Clinical trial NCT04439799
Conditions: Hypogonadism, Male
Keywords: Low T
Sponsor: University of Miami
Start date: 2020-08-07; Completion date: 2023-02-09
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate changes in vascular parameters and the prevalence of side effects in subjects receiving 1 cc (200mg) every 2 weeks intramuscular (IM) of Testosterone Cypionate versus subjects receiving 11mg three times daily (TID) Natesto to participant with clinical hypogonadism.

Detailed description:
Administration of exogenous testosterone as efficacious treatment for male hypogonadism has been part of medical practice for more than 50 years. Testosterone replacement therapy (TRT) is becoming more widely available and has seen a greater than three-fold increase in use in men 40 years and older. Current delivery systems of TRT include transdermal gels and patches, intranasal gels (currently marketed as Natesto), injection therapy, and long acting subcutaneous pellets.

Natesto is a short-acting formulation of testosterone delivered intranasally to men diagnosed with low T. This has the potential to avoid side effects related to TRT that are commonly seen with other delivery methods, namely polycythemia, acne, male-pattern hair loss, azoospermia and hyperestrogenemia.

Testosterone Cypionate injections are the most common form of TRT in the USA. Testosterone Cypionate has many reported side effects, the most common being polycythemia, gynecomastia, hair loss, acne, decreased spermatogenesis, and testicular atrophy. In a multicenter retrospective study, it has been shown that the prevalence of polycythemia in men on testosterone replacement (injections) was 11.2%. In this study, we will compare hematocrit changes caused by treatment with Testosterone Cypionate and Natesto in a parallel arm, randomized study. To date, there have been no direct head-to-haed comparisons of these formulations.

We hypothesize that the short-acting pharmacokinetics of Natesto more closely resembles the natural pulsatility of testosterone and therefore can avoid side effects traditionally seen in long-acting, exogenous testosterone formulations

Arms: arm 1: Participants in this group will receive the intramuscular Testosterone Cypionate intervention for four months arm 2: Participants in this group will receive the intranasal testosterone (Natesto) intervention for four months.
Interventions: intervention 1: Testosterone Cypionate 200 Mg/ML intervention 2: Intranasal Testosterone
Intervention descriptions: intervention 1: Participants in this group will receive intramuscular testosterone cypionate injections of 1 cc (200mg) once every 14 days for four months. intervention 2: Participant in this group will receive Intranasal testosterone administered using a multi-dose dispenser, as two or three daily doses (5.5 mg per nostril, 11.0 mg single dose) for 4 consecutive months,

Protocol documents:
Prot_SAP_000.pdf: 
A Comparison of Side Effects in Hypogonadal Men Treated with 
Natesto versus Testosterone Injections: A Phase IV, Prospective, 
Randomized, Non-Blinded, Multi-Institutional Study
______________________________________________________________________________
PRINCIPAL INVESTIGATOR
Ranjith Ramasamy, M.D
Associate Professor
Department of Urology
1120 N.W. 14th St #1560
Miami, Florida 33136
Phone: 305-243-4562
Email: Ramasamy@miami.edu
CO-INVESTIGATORS
Raul I. Clavijo, MD
Assistant Clinical Professor
UC Davis School of Medicine 
Department of Urologic Surgery
(916) 734-2893
Riclavijo@ucdavis.edu
Premal Patel, MD
Assistant Professor
University of Manitoba
Section of Urology
204-787-8520
Ppatel5@hsc.mb.ca
Nannan Thirumavalavan, MD
Assistant Professor
Urology Institute, University Hospitals,
Case Western Reserve University School of 
Medicine
216-844-7413
Nannan.thirumavalavan@uhhospitals.org
IRB#
NCT#
20200201
NCT04439799
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STUDY COORDINATOR:
Manuel Molina, MD
Clinical research Coordinator 
Phone: 305-243-4873
Email: m.molina.leyba@miami.edu
SPONSOR:
Acerus Pharmaceuticals
2486 Dunwin Dr
Mississauga, ON Canada L5L 1J9
Phone: 416-679-0771 


