A Prospective Study of Testosterone Supplementation in Hypogonadal Patients Receiving a Renal Transplant
Phase: PHASE1
Conditions: Hypogonadism, Male, End Stage Renal Disease (ESRD), Kidney Transplant
Sponsor: University of California, Los Angeles

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Clinical Research Protocol 
 
A prospective study of testosterone supplementation in hypogonadal patients receiving a renal 
transplant.  
 
Version Date: 
12.11.25 
Version Number: 
Version 13.0 
Sponsor: 
Nima Nassiri, MD 
Assistant Professor, Department of Urology UCLA Kidney 
Transplantation  
200 Medical Plaza, Suite #140  
University of California, LA 
Phone: 310-267-7727 
Fax: 424-529-6256 
E-mail: nnassiri@mednet.ucla.edu 
Funding Organization: 
Departmental Funds 
Principal Investigator: 
Name: Nima Nassiri, MD 
Telephone: 310-267-7727 
Fax: 424-529-6256 
E-mail: nnassiri@mednet.ucla.edu 
Coordinating Center: 
University of California, Los Angeles (single site) 
 
Approval: 
PI or Sponsor Signature (Name and Title)  
Date 
 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document may not 
be disclosed unless federal or state law or regulations require such disclosure. Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to know, with 
the obligation not to further disseminate this information.

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Sponsor-Investigator, my 
duties include ensuring the safety of the study subjects enrolled under my supervision and 
providing complete and timely information, as outlined in the protocol. It is understood that all 
information pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and 
myself, I agree to maintain the procedures required to carry out the study in accordance with 
accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Title: A prospective study in patients with ESRD of testosterone replacement therapy 
as an adjunct to an enhanced recovery after surgery (ERAS) protocol.   
   
 
 
Protocol Date: December 11, 2025 
 
 
Investigator Signature  
Date 
Nima Nassiri, M.D., Associate Professor  
Print Name and Title 
Site Name 
University of California, Los Angeles 
Address 
Department of Urology 
200 Medical Plaza, Suite #140 
Los Angeles, CA 90095-7366 
Phone Number 310-267-7727 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS  
ATG 
Antithymocyte Globulin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell count 
CFR 
Code of Federal Regulations Unit 
CMP 
Comprehensive metabolic panel 
CMV 
Cytomegalovirus 
CNI 
Calcineurin inhibitor  
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTSI 
Clinical & Translational Science Institute 
DDRT 
Deceased Donor Transplant 
DRE 
Digital Rectal Exam 
EBV 
Epstein-Barr Virus 
eGFR 
Estimated glomerular filtration rate 
ERAS 
Enhanced recovery after surgery  
ESRD 
End-Stage Renal Disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GVHD 
Graft-vs-host disease 
HIPAA    
Health Insurance Portability and Accountability Act of 1996 
INR 
International normalized ratio 
MACE 
Major Adverse Cardiac Events 
MD 
medical doctor 
MMF 
Mycophenolate mofetil 
NPO 
Nil Per Os (Nothing by Mouth) 
OHRPP 
Office of the Human Research Protection Program 
ORA 
Office of Regulatory Affairs 
PCA 
Patient Controlled Analgesia 
PI 
Principal investigator 
PJP 
Pneumocystis jiroveci pneumonia 
POD 
Post-Operative Day 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
SAE 
Serious adverse event 
TMP/SMX  
Trimethoprim- Sulfamethoxazole  
UCLA 
University of California, Los Angeles 
WBC 
White blood cell 

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Table of Contents 
1. 
PROTOCOL SYNOPSIS 
6 
2. 
BACKGROUND 
14 
3 STUDY RATIONALE 
14 
3.1 
Risk/Benefit Assessment 
15 
3.2.1 Blood Draw 
17 
4 
STUDY OBJECTIVES 
17 
4.1 Primary Objective: Safety 
17 
4.2 Secondary Objectives: Efficacy 
17 
5 
STUDY DESIGN 
17 
5.1 Study Overview 
17 
5.2 
Interim Safety Analysis 
18 
5.3 
Criteria for Evaluation 
19 
5.3.1 Primary Endpoint (Safety) 
19 
5.3.2 Secondary Endpoint (Efficacy) 
19 
5.4 
Schedule of Events 
20 
6 
SUBJECT SELECTION 
21 
6.1 Recipient Inclusion Criteria 
21 
6.2 
Recipient Exclusion Criteria 
21 
7     CONCURRENT MEDICATIONS 
21 
7.1 Allowed Medications and Treatments (Recipient) 
21 
7.2 Prohibited Medications and Treatments (Recipient) 
22 
8    STUDY PROCEDURES AND GUIDELINES 
22 
8.1 Clinical Assessments 
22 
8.1.1 Vital Signs 
22 
8.1.2 Physical Examination 
22 
8.1.3 Demographics 
22 
8.1.4 Medical History 
23 
8.1.5 Concomitant Medications 
23 
8.1.6 Clinical Laboratory Measurements 
23 
Hematology 
23 
Metabolic Profile 
23 
Blood Chemistry Profile 
23 
Coagulation Studies 
24 

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Renal Function 
24 
Lipid Panel 
24 
Urinalysis and Culture 
25 
9 ADVERSE EVENT REPORTING AND DOCUMENTATION 
26 
10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
26 
11 STATISTICAL METHODS AND CONSIDERATIONS 
27 
11.1 Hypothesis Testing Plan 
27 
11.2 Confounding Adjustment 
28 
11.3 Statistical Analysis Plan 
28 
12 DATA COLLECTION, RETENTION AND MONITORING 
29 
12.1 Data Collection Instruments 
29 
12.2 Data Management Procedures 
29 
12.3 Availability and Retention of Investigational Records 
29 
13 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
29 
13.1 Protocol Amendments 
29 
13.2 Institutional Review Boards 
30 
13.3 Informed Consent Form 
30 
13.4 Publications 
31 
13.5 Investigator Responsibilities 
31 
13.6 Standard ERAS (Enhanced Recovery After Surgery) Pathway for Kidney Transplantation 
31 
REFERENCES 
33 
 
 

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1. PROTOCOL SYNOPSIS 
 
This prospective study aims to evaluate the safety and efficacy of testosterone replacement 
therapy (TRT) as an adjunct to an enhanced recover after surgery (ERAS) protocol in men with 
end-stage renal disease (ESRD) undergoing kidney transplantation.  
 
Participants will be highly-listed hypogonadal men, defined as total testosterone level <300 or 
bioavailable testosterone <110 ng/dL or free testosterone <5 ng/dL on two occasions with 
clinical symptoms of hypogonadism, with ESRD who are expected to receive a kidney 
transplant within 6 months. Patients will be started on TRT, ideally for at least 3 months prior 
transplantation. We will perform a subset analysis to evaluate if there is a significant difference 
in our endpoints by comparing these two subgroups (Three months or more receiving TRT vs. 
Less than three months receiving TRT). There will be no cut-off time for pre-transplant TRT. 
Following the intervention period, a historical control cohort of age-matched and health-
matched patients will be identified, who have followed a standard transplant protocol that does 
not incorporate TRT. The primary outcome will evaluate safety, including 30- and 90-day 
adverse events, 3, 6, and 12-month allograft survival, and overall patient survival. Secondary 
outcomes will focus on (1) qualitative assessments of symptoms using validated questionnaires, 
(2) quantitative improvements in the hormonal profile before and after initiation of TRT and 
surgery, and (3) allograft function and incidence of delayed graft function. The results of this 
study could provide novel insights into the benefits of TRT in improving surgical outcomes in 
men with ESRD undergoing kidney transplantation. 
 
