that TRT improved motor function 
in hypogonadal men with incomplete SCI. However, only one small prospective (open label) 
clinical trial has evaluated the safety/efficacy of TRT in men with SCI. This study reported that 
low-dose TRT improved lower extremity lean mass and reduced risk of sudden cardiac death in 
men with motor complete SCI, demonstrating that TRT safely improves lean mass even in the 
absence of voluntary muscle activity. However, body composition was unaltered and bone mineral 
density (BMD) was not reported in this study likely because these deficits respond only to higher 
doses of TRT. Despite the potential benefits of TRT, some clinical concern exists regarding the 
safety of this therapy, with increased hematocrit (which is rarely detrimental), prostate 
enlargement, and potential cardiovascular risk remaining areas of concern. Interestingly, the 5α-
reduction of testosterone to dihydrotestosterone mediates prostate enlargement and may worsen 
cardiovascular risk, but this conversion is not required for the benefits of TRT. As evidence 
pharmacologic 5α-reductase inhibition (via finasteride) ablates prostate enlargement in 
neurologically healthy hypogonadal men receiving TRT, without inhibiting the substantial 
musculoskeletal and lipolytic benefits of this treatment. However, the safety and efficacy of this 
novel combination therapy remains to be determined in men with chronic motor incomplete SCI. 
For this double-blind placebo-controlled RCT, hypogonadal men >18 years of age with chronic 
motor incomplete SCI (AIS C/D) who present with ambulatory dysfunction will receive 
testosterone (125mg/week, i.m.) plus finasteride (5mg/day, p.o.) in FDA approved doses or 
vehicle/placebo for 12 months. At baseline and 3-6 month intervals, we will assess: BMD and 
body composition via DXA, thigh muscle cross-sectional area (CSA) via MRI, lower extremity 
neuromuscular function via dynamometry and muscle activation via twitch interpolation, 
circulating markers of musculoskeletal and metabolic health and metabolism, and safety 
measures including prostate health, electrocardiogram (EKG) and cardiovascular symptoms, 
hematocrit, and other putative health risks associated with TRT. Our primary hypotheses are that 
TRT plus finasteride will safely 1) regenerate BMD via antiresorptive actions, 2) enhance muscle 
CSA and improve neuromuscular force production, and 3) improve body composition.  
 
These findings will benefit Veterans with SCI who experience musculoskeletal impairments and 
may provide the VA with a novel cost-effective therapy able to improve musculoskeletal and 
metabolic health in this population. 
 
 

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List of Abbreviations 
AE – Adverse Events 
AIS – ASIA Impairment Scale 
BMD – Bone Mineral Density 
BRRC – Brain Rehabilitation Research Center 
CSA – Cross Sectional Area 
CTSI – Clinical and Translational Science Institute 
DAV – Disabled American Veterans 
DHT – Dihydrotestosterone 
DRE – Digital Rectal Exam 
DSMP – Data Safety Monitoring Plan 
DSMB – Data Safety Monitoring Board 
DXA – Dual X-ray Absorptiometry 
EKG – Electrocardiogram  
EMG – Electromyography  
fNIRS – Functional Near Infrared Spectroscopy 
HCT – Hematocrit 
i.m. – Intramuscular  
ISCD – International Society of Clinical Densitometry 
KE – Knee Extensors 
MRI – Magnetic Resonance Imaging 
NF/SG – North Florida/South Georgia 
PHI – Protected Health Information 
PVA – Paralyzed Veterans of America 
RCT – Randomized Clinical Trial 
SAE – Serious Adverse Event 
 
SAM – Step Activity Monitor 
SCI – Spinal Cord Injury 
T – Testosterone 
TRT – Testosterone Replacement Therapy 
TRUS – Transrectal Ultrasound Sizing 
UAP – Unanticipated Problem 
UF – University of Florida 
VA – Veterans Affairs 
VAMC – VA Medical Center 
VHS – Veterans Health System 
 
 

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Contents 
Protocol Title: ............................................................................................................................. 5 
1.0 
Study Personnel .............................................................................................................. 5 
2.0 
Introduction ..................................................................................................................... 6 
3.0 
Objectives ....................................................................................................................... 9 
4.0 
Resources and Personnel ............................................................................................... 9 
5.0 
Study Procedures ...........................................................................................................10 
5.1 Study Design ...................................................................................................................11 
5.2 Recruitment Methods.......................................................................................................17 
5.3 Informed Consent Procedures .........................................................................................19 
5.4 Inclusion/Exclusion Criteria ..............................................................................................19 
5.5 Study Evaluations ............................................................................................................20 
5.6 Data Analysis ..................................................................................................................25 
5.7 Withdrawal of Subjects ....................................................................................................26 
6.0 
Reporting ........................................................................................................................26 
7.0 
Privacy and Confidentiality .............................................................................................28 
8.0 
Communication Plan ......................................................................................................28 
9.0 
References ...................................................................................................................29 
 
 
 

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Protocol Title:  Testosterone Plus Finasteride Treatment After Spinal 
Cord Injury 
 
1.0 
Study Personnel 
 
Principal Investigator/Local Site Investigator (NF/SG VHS, Gainesville, FL):  
Joshua Yarrow, MS, PhD, Research Health Scientist, NF/SG VHS 
(352) 376-1611 x6477 
Joshua.Yarrow@va.gov 
 
Co-Investigators/Local Site Investigator (James A. Haley VAMC, Tampa, FL): 
Kevin White, MD, Chief – Spinal Cord Injury, James A. Haley VA Medical Center 
(813) 972-2000 x7517 
Kevin.White2@va.gov 
 
Co-Investigator 
Charles Plumlee, MD, Physical Medicine & Rehabilitation, NF/SG VHS 
(352) 376-1611 
Charles.Plumlee@va.gov  
 
Co-Investigator: 
Robert Sammel, MD, Chief – Spinal Cord Injury Primary Care, NF/SG VHS 
(352) 376-1611 x4142 
Robert.Sammel1@va.gov 
 
Co-Investigator: 
Anita Wokhlu, MD, Noninvasive Cardiologist, NF/SG VHS 
(352) 379-4014 
Anita.Wokhlu@va.gov 
 
Co-Investigator: 
Charles Levy, MD, Chief – Physical Medicine & Rehabilitation, NF/SG VHS 
(352) 374-6065 
Charles.Levy@va.gov 
 
Co-Investigator 
David Clark, PhD, Research Health Scientist, NF/SG VHS 
(352) 376-1611 x5244 
David.Clark1@va.gov 
 
Co-Investigator 
Dana Otzel, PhD, NF/SG VHS 
(352) 376-1611 x6917 
Dana.Otzel@va.gov 
 
Research Nurse Coordinator 
Larissa Nichols, BSN, RN, NF/SG VHS 
(352) 376-1611 x6917 

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Larissa.Nichols@va.gov  
2.0 
Introduction 
 
Relevance to VA: 270,000 individuals currently have a SCI in the US, with an estimated 12,000 
new SCIs occurring annually.2 Of these, 42,000 are eligible for treatment in the VHS,3 resulting in 
direct annual medical expenditures exceeding $716 million/year.4 The average direct/indirect per 
patient costs associated with the first-year medical treatment of incomplete motor SCIs is 
$218,000,5 with subsequent yearly expenditures averaging $21,450 per patient year within the 
VHS.4 These costs are exacerbated by the myriad of functional and physiologic deficits that occur 
following SCI, of which reduced lower limb musculoskeletal integrity, impaired neuromuscular 
force production, and elevated visceral adiposity are hallmark characteristics.6 Importantly, these 
maladaptive changes represent fundamental impediments to rehabilitation strategies intended to 
restore musculoskeletal and metabolic health after SCI.7 
 
Musculoskeletal Deficits after SCI: Neurologic impairment and reduced sublesional load-bearing 
are the primary factors underlying the musculoskeletal deficits after SCI.6 These impairments 
produce a progressive 30-40% reduction in lower limb muscle CSA2 and impaired voluntary 
muscle activation8 that combine to worsen neuromuscular force production and locomotor ability.8-
10 In this regard, the preservation and/or restoration of lower limb muscle strength/power is 
recognized as an important predictor of ambulatory recovery after motor incomplete SCI.10, 11  A 
progressive 50-60% loss of cancellous bone also occurs in the first 2-3 years after SCI and cortical 
bone loss persists for >10 years.12 These maladaptive responses result from elevated bone 
resorption and reduced bone formation,13 which contribute to the 20- to 100-fold greater fracture 
risk in those with SCI compared with healthy age-matched individuals.14 Importantly, each 
0.1gm/cm2 BMD decrement at the femoral neck increases fracture risk by 2.2 times,15 indicating 
that even small alterations in BMD strongly influence fracture risk within this population.  
 
Metabolic Consequences of SCI: SCI causes a plethora of metabolic consequences that increase 
risk for metabolic syndrome,16, 17 diabetes,18 and premature cardiovascular disease.17 Nearly all 
metabolic syndrome risk factors (i.e., elevated visceral adiposity, high fasting blood glucose, 
insulin resistance, elevated triglycerides, low HDL cholesterol, and high blood pressure) are 
exacerbated by SCI.17 For example, diabetes prevalence is 3 times higher in Veterans with SCI 
compared to the general population.18 The pathophysiology underlying these deleterious 
metabolic consequences is influenced by the reduced energy expenditure and the extensive 
muscle loss that occur after SCI,2 because muscle is the largest reservoir of metabolically active 
tissue and the primary site of postprandial glucose disposal.19 As evidence, physical rehabilitation 
strategies that increase energy expenditure20 or improve muscle mass21 result in reduced fasting 
glucose and improved insulin sensitivity in men with SCI. In addition, hypogonadism is a 
secondary metabolic consequence that occurs in ~40-60% of men with chronic motor incomplete 
SCI [ASIA Impairment Scale (AIS) C/D].22, 23 In particular, the median serum T concentration was 
220ng/dL (standard reference range 241-827ng/dL) in a large cohort of men whose duration of 
SCI was upwards of 14 years, with >50% of men with incomplete SCI exhibiting low T;23 
demonstrating the prevalence of hypogonadism after SCI is much higher than the general 
population.   
 