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Table of Contents
1.BACKGROUND.........................................................................................................................6
1.1
Study Disease ..............................................................................................................................6
1.2
Study Interventions ....................................................................................................................6
1.3
Study Rationale...........................................................................................................................6
2. HYPOTHESIS ...........................................................................................................................7
2.1 Alternate hypothesis..........................................................................................................................7
2.2 Null Hypothesis..................................................................................................................................7
3. OBJECTIVES............................................................................................................................7
3.1 Primary Efficacy Objective ..............................................................................................................7
3.2 Secondary Efficacy Objective...........................................................................................................7
4. STUDY DESIGN .......................................................................................................................7
4.1 Accrual goal .......................................................................................................................................7
4.2 Duration of Study Participation.......................................................................................................8
5 STUDY ENTRY, ENROLLMENT AND WITHDRAWAL...................................................8
5.1 Study Entry ........................................................................................................................................8
5.2 Enrollment Procedure.......................................................................................................................8
5.3 Cancellation Guidelines ....................................................................................................................8
6. SUBJECT SELECTION/ELIGIBILITY CRITERIA ...........................................................9
6.1 Inclusion (Eligibility) Criteria..........................................................................................................9
6.2 Exclusion (Eligibility) Criteria .........................................................................................................9
6.3 Study Population .............................................................................................................................10
7. STUDY DESIGN, CLINICAL, RADIOLOGICAL, LABORATORY AND SURGICAL 
EVALUATIONS..........................................................................................................................11
7.1 Study Design.....................................................................................................................................11
7.2 Screening Evaluations and Procedures .........................................................................................11
7.3 Pre-Treatment Procedures and Evaluations.................................................................................11
7.4 Follow-Up Procedures and Evaluations:.......................................................................................11
    7.5 Reimbursement……………………………………………………………………………11 
8. ADVERSE EVENTS ...............................................................................................................11
8.1 Expected Adverse Events................................................................................................................12
8.2 Serious Adverse Events...................................................................................................................12
9. DATA AND SAFETY MONITORING PLAN .....................................................................12
10. STATISTICAL CONSIDERATIONS.................................................................................12
10.1 Primary Study Endpoints .............................................................................................................12
10.2 Endpoint definitions ......................................................................................................................13
10.3 Sample size, accrual and study duration.....................................................................................13
10.4 Statistical Analysis and Power calculation..................................................................................13
11. INVESTIGATORS RESPONSIBLITIES...........................................................................13
11.1 Investigator Responsibility/Performance....................................................................................13
11.3 Confidentiality ...............................................................................................................................13


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11.4 Informed Consent and Permission to Use Protected Health Information ...............................14
11.5 Source Documentation and Investigator Files............................................................................14
11.6 Recording and Processing of Data ...............................................................................................15
11.7 Non-Protocol Research .................................................................................................................15
11.8 Ethics ..............................................................................................................................................15
11.9 Essential Documents for the conduct of a clinical trial..............................................................15
12. STUDY CALENDAR ............................................................................................................16
13 REFERENCES .......................................................................................................................17


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Investigator’s Statement
This clinical trial shall be conducted in compliance with the protocol, as referenced herein, and all 
applicable local, national, and international regulatory requirements to include, but not be limited 
to:
·
International Conference on Harmonization (ICH) Guidelines on Good Clinical Practice 
(GCP)
·
Ethical principles that have their origins in the Declaration of Helsinki 
·
Food and Drug Administration (FDA) Code of Federal Regulation (CFR):
o
Title 21CFR Part 50 and 45 CFR Part 46, Protection of Human Patients
o
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators
o
Title 21CFR Part 56, Institutional Review Boards
o
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA)
As the Principal Investigator, I understand that my signature on the protocol constitutes my 
agreement and understanding of PI responsibilities to conduct the clinical trial in accordance to 
the protocol and applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in writing from the 
Sponsor, shall be defined as a deviation from the protocol, and shall be formally documented as 
such.
I understand that my signature constitutes agreement and understanding of acceptance of the 
defined responsibilities of a Sponsor-Investigator as defined by the protocol, applicable FDA 
Regulations, and/or business contracts, but does not in any capacity relieve me of my 
responsibilities as the Sponsor-Investigator.  Additionally, my signature constitutes my 
understanding and agreement that any changes to the protocol shall be implemented timely with 
my review and approval prior to implementation.