TITLE 
Evaluating the role of testosterone replacement as an adjunct to 
enhanced recovery after surgery (ERAS) protocol in hypogonadal 
men with end-stage renal disease undergoing kidney transplantation. 
SPONSOR 
Nima Nassiri, MD 
FUNDING 
ORGANIZATION 
Departmental Funds 
NUMBER OF SITES 
1 
RATIONALE 
End-stage renal disease (ESRD) is often associated with 
hypogonadism in men, which can lead to muscle wasting, fatigue, 
decreased quality of life, and poor postoperative recovery outcomes. 
While ERAS protocols have been widely adopted to improve 
surgical outcomes across various specialties, they do not typically 
address the hormonal deficiencies seen in this population of critically 
affected patients. Testosterone replacement therapy (TRT) is a well-
established treatment for hypogonadism, known to improve muscle 
mass, strength, mood, and energy levels in men. 
In the context of kidney transplantation, where recovery is critical for 
long-term graft function and patient survival, addressing 
hypogonadism through TRT may help optimize and expedite 
recovery. Despite the known benefits of testosterone therapy, there 
has been limited exploration of its role as an adjunct to ERAS 

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protocols in patients undergoing major surgeries, including kidney 
transplantation. 
This study is designed to fill a critical gap by investigating the safety 
and efficacy of TRT as an addition to the ERAS protocol for 
hypogonadal men with ESRD undergoing kidney transplantation. 
The hypothesis is that TRT will enhance recovery, reduce 
postoperative complications, and improve overall outcomes, 
including graft survival and quality of life, compared to the standard 
ERAS protocol without TRT. If successful, this study could lead to 
broader integration of hormonal optimization strategies within ERAS 
frameworks for surgical patients, particularly in the field of organ 
transplantation 
 
STUDY DESIGN 
This is a prospective, single-center, prospective evaluation of the role 
of TRT in hypogonadal men with ESRD undergoing kidney 
transplantation. Participants will be followed for up to 12 months 
post-transplantation to assess the outcomes. At the conclusion of the 
trial, a subgroup of patients who receive TRT for at least 3 months 
prior to kidney transplantation will be compared to a historical 
control cohort of patients who followed a standard transplant 
protocol without TRT.  
PRIMARY 
OBJECTIVE 
To determine the safety and efficacy of testosterone replacement 
therapy (TRT) as an adjunct to the ERAS protocol in hypogonadal 
men with ESRD undergoing kidney transplantation.  
SECONDARY 
OBJECTIVES 
● To assess improvements in allograft function and patient survival, 
focusing on 3, 6, and 12-month outcomes post-transplantation. 
● To evaluate qualitative symptom improvements using validated 
symptom questionnaires related to fatigue, muscle strength, and 
recovery. 
● To assess quantitative changes in sarcopenia scores, testosterone 
levels and other laboratory profiles pre- and post-TRT initiation. 
● To evaluate the incidence of delayed graft function and length of 
hospitalization post-transplant. 
Graft Function and Survival will be determined by monitoring:   
● Creatinine/GFR  
● Time transplanted kidney remains functional without need for 
dialysis  
● Delayed graft function: The need for dialysis within the first week 
post-transplant  
TERTIARY  
OBJECTIVES 
To explore the long-term impact of TRT on metabolic and 
cardiovascular outcomes in the post-transplant population. 
 

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NUMBER OF SUBJECTS 50 subjects in the TRT group 
SUBJECT SELECTION 
CRITERIA 
Hypogonadal TRT cohort:  
Male patients older than 18 years old with confirmed end-stage renal 
disease (ESRD). 
Hypogonadal (testosterone level <300 ng/dL or bioavailable 
testosterone <110 ng/dL or free testosterone <5 ng/dL) with clinical 
symptoms of hypogonadism. 
Expected to undergo kidney transplantation within a 6-month period. 
Able and willing to comply with study procedures and follow-up 
visits. 
Exclusion Criteria 
Women or non-hypogonadal men. 
Any contraindications to testosterone therapy, as defined in Section 
6.2 
Participants who are already receiving testosterone or other androgen 
therapies. 
Severe cardiovascular or pulmonary conditions that pose a high 
surgical risk. 
Any condition that, in the opinion of the investigator, would make the 
subject ineligible for the study. 
Historical Control Group 
Age- and propensity-score matched patients from a prior time period 
(not to exceed 10 years from the start of the study) who met the same 
inclusion/exclusion criteria but did not receive testosterone therapy 
 
TEST PRODUCT, DOSE, 
& ROUTE OF 
ADMINISTRATION 
Subjects will receive testosterone cypionate injections at 100mg, 
dosed weekly for at least 3 months before kidney transplantation.  
Their serum testosterone panel will be monitored and dose-adjusted 
per clinical protocol as outlined on page 16 of this document. 
All patients will follow the ERAS protocol with adjustments made to 
include TRT. The standard ERAS protocol is described in Section 
13.6. 

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DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subject Participation: 
Each subject will participate in the study for approximately 15 
months. This includes: 
3 months of testosterone replacement therapy (TRT) prior to kidney 
transplantation.  
12 months of follow-up after kidney transplantation to assess 
postoperative recovery, graft function, and overall health outcomes. 
Study Duration: 
The total duration of the study, from recruitment to the final follow-
up, is expected to be 24 months. This includes: 
6 months of recruitment and screening. 
A 15-month participation period for each subject, as outlined above. 
3 months for data analysis and interpretation following the 
completion of follow-up. 
This timeline allows for comprehensive monitoring of both short-term 
and long-term outcomes, including allograft function, hormonal 
profiles, and patient survival. 
CONCOMITANT 
MEDICATIONS 
Subjects in the study may be on standard post-transplant medications, 
and certain medications will be allowed or prohibited during the study 
as outlined below: 
Allowed Medications and Treatments (not a complete list): 
Immunosuppressive therapies commonly used for kidney 
transplantation: 
Tacrolimus (brand or generic) 
MMF, brand or generic 
Prednisone or other corticosteroids (oral or intravenous), depending 
on clinical need 
Cyclosporine (for subject who are intolerant to tacrolimus) 
Antimicrobial prophylaxis: 
TMP/SMX for PJP prophylaxis 
Valganciclovir or ganciclovir for CMV prophylaxis 
Nystatin or fluconazole for antifungal prophylaxis, as indicated 
Other standard medications for ESRD or kidney transplant 
recipients, such as antihypertensive medications, antidiabetic agents, 
and lipid-lowering medications. 
Prohibited Medications (not a complete list): 
Any form of testosterone therapy or other androgenic agents in the 
control group. 

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Anabolic steroids that are not part of the testosterone replacement 
therapy protocol. 
Medications known to have significant interactions with 
immunosuppressants (such as CYP3A4 inhibitors) that may lead to 
altered levels of drugs like tacrolimus or cyclosporine, unless deemed 
necessary by the investigator and managed with dose adjustments. 
Non-essential medications that could impact testosterone metabolism 
or renal function, unless essential for the management of the patient's 
health condition. 
All medications will be reviewed and recorded at each visit to ensure 
compliance with the study protocol and to monitor for any potential 
interactions with the investigational treatment. Subjects are expected 
to remain on the same medications throughout the study period unless 
medical circumstances dictate a change.  

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THE STUDY WILL BE 
STOPPED IF: 
There is an unacceptable increase in the incidence of serious adverse 
events (SAEs) with testosterone replacement therapy. Please see 
Section 5 for additional discussion. 
PRIMARY ENDPOINT 1. Safety: 
● Incidence of adverse events at 30- and 90-days post-transplant 
● Complications categorized by the CTCAE classification 
(grades 1-5). 
● Overall survival (study duration) 
● Graft survival (study duration) 
● Hospital readmission rates and infection rates 
● Reoperation rates  
● Length of hospitalization 
SECONDARY 
ENDPOINTS 
 
1. Allograft Function: 
At 3-, 6-, and 12-months post-transplantation, allograft function 
will be assessed through: 
● Serum creatinine levels and estimated glomerular filtration 
rate (eGFR) to determine renal function. 
● Rate of delayed graft function, defined as the need for 
dialysis within the first week post-transplant. 
 