Testosterone Replacement Therapy (TRT): In neurologically healthy men, low T is associated 
with reduced BMD24 and muscle mass,25 elevated visceral adiposity, increased metabolic 
syndrome risk26 [i.e., elevated fasting glucose, insulin, and hemoglobin (Hb)A1c values],27 and 

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sexual dysfunction.28 TRT is commonly prescribed to hypogonadal men29 because it is the sole 
FDA-approved agent able to increase BMD and muscle mass and reduce adiposity, and because 
it improves sexual function in men with low T.28 However, inconsistency exists in the literature 
regarding the efficacy of TRT, with some studies reporting only slight musculoskeletal benefit24, 25 
and others reporting more substantial effects;30 likely because studies utilize a wide range of TRT 
doses [up to the FDA-approved maximum (200mg/week, i.m.)]. As evidence, meta-analyses 
indicate more substantial musculoskeletal benefit from higher doses of long-acting T esters (i.e., 
≥100mg/week, i.m.)24, 25 because these formulations produce higher peak T concentrations. In 
contrast, transdermal patch/gel TRT formulations produce low- or mid-range T values that result 
in only minor myotrophic25 effect and no BMD improvement.24 Similarly, higher dose TRT is 
required for reductions in visceral adiposity30 and perhaps for improvements in other metabolic 
syndrome markers.31 In this regard, a lesser known effect of T is regulation of glycometabolic 
control, evidenced by the ability of TRT to reduce insulin resistance and lower blood glucose in 
men with abdominal obesity32 and improve several metabolic syndrome risk factors (i.e., insulin 
sensitivity, fasting glucose, HbA1c, triglycerides, and C-reactive protein) in men with type II 
diabetes.33  
 
TRT After SCI: Members of our research team were the first to report that TRT ameliorates muscle 
loss in rodents after SCI,34 results that have been verified by others.35 Specifically, spinal cord 
transection reduced hindlimb muscle fiber size by 49% and the percentage of slow fibers in the 
soleus by >80%. In comparison, animals receiving TRT exhibited a 58% larger fiber size and a 
152% increase in the percentage of slow fibers in the soleus,34 demonstrating T produces robust 
myotrophic effects in the complete absence of neural input. We have expanded on these findings 
by demonstrating TRT dose-dependently improves bone and muscle mass in rats receiving 
severe contusion SCI, with high-dose TRT fully preventing bone loss and partially alleviating 
muscle loss; while low-dose TRT produced much less profound benefit36. Our group36 and 
others37 have also reported that androgens partially restore hindlimb locomotor function after 
contusion SCI, with animals receiving high-dose TRT exhibiting greater functional improvement 
than those administered low-dose TRT or placebo.36 In 2008, Clark et al., published a 
retrospective analysis reporting that high-dose TRT improved motor function in men with 
incomplete SCI (AIS C/D), while those with motor complete SCI obtained no functional benefit.1 
The mechanisms through which TRT improved motor function were not examined, but likely 
involved elevated muscle mass and/or enhanced voluntary muscle activation (which are both 
impaired after incomplete SCI)8, 
9 and likely occurred via direct androgen-mediated 
neuroprotection38 of spinal motor neurons,39 as observed in rodent SCI models35 and other nerve 
injury models.40-42 Despite this promising evidence, no prospective RCT has examined whether T 
enhances muscle function in men with motor incomplete SCI.  
 
In 2011, Bauman et al., published findings from a small prospective trial indicating men with motor 
complete SCI exhibited improved lean body mass and energy expenditure43 and reduced sudden 
cardiac death risk due to arrhythmia after 12 months TRT,44 with no serious (S)AEs reported. 
Interestingly, relative improvements in lean mass were consistent in all body compartments above 
(e.g., arm) and below the level of lesion (e.g., leg),43 providing direct evidence that TRT enhances 
lean mass even in the absence of voluntary muscle activity (similar to our preclinical findings).34 
While these preliminary results are promising, Bauman et al., administered low-dose transdermal 
TRT that only slightly elevated circulating T and failed to reduce adiposity.43 Not surprising, given 
that higher dose TRT is required for fat loss30 and bone accretion.24, 25  Additionally, other 
measures of metabolic health, such as fasting glucose and insulin sensitivity were not reported. 
To-date, the above mentioned studies remain the sole analyses evaluating the efficacy of TRT 
after SCI. As such, prospective RCTs are required to verify whether TRT improves 
musculoskeletal and metabolic health in this population.  

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TRT Health Risks: Meta-analyses have confirmed three health risks resulting from TRT: 1) 
elevated HCT, 2) increased prostate-related AEs45, and 3) increased cardiovascular-related risk. 
In most cases, the HCT increase is not detrimental and may benefit some individuals because 
anemia is common in men with low T46 and men with SCI.47 However, a small proportion of men 
receiving TRT exhibit polycythemia (HCT >54%),45 which is completely reversible upon 
discontinuation of TRT. In contrast, the higher incidence of prostate-related AEs produces more 
serious clinical concern because most men receiving TRT exhibit progressive prostate 
enlargement,48 which is suspected of being related to prostate cancer development.49 However, 
meta-analyses indicate that TRT does not increase prostate cancer risk nor Gleason grade of 
prostate cancer (even in men with a history of prostate cancer),49 suggesting that TRT induces 
trophic (but not neoplastic) effects on the prostate. Additionally, a higher incidence of 
cardiovascular-related AEs raises clinical concern for those on TRT.50 Although, the extent of 
cardiovascular risk is unknown because conflicting evidence exists in the literature, with several 
meta-analyses reporting TRT does not increase cardiovascular AEs in elderly men45, 51, 52 or in 
heart failure patients,53 while a recent retrospective analysis reports adverse health outcomes 
after TRT in Veterans with pre-existing cardiovascular co-morbidities.54 In contrast, data from a 
recent meta-analysis55 and separate retrospective analyses56 indicate men with low T who are 
not receiving TRT exhibit heightened cardiovascular risk and increased all-cause mortality. In this 
regard, hypogonadal men with SCI exhibit pathologic cardiac adaptations when compared to 
eugonadal men with SCI,57 and TRT has been shown to reduce sudden cardiac death risk after 
SCI by normalizing cardiac electrophysiology.44 Regardless, prostate-58 and cardiovascular-
related56 AEs remain a clinical concern that should be evaluated when administering TRT. Other 
putative (unproven) risks of TRT include fluid retention (edema), gynecomastia, breast 
tenderness, elevated liver enzymes, injection site irritation, emotional lability, worsening of 
untreated sleep apnea, and decreased spermatogenesis;58 although, the incidence of these 
putative health risks are quite low and none have been confirmed by meta-analysis.45  
 
5α-reductase and Prostate Enlargement: The localized intraprostatic 5α-reduction of T to DHT59 
worsens prostate enlargement45 and prostate cancer development60 because DHT is a more 
potent and longer acting androgen than T.59 In contrast, pharmacologic 5α-reductase inhibitors 
prevent prostate enlargement resulting from endogenous T59 and from TRT61-63, and are known 
to reduce prostate cancer risk by >25%.60 Interestingly, the conversion of T to DHT is not required 
for the musculoskeletal or lipolytic benefits of androgens19-21 because bone, muscle, and fat only 
mildly express 5α-reductase.59 As evidence, high-dose TRT increases prostate mass in 
orchiectomized rodents by >50% (resulting from elevated intraprostatic DHT), while co-
administration of a rodent 5α-reductase inhibitor prevents prostate growth without inhibiting the 
musculoskeletal or lipolytic benefits of TRT.64 Finasteride also blocks prostate enlargement 
resulting from TRT (in elderly hypogonadal men) without altering the beneficial effects of this 
therapy on bone, muscle, or adiposity,61, 62, 65 demonstrating that 5α-reductase inhibitors prevent 
a prominent health risk resulting from TRT (i.e., prostate enlargement) without reducing the 
overwhelming benefits of this treatment. This provides rationale for the prophylactic use of 
finasteride as a safety measure when administering TRT.63 However, several (infrequent and 
reversible) side-effects may also result from finasteride, the most prevalent of which is sexual 
dysfunction (i.e., decreased libido, erectile dysfunction, and ejaculation disorder) that occurs in 
<5% of men on long-term finasteride treatment.60 Thus, TRT plus finasteride appears to be a 
promising means of safely improving musculoskeletal and metabolic health; although the safety 
and efficacy of this novel combination pharmacologic therapy requires verification prior to clinical 
implementation in the SCI population.  

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3.0 
Objectives 
 
The purpose of this study is to determine whether TRT plus finasteride will safely improve 
musculoskeletal health, neuromuscular function, body composition, and metabolic health in men 
with incomplete SCI. We will conduct a double-blind, placebo-controlled RCT in which 
hypogonadal men >18 years old with ambulatory dysfunction subsequent to chronic motor 
incomplete SCI will receive TRT (125mg/week T-enanthate, i.m.) plus finasteride (5mg/day, p.o.) 
in FDA-approved doses vs. vehicle/placebo for 12 months. This proposal addresses the following 
three Specific Aims: 
 
AIM 1: Evaluate the effects of 12 months of TRT plus finasteride on bone mineral characteristics 
and bone turnover in hypogonadal male men with motor incomplete SCI.  
 
Hypothesis 1: TRT plus finasteride will improve BMD via antiresorptive actions in this 
population. The primary outcome will be hip BMD [measured via dual x-ray absorptiometry 
(DXA)]. Secondary outcomes will be serum markers of bone metabolism.  
 
AIM 2: Determine the effects of TRT plus finasteride on the recovery of muscle integrity and 
neuromuscular force production in hypogonadal men with motor incomplete SCI. 
 
Hypothesis 2: TRT plus finasteride will enhance muscle CSA and improve neuromuscular 
force production in this population. The primary outcomes will be thigh muscle CSA [via 3D-
magnetic resonance imaging (MRI)] and KE torque (via dynamometry). A secondary outcome 
will be KE voluntary muscle activation.  
 
AIM 3: Examine the effects of TRT plus finasteride on body composition and the pathophysiology 
underlying metabolic syndrome in men with motor incomplete SCI. 
 
Hypothesis 3: TRT plus finasteride will improve body composition and risk factors 
associated with metabolic syndrome. Primary outcomes will be total body and visceral fat mass 
(via DXA). Secondary outcomes will be metabolic syndrome risk factors (fasting glucose, 
hemoglobin A1c, insulin resistance, serum lipids, and blood pressure). 
4.0 
Resources and Personnel 
Recruitment will be handled cooperatively through the NF/SG VHS, James A. Haley VAMC 
(Tampa, FL), and the University of Florida (UF) Clinical and Translational Science Institute 
(CTSI).  All testing will be conducted at the NF/SG VHS. MRI may also be conducted by trained 
medical staff at our academic affiliate, University of Florida (UF). The following individuals or VA 
Services will be involved in data collection: 
▪ 
Joshua Yarrow, PhD (Study PI, NF/SG VHS) is the Local Site Investigator at NF/SG 
VHS and will have access to participant protected health information (PHI) and has the 
responsibilities for all supervisory and regulatory aspects of the study, study 
management, participant recruitment, screening and consenting, administering 
survey/interview procedures, performing functional assessments and evaluation of 
physical function on participants, and data analysis. 
▪ 
Larissa Nichols, BSN, RN (Study Nurse, NF/SG VHS) will have access to participant PHI 
and will assist in daily operations of the study and be responsible for CPRS records 
screening and creation, participant recruitment, screening, and consenting, blood 

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acquisition, training participants on drug administration, performing health assessments, 
administering survey/interview procedures, performing functional assessments and 
evaluation of physical function on participants.  
▪ 
Dana Otzel, PhD (Research Investigator, NF/SG VHS) will have access to participant 
PHI and will assist in daily operations of the study and be responsible for CPRS records 
screening and creation, participant recruitment, screening, and consenting, performing 
health assessments, administering survey/interview procedures, performing functional 
assessment, evaluating physical function, knee extensor muscle function, and knee 
extensor voluntary activation of study participants, and data analysis. 
▪ 
Kevin White, MD (Chief – Spinal Cord Injury, James A. Haley VAMC) is the Local Site 
Investigator at James A. Haley VAMC (Tampa, FL) and the Medical Director for this 
study and will have access to participant PHI.  He has the responsibilities of ensuring the 
safety of all participants and may perform health/safety evaluations of participants if 
adverse events occur.  Dr. White (in conjunction with the Study Physician or other 
Physicians) will determine participant withdrawal based on established study criteria. 
▪ 
Robert Sammel, MD (Chief – Spinal Cord Injury Primary Care, NF/SG VHS) will have 
access to participant PHI and has the responsibility of evaluating the overall health and 
physical function of study participants.   
 