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INVESTIGATOR'S AGREEMENT
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable federal, state, and local laws, rules, 
and regulations relating to the conduct of the protocol.  
I have read and understand the information in the Instructions for Use (and/or other such pertinent 
safety information) regarding the risks and potential benefits.  
I agree to inform all those who assist/collaborate with me in the conduct of this study of their 
responsibilities and obligations. 
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) I 
understand that any change(s) made during the course of the study must also (first) be approved 
by the IRB prior to implementation, except when such modification is made to remove any 
immediate hazard(s) to the subject(s).  
I certify that I, and the study staff responsible, have received the requisite training to conduct this 
research protocol.  
I agree to maintain adequate and accurate records in accordance with the University of Miami 
policies, federal, state and local laws and regulations.  
I agree to maintain the confidentiality of all information received and/or developed in connection 
with this protocol.
Ranjith Ramasamy
Print Name of Physician
                                                                                      02/17/2020
Physician’s Signature
Date


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1.BACKGROUND
1.1 Study Disease
Administration of exogenous testosterone as efficacious treatment for male hypogonadism has been 
part of medical practice for more than 50 years. Testosterone has both anabolic and androgenic 
properties serving as the primary male hormone promoting development of male reproductive 
tissues such as the prostate and testis. Several androgen replacement modalities are FDA approved 
and commercially available or are under clinical investigation. Options for testosterone replacement 
include intramuscular injection of testosterone esters, subcutaneous implants, transdermal patches, oral 
tablets and capsules, buccal and sublingual forms, topical gel formulations of testosterone and 5α-
dihydrotestosterone (DHT), and intranasal gels, currently marketed as name brand Natesto.
Testosterone can activate androgen receptors in its native form or it can be converted to 5α-
dihydrotestosterone (DHT) by the enzyme 5α reductase before binding to the androgen receptor. 
Once bound, the receptor-hormone complex moves into the cell nucleus inducing cell specific 
gene expression profiles, therefore promoting protein synthesis and growth/differentiation of 
tissues that are sensitive to its action.1    
Hypogonadism, or low testosterone (Low T), is defined by a deficiency in producing normal 
amounts of testosterone due to a failure of the testicles (primary hypogonadism), pituitary gland 
(secondary hypogonadism).  Hypogonadism is accompanied by symptoms, such as decreased 
libido, depression and/or lack of energy. Low T affects more than 10% of men worldwide, with 
higher incidence in the elderly.2 It typically occurs in association with aging, chronic disease, 
physical trauma, chemotherapy and other modifiable risk factors such as obesity and diabetes.1 
Testosterone deficiency has been associated with less muscle mass4, lower bone mineral density5, 
anemia6, diminished energy and sexual dysfunction.8,9
1.2 Study Interventions
Testosterone replacement therapy (TRT) is becoming more widely available and has seen a greater 
than three-fold increase in use in men 40 years and older.10 Current delivery systems of TRT 
include transdermal gels and patches11, intranasal gels (currently marketed as Natesto)12, injection 
therapy13, and long acting subcutaneous pellets.14 TRT has been shown to improve bone mineral 
density, and sexual function with some studies suggesting improvement in energy, vitality, and 
depression symptoms.9 
Advantages of testosterone nasal gel (Natesto) over other TRT options includes ease of 
administration, relatively low dose exposure, and no risk of secondary transference. Natesto, 
administered, using a multiple-dose dispenser, as three daily doses (5.5 mg per nostril, 11.0 mg 
single dose restores normal serum total testosterone (≥300 ng/dL, ≤1050 ng/dL) levels in most 
hypogonadal men after 90 days of use. More recently, it was found that 90.9% of men on 
Natesto 11mg TID achieved normal testosterone levels (≥300 ng/dL) after 6 months of use).12 