2. Symptom Assessment: 
● Qualitative assessments of symptoms will be conducted using 
validated questionnaires (qADAM) to evaluate: 
○ Fatigue levels and overall quality of life before and 
after TRT and post-transplantation. 
○ Changes in muscle strength and recovery perceptions. 
3. Metabolic Profile: 
● Quantitative evaluations of testosterone levels and other 
hormonal profiles will be conducted: 
○ Serum testosterone, FSH, prolactin and LH levels 
before and after TRT initiation. 
○ Hormone levels will be checked at the 1 month, 3 
month, and 6 month mark after TRT initiation, and then 
every 6 months until therapy concludes. 
Discontinuation of TRT is discussed in Section 5.1. 
● Quantitative evaluations of immunosuppression 
○ Tacrolimus levels and dosages at baseline, 1 month 
after TRT initiation, and at 3-, 6-, and 12-months post-
transplant 

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● Quantitative evaluations for prostate cancer 
○ PSA levels at baseline, and every 3-6 months during 
active hormone therapy. A clinically significant rise in 
PSA (defined as > 4.0, or a PSA doubling time 
(PSADT) < 12 months will trigger further urologic 
evaluation and possible cessation of testosterone 
therapy.  
● Quantitative evaluations for anemia  
○ Hemoglobin/Hematocrit levels at baseline, 1 month 
after TRT initiation, and at 3-, 6-, and 12-months post-
transplant 
4. Sarcopenia scores 
• Patient changes in body composition will be assessed using 
InBody® Body Composition Analyzer  
 
PLANNED INTERIM 
ANALYSES 
An interim analysis for safety will be conducted at 6 months or after 
50% of participants have been enrolled and completed 3 months of 
follow-up post-transplant (whichever date comes first). The interim 
analysis for safety will be conducted by the PI, PI Proxy, and staff 
biostatistician. This analysis will focus on evaluating the incidence of 
serious adverse events (SAEs) such as mortality, graft rejection, and 
significant complications related to testosterone replacement therapy 
(TRT). Based on the results, modifications to the study or early 
termination may be recommended if there are safety concerns. 
STATISTICS 
The primary analysis will involve evaluation of the primary endpoint 
(safety) and secondary endpoints (efficacy) between the testosterone 
replacement therapy (TRT). Descriptive statistics will summarize 
baseline demographics, comorbidities, and laboratory values. A 
subset analyses will be conducted examining differences between 
patients who received TRT for at least 3 months prior to transplant 
and patients who received TRT for less than 3 months prior to 
transplant.  
Analysis will then be done comparing the TRT cohort with an age- 
and propensity-score matched patients from a prior time period (not 
to exceed 10 years from the start of the study) who met the same 
inclusion/exclusion criteria but did not receive testosterone therapy. 
This will be performed using statistical methods such as t-tests for 
continuous variables (e.g., creatinine and eGFR) and chi-squared 
tests for categorical outcomes (e.g., delayed graft function, graft 
survival). Given the non-randomized design, statistical methods 
including propensity score matching and Cox proportional hazards 
models will be applied to adjust for potential confounding factors. 
A Kaplan-Meier survival analysis may also be conducted to compare 
graft survival rates between the groups over time, and a log-rank test 
will be used to assess statistical significance 

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Rationale for Number of 
Subjects 
To determine the appropriate sample size for this study, we calculated 
the number of participants based on achieving a Type I error rate (α) of 
0.05 and a Type II error rate (β) of 0.2, corresponding to 80% power. 
For the time-to-event outcome, a log-rank test will be used to compare 
survival distributions between the treatment and control groups. The 
expected effect size was derived from previous studies indicating a 
clinically significant difference in event rates. Additionally, our 
primary and secondary endpoints involve evaluation of time-to-event, 
continuous, and binary outcomes. Thus,  based on these statistical 
methods and assumptions, the sample size was calculated to ensure the 
study is adequately powered to detect both time-to-event differences 
and differences in categorical outcomes, while accounting for potential 
dropouts and missing data. A further power calculation is provided 
below in Section 12.  

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2.  BACKGROUND 
Testosterone plays a significant role in wound healing, influencing various phases such as inflammation, 
collagen synthesis, and tissue remodeling (Hernandez et al., 2020). It has been shown that testosterone not only 
accelerates the inflammatory phase but also enhances collagen deposition, which is critical for effective tissue 
repair (Zhao et al., 2021). The mechanisms through which testosterone promotes tissue repair involves the 
modulation of inflammatory responses and the stimulation of cellular processes necessary for regeneration 
(Mazzoccoli et al., 2018). 
Research indicates that androgens, including testosterone, enhance wound healing and overall tissue repair 
processes. This suggests potential clinical implications, particularly in surgical recovery. Increased testosterone 
levels are associated with enhanced collagen synthesis (the primary protein in the extracellular matrix), crucial 
for tissue structural integrity and healing (Hughes et al., 2019). Additionally, the positive effects of testosterone 
on healing go beyond effects on soft tissue, including an additional role in bone fracture healing, emphasizing 
the potential broader impact on surgical outcomes of testosterone supplementation in hypogonadal individuals 
(Huang et al., 2022). 
In addition to promoting healing, testosterone deficiency is associated with impaired wound healing processes. 
Studies have linked low testosterone levels with delayed recovery and adverse surgical outcomes, underscoring 
the importance of adequate hormonal levels in the context of tissue repair (Bhasin et al., 2020). Patients with 
low testosterone levels often experience increased inflammation and a reduced ability to regenerate tissues, 
which can contribute to prolonged healing times and an elevated risk of surgical complications such as 
infection and delayed graft function (Hughes et al., 2019; Huang et al., 2022). Furthermore, the psychological 
impacts of hypogonadism, including fatigue and decreased motivation, may also impede a patient's engagement 
in postoperative rehabilitation, further delaying recovery (Bhasin et al., 2020; Catania et al., 2017).  
A few clinical studies have shown that testosterone replacement therapy (TRT) can significantly enhance 
recovery outcomes for patients undergoing surgery. For example, patients receiving TRT experienced faster 
wound healing, reduced rates of infection, and improved overall recovery compared to their hypogonadal 
counterparts who did not receive hormonal intervention in multiple studies (Nieschlag et al., 2019; Traish et al., 
2018). These findings suggest that maintaining adequate testosterone levels is crucial, not only for optimal 
tissue repair, but also for minimizing the risk of complications during the postoperative period (Argalious et al., 
2017). 
Given these findings, it is crucial to explore the potential benefits of testosterone replacement therapy (TRT) in 
enhancing surgical recovery and improving outcomes for hypogonadal men undergoing kidney transplantation. 
Investigating TRT within the framework of ERAS protocols could provide novel insights into hormonal 
therapies' roles in organ transplantation. 
3 STUDY RATIONALE 
End-stage renal disease (ESRD) is frequently associated with hypogonadism in men, leading to muscle 
wasting, fatigue, reduced quality of life, and suboptimal postoperative recovery. While Enhanced Recovery 
After Surgery (ERAS) protocols aim to optimize perioperative outcomes, they do not address the hormonal 
deficiencies prevalent in this population. Testosterone replacement therapy (TRT) is a well-established 
treatment for hypogonadism, known to improve muscle mass, strength, mood, and energy, but its role as an 
adjunct to ERAS protocols in kidney transplantation has not been thoroughly studied. Given the critical 
importance of effective recovery for long-term graft function and patient survival, integrating TRT into 

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ERAS protocols could enhance recovery, reduce complications, and improve allograft and patient outcomes 
in hypogonadal men. This study aims to fill this gap by evaluating the safety and efficacy of TRT in men 
with ESRD undergoing kidney transplantation, with the potential to inform future perioperative care 
strategies that incorporate hormonal optimization. 
 