▪ 
Charles Plumlee, MD (Physical Medicine & Rehabilitation (PMR), NF/SG VHS) will have 
access to participant PHI and has the responsibility of evaluating the overall health and 
physical function of study participants, for writing prescriptions for study drugs, and may 
oversee PMR related assessments. 
 
▪ 
Anita Wokhlu, MD (Noninvasive Cardiologist, NF/SG VHS) and Cardiology Service 
(NF/SG VHS) will have access to participant PHI and has the responsibility of evaluating 
the cardiovascular health of study participants and interpreting cardiovascular-related 
testing procedures.   
 
▪ 
David Clark, PhD (Research Health Scientist, NF/SG VHS) will have access to 
participant PHI and has the responsibility of evaluating and interpreting physical function, 
knee extensor muscle function, and knee extensor voluntary muscle activation of study 
participants.  
 
▪ 
Charles Levy, MD (Chief – Physical Medicine & Rehabilitation (PMR), NF/SG VHS) will 
have access to participant PHI and has the responsibility of writing prescriptions for 
study drugs and may oversee PMR related assessments. 
 
In addition, Nuclear Medicine Service and Radiology Service (NF/SG VHS) will conduct MRI 
and DXA scans, respectively, Urology Service (NF/SG VHS) will conduct prostate digital rectal 
exams (DRE), transrectal ultrasound sizing (TRUS) of the prostate, and prostate biopsy (if 
required), and Cardiology (NF/SG VHS), will perform EKG. Trained medical staff at UF, our 
academic affiliate, may also perform MRI. 
 
Statistical analyses will be performed by the University of Florida, Center for Translational 
Science Institute (CTSI).  Preliminary analyses will be performed during years 2 and 3 and the 
final statistical analysis will be performed during year 4.  All data provided for statistical analysis 
will be coded. 

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5.0 
Study Procedures 
 
5.1 Study Design 
 
Experimental Design 
There are four phases to this study: recruiting/screening, testing, treatment, and follow-up.  All 
interventions in this study are for research purposes and none represent standard of care.  A 
brief study overview is included below and an in-depth description of each phase follows. 
  
Study Overview:  For this double-blind, placebo-controlled RCT we will recruit men >18 years of 
age who have experienced a chronic motor incomplete SCI (AIS C/D) between C2-L3 with 
upper motor neuron signs.  Individuals will undergo comprehensive screening and safety 
assessments to determine eligibility.  Men with low serum T (≤325 ng/dL) or low bioavailable T 
(≤70 ng/dL) and locomotor dysfunction will qualify.  Those qualifying (n=30) will be stratified by 
walking speed to ensure an equal number of persons with a low- and high-level of ambulatory 
dysfunction are present in each group.  Participants (n=15/group) will then be randomized into 
one of two groups: 1) T-enanthate (125mg/week, i.m.) + finasteride (5mg/day, p.o.) or 2) vehicle 
(sesame oil, i.m.) plus placebo (p.o.) for 12 months.  Prior to beginning the study treatment 
participants will also undergo testing. Primary outcomes will be hip BMD, thigh muscle CSA, KE 
torque, and body composition. Secondary outcomes include circulating markers of 
musculoskeletal and metabolic health, KE voluntary muscle activation, and metabolic risk. 10m 
walk tests will be performed and blood will be acquired at 1, 2, and 3 months of treatment and at 
3 month intervals thereafter and other safety assessments and outcomes testing will be 
repeated at 3 or 6 month intervals throughout the intervention.  The study treatment will be 
discontinued after 12 months.   
 
Recruitment/Screening:  Participants will be recruited from the NF/SG VHS or the James A. 
Haley VA Medical Center (Tampa, FL), from Paralyzed Veterans of America (PVA), Disabled 
American Veterans (DAV), Veterans of Foreign Wars (VFW), American Legion Posts, or other 
Veteran-centric offices or centers located in Florida/Georgia, from local area long-term care 
centers, rehabilitation centers, or hospitals (e.g., UF Health, the Center for Independent Living 
of North Central Florida, Brooks Rehabilitation, or others), from other VA hospitals and 
outpatient clinics throughout Florida/Georgia, or from an existing University of Florida IRB-
approved SCI registry of individuals who have agreed to be contacted to query their interest in 
participating in research studies [access provided by the VA-funded Brain Rehabilitation 
Research Center (BRRC) Center of Excellence]. We may travel to these locations or phone 
these locations to engage staff in a brief conversation to explain the study and ensure they will 
allow placement of VA CIRB approved flyer in their offices. Staff at locations other than NF/SG 
VHS or Tampa VAMC will not be engaged in participant recruitment or any other aspect of the 
research. We may also recruit via advertisements in magazines, newspapers, newsletters or 
other print media and via the websites and email listservs of these print media outlets, on the 
UF Health Study Listings website (https://ufhealth.org/research-studies-clinical-trials), through 
the ResearchMatch.org national recruitment database, through posts to the Facebook pages of 
the NF/SG VHS or the James A. Haley VA Medical Center, through posts to individual 
Facebook pages or groups that have a veteran or SCI support focus, through advertisements 
placed on Facebook, or via http://www.clinicaltrials.gov. A separate document outlines our 
Facebook advertising strategy, including monitoring of Facebook pages and advertisements. 
 

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Prescreening: We will prescreen individuals who are interested in participating to determine if 
they meet criteria to enroll.  During the prescreening we will query individuals about their 
complete medical history and previous six months use of physician prescribed and over-the-
counter medications (via phone or in-person) and we will conduct a review of their CPRS 
medical records (if applicable) to determine if they meet prescreening criteria.  If individuals 
meet prescreening criteria we will obtain informed consent and HIPAA authorization and 
participants will undergo additional hands-on screening to determine eligibility.  We have 
requested a waiver of informed consent and a waiver of HIPAA authorization (for recruitment 
and screening purposes) that will ensure that we are able to screen individuals with a high 
likelihood of qualifying for our study and that we are not placing an undue burden on individuals 
who may not qualify due to past medical diagnoses that can easily be identified through health 
history and CPRS reviews.  An in-depth description of the prescreening process is included in 
Sections 5.5 of this document.  The prescreening is being done solely for the purposes of 
research and will take approximately 1 hour to complete. 
 
Screening: Informed consent and HIPAA authorization will be obtained from individuals who 
meet prescreening criteria and decide to enroll.  These participants will undergo additional 
hands-on screening at the NF/SG VHS to determine whether they qualify.  Study 
Inclusionary/Exclusionary Criteria are explained in-depth in Section 5.4 of this document.  If 
individuals do not meet criteria, they will be considered screen-failures.  Individuals qualify they 
will be invited to participate in the study.  The screening is being done solely for the purposes of 
research and will take approximately 1-2 days to complete.  
 
Testing:  Individuals who qualify and decide to participate will undergo testing that is being done 
solely for the purposes of research.  All testing will be performed at the NF/SG VHS.  Testing 
will occur at baseline (before beginning the study treatment) and at 3-6 month intervals 
thereafter, until completion of the study treatment.  Tests will take 1-2 days to complete.   
Participants will be allowed a 1 month window surrounding the scheduled testing dates to 
ensure completion of all testing procedures.  Tests that are completed during Screening will not 
be repeated at baseline.  A detailed explanation of all testing is included in Section 5.5 of this 
document.   
 
Treatment:  The Study Pharmacist will randomize participants using RanPro® (Applied Logic 
Associates, Houston, TX) or another similar program into one of the two following treatment 
groups, with equal allotment (n=15) per group:  
 
▪ 
Placebo injection plus placebo tablet for 12 months 
▪ 
Testosterone injection plus finasteride tablet for 12 months 
 
Study drugs will be administered in FDA approved doses.  T-enanthate (125mg/week 
Delatestryl®) will be administered via i.m. injection into the thigh or buttock because this is the 
preferred method of administration according to VA formulary.  Finasteride (5mg/day Proscar®) 
will be administered orally according to VA formulary guidelines.  T-enanthate will be purchased 
commercially through the Research Pharmacy at the NF/SG VHS.  Matching vehicle (1ml sterile 
sesame oil/week, i.m.) and placebo (5mg/day pill, p.o.) will be manufactured by an FDA-regulated 
compounding pharmacy.  Finasteride will also be purchased through the above mentioned 
compounding pharmacy or may be purchased by the VA Research Pharmacy. Medications will 
be distributed in identical packaging to ensure double blinding is maintained to the Research 
Nurse for initial administration.  In order to reduce travel burden, participants have the option to 
self-administer the injections and prescription refills may be mailed to participants (both standard 
VA practices).  The Study Nurse will instruct each participant on proper drug administration and 

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will reinforce procedures via weekly telephone calls to verify that they have administered the drug.  
Alternatively, the participant can choose to have the Study Nurse administer the once weekly 
injection which will require travel to the NF/SG VHS.  All procedures for the matching 
vehicle/placebo will be handled in an identical manner.  Importantly, i.m. T-enanthate is a common 
TRT formulary in the VHS and routine clinical practice includes i.m. self-injection.  We will also 
measure the volume of remaining study medications at regular intervals (3 month or less) to 
evaluate participant adherence.  Drug administration is expected to take about 10 minutes per 
week.  The study treatment is being done solely for research purposes and will last 12 months.  
During the study treatment, the participants will also be asked to undergo regularly scheduled 
testing that is discussed in detail in Section 5.5 of this document. 
 
Study Completion and Follow-up:  At the completion of the intervention the study treatment will 
be discontinued.  We will follow-up with participants monthly (via phone call) and perform a 
monthly review of their medical records for 3 months to assess potential AEs after study 
discontinuation. In addition, we will reassess blood values, perform physical exam, and EKG at 
6 months following study completion to ensure participant safety.  A detailed description of what 
blood markers will be assessed is included in Section 5.5.  Participants will be referred to their 
Primary Care Provider if AEs appear after study completion.  The phone call should take about 
10 minutes.  The phone call and medical records check are done solely for the purposes of 
research.   
 
Some participants may report a transient depression of mood following TRT cessation because 
reduced circulating T occurs after TRT discontinuation. If this occurs, participants have the option 
of tapering to a lower dose of T (125mg T-enanthate biweekly, i.m.) for 4 weeks (administered 
through the VA Research Pharmacy).  This should assist in alleviating symptoms. 
 