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Natesto is a short-acting formulation of testosterone delivered intranasally to men diagnosed with 
low T. This has the potential to avoid side effects related to TRT that are commonly seen with 
other delivery methods, namely polycythemia, acne, male-pattern hair loss, azoospermia and 
hyperestrogenemia. Daily topical applications present a risk of transfer of testosterone to partners 
and family members which is minimized with Natesto since it is dispensed with a device high 
into the nostril and thereby does not come in contact with the hands, and further, the formulation 
is designed not to be absorbed through the skin (contains no lower alcohols or permeation 
enhancers). 
1.3. Study Rationale: 
Testosterone Cypionate injections are the most common form of TRT in the USA17. Testosterone 
Cypionate has many reported side effects, the most common being polycythemia, gynecomastia, 
hair loss, acne, decreased spermatogenesis, and testicular atrophy. In a multicenter retrospective 
study, it has been shown that the prevalence of polycythemia in men on testosterone replacement 
(injections) was 11.2%16. Uniquely, the incidence of polycythemia in patients using Natesto is 
1.3%.15 In this study, we will compare hematocrit changes caused by treatment with f 
Testosterone Cypionate and Natesto in a parallel arm, randomized study. To date, there have been 
no direct head-to-haed comparisons of these formulations.
Treatment was well tolerated; adverse event rates were
low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.)
Treatment was well tolerated; adverse event rates were
low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.)
2. HYPOTHESIS 
We hypothesize that the short-acting pharmacokinetics of Natesto more closely resembles the 
natural pulsatility of testosterone and therefore can avoid side effects traditionally seen in long-
acting, exogenous testosterone formulations.
2.1 Alternate hypothesis
The prevalence of side effects in subjects receiving 1 cc (200mg) every 2 weeks IM Testosterone 
Cypionate is greater than in the subjects receiving 11mg TID Natesto.
2.2 Null Hypothesis
The prevalence of side effects in subjects receiving 1 cc (200mg) every 2 weeks IM Testosterone 
Cypionate the same as in the subjects receiving 11mg TID Natesto.
3. OBJECTIVES
3.1 Primary Efficacy Objective
Primary outcome will be changes in Hematocrit (Hct) from baseline to 4 months.


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3.2 Secondary Efficacy Objective
Secondary objectives will be changes in Testosterone (T), Estrogen (E), FSH, LH, 17-
hydroxyprogesterone (17-OHP), Dihydrotestosterone (DHT), testicular volume, PSA, and SF-15 
and IIEF-15 questionnaires from baseline to 4 months.
4. STUDY DESIGN
4.1 Accrual goal
A total of 200 subjects (estimate 10% dropout rate with 90 men in each arm) with low testosterone 
(<300ng/dL) on 2 morning measurements meeting the eligibility criteria will be recruited from the 
Department of Urology clinic. 
4.2 Duration of Study Participation
Total study duration will be 4 months (120 days) and subjects will be provided enough testosterone 
to last until their next visit. Subjects will receive Natesto 11mg TID or Testosterone Cypionate 
200mg IM injections once every 2 weeks. 
5. STUDY ENTRY, ENROLLMENT AND WITHDRAWAL
5.1 Study Entry
Study entry, as used in this protocol, will be defined as a subject signing informed consent.  Study 
enrollment, as used in this protocol, will be defined as the investigator’s confirmation of the 
subject’s eligibility by signing an eligibility checklist.  As per University of Miami policy, each 
study participant, including participants who have screened failed, who sign an informed consent 
form, should be entered into the study database. 
5.2 Enrollment Procedure
Completed and signed protocol-specific eligibility checklist; 
All pages of the original signed informed consent forms (ICFs), including HIPAA Form B; 
Relevant source documents or medical records such as:  subject medical history and physical 
exam, admission or discharge notes, diagnostic reports, pathologic confirmation of diagnosis, and 
relevant subject-specific written communication.
Documentation from the Investigator that he/she has determined the subject meets eligibility 
criteria. 