3.1 Risk/Benefit Assessment 
The use of testosterone replacement therapy (TRT) in hypogonadal men with end-stage renal disease 
(ESRD) undergoing kidney transplantation carries both potential risks and benefits. The primary risks 
associated with TRT include side effects such as elevated blood pressure, liver damage, hair loss, acne, and 
mood changes, although many of these effects are seen at anabolic steroid dosages that exceed TRT doses 
given in hypogonadal men. Exogenous testosterone will also temporarily compromise fertility and in some 
cases lead to testicular atrophy, with restored sperm counts seen in 90% of men at 12 months and virtually 
all men at 24 months (Grech et al 2014; Rhoden & Morgentaler 2004; Liu et at 2006). Rarely, some males 
taking supratherapeutic anabolic steroids never fully recover their sperm production despite cessation of 
testosterone therapy  and may require future fertility treatments (Ledesma et at 2023).  
TRT has been associated with greater increase in prostate-specific antigen, but whether it increases the risk 
of prostate safety events in men with hypogonadism remains controversial. Several studies including 4 
larger randomized trials have been carried out to evaluate any true increased incidence in hypogonadal 
patients without other risk factors for prostate cancer. The largest of these trials, the TRAVERSE Trial, 
showed that the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure 
for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract 
symptoms were low and did not differ between the testosterone and placebo groups.  
Surgical risks related to kidney transplantation, including bleeding, infection, and delayed graft function, 
also present concerns. Furthermore, the interaction between TRT and immunosuppressive therapies, which 
are critical for transplant success, remains unclear and could lead to unanticipated adverse effects. 
However, there is no known increased risk of testosterone replacement therapy in solid organ transplant 
cohorts, with one retrospective review of 87 hypogonadal transplant recipients demonstrating no difference 
in prostate cancer diagnoses, erythrocytosis, rejection, infections, unplanned admissions, or other measured 
adverse effects related to treatment of hypogonadism or solid organ transplant (Thirumavalavan et al 2022). 
However, TRT remains contraindicated in those with metastatic or locally advanced prostate cancer and 
also in those with breast cancer and polycythemia (hematocrit ≥54%), and this is reflected in our exclusion 
criteria (EAU Guidelines, 2024).   
By integrating TRT into ERAS protocols, this study has the potential to optimize recovery and improve the 
overall quality of life for a vulnerable population, potentially outweighing the associated risks when 
carefully monitored. 
However, the potential benefits of this study are substantial. TRT has been shown to improve muscle 
strength, energy levels, and overall well-being in hypogonadal men, which may translate into faster 
postoperative recovery and enhanced physical rehabilitation following kidney transplantation. These 
improvements could lead to better functional outcomes, ultimately supporting longer-term graft survival 
and patient outcomes. 
3.2 Potential Adverse Reactions and Risks of TRT  

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TRT offers benefits like improved muscle mass, libido, and energy levels, but it also comes with potential 
adverse reactions and risks. 
 
One of the main concerns is cardiovascular risk. TRT has been associated with a potential to exacerbate 
heart disease, particularly in older men and those with preexisting heart conditions. Though debated, there 
is a potential risk of blood clots (venous thromboembolism), secondary to elevations in hematocrit levels. 
Finally, Testosterone replacement therapy may lead to increased retention of sodium and other electrolytes 
that can cause the body to hold onto extra fluid leading to swelling most commonly of the legs, feet, or 
hands. Water retention may also affect blood pressure. Testosterone levels may also be associated with 
increased cholesterol levels. 
 
Prostate health is another area of concern. TRT can stimulate the prostate, worsening symptoms in men 
with benign prostatic hyperplasia (BPH), and though the connection to prostate cancer is debated, it is 
generally avoided in men with suspected or diagnosed prostate cancer. There is a known risk that patients 
with BPH could develop worsening urinary obstruction from increased size of the prostate. However, we do 
not believe that obstructed urination secondary to BPH (Benign prostatic hyperplasia) is a contraindication 
to TRT in hypogonadal men. Outside of the kidney transplant population, men with BPH may be started on 
TRT with a discussion that they may develop worsening of their symptoms. A meta-analysis encompassing 
28 randomized controlled trials with 3,461 patients revealed that TRT did not significantly affect prostate 
volume (Chen et al 2023). Moreover, another meta-analysis found that TRT did not worsen LUTS and 
long-term intramuscular TRT actually significantly decreased the International Prostate Symptom Score 
(IPSS) (Zhang et al 2023), indicating that TRT does not exacerbate LUTS and may even improve urinary 
symptoms in certain populations. 
 
Hormonal and reproductive issues can arise as well. TRT suppresses the body’s natural testosterone 
production, leading to testicular shrinkage, reduced sperm production, and infertility. Some men may 
experience breast enlargement (gynecomastia) due to increased estrogen levels, and hormonal imbalances 
can cause mood swings, irritability, and aggression. 
 
 
Hematological effects, such as polycythemia, can also occur with TRT, as it increases red blood cell count, 
raising the risk of stroke and heart attack. Regular monitoring of hematocrit is essential to manage this risk. 
In the ESRD population, patients generally suffer from low hematocrit levels because of anemia of chronic 
disease and the failure of their native kidneys to produce erythropoietin.  
 
Skin and hair changes are common side effects, with some men developing acne and oily skin or 
experiencing accelerated hair loss due to higher androgen levels. TRT may affect cholesterol levels. 
 
Psychological effects can include mood swings, irritability, and aggression, with some men reporting 
worsened mental health conditions like depression or anxiety. TRT may also exacerbate sleep apnea, 
leading to poorer sleep quality and increased health risks. 
 
To minimize these risks, it’s crucial to monitor blood counts, lipid profiles, and cardiovascular health 
regularly. TRT can cause infertility. Patients will need to discuss fertility goals before starting therapy. 
Additionally, addressing underlying health issues, particularly those related to the heart and prostate, is 
important before initiating treatment. Patients will be followed closely throughout this study.  

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3.2.1 Blood Draw 
Blood draws are generally safe, but they do come with a few potential risks. The most common side effect is 
mild pain or bruising at the site where the needle is inserted. Some people may experience dizziness or 
fainting, especially if they are anxious about needles or sensitive to blood loss. In rare cases, a blood draw 
can cause more significant bruising (hematoma) or infection if the area is not properly sterilized. 
Occasionally, there may be difficulty finding a vein, leading to multiple needle sticks, which can increase 
discomfort. In people with certain conditions, such as bleeding disorders, there may be a slightly higher risk 
of prolonged bleeding after the procedure. 
 
4 STUDY OBJECTIVES 
4.1 Primary Objective: Safety  
To determine the safety of TRT as an adjunct to ERAS protocol in hypogonadal men with ESRD 
undergoing kidney transplantation. Outcomes measured will include incidence of adverse events, allograft 
survival, and overall survival. Specific attention will be paid to development of venous thromboembolic 
events.  
4.2 Secondary Objectives: Efficacy 
1. Allograft function (eGFR, Cr) 3-, 6-, and 12-month outcomes post-transplantation. 
2. Qualitative symptom improvements using validated symptom questionnaires (qADAM) related 
to fatigue, muscle strength, and recovery. 
3. Quantitative changes in testosterone levels and hormonal profiles pre- and post-TRT initiation. 
4. Evaluation of length of hospitalization post-transplant in patients receiving TRT 
5. Evaluate improvement in sarcopenia, measured through InBody ® Body Composition Analyzer 
in patients receiving TRT 
 
5 STUDY DESIGN 
5.1 Study Overview 
This prospective cohort study will enroll hypogonadal men with ESRD, not interested in fertility 
preservation, who are scheduled for kidney transplantation. Participants will receive TRT in alignment with 
established ERAS principles, which emphasize early mobilization, optimized pain management, and 
perioperative nutritional support. Serum testosterone levels will be closely monitored, and participants will 
be stratified based on baseline characteristics to ensure comparability between those receiving TRT and 
controls. We anticipate recruiting 102 recipients in each group. 
 