Minimization of Risk 
We have assembled a strong and experienced Research Team with multidisciplinary 
backgrounds to ensure participant safety and minimize risk throughout this intervention. The 
Research Team includes an SCI Physician, Cardiologist, Physical Medicine and Rehabilitation 
Physician, Research Pharmacist, Exercise Physiologist, and several PhD level Researchers 
with clinical trial experience.  Each member of the Research Team will be focused on monitoring 
participant safety and minimizing risk throughout the intervention.  Specific procedures and 
monitoring activities are addressed below. 
 
Informed Consent: The PI, Study Nurse, or another member of the research team will obtain a 
signed informed consent document from all participants prior to study enrollment.  A complete 
description of the study, eligibility criteria, the potential risks and benefits, expected time 
involvement, and the importance of the knowledge to be gained will be discussed with the 
participants.  An in-depth description of the informed consent process is included in Section 5.3 
of this document. 
    
General and Cardiovascular Exclusionary Criteria: We have developed stringent Exclusionary 
Criteria to ensure participant safety and minimize risk. An in-depth description of the General 
Exclusionary Criteria and Cardiovascular Exclusionary Criteria are included in Section 5.4 of this 
document. 
 
Baseline Safety Screening: Individuals who give informed consent will undergo a comprehensive 
Safety Screening to determine if they qualify.  This safety screening is addressed in detail in 
Section 5.5 of this document.  
 

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Follow-up Safety Assessments: Participants will have their blood drawn monthly for the first three 
months of treatment and at 3 month intervals thereafter to evaluate serum markers of health and 
will also undergo comprehensive Safety Screenings at 3 or 6 month intervals throughout the 
study. These safety assessment are identical to that performed at baseline and are outlined in 
Section 5.5 of this document.  In addition, the Study Nurse or another member of the study team 
will phone participants on a weekly basis to determine their general health / well-being and will 
perform a monthly formal medical records review to assess for potential AEs. Patients will be 
interviewed regarding the cardiovascular symptoms of chest pain, edema, palpitations, and 
dyspnea and other health related issues. To ensure participant safety we have also developed 
study removal criteria that are addressed in Section 5.7 of this document.  
 
Titration of Testosterone Dose: The dose of T-enanthate will be evaluated monthly for the first 
three months of treatment and at three month intervals thereafter.  The prescribed testosterone 
dose will be continued if the nadir serum testosterone concentration (assessed one week 
following injection) remains below the normal upper limit for the VA Clinical Laboratory (869 
ng/dL).  If the nadir serum testosterone concentration exceeds the normal upper limit, the serum 
testosterone value will be reevaluated to ensure accuracy of the test.  If the reevaluated nadir 
value remains higher than the normal upper limit, the weekly T-enanthate dose will be reduced 
by 25 mg/week and nadir serum testosterone value will be reevaluated. At reevaluation, if nadir 
serum testosterone remains higher than the normal upper limit, the dose of testosterone will be 
reduced by another 25 mg/week. This titration pattern will continue until nadir serum testosterone 
is below the normal upper limit.  In contrast, if nadir serum testosterone is <400 ng/dL the dose 
of T-enanthate will be increased by 25 mg/week and nadir serum testosterone will be reevaluated 
in the manner described above.  However, at no point will administered T-enanthate exceed 125 
mg/week.  
 
Data Safety Monitoring Plan (DSMP): We have established a comprehensive DSMP that abides 
to VA RR&D guidelines to ensure participant safety.  The Study Nurse or another member of the 
study team will compile AE incidence and all AEs will be immediately reported to the Study 
Medical Director and/or Study Physician.  If SAEs or deaths occur, they will be immediately 
reported to the independent DSMB, IRB, and VA RR&D.  Other less serious AEs will be compiled 
and reported at semi-annual intervals to the DSMB, IRB, and VA RR&D.  The independent DSMB 
will consist of one Physician / Subject Matter Expert, one Biostatistician, and one Cardiologist 
(none of whom are involved in the study).  The DSMB will meet at 3-6 month intervals during the 
first year and semi-annually thereafter, and a charter will be developed prior to beginning 
participant accrual. DSMB meetings will have two parts: open and closed.  In the open meetings, 
the safety reports will be presented by the PI / Co-Is and discussed.  After, the PI / Co-Is will be 
excused, and the DSMB will write its recommendation, which may include: Continue, Continue 
with Modifications, or Discontinue the Study.  Minutes will be provided after each meeting.  
Additionally, a list of participant demographics, outcome measures collected, missing data, and 
participant adherence will be compiled and the total number of participants screened, enrolled, 
active (and duration of participation), withdrawn, and completed will be reported semi-annually to 
ensure enrollment proceeds as planned.  The DSMB may recommend study discontinuation if a 
disproportionate number of SAEs occur in one group.  
 
Specific Risks and Risk Aversion Plan 
Specific procedures that we will incorporate to minimize risk associated with the interventions and 
testing involved in this study are described below. 
Blood Acquisition: The risks of drawing blood from a vein include discomfort at the site of puncture, 
possible bruising and swelling around the puncture site, rarely an infection, and uncommonly 

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faintness from the procedure.  The Study Nurse or a phlebotomist will draw blood to minimize 
risk.  We may provide the participant with ice if bruising or swelling occur.  The participant will be 
referred to the Study Physician in the rare instance that an infection occurs at the puncture site. 
 
Functional Assessments: The risks associated with muscle strength testing, assessments of 
voluntary muscle activation, walking speed assessments, and other assessments of physical 
function include muscle soreness and rarely musculoskeletal injury.  Functional near infrared 
spectroscopy (fNIRS) sensors may be taped or strapped to the participants’ head during walking 
speed assessments. These fNIRS sensors use harmless infrared light to estimate changes in 
hemoglobin concentration and pose no risk to the participant.  An exercise specialist who is 
trained in conducting exercise tests will perform the muscle function tests to minimize risk.  We 
may provide the participant with ice if muscle pain occurs.  The participant may be referred to the 
Study Physician in the rare instance that a musculoskeletal injury occurs.   
 
DXA: The risks associated with DXA scan include exposure to ionizing radiation. Radiation 
exposure in this study is thought to be minor. However, the effects of radiation add up over the 
life span. Repeated exposures may increase risk of injury or disease. Examples would include 
x-rays taken for a broken bone or radiation therapy treatments for cancer.  The radiation 
exposure from each scan varies from 0.2 to 1 millirem.  For comparison, this exposure is 
equivalent to 1 day of radiation exposure that people in the United States receive from natural 
background.  The risk from radiation exposure of this magnitude is too small to measure directly 
and is considered to be low when compared with everyday risks.  To minimize risk, all DXA 
testing will be conducted according to normal clinical guidelines under the supervision of VA 
Radiology Service.  The participant will be monitored during all DXA scans in case any 
problems occur.  We will provide the participant with the contact information for the Radiation 
Safety Officer at NF/SG VA Medical Center if they would like more information about radiation 
exposure.   
 
MRI: MRI exposes the participant to a strong magnetic field and radio waves for imaging. There 
are no harmful side-effects associated with temporary exposure to the strong magnetic field used 
by MRI scanners. Because MRI acts like a large magnet, it could move iron-containing objects in 
the MRI room, which could in the process possibly harm the participant.  Additionally, there is 
minor risk of claustrophobia and for hearing loss resulting from MRI noise.  To minimize risk, all 
MRI will be performed according to normal clinical guidelines under the supervision of VA Nuclear 
Medicine Service or trained medical staff at UF, our academic affiliate.  Standard precautions are 
in place to ensure loose metal objects are not allowed in the MRI room.  Participants with metal 
in their body, such as a fragment in your eye, aneurysm clips, ear implants, spinal nerve 
stimulators, or a pacemaker, will only be allowed in the MRI room if they pass screening by 
Nuclear Medicine, which is standard of care. If MRI screening is not passed, participants cannot 
have an MRI. MRI will not be conducted on individuals with severe claustrophobia. Individuals 
may be asked to wear earplugs to reduce the minor possibility of hearing loss during MRI. 
 
Prostate Exams: The risks associated with prostate DRE and prostate TRUS are relatively 
minor and include occasional bleeding from the rectum, especially if hemorrhoids or anal 
fissures are present. In rare cases, the individual may feel lightheaded and faint. This feeling is 
called vasovagal syncope and is caused by fear or pain when the doctor inserts his finger into 
the rectum.  Trained medical staff from VA Urology Service will perform the prostate exam to 
minimize risk.  If a prostate nodule/induration (bump) is found, the participant will be referred for 
a prostate biopsy to check for prostate cancer, which is the standard of care.  The participant 
can refuse to have a prostate biopsy, but will not be allowed to continue in the study if the 
biopsy is refused.  The participant will be referred to VA Urology Service to discuss treatment 

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options if prostate cancer is found.  The participant will be allowed to continue in the study if 
prostate cancer is not detected. 
 
Study Treatment: Side effects observed in patients receiving TRT include increased hematocrit, 
increased blood prostate specific antigen (PSA), prostate growth, headache, increased blood 
pressure, acne, breast enlargement, breast tenderness, baldness, leg swelling, elevated liver 
enzymes, worsening of sleep apnea, decreased sperm count, thromboembolic events, peliosis 
hepatitis, hepatic neoplasms, and worsening of congestive heart failure.  Rare side effects include 
pain or swelling at the injection site in the muscle, painful prolonged erection, stroke, or heart 
attack.  There is no evidence that TRT increases prostate cancer or other cancer risk.  However, 
it remains possible that TRT may stimulate undiagnosed prostate cancer risk. Some subjects may 
experience transient depression of mood following cessation of TRT. Other unknown side-effects 
may result from TRT. 
 
There are relatively uncommon risks associated with finasteride, including: impotence, decreased 
libido, reduced volume of ejaculation, ejaculation disorder, gynecomastia, breast tenderness, 
breast cancer, and rash.  Other unknown side-effects may result from finasteride treatment. 
 
The risks associated with co-administration of TRT and finasteride include those listed above. 
However, studies have reported fewer prostate-related side effects when combining TRT and 
finasteride.61-63 
 
All drugs have the potential to cause allergic reactions.  Allergic reactions may be mild to severe, 
and include the following symptoms: skin rash, itching, difficulty breathing, severe low blood 
pressure, and even death.   
 
To minimize risk we will administer TRT and finasteride in FDA approved doses, according to VA 
formulary, and in accordance with the Endocrine Society Clinical Practice Guidelines for 
Testosterone Therapy in Adult Men.58  We will also titrate the T-enanthate dose to ensure the 
nadir serum testosterone does not exceed the normal upper limit. The specific titration pattern for 
T-enanthate is outlined above in the Section titled “Titration of Testosterone Dose”. Study drugs 
will be dispensed by the Research Pharmacy at the NF/SG VHS to the Study Nurse who will train 
participants on proper drug administration procedures.  Participants will have the choice of self-
administering weekly TRT injections or having the Study Nurse administer injections.  All 
participants will be contacted weekly to ensure compliance with the study protocol, to reinforce 
proper drug administration procedures, and to evaluate participant health.  During the study, 
participants will receive physical exams, blood tests, and other medical tests to check their 
prostate, heart, and overall health.  A description of all study exams is included in Section 5.5 of 
this document.  Participants will also complete questionnaires that are specific to sexual function.  
Participants will be removed if they develop side effects that are considered severe or if the Study 
Physician feels it is within their best interest.  Specific withdrawal criteria are discussed in Section 
5.7 of this document. 
 