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5.3 Cancellation Guidelines
The following are reasons for withdrawal of subjects from the study:
A subject does not meet the eligibility criteria; (the subject will be considered a screen 
failure).  
A subject withdraws consent, 
A subject dies during protocol participation from causes other than the study treatment 
(not due to adverse events) or 
A study investigator decides the subject should be withdrawn from the study (e.g. 
subject non-compliance) 
Regardless of reason for withdrawal, an intention to treat analysis will be performed. 
All subjects who either screen fails, is withdrawn from the study or has completed all visits should 
be de-enrolled from the research database within 48 hours.  
6. SUBJECT SELECTION/ELIGIBILITY CRITERIA
6.1 Inclusion (Eligibility) Criteria
Subjects must meet the following criteria:
1. Voluntarily sign and date the study consent form(s), which have been approved by an 
Institutional Review Board (IRB). Written consent must be obtained prior to the 
initiation of any study procedures. 
2. Male between 18 and 75 years of age.  
3. Documented diagnosis of primary hypogonadism (congenital or acquired) or 
hypogonadotropic hypogonadism (congenital or acquired).
4. Serum total testosterone < 300 ng/dL on 2 measurements 
5. Naïve to androgen replacement or has discontinued current treatment and completed a 
washout of 4 months following androgen treatment. 
6. Men deemed to be candidates for TRT based on the results of a medical history, physical 
examination, vital signs, laboratory profile and a 12-lead electrocardiogram (ECG).
6.2 Exclusion (Eligibility) Criteria
Subjects meeting any of the following criteria will be excluded from the study:


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1. History of significant sensitivity or allergy to androgens, or product excipients.
2. Clinically significant findings in the pre-study examinations including abnormal breast 
examination requiring follow-up, abnormal ECG. 
3. Abnormal prostate digital rectal examination (DRE) with palpable nodule(s) 
4. Body mass index (BMI) ≥ 40 kg/m2. 
5. Clinically significant abnormal laboratory value, in the opinion of the investigator, in 
serum chemistry, hematology, or urinalysis including but not limited to: 
a. Baseline hemoglobin > 16 g/dL or HCT 48%
b. PSA > 4 ng/mL 
6. History of seizures or convulsions, including febrile, alcohol or drug withdrawal 
seizures. 
7. History of any clinically significant illness, infection, or surgical procedure within 4 
weeks prior to study drug administration.
8. History of stroke or myocardial infarction within the past 5 years. 
9. History of, or current or suspected, prostate or breast cancer. 
10. History of diagnosed, severe, untreated, obstructive sleep apnea. 
11. History of abuse of alcohol or any drug substance in the opinion of the investigator 
within the previous 2 years. 
12. Donation or loss of 550 mL or more blood volume (including plasmapheresis) or receipt 
of a transfusion of any blood product within 12 weeks prior to the start of treatment. 
13. Inadequate venous access for collection of serial blood samples required for 
pharmacokinetic profiles. 
14. Receipt of any subcutaneous testosterone pellets within the last 6 months. 
15. Inability to understand and provide written informed consent for the study. 
6.3 Study Population
The study will consist of 200 males suffering from low testosterone.


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6.4 Setting
Subjects will be identified from those visiting the University of Miami – Department of Urology 
and the UHealth Fertility Center, and receiving the diagnosis of idiopathic hypogonadism. If they 
meet the inclusion criteria, the subjects will receive an explanation of the study. Subjects will be 
informed both verbally and in written form of the study and procedures involved. The PI, Resident, 
Fellows and/or the study coordinator will obtain a signed/dated Informed Consent Document 
(ICD) before enrolling each subject. Subsequent visits will take place in the same Clinic. Study 
data will be safely stored in a RedCap database. 
7. STUDY DESIGN, CLINICAL, RADIOLOGICAL, LABORATORY AND SURGICAL 
EVALUATIONS
7.1 Study Design 
This is a Phase IV, multicenter, prospective, randomized, non-blinded clinical study aimed to 
evaluate the comparison between Natesto vs Testosterone Cypionate for men with low 
testosterone. Subjects will be enrolled in the study based on selection criteria designed to represent 
the general population of hypogonadal men while minimizing risk to study participants. 
Approximately 180 subjects will be enrolled to meet scientific and regulatory objectives. After 
meeting the selection criteria, the subjects will be randomly assigned in a 1:1 ratio such that 90 
subjects will receive Natesto and 90 subjects will receive Testosterone Cypionate (200mg) one 
every two weeks and be followed for 4 months. Subjects may be naive to testosterone treatment 
or may enroll after stopping current treatment and completing an adequate washout period. 
7.2 Screening Evaluations and Procedures
The first visit of the subjects will be for screening and medical evaluation. Subject’s medical 
history will be collected and documented and a physical examination will be performed. 
Previous blood test results will be reviewed including a general chemistry panel and Testosterone 
levels during chart review.
Subjects will sign an informed consent and in case they meet all inclusion criteria (and do not meet 
any exclusion criteria), they will be recruited to the study. 
7.3 Pre-Treatment Procedures and Randomization
The results of all screening evaluations must be within clinically acceptable limits, reviewed and 
approved by the investigator, prior to the start of treatment. Subjects who meet the inclusion 
criteria and do not meet any of the exclusion criteria may proceed to randomization. A central 
randomization scheme of 1:1 will be used. To account for a 10% dropout rate, 200 randomization 