The subjects will meet all standard criteria listed and receive standard transplant preparation and 
treatment. Patients who meet selection criteria will receive testosterone cypionate intramuscular 
injections. Patients will have to demonstrate symptomatic hypogonadism, defined as total 
testosterone < 300 ng/dL or bioavailable testosterone <110 ng/dL or free testosterone  
<5 ng/dL on two separate blood draws, plus the presence of associated symptoms. Patients receiving 
exogenous testosterone will have to acknowledge and consent to the impact of exogenous 
testosterone on fertility before proceeding. The comparator group will consist of age- and health-
matched standard protocol kidney transplant recipients. If for any reason testosterone is not tolerated, 
the patient will be removed from study and will continue to receive standard ERAS and follow up. 
Subjects who meet criteria will be started on intramuscular (IM) testosterone cypionate at 100mg, 
dosed weekly. Subsequent titrations will be based on testosterone level response. Regimen and 

Version 2.0 10/21/2024 
 
Page 18 of 35 
 
targeted dose responses will be carried out using the guidelines put forward by the American 
Urologic Association (AUA). The initial testosterone level will be measured at 1 month (as panel 
recommends this be completed no earlier than 3-4 cycles) and will be measured at the end of the 
cycle (day 5 or 6 of the 7-day course). We will adjust testosterone therapy dosing to achieve a total 
testosterone level in the middle tertile of the normal reference range, defined as a range of 450-600 
ng/dL (Conditional Recommendation; Evidence Level: Grade C)1. They will be followed for a total 
of 12 months after transplant.  
All subjects will be followed for 12 months post-transplant, with a focus on evaluating safety, including the 
occurrence of 30- and 90-day adverse events, as well as 3-, 6-, and 12-month allograft survival and overall 
patient survival. PSA levels will be obtained at 3- to 6-month intervals. A clinically significant rise in PSA 
(defined as > 4.0, or a PSA doubling time (PSADT) < 12 months will trigger further urologic evaluation 
and possible cessation of testosterone therapy. Efficacy endpoints will monitor kidney function (serum 
creatinine, eGFR), incidence of delayed graft function, qualitative assessments of symptoms with validated 
questionnaires (focusing on fatigue, muscle strength, and overall recovery), quantitative hormonal profiles 
before and after the initiation of TRT and surgery, and improvements in sarcopenia after initiating TRT.  
Regarding therapy discontinuation, we will follow AUA guideline statement 31: “Clinicians should discuss 
the cessation of testosterone therapy three to six months after commencement of treatment in patients who 
experience normalization of total testosterone levels but fail to achieve symptom or sign improvement. 
(Clinical Principle)”. Otherwise, TRT can be continued indefinitely if within the preferences of the patient. 
For the purpose of our protocol, we will set an analysis endpoint time of 6 months after TRT. Additionally, 
TRT will be stopped if there are intolerable adverse effects or other concerns for safety (i.e. a significant 
rise in PSA)  experienced by the patient. 
This investigation will address a significant gap in perioperative care for ESRD patients undergoing kidney 
transplantation, offering insights into the potential benefits of hormone optimization during recovery, 
including improving graft outcomes and reducing healthcare costs. The study's findings may inform future 
guidelines on integrating TRT as a novel adjunct therapy in ERAS protocols for hypogonadal patients, 
thereby improving recovery trajectories and long-term outcomes in transplant recipients.  
5.2 Interim Safety Analysis 
The study includes predefined stopping criteria to ensure participant safety and ethical integrity. These 
criteria are based on the occurrence of severe adverse events (SAEs), unexpected safety signals, and interim 
analysis findings. 
Serious Adverse Events (SAEs) Leading to Study Pause/Termination: If ≥3 participants experience a 
Grade 3 or higher SAE (based on CTCAE v5.0 or another appropriate grading system) that is attributed to 
the study treatment (TRT), enrollment and study treatment will be paused. The PI and study team will 
conduct an independent safety review before deciding whether to resume enrollment or modify the 
protocol. Events of particular concern include: 
• Major Adverse Cardiovascular events (will adopt the MACE-3 standardized definition including 
cardiovascular death, nonfatal MI, and nonfatal stroke) 
 
1 Mulhall JP, Trost LW, Brannigan RE et al: Evaluation and management of testosterone deficiency: AUA guideline. J Urol 
2018; 200: 423. 

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• Polycythemia requiring phlebotomy (Hematocrit >54%) 
• Graft dysfunction or rejection 
Interim Analysis Stopping Criteria: A pre-planned interim analysis will be conducted after 25 
participants (50%) have completed at least 3 months of TRT. The study will be paused or stopped if interim 
analysis shows: 
• A ≥2-fold imbalance in SAEs between TRT recipients and historical complication rates 
• More than 30% of participants experiencing Grade 2 or higher adverse events related to TRT 
• A clear trend of harm, particularly in cardiovascular or renal outcomes. 
Delayed graft function (DGF) is a common complication in deceased donor kidney transplants, with 
incidence rates ranging from 25% to 30%2. Acute rejection rates within the first year post-transplant are 
approximately 10% to 15%3. Perioperative infection rates have been reported between 14% and 41%4. 
Incidence of MACE occur in 2.6% of all kidney transplant procedures5, with 86% of all cases occurs within 
the first year following transplant6. 
If safety concerns emerge, the PI and research team will determine whether modifications (e.g., dose 
adjustments, additional monitoring) are required before resuming the study. If the study is paused, 
modifications (e.g., dose adjustments, additional monitoring) may be implemented before resuming 
enrollment. 
5.3 Criteria for Evaluation 
 5.3.1 Primary Endpoint (Safety) 
1. Overall survival, allograft survival, and incidence of adverse events between the testosterone 
replacement therapy (TRT) group and the control group at 3, 6, and 12 months post-transplantation. 
Graft survival is measured by the time the transplanted kidney remains functional without the need 
for return to dialysis. 
a. Adverse Events: 
i. 
Incidence of adverse events at 30- and 90-days post-transplant. 
ii. 
Complications categorized by the CTCAE classification (grades 1-5). 
iii. 
Emphasis on incidence of venous thromboembolic events 
b. Hospital readmission rates 
 5.3.2 Secondary Endpoint (Efficacy) 
1. Symptom Assessment: 
a. Qualitative assessments of symptoms will be conducted using validated questionnaires 
(qADAM) to evaluate: 
 
2 Hall IE, Reese PP, Weng FL, Schröppel B, Doshi MD, Hasz RD, et al. Delayed graft function rates in deceased donor kidney 
transplantation: A contemporary analysis. Clin J Am Soc Nephrol. 2012;7(3):472-479. doi:10.2215/CJN.09450911. 
3 Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: A critical reappraisal. Am J 
Transplant. 2011;11(3):450-462. doi:10.1111/j.1600-6143.2010.03283.x. 
4 Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017;17(4):856-879. doi:10.1111/ajt.14208. 
5 Lentine KL, Brennan DC, Schnitzler MA, et al. Cardiovascular risk and management in chronic kidney disease and kidney 
transplantation. Nat Rev Nephrol. 2014;10(12):704-719. doi:10.1038/nrneph.2014.184. 
6 Patel RK, Jardine AG, Mark PB. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 
2019;103(8):1705-1713. doi:10.1097/TP.0000000000002713. 