Data Security: As part of this study, medical/health information and blood samples will be 
collected and stored. There is a slight risk that health information could be revealed 
inappropriately or accidentally.  Depending on the nature of the information, such a release could 
upset or embarrass you, or possibly affect your insurability or employability. The PI and his staff 
will be responsible for ensuring that health information and blood samples are protected and that 
medical information is kept confidential. Only persons involved with this study will have access to 
your information.  Any personally identifiable information will be stored in locked filing cabinets in 
locked offices or on computer servers with secure passwords, or encrypted electronic storage 

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devices behind the VA firewall. Blood samples will be linked to a specific participant by a code 
number rather than a direct identifier to ensure that personally identifiable information is protected.  
The code will be maintained by the Study Coordinator and/or the Research Pharmacist who are 
the only study personnel that will have direct access to the code. The code will be maintained by 
the Study Coordinator and/or Research Pharmacist who are the only study personnel that will 
have direct access to the code. Access to research study data will be removed for study personnel 
when they are no longer part of the research team.  The ISO and Privacy Officer will be notified 
within one hour of any improper disclosure. 
 
Financial Risk:  Participants will be required to travel to the NF/SG VHS and may be required to 
take time of work to take part in this study.  There will be no cost to participants in this study, for 
specimen collection, or for storage of specimens.  Participants will be reimbursed for gas or 
another form of travel to offset costs of attending the screening, baseline, 1 month, 2 month, 3 
month, 6 month, 9 month, 12 month, and 18 month testing sessions and will receive 
compensation for their time involvement in these testing sessions.  The specific compensation 
plan is discussed in Section 5.2 of this document.  Any overnight stay that is required for these 
testing sessions will be provided at no cost.  
 
Other Risk: This study may include risks that are unknown at this time. 
 
Potential Benefits 
Participants may benefit directly from this study by learning additional information about their 
musculoskeletal, metabolic, cardiovascular, and prostate health, body composition, and general 
health. This information would be obtained through physical exams, blood draws, DXA and MRI 
scans, evaluations of muscle function, EKG, and prostate exams. The participant may also benefit 
directly by improving musculoskeletal and metabolic health, which may reduce the risk of future 
bone fracture or other musculoskeletal related health conditions or may reduce metabolic 
syndrome risk.  
The findings of this research study may benefit Veterans and non-veterans with SCI who are not 
involved in the study. Specifically, persons with SCI who exhibit low BMD, low muscle mass, or 
elevated visceral adiposity may benefit from this research because it is intended to delineate the 
safety/efficacy of a combination pharmacologic therapy intended to improve musculoskeletal and 
metabolic health. 
 
The VHS and Department of Veterans Affairs may benefit from this study because it is intended 
to evaluate a cost-effective means of improving BMD, muscle mass, physical function, and body 
composition. If successful, the strategy evaluated in this study could be implemented to safely 
improve musculoskeletal and metabolic health in Veterans with SCI. 
 
The PI, his staff, and the Department of Veterans Affairs may benefit if the results of this study 
are presented at scientific meetings or in scientific journals because presenting research helps 
the career of a scientist and the reputation of an institution. 
 
Risk/Benefit Analysis 
The risks associated with this study occur infrequently and are relatively minor. As such, the 
benefits of this intervention outweigh the potential risks. 
 
5.2 Recruitment Methods 
 

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Recruitment 
Recruitment will be handled cooperatively through the NF/SG VHS, the James A. Haley VAMC 
(Tampa, FL), and the UF CTSI. We will prescreen up to 500 individuals.  Of these, we will enroll 
up to 200 participants in order to find 30 participants who qualify.  Prescreening and enrollment 
will be completed once we have identified 30 participants who qualify. Participants who qualify 
will be randomized into two groups (n=15/group). Participants will be recruited beginning at the 
initiation of funding (following development of the DSMB Charter) and continuing until 
recruitment is completed. Participants will be recruited by physician referral, verbally (in person) 
in the above hospitals, by flyers posted in the above hospitals, or by direct mailings to potentially 
eligible individuals seen in the above hospitals. In addition, we will recruit individuals through 
PVA, DAV, VFW, and America Legion Posts, other Veteran-centric offices or centers located in 
Florida/Georgia, local area long-term care centers, rehabilitation centers, or hospitals, and from 
other VA hospitals and outpatient clinics located in Florida and Georgia  through flyers posted in 
these offices and through use of a University of Florida IRB-approved SCI registry that lists 
individuals who have agreed to be contacted to query their interest in participating in research 
studies. The referring physician from NF/SG VHS or James A. Haley VAMC will instruct 
potential participants to contact the PI or his staff directly via phone or in-person (no cold calls 
will be made) and the referring physician will not directly consent the potential participant. We 
may also travel to the locations listed above or phone these locations to engage staff in a brief 
conversation to explain the study and ensure they will allow placement of VA CIRB approved 
flyers in their offices. Staff at these locations will not be engaged in participant recruitment or 
any other aspect of the research. Under all other circumstances the initial contact will be made 
by the potential participant.  We may also recruit via advertisements in magazines, newspapers, 
newsletters, or other print media and via the websites of these print media outlets and their 
email listservs, on the UF Health Study Listings website (https://ufhealth.org/research-studies-
clinical-trials), through the ResearchMatch.org national recruitment database, through posts to 
the Facebook pages of the NF/SG VHS or the James A. Haley VA Medical Center, through 
posts to individual Facebook pages or groups that have a veteran or SCI support focus, through 
advertisements placed on Facebook, and via www.clinicaltrials.gov. A separate document 
outlines our Facebook advertising strategy, including monitoring of Facebook pages and 
advertisements.  
 
Compensation and Reimbursement 
Significant participant time involvement is required for this RCT due to the comprehensive 
evaluations we propose. We will inform participants of the estimated time involvement prior to 
enrollment. This includes: screening, baseline, 3 month, 6 month, 9 month, and 12 month testing 
sessions (~8 hours/visit), ~1 hour visits at 1 month, 2 month, and 18 month, and ~1 hour of home 
care per week, including drug administration and weekly phone calls from the Study Nurse. 
Participants will receive compensation for their participation in the study.  Total compensation for 
the study will be $400, which will be disbursed in $80 increments during baseline, 3 month, 6 
month, 9 month, and 12 month testing sessions.  We will reimburse participants for transportation 
expenses at a rate of $0.415 per mile for the screening, baseline, 1 month, 2 month, 3 month, 6 
month, 9 month, 12 month, and 18 month testing sessions. Any overnight lodging required for 
study participation in the screening, baseline, 1 month, 2 month, 3 month, 6 month, 9 month, 12 
month, and 18 month testing sessions will be provided for free.  Payment for participation will be 
provided through the VA Finance Office and will be pro-rated for study participation.  The VA 
Finance Office will issue payment by direct deposit to the participant’s bank account.  If it is not 
possible for the participant to receive payment by direct deposit, they may have payment sent to 
a pre-paid debit card or they may decline payment for participation. Participants will not receive 
travel reimbursement, compensation, or overnight lodging for any other study visit.  If the 

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participant chooses to have the Study Nurse provide the weekly injection, they will not receive 
any travel reimbursement, compensation, or overnight lodging.   
5.3 Informed Consent Procedures 
 
Individuals who contact us and are interested in participation will undergo prescreening to 
determine if they meet criteria to enroll.  We have requested a Waiver of Informed Consent and 
a Waiver of HIPAA Authorization for purposes of recruitment and prescreening.  Prescreening will 
be conducted by the PI, Study Nurse, or another member of the study team over the phone or in-
person.  We will query interested individuals about their complete medical history and conduct a 
review of their CPRS medical records (if applicable) to determine if they meet prescreening 
criteria.  An in-depth description of the prescreening procedures is included in Section 5.5 of this 
document.  We will obtain informed consent and HIPAA authorization from those individuals who 
meet prescreening criteria.  Informed consent will be obtained by the PI, Study Nurse, or another 
member of the study team.  Referring physicians will not be involved in the informed consent 
process. 
5.4 Inclusion/Exclusion Criteria 
 
Participants who meet prescreening criteria and provide informed consent and HIPAA 
authorization will undergo additional hands-on screening to determine eligibility.  An in-depth 
description of the prescreening and screening process is included in Section 5.5 of this document.  
Participants who meet Inclusionary Criteria or who do not exhibit Exclusionary Criteria will be 
allowed to continue in the study.  Those who do not meet criteria will be considered screen failures 
and will not continue in the study.  The Inclusionary and Exclusionary Criteria for this study are 
listed below.  
 
Inclusionary Criteria  
 
▪ 
Men >18 years of age. 
▪ 
SCI >12 months prior to enrollment. 
▪ 
Motor incomplete SCI (AIS C/D) between C2-L3. 
▪ 
Low serum total T (≤325ng/dL) or bioavailable T (≤70ng/dL). 
▪ 
Ambulatory dysfunction, defined as self-selected gait speed between 0.10 m/s – 1.30 m/s 
on 10m walk test, and/or impaired gait parameters, as identified by a trained observer. 
▪ 
Diagnosis of first time SCI including etiology from trauma, vascular, or orthopaedic 
pathology. 
▪ 
Medically stable condition that is asymptomatic for bladder infection, decubiti, 
cardiopulmonary disease, or other significant medical conditions that will interfere with 
study design. 
▪ 
Documented medical approval from the from the Study Physician and/or Medical Director 
verifying medical status.  
▪ 
Persons using anti-spasticity medication may participate; however, the medication dosage 
must have been stable for the preceding 3 months and remain stable throughout 
participation.  
 
Exclusionary Criteria 
 
▪ 
Currently participating in another research protocol that may influence study outcomes. 