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codes will be generated. As subjects are enrolled in the study, they will be assigned unique 
consecutive numbers starting at 001. At least 180 subjects who meet all the entry criteria will be 
randomized 1:1 such that approximately 90 subjects are assigned to the Natesto treatment arm 
and 90 subjects are assigned to the Testosterone Cypionate arm in order to reach statistical power 
of 81.3% (randomization will be performed by a computer software maintained by the Department 
of Urology). Subjects enrolled in trial will be instructed to stop any use of androgen replacement 
therapy for 4 months prior to first treatment session and refrain from using any other testosterone 
therapy option during the study. 
7.4 Treatment procedures
Intranasal testosterone will be administered using a multiple-dose dispenser, as two or three daily 
doses (5.5 mg per nostril, 11.0 mg single dose) for 4 consecutive months vs. intramuscular 
testosterone cypionate injections 1 cc (200mg) every 14 days for four months. Teaching session 
(for men to self medicate) will be conducted at the University of Miami, Professional Art center 
building unit 309 at the time of enrollment. 
7.5 Follow-Up Procedures and Evaluations:
Follow-up visits will be conducted at 4 weeks and 16 weeks and include: 

Taking serum HCT, T, E, FSH, LH, 17-hydroxyprogesterone, DHT and PSA levels along 
with SF-15 and IIEF-15 questionnaires.  

Reporting and recording adverse events.
7.6 Reimbursement 
The subjects prior to enrollment in the trial will be billed to the insurance or self-pay. Once 
enrolled in the trial, the medications and the visits will be covered as part of the study. Subjects 
will be provided testosterone study medication, injection or nasal, free of charge. For 
transportation and parking for the 2 study visits, the subjects will be provided a gift card for $50 
at the end of the study. 
8. ADVERSE EVENTS
8.1 Expected Adverse Events 
In a 90-day clinical study, the most commonly reported adverse reactions to Natesto were 
increased prostate specific antigen (PSA), headache, rhinorrhea, epistaxis, nasal discomfort, 
nasopharyngitis, upper respiratory tract infection (URI), sinusitis, bronchitis and nasal scab.
More common adverse reactions to Testosterone Cypionate include erythrocytosis, urinary 
retention, acne, reduced sperm production/infertility, and testicular atrophy/failure. Less 