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i. 
Fatigue levels and overall quality of life before and after TRT and post-
transplantation. 
ii. 
Changes in muscle strength and recovery perceptions. 
2. Hormonal Profile: 
a. Quantitative evaluations of testosterone levels and other hormonal profiles will be 
conducted: 
i. 
Serum testosterone levels before and after TRT initiation. 
ii. 
Will obtain total testosterone, free testosterone, bioavailable testosterone 
panel, FSH/LH, and Prolactin levels 
iii. 
Changes in hormone levels at baseline, 1 month after TRT initiation, and at 3-, 6-, 
and 12-months post-transplant. 
3. Sarcopenia: 
a. Evaluating changes in body composition using InBody ® Body Composition Analyzer 
5.4 Schedule of Events 
 
Appendix A: Procedure Table 
 
Procedures 
Before 
you 
begin 
the 
study 
3 
months 
before 
Surgery 
Surgery 
 Within 
3 
months 
of 
starting 
TRT 
Every 
3-6 
months 
after 
starting 
TRT 
Inpatient* 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
(about 7 
days) 
(30 
days 
post-
surgery) 
(90 
days 
post-
surgery) 
(180 
days 
post-
surgery) 
(270 
days 
post-
surgery) 
(360 
days 
post-
surgery) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
CBC/BMP and 
other Blood 
Chemistry tests as 
part of standard 
transplant workup 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
FSH/LH/Prolactin 
X 
 
 
 
 
 
 
 
 
 
 
PSA 
X 
 
 
X 
X 
 
 
 
 
 
 
Testosterone 
(total, free and 
bioavailable) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Collection 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Questionnaires 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Kidney 
Transplant 
 
 
X 
 
 
 
 
 
 
 
 
Muscle 
Composition 
Analysis 
 
X 
 
  
  
 
X 
 
X 
 
X 
Testosterone 
Replacement 
Therapy 
 
X 
X 
  
  
X 
X 
X 
X 
X 
X 
Medication 
Review 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Review of Side 
Effects 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
*While you are inpatient, you will have a physical exam and blood test daily. If you experience side effects during 
this time, urine collection, additional ultrasound, CT or MRI scans may be done.  
 

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6 
SUBJECT SELECTION 
6.1 Recipient Inclusion Criteria 
1. Male patients aged 18-65 with confirmed end-stage renal disease (ESRD). 
2. Hypogonadal (testosterone level <300 ng/dL or bioavailable <110 ng/dL or free testosterone <5 
ng/dL on two separate blood draws ) with clinical symptoms of hypogonadism. 
3. Expected to undergo kidney transplantation within a 6-month period. 
4. Able and willing to comply with study procedures and follow-up visits. 
5. Consenting of the impact of exogenous testosterone in fertility. 
6.2 Recipient Exclusion Criteria 
1. Women or non-hypogonadal men. 
2. Any contraindications to testosterone therapy, including: 
• 
History of Breast Cancer 
• 
Severe untreated OSA 
• 
Polycythemia (Hct >54%) 
• 
Uncontrolled chronic heart failure (CHF) 
• 
A history of a Major Adverse Cardiac Event (MACE) within the past 6 months 
• 
Interest in fertility within 1 year 
• 
An unevaluated PSA >4.0 ng/mL or a PSA >3.0 ng/mL in individuals with risk factors for 
prostate cancer defined as: 
o Men with African ancestry 
o Men with first-degree relative with prostate cancer 
o Known genetic mutations including BRCA1/2 
o A history of Lynch Syndrome 
o Abnormal DRE 
 
3. Participants already receiving testosterone or other androgen therapies. 
4. Severe cardiovascular or pulmonary conditions that pose a high surgical risk. 
5. Any condition that, in the opinion of the investigator, would make the subject ineligible for the 
study. 
 
7     CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
 
7.1 Allowed Medications and Treatments (Recipient) 
All medications will be reviewed and recorded at each visit to ensure compliance with the study 
protocol and to monitor for any potential interactions with the investigational treatment. Subjects are 
expected to remain on the same medications throughout the study period unless medical circumstances 
dictate a change. 
Standard of care kidney transplant treatments – such as tacrolimus, cyclosporine (for subjects 
who do not tolerate tacrolimus), and MMF – may be given in branded or generic form. 

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Systemic corticosteroids (oral or intravenous) may be acceptable depending on clinical 
indication.  
 
Allowed Medications and Treatments (not complete list): 
● Immunosuppressive therapies commonly used for kidney transplantation: 
○ Tacrolimus (brand or generic) 
○ MMF, brand or generic 
○ Prednisone or other corticosteroids (oral or intravenous), depending on clinical need 
○ Cyclosporine (for subjects’ intolerant to tacrolimus) 
● Antimicrobial prophylaxis: 
○ TMP/SMX for PJP prophylaxis 
○ Valganciclovir or ganciclovir for CMV prophylaxis 
○ Nystatin or fluconazole for antifungal prophylaxis, as indicated 
● Other standard medications for ESRD or kidney transplant recipients, such as 
antihypertensive medications, antidiabetic agents, and lipid-lowering medications. 
7.2 Prohibited Medications and Treatments (Recipient) 
Prohibited Medications: 
● Any form of testosterone therapy or other androgenic agents in the control group. 
● Anabolic steroids that are not part of the testosterone replacement therapy protocol. 
● Medications known to have significant interactions with immunosuppressants (such as 
CYP3A4 inhibitors) that may lead to altered levels of drugs like tacrolimus or cyclosporine, 
unless deemed necessary by the investigator and managed with dose adjustments. 
● Non-essential medications that could impact testosterone metabolism or renal function, unless 
essential for the management of the patient's health condition.  
 
 
8    STUDY PROCEDURES AND GUIDELINES 
8.1 Clinical Assessments 
 
8.1.1 Vital Signs 
Body temperature, blood pressure, pulse, and weight will be measured during each visit with a 
physical examination. Height will be measured at Screening. 
 
8.1.2 Physical Examination 
A complete physical examination will be performed by an investigator who is a physician at 
Pre- Screening and Screening. Qualified staff (MD, NP, RN, and PA) may complete an 
abbreviated physical exam at all other visits. New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled 
visit. 
 
8.1.3 Demographics 

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Demographic information (age, gender) will be recorded at Pre-Screening and/or Screening for 
donors and recipients. Race, marital and employment status, and highest level of education will 
be recorded for recipients. 
 
8.1.4 Medical History 
Relevant medical history, including history of current disease, past medical history, social and 
family history will be recorded at Pre-Screening and/or Screening for donors and recipients. 
 
Information regarding the original etiology of end-stage renal disease will be determined for 
recipients at Pre-Screening. Any workup completed as part of the original kidney transplant will 
be considered during the Pre-Screening process. 
 
Screening for human transmissible spongiform encephalopathy and Creutzfeld-Jakob disease 
will be completed at Screening for donor and recipients based on relevant clinical factors and as 
per routine guidelines of the BMT team. 
 
8.1.5 Concomitant Medications 
Donor and recipient concomitant medication and concurrent therapies will be documented as 
indicated in Section 7.1. Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured beginning at the Pre-screening visit and 
updated at subsequent visits as needed. 
 
8.1.6 Clinical Laboratory Measurements 
Hematology 
Complete Blood Count testing will be completed. The following assessments will be 
performed: white blood cell (WBC) count with differential, red blood cell (RBC) count, 
platelet count, hemoglobin, hematocrit, PT, PTT, and INR. At Pre- Screening, results from 
previous testing done within the past 6 months may be accepted as part of their evaluation; 
however, CBC will be done at UCLA at Screening to verify subject eligibility for the study. 
 
Metabolic Profile 
Markers of hypogonadism will be obtained through obtaining the following assessments:  total 
testosterone, free testosterone, bioavailable testosterone panel, FSH/LH, and Prolactin. These 
will be done at UCLA at Screening to verify subject eligibility for the study as well as discrete 
intervals every 4-8 weeks throughout the study period. 
 
Blood Chemistry Profile 
Comprehensive Metabolic Panel (CMP) testing will be completed with the following lab 
assessments: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen (BUN), 
creatinine, albumin, total bilirubin, calcium, alkaline phosphatase, total protein, aspartate 
aminotransferase (AST/SGOT), and alanine aminotransferase (ALT/SGPT). At Pre-Screening, 
laboratory results from previous testing done within the past 6 months may be accepted as part 
of the routine HPSC transplant evaluation. 
However, Comprehensive Metabolic Panel will be done at UCLA at Screening to verify subject 
eligibility for the study. 

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Serum magnesium (for recipients only), phosphorus, uric acid, Vitamin D, and LDH will also be 
performed at Screening as part of standard transplant evaluation. 
 
Ionized calcium will be checked in the donor after apheresis since it may be decreased due to use 
of EDTA as an anti-coagulant. 
 