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▪ 
Life expectancy <1 years. 
▪ 
History of or current congenital SCI (e.g., Chiari malformation, myelomeningocele, 
intraspinal neoplasm, Frederich’s ataxis) or other degenerative spinal disorder (e.g., 
spinocerebellar degeneration, syringomyelia) that may complicate the study procedures. 
▪ 
Multiple sclerosis, amyotrophic lateral sclerosis, or other neurologic impairment/injury. 
▪ 
Any poorly compensated or uncontrolled cardiovascular disease (see next section). 
▪ 
History of venous thromboembolism within the last 6 months, specifically deep venous 
thromboembolism 
and 
pulmonary 
embolism, 
history 
of 
recurrent 
venous 
thromboembolism or known hereditary thrombophilia. 
▪ 
Current prostate, breast, or other organ cancer. 
▪ 
History of prostate, breast, or other organ cancer, with the exceptions of completely 
resolved basal or squamous cell carcinoma for a duration of >24 months or completely 
resolved melanoma for a duration of >24 months. 
▪ 
Serum PSA >3.0ng/ml. 
▪ 
Benign prostate enlargement (BPE) >40cc, evaluated via TRUS. 
▪ 
HCT >49%. 
▪ 
Liver enzymes (AST / ALT) above normal upper limit. 
▪ 
Creatinine level >1.4mg/dl. 
▪ 
Serum calcium >10.5mg/dl. 
▪ 
Gynecomastia. 
▪ 
Mental state that precludes understanding of the protocol. 
▪ 
Diagnosed, but untreated moderate or severe sleep apnea. 
▪ 
High risk for malnutrition (score >15 on Spinal Nutrition Screening Tool). 
▪ 
Severe claustrophobia that precludes MRI testing. 
▪ 
Current anticoagulant therapy (contraindication for i.m. injections). 
▪ 
Use of any of the following pharmacologic agents that alter sex-steroid metabolism in the 
previous 3 months (i.e., TRT, leuprolide, androgenic hormones, growth hormone, oral 
androgen precursors, 5α-reductase or aromatase inhibitors). 
▪ 
Use of anti-resorptive or bone anabolic drug therapy in the previous 6 months.  
▪ 
Known allergy to sesame oil 
 
Cardiovascular Exclusionary Criteria Include:  
 
▪ 
Any major cardiovascular event within the last 12 months (defined as a history of acute 
myocardial infarction, any cardiac revascularization procedure including angioplasty, 
stenting, or coronary artery bypass grafting, hospitalization due to unstable angina, 
transient ischemic attack, or stroke). 
▪ 
Any angina that is not controlled on a current medical regimen (Canadian class II, III, or 
IV). 
▪ 
Poorly compensated congestive heart failure (NYHA class III or IV). 
▪ 
Poorly controlled hypertension (consistently measured systolic blood pressure ≥ 160 
mmHg or diastolic blood pressure ≥ 100 mmHg). 
▪ 
Poorly controlled arrhythmia. 
▪ 
Severe valvular heart disease. 
▪ 
LDL cholesterol >160 mg/dl with known history of any major cardiovascular event, as 
defined above, within the last 12 months. 
▪ 
Baseline EKG findings such as left bundle branch block or marked EKG abnormalities that 
would preclude serial screening evaluations for occult ischemic events. 
5.5 Study Evaluations 
 

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Prescreening 
We will prescreen individuals who contact us and are interested in participating to determine if 
they meet criteria to enroll.  This is necessary in order to determine whether interested individuals 
meet the stringent inclusionary/exclusionary criteria to qualify for our study (discussed above in 
Section 5.4).  We have requested a Waiver of Informed Consent and a Waiver of HIPAA 
Authorization, which will be used for recruitment purposes and prescreening. During the 
prescreening we will query individuals about their complete medical history and previous six 
months of physician prescribed and over-the-counter medications (via phone or in-person) and 
conduct a review of the CPRS medical records (if applicable) to determine if they meet 
prescreening criteria.  Additionally, we will collect the following identifiers: 
 
▪ 
Names 
▪ 
Social security numbers 
▪ 
Telephone numbers 
▪ 
State, City, Zip Code, Address 
▪ 
Age 
▪ 
Date of birth 
▪ 
Date of past medical procedures/diagnoses 
▪ 
Medical records number 
 
Informed consent and HIPAA authorization will be obtained from individuals who meet 
prescreening criteria. These individuals will then undergo additional hands-on screening to 
determine eligibility.  
 
Safety Screening 
Individuals who give informed consent will undergo a Safety Screening and Functional 
Assessment prior to study enrollment to determine eligibility. All screening and assessments will 
take place at the NF/SG VHS and will be conducted over a 1-2 day period to reduce participant 
transportation, time, and travel burden.  
 
The Safety Screening includes the following:  
▪ 
Comprehensive physical exam  
▪ 
CPRS medical records review (if applicable) and health history questionnaire 
encompassing the complete medical history including cardiovascular disease history and 
review of systems 
▪ 
Fasting blood collection 
▪ 
Comprehensive prostate exam 
▪ 
Electrocardiogram (EKG) 
▪ 
Questionnaire evaluating previous six months use of physician prescribed and over-the-
counter medications 
▪ 
Spinal Nutrition Screening Tool assessing nutritional status 
▪ 
Questionnaires assessing perceived erectile quality [International Index of Erectile 
Function (IIEF)] and sexual function [Brief Sexual Function Inventory (BSFI)] 
 
The Study Nurse and/or Study Physician will perform the comprehensive physical exam and 
administer questionnaires. Fasting blood samples will be acquired twice (between 0:700-
10:00am, separated by 30 minutes) by the Study Nurse and/or a VA hospital phlebotomist which 
is standard practice when measuring serum T. The VA Clinical Lab will evaluate blood samples 
for total T, complete blood count (CBC), comprehensive metabolic panel, lipid panel, fasting 
insulin and glucose, HbA1C, C-reactive protein, erythropoietin, and PSA (a serum marker of 

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prostate growth).  Urology Service will perform the prostate exam, which includes DRE to evaluate 
for prostate nodules/indurations and prostate TRUS to assess prostate volume according to 
standard clinical guidelines. If prostate nodules are detected via DRE, participants will be referred 
to VA Urology Service for prostate biopsy, which is standard of care. The participant can refuse 
to have a prostate biopsy, but will not be allowed to continue in the study if the biopsy is refused.  
The participant will be referred to VA Urology Service to discuss treatment options if prostate 
cancer is found.  The participant will be allowed to continue in the study if prostate cancer is not 
detected. Cardiology Service will perform EKG to evaluate cardiac abnormalities.  The 
questionnaires will be completed by the participant and assistance will be provided if necessary. 
 
The Functional Assessment will evaluate (self-selected) walking speed during 10m walk tests that 
are performed with and without brief cognitive tasks. Examples of the brief cognitive tasks include 
listing words starting with the letter “A”, performing basic math calculations like continuously 
adding or subtracting by 7, or other similar tasks. During the 10m walking tests sensors may be 
taped or strapped to the participants’ head to allow us to estimate brain activity via fNIRS, which 
uses harmless and non-invasive infrared light to estimate changes in blood flow by determining 
changes in hemoglobin concentrations. Individuals with gait speeds between 0.10 m/s – 1.30 m/s 
on 10m walk test and/or impaired gait parameters, as identified by a trained observer, will qualify 
for the study because these values are below typical healthy adult preferred walking speed and 
common to the AIS C/D population. Furthermore, individuals who fit these criteria will have 
sufficient KE motor function to engage in the proposed muscular strength assessments. 
Additionally, we will perform the following assessments which are standard in SCI rehabilitation 
trials and which will allow us to appropriately classify participant functional, cognitive, and 
emotional status:  
▪ 
Modified Ashworth Scale for lower limbs spasticity 
▪ 
Spinal Cord Independence Measure (SCIM) III 
▪ 
Berg Balance Scale 
▪ 
Walking Index for Spinal Cord Injury (WISCI) II  
▪ 
Craig Handicap Assessment & Reporting Technique (CHART) Questionnaire 
▪ 
Veteran Rand 12 Item Health Survey (VR-12) 
 
Participants who meet the above inclusionary criteria will be allowed to continue in the study and 
will undergo Baseline Testing.  Those who do not meet the above criteria will be considered 
screen failures and will not continue in the study. 
 
Baseline/Follow-up Testing: Participants who qualify for the study will undergo Baseline Testing 
to assess:  
 
▪ 
Total body and region-specific bone mineral density (BMD) and body composition  
▪ 
Blood markers of musculoskeletal and metabolic health and metabolism 
▪ 
Thigh musculoskeletal and adipose cross-sectional area (CSA) 
▪ 
Neuromuscular function and voluntary neuromuscular activation 
▪ 
Daily activity 
▪ 
Metabolic syndrome risk 
 
Tests that are completed during Screening will not be repeated at baseline.  Follow-up testing will 
occur at 3-6 month intervals and will include all Safety Screening and Baseline Testing measures. 
The table below illustrates when testing will occur. Additionally, 10m walk tests and blood tests 
will occur at 1, 2, and 3 months of treatment and at 3 month intervals thereafter.  Participants will 

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be allowed a 1 month window surrounding the scheduled testing dates to ensure completion of 
all testing procedures.  A specific explanation of all tests follows.   
 
Table 1. Testing Schedule 
Test 
Rationale Baseline 3 month 6 month 9 month 12 month 
Physical exam 
Safety 
X 
X 
X 
X 
X 
Blood collection 
Safety 
X 
X (1-3)  
X 
X 
X 
EKG  
Safety 
X 
X 
X 
X 
X 
Questionnaires 
Safety 
X 
X 
X 
X 
X 
Functional status 
Safety 
X 
X 
X 
X 
X 
Prostate exam 
Safety 
X 
 
X 
 
X 
BMD / body 
composition 
Aim 1 & 3 
X 
 
X 
 
X 
Blood measures 
Aim 1 
X 
X 
X 
X 
X 
Thigh CSA 
Aim 2 
X 
 
X 
 
X 
Neuromuscular function 
Aim 2 
X 
X 
X 
X 
X 
Daily activity 
Aim 2 
X 
X 
X 
X 
X 
Metabolic syndrome 
Aim 3 
X 
X 
X 
X 
X 
Body Composition and Bone Assessments: VA Radiology Service will perform total body DXA 
(for body composition) and region-specific DXA to evaluate bone mineral characteristics 
according to established ISCD guidelines.66 Scans will be performed on DXA densitometer with 
software for evaluation of both standard and non-standard regions of interest (e.g., distal femur). 
The DXA is calibrated daily using multi-stage hydroxyapatite and soft-tissue phantoms. 
Participants will arrive fasted and will be placed supine for the total body scan, as previously 
reported62. Care will be taken to ensure identical body positions during each scan. Region-specific 
BMD scans will be performed on the non-dominant hip/knee, unless surgical hardware or previous 
fracture is present. Hip DXA will be performed with knee stabilized in full extension at ~20° internal 
rotation of the hip. For the distal femur, the knee is stabilized in full extension with 0° internal 
rotation against a 90° support and the region of interest is determined according to published 
protocol.67 Participants will remain supine for the lumbar scan with the lower limbs stabilized on a 
box to allow 90° hip and knee flexion with back flat on the scanning surface. The lumbar scan is 
performed in the anterior-posterior (A-P) direction.68   
 
Circulating Markers of Musculoskeletal and Metabolic Health and Metabolism: Circulating 
markers of musculoskeletal and metabolic health and metabolism will be evaluated on previously 
collected blood samples in order to determine potential mechanisms through which testosterone 
alters these measures.  These analyses may be performed by the VA Clinical Lab or a commercial 
lab subcontracted by the VA Clinical Lab to complete such analyses when in-house assessments 
are not possible (e.g., Quest Diagnostics), which is standard practice at NF/SG VHS.  
Alternatively, these analyses may be performed in the PIs laboratory, who is experienced in these 
techniques, because some tests are not standard in the VA Clinical Laboratory or available in VA-
subcontracted labs.  These will include circulating markers of: bone formation (e.g., osteocalcin 
and bone alkaline phosphatase), bone resorption (e.g., C-telopeptide and tartrate resistant acid 
phosphatase 5b), bone metabolism (e.g., osteoprotegerin, RANKL, sclerostin), muscle 
metabolism (e.g., myostatin, brain-derived neurotrophic factor, adiponectin, leptin), and perhaps 
others. All samples will be linked to a specific participant by a code number rather than a direct 
identifier to ensure that personally identifiable information is protected, as described in Sections 
5.0 “Minimization of Risks / Data Security” and 7.0 “Privacy and Confidentiality”.  Unused samples 
will be returned to VA for storage or will be destroyed. 