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common adverse reactions include gynecomastia, adrenergic alopecia, worsening benign 
prostatic hyperplasia, obstructive sleep apnea or worsening of already existing obstructive sleep 
apnea, fluid retention, growth of an already existing prostate cancer, and breast cancer.18
8.2 Serious Adverse Events 
Serious injury or death 
Any adverse event and eventual complication must be recorded at any time during the treatments 
and the follow up visits, and throughout the entire study duration. Subjects will be instructed to 
alert the study investigator by telephone of any side effects occurring in the period after the 
treatment and until the study end. 
9. DATA AND SAFETY MONITORING PLAN
The study investigators will report to a surgeon monitor Dr. Sanjay Swain in the department of 
urology (who is not involved in the study) to ensure data quality and subject safety. The 
investigators will conduct continuous reviews of the data and subject safety; keeping track of the 
number of subjects, significant toxicities in accordance with the protocol and observed responses, 
which will be discussed at research committee meetings. All grade 3-5 adverse events (CTCAE 
v4.0), regardless of association with the subcutaneous testosterone, will be entered into study 
database and reviewed at research committee meetings. In addition, all adverse reactions 
considered “serious”, will be entered into the research database and reviewed by the Surgeon 
monitor on an ongoing basis. If a death occurs within 30 days of subcutaneous testosterone 
implantation treatment and is determined to be related to the study, the investigators will notify 
the Department Chair Dr. Dipen Parekh within 1 business day. If an increase in the frequency of 
grade 3 or 4 adverse events is noted in the study, a report will be submitted to the Department 
Chair Dr. Dipen Parekh at the time the increased rate is identified. If at any time the principal 
investigator stops enrollment or stops the study due to safety issues, the Department Chair (Dr. 
Dipen Parekh) will be notified within 1 business day and a formal letter will be sent to the 
Department Chair (Dr. Dipen Parekh) to be received within 10 business days. Additionally to 
reporting to the Department chair, all serious events will also be reported to the supervising IRB 
in the same timely manner. 
10. STATISTICAL CONSIDERATIONS
10.1 Primary Study Endpoints
The primary endpoint will be change in Hematocrit levels after 4 months of treatment. 
10.2 Secondary Study Endpoints


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The secondary endpoints will be changes in T, E, FSH, LH, 17-hydroxyprogesterone, DHT, 
testicular volume, PSA levels and SF-15 and IIEF-15 questionnaires after 4 months of treatment.
10.3 Endpoint definitions
Total testosterone will be expressed in ng/dL, HCT(%), E (pg/ml), FSH (mlU/ml), LH (mlU/ml), 
17-hydroxyprogesterone (ng/dL), DHT (ng/dl), testicular size (cc), PSA (ng/ml), and SF-15 and 
IIEF-15 questionnaires.  Hormone determinations will be done by peripheral venous puncture 
blood draw. 
10.4 Sample size, accrual and study duration
TOTAL SAMPLE SIZE: 180
TOTAL ACCRUAL: 200
ACCURAL DURATION: 12 months
STUDY DURATION: 4 months
10.5 Statistical Analysis and Power calculation  
The average and standard deviation of all relevant variables and baseline characteristics, primary 
and secondary outcomes will be calculated. 
The chi-square test will be used to evaluate difference of prevalence of polycythemia. Changes in 
testosterone, estrogen, 17-hydroxyprogesterone, DHT, testicular volume, PSA, and SF-15 and 
IIEF-15 questionnaires will be analyzed using means and standard deviations. 
In a multicenter retrospective study, it has been shown that the prevalence of polycythemia in 
men on testosterone replacement (injections) was 11.2%16. Uniquely, the incidence of 
polycythemia in subjects using Natesto is 1.3%.15  In order for a power of at least 80% with an 
alpha of 0.05 we need to collect 90 subjects in each treatment arm. 
10.6 Randomization:
180 subjects will be randomized 1:1 to 90 Natesto vs 90 subjects in the Testosterone Cypionate 
injections. An online-based randomization tool called Redcap.com will be used. The PI will not 
have the knowledge of subject’s treatment group beforehand. However, the study coordinator will 
be aware of the Natesto vs Testosterone Cypionate injections randomization.
11. INVESTIGATORS RESPONSIBLITIES
11.1 Investigator Responsibility/Performance