All Screening laboratory assessments are done as part of the participant’s routine transplant 
evaluation. Assessments may be omitted per clinician judgment. Past assessments and results 
from facilities outside of UCLA will be accepted as per standard of care and may be used to 
establish subject eligibility. Standard pre-transplant clinical and laboratory assessments for 
allogeneic HPSC transplant recipients will be completed as needed. Tests may need to be 
repeated to fulfill HPSC transplant evaluation guidelines. 
 
Coagulation Studies 
Prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio 
(INR) are evaluated at Pre-Screening if previously performed within the past six months or 
will be collected at screening for both donors and recipients. At Pre-Screening, results from 
previous testing done at outside laboratories within the past 6 months may be accepted per 
routine guidelines; however, coagulation studies will be done at UCLA at Screening to verify 
subject eligibility for the study. Coagulation tests may be repeated in recipients at pre-HPSC 
infusion per clinician judgment. 
 
Fibrinogen may be measured at Screening for both donors and recipients as required per HPSC 
transplant evaluation guidelines. 
 
All Screening laboratory assessments are done as part of the participant’s routine transplant 
evaluation. Assessments may be omitted per clinician judgment. Past assessments and results 
from facilities outside of UCLA will be accepted as per standard of care and may be used to 
establish subject eligibility. At investigator discretion other coagulation studies will be 
conducted or repeated in order to establish subject eligibility and to fulfill HPSC transplant 
evaluation guidelines. 
 
Renal Function 
Renal function in recipients may be assessed at Pre-Screening based on prior laboratory findings 
or by 24-hour creatinine clearance at Screening. 
 
Assessments may be omitted per clinician judgment. Past assessments and results from facilities 
outside of UCLA will be accepted as per standard of care and may be used to establish subject 
eligibility. 
 
 
 
Lipid Panel 

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Lipid Panel testing will be completed for recipients and donors. The following assessments are 
to be performed: cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, and low-
density lipoprotein (LDL) cholesterol (calculated). 
 
All Screening lipid panel assessments are done as part of the participant’s routine transplant 
evaluation. Assessments may be omitted per clinician judgment. Past assessments and results 
from facilities outside of UCLA will be accepted as per standard of care and may be used to 
establish subject eligibility. 
 
Urinalysis and Culture 
 
Screening urinalysis assessments may be done to evaluate the pre-existing allograft. Assessments 
may be omitted per clinician judgment. Past assessments and results from facilities outside of 
UCLA will be accepted as per standard of care and may be used to establish subject eligibility. 
 
Standard pre-transplant clinical and laboratory assessments for allogeneic HPSC transplant 
recipients will be completed as needed. Tests may need to be added or repeated to fulfill HPSC 
transplant evaluation guidelines.  

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9 ADVERSE EVENT REPORTING AND DOCUMENTATION 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
the treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product. An unexpected AE is 
one of a type not identified in nature, severity, or frequency in this protocol/investigational plan, or of 
greater severity or frequency than expected based on this protocol/investigational plan. 
 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents. When an adverse event 
occurs, it is the responsibility of the investigator to evaluate and record into the source documents the 
nature of the symptom and prescribe the appropriate remedy and to report the event. 
 
Adverse events will be recorded in the participant CRF. Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment, and relation to study drug, or 
if unrelated, the cause. 
 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
● death 
● a life-threatening adverse experience 
● inpatient hospitalization or prolongation of existing hospitalization 
● a persistent or significant disability/incapacity 
● a congenital anomaly/birth defect 
 
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the subject or require intervention to prevent one of the outcomes listed. 
 
AEs and SAEs that occur will be documented and reported to the UCLA IRB per UCLA OHRPP 
Guidelines. The collection period for all SAEs will begin after informed consent is obtained and end 
after procedures for the final study visit have been completed. 
 
10 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
A recipient subject may be discontinued from investigational product if the subject or investigator 
feels that it is not in the subject’s best interest to continue. The following is a list of possible reasons 
for treatment discontinuation: 
● Subject withdrawal of consent (or assent) 
● Subject is not compliant with study procedures 
● Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment (additional details below) 
● Protocol violation requiring discontinuation of study treatment 
● Lost to follow-up 
 
If a recipient subject experiences any life-threatening Grade 4 adverse events – such as stroke, 
myocardial infarction, anaphylaxis that cannot be readily reversed, acute respiratory distress 
syndrome (ARDS), cardiac arrhythmias, encephalopathy, hypotension, and acute renal failure – 

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during administration of testosterone no further injections will  be continued. Investigators may 
also decide to abort the testosterone injections and remove the subject from the study per their 
discretion. 
 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 
 
All recipient subjects who receive testosterone injection but are removed from the protocol will 
be followed for subject survival, graft survival, and complications for 48 months. They will be 
seen by the transplant nephrology team once a year (during Months 12, 24, 36, and 48) for 
follow-up. 
 
A subject may be withdrawn from the study at any time if the subject or investigator feels that it 
is not in the subject’s best interest to continue. All subjects are free to withdraw from 
participation at any time, for any reason, specified or unspecified, and without prejudice. 
 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 
 
11 STATISTICAL METHODS AND CONSIDERATIONS 
 
11.1 Hypothesis Testing Plan 
Given the presence of seven primary endpoints, a multiple hypothesis testing strategy will be employed to 
control the overall Type I error rate. The following procedures will be used: 
1. Bonferroni Correction: 
o The Bonferroni correction will adjust the significance threshold to α/7 = 0.0071 per endpoint 
to maintain the family-wise error rate (FWER) at 0.05. 
o Each of the seven endpoints will be tested independently using this corrected threshold. 
2. Holm-Bonferroni Method: 
o A sequential testing approach will also be applied using the Holm-Bonferroni method: 
▪ 
P-values for the seven endpoints will be ordered from smallest to largest. 
▪ 
The smallest p-value will be tested at α/7; if significant, the next p-value will be 
tested at α/6, and so on. 
▪ 
Testing will continue until a null hypothesis fails to be rejected, at which point testing 
will stop. 
3. Interpretation of Results: 
o Results will be reported both with the Bonferroni correction and Holm-Bonferroni 
adjustments to provide a comprehensive interpretation of findings. 
 

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11.2 Confounding Adjustment 
Propensity scores will be calculated for baseline covariates, and adjusted analyses will be conducted as 
sensitivity analyses. We will plan to use propensity score adjustments as we do not anticipate needing to 
balance large difference across covariates given both the treatment and control group will be determined 
using the same inclusion/exclusion criteria.  Propensity score adjustment will also allow us to control for 
confounding directly within regression models. Propensity scores will be calculated for baseline covariates, 
and adjusted analyses will be conducted as sensitivity analyses. If deemed necessary, IPW will also be 
applied as an alternative approach to verify the robustness of results. 
11.3 Statistical Analysis Plan  
 
The primary analysis will involve evaluation of the primary endpoint (safety) and secondary endpoints 
(efficacy) between the testosterone replacement therapy (TRT). Descriptive statistics will summarize 
baseline demographics, comorbidities, and laboratory values. A subset analyses will be conducted 
examining differences between patients who received TRT for at least 3 months prior to transplant and 
patients who received TRT for less than 3 months prior to transplant.  
 
Analysis will then be done comparing the TRT cohort with an age- and propensity-score matched patients 
from a prior time period (not to exceed 10 years from the start of the study) who met the same 
inclusion/exclusion criteria but did not receive testosterone therapy. This will be performed using 
statistical methods such as t-tests for continuous variables (e.g., creatinine and eGFR) and chi-squared 
tests for categorical outcomes (e.g., delayed graft function, graft survival). Given the non-randomized 
design, statistical methods including propensity score matching and Cox proportional hazards models will 
be applied to adjust for potential confounding factors. 
 