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Musculoskeletal and adipose cross-sectional area: The Nuclear Medicine Service at NF/SG VHS 
or trained medical staff at UF, our academic affiliate, will perform MRI screening and testing 
according to standard clinical guidelines.  Briefly, MRI will be used to quantify maximal CSA of 
the flexor and extensor compartments of the thigh. Participants will remain in a supine position 
for approximately 30 minutes prior to MRI.  Padding will be provided to limit pressure sores/ulcers.  
MRI will be performed using either a body coil or a standard quadriture extremity coil and should 
take approximately 30 minutes.   
 
Neuromuscular function: Neuromuscular assessments will be supervised by a trained Exercise 
Physiologist.  Participants will undergo a warm-up and familiarization prior to beginning testing. 
Subsequently, participants will perform submaximal and maximal effort contractions of knee 
extensor and flexor muscle groups.  Isometric and dynamic force production will be measured by 
a Biodex dynamometer.  During these assessments, participants will be instructed to contract the 
muscle as forcefully and rapidly as possible and hold the contraction for up to 5 seconds. 
Neuromuscular activation will be assessed using surface electromyography (EMG), which is a 
non-invasive technique that measures the bioelectrical signals associated with muscle 
contraction.  EMG electrodes will be taped to the skin over the muscle(s) of interest.  For proper 
application of electrodes, it may be necessary to shave hair from the skin and clean the site with 
an alcohol wipe.  To evaluate spasticity and abnormal co-activation between agonist/antagonist 
muscle groups we will quantify the co-activation index as the ration of agonist/antagonist EMG 
magnitude. 
 
Voluntary Neuromuscular Activation: Voluntary neuromuscular activation will be assessed by 
the twitch interpolation technique.  Short bursts (i.e., < 1 second) of electrical stimulation will be 
used to evoke activation of the knee extensor (quadriceps) muscle group.  This is a safe and 
well tolerated procedure that is performed with specialized equipment that is designed for use 
with human subjects.  Electrical stimulation will be delivered using a Grass-Telefactor square 
pulse stimulator and Model SIU5 stimulus isolation unit (Astro-Med, West Warwick, RI).  Two 
stimulating electrodes coated with non-allergenic electrode gel will be placed over motor nerve. 
Optimal positioning of the stimulating electrodes will be determined by palpation and visual 
observation of muscle contractions during low-intensity stimulation.  Stimulation will be delivered 
at rest and during voluntary muscle contractions.  For proper application of some electrodes, 
shaving hair from the skin and wiping with alcohol may be necessary.  To familiarize the 
participant with the sensation of the stimulation, a series of four to five trials will be delivered 
with gradually increasing intensity.  We will ensure the participant is comfortable with the 
sensation and willing to proceed before moving on to the next trial.  During testing, stimulation 
will be delivered during maximal and submaximal muscle contractions.  An estimated total of 
about 25 stimulations will be performed.  The participant will be reminded that they are free to 
end the testing session at any time if they are uncomfortable with the sensation of the 
stimulation, or for any other reason. 
 
Metabolic Syndrome Risk: We will assess metabolic syndrome risk according to the American 
Heart Association criteria, which considers men with ≥3 of the following conditions at-risk for 
metabolic syndrome: abdominal obesity; systolic blood pressure ≥130mmHg; diastolic blood 
pressure ≥85mmHg; serum triglycerides ≥150mg/dL; HDL cholesterol <40mg/dL (in men); fasting 
glucose ≥100mg/dL; or presence of insulin resistance [Homeostasis model assessment (HOMA)].  
Blood pressure will be obtained during the physical exam, blood markers will be evaluated by the 
VA Clinical Lab using previously collected samples, and total body and trunk/android fat mass 
(assessments of visceral adiposity) will be measured via DXA, as previously discussed. HOMA 
will be determined with the following equation: 
 

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HOMA-IR = FASTING GLUCOSE x FASTING INSULIN 
22.5 
 
Daily Activity Assessment: We will assess daily activity using the Stanford 7-Day Physical Activity 
Recall (PAR) questionnaire, which is a valid and reliable research tool for assessing cumulative 
daily activity. This PAR assesses a variety of physical activities, such as aerobic exercise, work-
related activities, gardening, walking, recreation, and leisure-time physical activities that occurred 
over the previous 7 days, as recalled by the participant.   
 
Safety Assessments: Participants will also undergo comprehensive Safety Screenings at 3 or 6 
month intervals throughout the intervention and additional blood tests at 1, 2, and 3 months of 
study treatment and 3 month intervals thereafter.  These assessments will be identical to that 
outlined above in the Participant Safety Screening section above.  In addition, the Study Nurse 
will phone participants on a weekly basis to determine their general health / well-being and will 
perform a monthly formal CPRS medical records review to assess for potential AEs.  Patients will 
be specifically interviewed regarding the cardiovascular symptoms of chest pain, edema, 
palpitations, dyspnea, and other health-related matters.  
 
Study Completion: Participants will be referred to their VA or non-VA Primary Care Provider at 
the completion of the RCT.  Some participants may report a transient depression of mood 
following TRT cessation because reduced circulating T occurs after TRT discontinuation.  If this 
occurs, participants have the option of tapering to a lower dose of T (125mg T-enanthate biweekly, 
i.m.) for 4 weeks (administered through the VA Research Pharmacy).  We will also provide 
participants with information for their Primary Care Provider to assist in deciding whether 
continuing TRT is appropriate. We will follow-up with participants monthly (via phone call) and 
perform monthly medical chart reviews for 3 months to assess potential AEs after study 
discontinuation.  In addition, we will reassess blood values, perform a physical exam, EKG, and 
10m walk tests at 6 months following study completion to ensure participant safety and to evaluate 
patient safety measures and persistence of any walking changes after discontinuation of study 
medication. Blood will be collected and blood tests will be performed in an identical to that 
previously discussed.  Participants will be referred to their Primary Care Provider if AEs appear 
after study completion. 
5.6 Data Analysis 
 
Statistical Methods: Statistical analysis will be performed by the Study Statistician through the 
UF CTSI. All data will be provided to the statistician in a coded form.  Preliminary analyses will 
be performed during years 2 and 3 and the final statistical analysis will be performed during year 
4. All data provided for statistical analysis will coded. The primary analysis will be a repeated 
measures ANOVA using the SAS 9.3 PROC MIXED software, with dependent variable change 
from baseline, independent variables time  (6 Mo vs. 12 Mo) and subject (random effect), and a 
compound symmetric covariance structure. The contrast of primary interest is the arithmetic 
mean of the 6 month and 12 month changes. The relative efficiency of the repeated measures 
analysis is 133% compared to using only the change from baseline to 12 months. If there is no 
missing data, the mixed model and two-sample t-test using the mean of the 6 and 12 month 
differences from baseline on each subject will lead to identical point estimates and 
asymptotically equivalent standard errors. However, the mixed model handles missing data 
more efficiently. Secondary analyses:  We shall also present descriptive statistics and 
confidence intervals for changes from baseline for each treatment (2) by time (2), and provide 
Satterthwaite corrected t-tests comparing the treatments for changes from baseline at each of 

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the two time points. Other variables will be analyzed in like manner, but the following six are the 
primary outcomes for which the study was powered: Total hip BMD, lumbar spine BMD, knee 
extensor force production, total body fat mass, visceral fat mass, thigh muscle CSA.  
 
Sample Size/Power Analysis: Our a priori power analysis indicates that the repeated measures 
method has 80% power to detect a difference of 1.15 standard deviations in the change from 
baseline for all primary outcomes in Aims #1-3 at P=0.05 (two-sided) with n=10 completers per 
group. In order to provide sufficient power for all primary outcomes we will recruit n=15 per group 
(to account for potential participant dropouts that are characteristic of long duration RCTs), which 
exceeds that indicated by our power analysis by 50%. It is difficult to determine the anticipate rate 
of screen failures; although, we conservatively estimate that we will need to screen up to 200 
individuals to find 30 participants who qualify. 
 
5.7 Withdrawal of Subjects 
 
Participants may be withdrawn from the study for medical reasons:  
 
▪ 
HCT >52% 
▪ 
Hemoglobin >17.5 g/dL 
▪ 
Serum PSA >4.0ng/ml 
▪ 
Increase in serum PSA of >1.4ng/ml vs. baseline 
▪ 
Liver enzymes (AST / ALT) >1.5 times normal upper limit 
▪ 
Serum calcium between 10.5 – 11.2mg/dL with symptoms of hypercalcemia 
▪ 
Serum calcium >11.2mg/dL (whether symptomatic or asymptomatic for hypercalcemia) 
▪ 
Gynecomastia 
▪ 
Prostate, breast, or other organ cancer development 
▪ 
Development of severe peripheral edema, as classified as 2+ or higher 
▪ 
Occurrence of any of the following adverse cardiovascular events: acute myocardial 
infarction, acute coronary syndrome, congestive heart failure (new onset), newly 
diagnosed 
flow-limiting 
coronary 
artery 
disease, 
any 
cardiovascular-related 
hospitalization, stroke, or cardiac arrest, and the development of new significant ischemic 
findings or symptoms during the course of the study (including development of new major 
abnormalities on serial EKGs or symptoms of typical angina) 
▪ 
Development of any other SAE that the Medical Director feels necessitates study 
withdrawal for participant safety  
 
Treatment will be immediately discontinued for those experiencing any AE listed above and 
participants will be referred to the Study Physician and/or Medical Director for monitoring and 
reevaluation of laboratory values. Participants will be withdrawn from the study if aberrant results 
are verified upon rescreening, with the exception of elevated PSA or HCT (see below). If serum 
calcium is elevated the Study Physician and/or Medical Director will determine whether the 
participant is symptomatic or asymptomatic for hypercalcemia. If asymptomatic for hypercalcemia 
and serum calcium is between 10.5 – 11.2 mg/dL, the participant will be allowed to continue in 
the study and if symptomatic for hypercalcemia and serum calcium is >10.5 mg/dL the participant 
will be withdrawn from the study.  The Study Physician and/or Medical Director may order 
additional testing (as needed) to assist in the decision regarding participant withdrawal and may 
consult with other Physicians (as needed). Prostate withdrawal criteria: In the unlikely instance 
that a prostate nodule is detected via DRE or that elevated PSA occurs, participants will 
discontinue TRT and will be referred to VA Urology Service for reevaluation and monitoring. While 

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undergoing reevaluation, participants will remain enrolled, but will not receive TRT. Participants 
will be assessed for prostatitis and lower urinary tract infection (standard-of-care), which can 
occur due to intermittent urinary catheterization, and will be offered treatment if infection is noted. 
The participant will remain enrolled if they choose to receive treatment but will not receive TRT 
until PSA renormalizes and study physician re-approves TRT. The participant will be withdrawn if 
they choose not to receive treatment or if elevated PSA persists for >4-weeks, as extended TRT 
withdrawal may compromise study validity. If prostate nodule is verified upon reevaluation, 
participants will be referred to VA Urology Service to undergo prostate biopsy to assess for 
prostate cancer, which is standard of care.  The participant can refuse to have a prostate biopsy, 
but will not be allowed to continue in the study if the biopsy is refused.  The participant will be 
referred to VA Urology Service to discuss treatment options if prostate cancer is found.  The 
participant will be allowed to continue in the study if prostate cancer is not detected, with approval 
from study physician.  HCT withdrawal criteria: If HCT >52% is noted, participants will discontinue 
TRT and will be referred to the study physician for reevaluation and monitoring. While undergoing 
reevaluation, participants will remain enrolled, but will not receive TRT. Participants can resume 
TRT if HCT renormalizes within 4-weeks, with approval of the study physician. Participants will 
be withdrawn if elevated HCT persists for >4-weeks because extended TRT withdrawal may 
compromise study validity. Participants experiencing any other SAE will be immediately referred 
to the Study Physician and/or Medical Director for monitoring and additional testing (as needed) 
or to Urgent Care for unexpected potentially life-threatening emergencies. The Medical Director 
may withdraw participants who experience SAEs if they feel this is necessary to ensure participant 
safety.  Under all conditions described above, participants will be followed until resolution of AEs. 
 