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The investigator (or a person designated by the investigator) should inform the subject of all 
pertinent aspects of the study, including the written information.
The investigator should provide the subject ample time and opportunity to inquire about details of 
the study and to decide whether to participate in the study or not.  All questions about the study 
should be answered to the satisfaction of the subject. Neither the investigator, nor the study staff, 
should coerce or unduly influence a subject to participate or to continue to participate in a study.
11.3 Confidentiality
The identity of the subjects in this study will be treated as confidential. subjects eligible to 
participate in the study following the pre-treatment visit will be assigned a unique subject code. 
The results of the study, including any other data, may be published for scientific purposes but will 
not give the subjects' name or include any identifiable references to them. However, any records 
or data obtained as a result of the subject participation in this study may be inspected by the 
sponsor, by any relevant governmental agency, by the Hospital Ethics Committee, or by the 
persons conducting this study, provided that such inspectors are legally obligated to protect any 
identifiable information from public disclosure, except where disclosure is otherwise required by 
law or a court of competent jurisdiction. These records will be kept private as permitted by law. 
11.4 Informed Consent and Permission to Use Protected Health Information 
It is the responsibility of the investigator to obtain written informed consent from each subject 
participating in this study after adequate explanation, in lay language, of the methods, objectives, 
anticipated benefits, and potential hazards of the study.  The investigator must also explain that 
the subject is completely free to refuse to enter the study or to discontinue participation at any time 
(for any reason) and receive alternative conventional therapy as indicated.  Prior to study 
participation, each subject will sign an IRB approved informed consent form and receive a copy 
of same (and information leaflet, if appropriate). 
The investigator or designee must explain to the subject before enrollment into the study that for 
evaluation of study results, the subject’s protected health information obtained during the study 
may be shared with the study sponsor, regulatory agencies, and the IRB.  It is the investigator’s 
(or designee’s) responsibility to obtain permission to use protected health information per HIPAA 
from each subject, or if appropriate, the subjects’ parent or legal guardian.
11.5 Source Documentation and Investigator Files
The investigator will maintain adequate and accurate records to document the conduct of the study 
and to ensure that study data can be subsequently verified.  These documents will be classified into 
two separate categories: (1) investigator study file and (2) subject clinical source documents that 
corroborate data collected on the CRF’s.  Subject clinical source documents would include 
hospital/clinic subject records; physician's and nurse's notes; original laboratory, radiology, 
pathology, and special assessment reports; QOL forms, signed informed consent forms.  When the 


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CRF or any form is used as the source document, this will be clearly stated in the investigator 
study file.
At a minimum, the following be documented in source documents:

Medical history/physical condition and diagnosis of the subject before involvement 
in the study sufficient to verify protocol entry criteria.

Study number, assigned subject number, and verification that written informed 
consent was obtained (each recorded in dated and signed notes on the day of entry 
into the study)

Progress notes for each subject visit.

Laboratory test results.

Condition and response of subject upon completion of or early termination from 
the study.
11.6 Recording and Processing of Data
Data for this study will be entered into electronic CRFs in research database (a web-based clinical 
research management application).  A CRF is required for every subject who received any study 
intervention.  The investigator will ensure that the CRF’s are accurate, complete, legible and 
timely. Separate source records are required to support all CRF entries.  All corrections to study 
data will be made by drawing a single line through the information to be corrected without 
obscuring it.  All corrections will be initialed, dated, and explained, if necessary. Do not use 
“white-out” or obscuring correction tape.  
11.7 Non-Protocol Research
No investigative procedures other than those described in this protocol will be undertaken on the 
enrolled subjects without the agreement of the IRB.
11.8 Ethics
The investigator agrees to conduct the study in compliance with the protocol, current good clinical 
practices, and all applicable (local, FDA) regulatory guidelines and standard of ethics
11.9 Essential Documents for the conduct of a clinical trial
Essential documents are those documents with individually and collectively permit evaluation of 
the conduct of a trial and the quality of the data produced.
The following documents will be on file:

CV’s and license of all investigators.


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
IRB documentation/correspondence.

Documentation of IRB certification.
12. STUDY CALENDAR
          Visit #, Time
Activity
Visit 1 (Week 1)
Screening/
Enrollment
Visit 2 
(Week 4)
Visit 3 
 (Week 16)
Medical 
& 
Urological 
History
●
Physical 
Examination 
&ECG
●
●
Informed Consent
●
Inclusion & Exclusion 
Criteria
●
Blood Analysis (HCT, E, 
T, PSA, 17 OHP) and 
Questionnaires 
(SF-15 
and IIEF-15)
●
●
Dispense 
medication 
intranasal 
T 
or 
TC 
injections
●
●

Medications will be provided by sponsor 


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