A Kaplan-Meier survival analysis may also be conducted to compare graft survival rates between the 
groups over time if  subject accrual sample size allows for it, and a log-rank test will be used to assess 
statistical significance. 
Parameters used include a significance level of 0.05 and an 80% power. The choice of effect size depends 
on several factors including the expected magnitude of the treatment effect and the clinical relevance of the 
measured outcomes (i.e. graft function, hospital stay, sarcopenia score, and side effects of therapy). Based 
on prior studies evaluating testosterone replacement therapy, it is reasonable to anticipate a small to 
moderate effect size. Power calculations were done in R. Below is the table summary of the power 
calculation parameters using a moderate effect size for the anticipated statistical analyses: 
 
Test 
Significance 
Level (α) 
Power 
(1−β1) 
Effect 
Size 
Sample 
Size per 
Group 
Chi-Square Test 
Assumes expected proportion of 0.5 for each group 
in a 2x2 table 
0.05 
0.8 
Cohen's 
w=0.4 
50 
Kaplan-Meier/Log-Rank Test 
Assumes a censoring rate of 20% and a 12-month 
follow-up time 
0.05 
0.8 
Hazard 
Ratio = 
0.6 
60 

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Cox Proportional Hazards Model 
Assumes a censoring rate of 20%, a 12-month 
follow-up time, and multiple potential covariates 
including age, race, kidney function, comorbidities, 
BMI, and length of dialysis prior to transplant 
0.05 
0.8 
Hazard 
Ratio = 
0.6 
60 events 
Two-Sample t-test 
Assumes a normal standard deviation in a two-
tailed test 
0.05 
0.8 
Cohen's 
d=0.5 
64 
 
 
12 DATA COLLECTION, RETENTION AND MONITORING 
12.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record 
all observations and other pertinent data for each subject treated with the investigational treatment. All 
data collected during this study must be reviewed and verified for completeness and accuracy by the 
Investigator. A copy of the CRF will remain at the Investigator’s site at the completion of the study. 
 
12.2 Data Management Procedures 
The data will be entered into a database stored on the Department’s server, which will be 
safeguarded against unauthorized access by established security procedures; appropriate backup 
copies of the database and related software files will be maintained. Databases are backed up by the 
database administrator in conjunction with any updates or changes to the database. 
 
12.3 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives of 
the Sponsor (or designee), and IRB upon request. A file for each subject must be maintained that 
includes the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject. The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
 
 
13 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will 
be identified by a coded number and initials only. All paper study records will be kept in a locked file 
cabinet. Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA. The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data Protection 
Directive 95/46/EC). 
 
13.1 Protocol Amendments 

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Any amendment to the protocol will be written by the Sponsor/Investigator. Protocol amendments 
cannot be implemented without prior written IRB approval except as necessary to eliminate 
immediate safety hazards to participants. A protocol amendment intended to eliminate an apparent 
immediate hazard to participants may be implemented immediately, provided the IRBs are notified 
within five working days. 
 
13.2 Institutional Review Boards 
The protocol and consent form will be reviewed and approved by the IRB of each participating 
center prior to study initiation. Serious adverse experiences regardless of causality will be reported to 
the IRB in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study. The Investigator will obtain 
assurance of IRB compliance with regulations. Any documents that the IRB may need to fulfill its 
responsibilities (such as protocol, protocol amendments, Investigator’s Brochure, consent forms, 
information concerning participant recruitment, payment or compensation procedures, or other 
pertinent information) will be submitted to the IRB. The IRB’s written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator before the 
study is initiated. 
 
Protocol and/or informed consent modifications or changes may not be initiated without prior written 
IRB approval except when necessary to eliminate immediate hazards to the participants or when the 
change(s) involves only logistical or administrative aspects of the study. Such modifications will be 
submitted to the IRB and written verification that the modification was submitted and subsequently 
approved should be obtained. 
 
The IRB must be informed of revisions to other documents originally submitted for review; serious 
and/or unexpected adverse experiences occurring during the study in accordance with the standard 
operating procedures and policies of the IRB; new information that may affect adversely the safety of 
the participants of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
 
13.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and 
CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. The informed consent will only be obtained by Drs. Jolie Shen (PI 
Proxy), Nima Nassiri (PI), and Rajiv Jayadevan.  
 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents for approval prior to submission to the IRB. The consent form generated by 
the Investigator must be acceptable to the Sponsor and be approved by the IRB. The written consent 
document will embody the elements of informed consent as described in the International 
Conference on Harmonisation and will also comply with local regulations. The Investigator will keep 
an IRB-approved copy of the Informed Consent Form for the study file. 
 
A properly executed, written, informed consent will be obtained from each subject prior to entering 
the subject into the trial. Information should be given in both oral and written form and subjects (or 
their legal representatives) must be given ample opportunity to inquire about details of the study. If 

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appropriate and required by the local IRB, assent from the subject will also be obtained. If a subject is 
unable to sign the informed consent form (ICF) and the HIPAA authorization, a legal representative 
may sign for the subject. A copy of the signed consent form (and assent) will be given to the subject 
or legal representative of the subject, and the original will be maintained with the subject’s records. 
 
13.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
determined by the Sponsor/Investigator. The publication or presentation of any study results shall 
comply with all applicable privacy laws, including, but not limited to, the Health Insurance 
Portability and Accountability Act of 1996. 
 
13.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report any AEs that occur in the course of the study, in accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others. 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the participants/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
13.6 Standard ERAS (Enhanced Recovery After Surgery) Pathway for Kidney Transplantation 
 
POD 0 (day of surgery):  
• 
Diet: NPO 
• 
Infusion:  fluid repletion based on urine output 
• 
Antibiotics: perioperative Ancef for 24 hours 
• 
Pain: Dilaudid PCA• 
• 
Prophylaxis: Sequential Compression Device 
 
POD 1 
• 
Diet: Advance to bariatric clear diet (sugar free). If tolerating diet without nausea vomiting by 
afternoon rounds, ca advance diet  
o Deceased Donor Transplant: Low potassium, low phopspohate, carb control diet  
o Living Donor: Regular diet (or Carb Control if diabetic) 

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• 
Infusion:  fluid repletion based on urine output 
• 
Antibiotics: per nephrology team  
• 
Pain: Discontinue PCA and transition to oral pain regimen  
o Tylenol 650mg every 6 hours scheduled 
o Oral oxycodone 5mg to 10mg every 4-6 hours as needed 
o +/- Dilaudid 0.2mg every 2 hours for breakthrough pain 
• 
Prophylaxis: Sequential Compression Device, Start Miralax daily & Colace twice daily 
POD 2 
• 
Diet: Advance to regular diet (as above) if not advanced previously. Start Golytely 100 ml per 
hour until patient has bowel movement  
• 
Fluids: Heparin Lock intravenous fluids if oral intake is more than 500ml 
• 
Antibiotics: per nephrology team 
• 
Pain: Oral regimen as above 
• 
Prophylaxis: Sequential Compression Device, can discontinue cardiac monitor 
 
POD 3 
• 
As above 
• 
Living Donor Transplants on Simulect induction or DDRT on ATG “light” (3 doses, instead of 
4) eligible for discharge if good renal function and meeting all milestones 
o Remove foley catheter for voiding trial, check post void residual 
▪ 
if no bowel movement still, offer Dulcolax in addition to prior bowel regimen 
o Remove drain if output <55cc, otherwise home with drain 
• 
Anyone receiving full-dose ATG (sensitized Living and most DDRT) 
o Typically, no changes unless POD2 advancements were delayed 
o If no BM, offer Dulcolax PO & PR  
POD 4 
• Remove foley catheter for voiding trial, check post void residual (if not done previously) 
• Remove JP drain if output <55cc, otherwise home with drain 
• If no bowel movement, offer enema (tap water, soap suds, or mineral oil) 
o No Fleet enema in transplant patients (contains phosphorus)  
 
Patients are typically discharged on POD 5 pending completion of all postoperative milestones including: 
• Tolerating diet 
• Having bowel movements 
• Able to ambulate at baseline 
• Pain well-controlled with oral medications 
• No active medical problems requiring continued admission 
 
 

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