Participants may also be withdrawn from the study for the following reasons: 
 
▪ 
Failure to comply with the study protocol 
▪ 
Use of anticoagulant medications that are contraindications for i.m. injections 
▪ 
Use of any pharmacologic agent that alters muscle/bone metabolism or sex-steroid 
metabolism (defined in Exclusionary Criteria)  
 
Participants also have the option to discontinue study participation at will and without 
consequence.  If they choose to do so, they will be asked to contact the PI or Study Nurse to 
schedule an end of study visit for the purposes of evaluating potential safety concerns and 
obtaining any final testing.  For 3 months after study discontinuation we will follow-up with 
participants monthly (via phone) and perform monthly medical chart reviews to assess potential 
AEs after study discontinuation.  Participants will be referred to their Primary Care Provider if AEs 
appear in the follow-up period after study completion and will be followed until resolution of AEs. 
6.0 
Reporting 
 
We have established a comprehensive Data Safety Monitoring Plan (DSMP) to ensure participant 
safety and reporting of potential unanticipated problems (UAPs), SAEs, and protocol deviations. 
The Study Nurse or another member of the study team will compile AE incidence and all AEs will 
be immediately reported to the Study Medical Director and Study Physician. If SAEs, deaths, or 
protocol deviations occur, they will be immediately reported to the independent DSMB, IRB, and 
VA RR&D. Other less serious AEs will be compiled and reported at semi-annual intervals to the 
DSMB, IRB, and VA RR&D. The independent DSMB will consist of one Physician, one 
Biostatistician, and one Cardiologist (none of whom are involved in the study). The DSMB will 
meet at 3-6 month intervals during the first year and semi-annually thereafter, and a charter will 

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be developed prior to beginning participant accrual. DSMB meetings will have two parts: open 
and closed. In the open meetings, the safety reports will be presented by the PI / Co-Is and 
discussed. After, the PI / Co-Is will be excused, and the DSMB will write its recommendation, 
which may include: Continue, Continue with Modifications, or Discontinue the Study. Minutes will 
be provided after each meeting. Additionally, a list of participant demographics, outcome 
measures collected, missing data, and participant adherence will be compiled and the total 
number of participants screened, enrolled, active (and duration of participation), withdrawn, and 
completed will be reported semi-annually to ensure enrollment proceeds as planned. The DSMB 
may recommend study discontinuation if a disproportionate number of SAEs occur in one group. 
Once the charter has been developed it will be provided to IRB.    
 
Participants will be immediately notified (in person or via telephone) if any AE occurs that may 
affect their health or welfare. Participants will be referred to the Study Physician and/or Medical 
Director for monitoring and reevaluation of laboratory values. Participants will be removed from 
the study if aberrant results are verified upon rescreening. The Study Physician or Medical 
Director may also order additional testing (as needed) to assist in their decision regarding whether 
participants need to be removed from the study, including consulting other Physicians. In the 
unlikely event that prostate nodules / indurations are detected, participants will be referred to VA 
Urology Service for prostate biopsy to assess for prostate cancer. Participants will be immediately 
withdrawn from the study if prostate cancer is detected, but will be allowed to continue 
participation if prostate cancer is not found. Participants experiencing any other SAE will be 
immediately referred to the Study Physician and/or Medical Director for monitoring and additional 
testing (as needed) or to Urgent Care for unexpected potentially life-threatening emergencies. 
The Medical Director may withdraw participants who experience SAEs if he feels this is necessary 
to ensure the safety of the participant.  Under all conditions described above, participants will be 
followed until resolution of AEs. 
7.0 
Privacy and Confidentiality 
 
This study will collect and use PHI. The PI and his staff will be responsible for ensuring that health 
information and blood samples are protected and that medical information is kept confidential. 
Individuals will only be allowed access to PHI if necessitated by the study protocol. All personnel 
with access to PHI will complete the necessary training as required by VA. Data and samples will 
be linked to a specific participant by a code number rather than a direct identifier to ensure that 
personally identifiable information is protected. While the data may contain some protected health 
information, only someone possessing the code can link the data to a particular participant.  The 
code will be maintained by the Study Coordinator and/or Research Pharmacist who are the only 
study personnel that will have direct access to the code.  In the case of SAEs/UAPs, the code 
may be provided to the Medical Director to ensure participant safety. Any personally identifiable 
information will be stored in locked filing cabinets in locked offices or on computer servers with 
secure passwords or encrypted electronic storage devices behind the VA firewall. Access to 
research study data will be removed for study personnel when they are no longer part of the 
research team. The ISO and Privacy Officer will be notified within one hour of any improper 
disclosure. 
8.0 
Communication Plan 
 

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We will recruit participants from the NF/SG VHS and James A. Haley VA Medical Center and 
through other approved methods, but all testing and follow-up will be completed at NF/SG VHS 
under the supervision of the PI and his staff.  This plan greatly simplifies the communication plan 
and ensures the study will be conducted according to the IRB approved protocol. In particular, 
the PI and his staff will be responsible for recruiting, screening/consenting, enrollment, and data 
collection. The PI and his staff will inform the local site investigators of any changes to the 
protocol, informed consent, and HIPAA authorizations via email immediately following IRB 
approval and at regularly scheduled semi-annual meetings. The PI and his staff (in cooperation 
with the local site investigator) will be responsible for ensuring all required local site approvals are 
obtained and that facilities remain engaged. If necessitated, the PI or his staff may contact the 
local site investigator at James A. Haley VA Medical Center to ensure the facility remains engaged 
in recruiting. All SAEs, UAPs, and interim results will be immediately reported to the local site 
investigator at James A. Haley VAMC.  Additionally, SAEs/UAPs will be reviewed semi-annually 
at regularly scheduled meetings. The LSI at James A. Haley VAMC will remain engaged 
throughout the completion of this study because he is the study Medical Director and will be 
notified by the PI or his staff upon completion of the study.     
9.0 
References 
 
1. 
Clark MJ, Petroski GF, Mazurek MO, Hagglund KJ, Sherman AK, Lammy AB, Childers 
MK, Acuff ME. Testosterone replacement therapy and motor function in men with spinal 
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2. 
Qin W, Bauman WA, Cardozo C. Bone and muscle loss after spinal cord injury: Organ 
interactions. Ann N Y Acad Sci. 2010;1211:66-84 
3. 
http://www1.va.gov/opa/fact/spinalcfs.asp. Department of veteran's affairs spinal cord 
injury fact sheet. Accessed: February 24, 2010 
4. 
French DD, Campbell RR, Sabharwal S, Nelson AL, Palacios PA, Gavin-Dreschnack D. 
Health care costs for patients with chronic spinal cord injury in the veterans health 
administration. The journal of spinal cord medicine. 2007;30:477-481 
5. 
https://www.nscisc.uab.edu/public_content/facts_figures_2009.aspx. The national spinal 
cord injury statistical center. Accessed: February 24, 2010;2010 
6. 
Giangregorio L, McCartney N. Bone loss and muscle atrophy in spinal cord injury: 
Epidemiology, fracture prediction, and rehabilitation strategies. The journal of spinal cord 
medicine. 2006;29:489-500 
7. 
Kocina P. Body composition of spinal cord injured adults. Sports medicine (Auckland, 
N.Z. 1997;23:48-60 
8. 
Jayaraman A, Gregory CM, Bowden M, Stevens JE, Shah P, Behrman AL, 
Vandenborne K. Lower extremity skeletal muscle function in persons with incomplete 
spinal cord injury. Spinal Cord. 2006;44:680-687 
9. 
Shah PK, Stevens JE, Gregory CM, Pathare NC, Jayaraman A, Bickel SC, Bowden M, 
Behrman AL, Walter GA, Dudley GA, Vandenborne K. Lower-extremity muscle cross-
sectional area after incomplete spinal cord injury. Arch Phys Med Rehabil. 2006;87:772-
778 
10. 
Gregory CM, Bowden MG, Jayaraman A, Shah P, Behrman A, Kautz SA, Vandenborne 
K. Resistance training and locomotor recovery after incomplete spinal cord injury: A case 
series. Spinal Cord. 2007;45:522-530 
11. 
Crozier KS, Cheng LL, Graziani V, Zorn G, Herbison G, Ditunno JF, Jr. Spinal cord 
injury: Prognosis for ambulation based on quadriceps recovery. Paraplegia. 
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12. 
Zehnder Y, Luthi M, Michel D, Knecht H, Perrelet R, Neto I, Kraenzlin M, Zach G, 
Lippuner K. Long-term changes in bone metabolism, bone mineral density, quantitative 
ultrasound parameters, and fracture incidence after spinal cord injury: A cross-sectional 
observational study in 100 paraplegic men. Osteoporos Int. 2004;15:180-189 
13. 
Roberts D, Lee W, Cuneo RC, Wittmann J, Ward G, Flatman R, McWhinney B, Hickman 
PE. Longitudinal study of bone turnover after acute spinal cord injury. J Clin Endocrinol 
Metab. 1998;83:415-422 
14. 
Frisbie JH. Fractures after myelopathy: The risk quantified. The journal of spinal cord 
medicine. 1997;20:66-69 
15. 
Lazo MG, Shirazi P, Sam M, Giobbie-Hurder A, Blacconiere MJ, Muppidi M. 
Osteoporosis and risk of fracture in men with spinal cord injury. Spinal Cord. 
2001;39:208-214 
16. 
Maruyama Y, Mizuguchi M, Yaginuma T, Kusaka M, Yoshida H, Yokoyama K, Kasahara 
Y, Hosoya T. Serum leptin, abdominal obesity and the metabolic syndrome in individuals 
with chronic spinal cord injury. Spinal Cord. 2008;46:494-499 
17. 
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 
18. 
Lavela SL, Weaver FM, Goldstein B, Chen K, Miskevics S, Rajan S, Gater DR, Jr. 
Diabetes mellitus in individuals with spinal cord injury or disorder. The journal of spinal 
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