Clinical trial NCT03203681
Conditions: Hypogonadism, Male
Sponsor: University of Miami
Start date: 2017-10-27; Completion date: 2020-06-01
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Low testosterone affects more than 10% of men worldwide, with high incidence in the elderly.This will be a prospective case study. The investigators will identify men with hypogonadism in our clinic interested in Natesto for testosterone replacement therapy (TRT). Natesto is a relatively new form of testosterone replacement therapy that is delivered intranasal to men diagnosed with low testosterone. Current advantages to Natesto include ease of delivery and decreased risk of transference. Recently Natesto 4.5% (125 uL/nostril, 11.0mg testosterone/dose), three times a day (TID) dosing was shown to also increase serum testosterone while maintaining normal, though decreased, serum levels of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone(FSH). 40 participants will be enrolled and receive treatment with Natesto.The study will identify men with confirmed hypogonadism (testosterone (T) \<350 on 2 consecutive Testosterone samples collected greater than 1.5 hours apart between 6am and 10am with demonstrated symptoms of hypogonadism). Participants with a history of prostate cancer, testis cancer, azoospermia, or genetic cause of hypogonadism will be excluded.

Detailed description:
Low testosterone affects more than 10% of men worldwide, with high incidence in the elderly). While Natesto has been shown to have positive effects on Testosterone while maintaining LH and FSH, the impact on sperm count has not yet been proven.

Study Design and Duration of Treatment: Participants will take Natesto 11g intra nasally there times a day (TID) for 16 weeks (120 days) between serum and semen evaluations.

Subject Population: The study will identify men with confirmed hypogonadism (testosterone (T) \<350 on 2 consecutive Testosterone samples collected greater than 1.5 hours apart between 6am and 10am with demonstrated symptoms of hypogonadism). Subjects with a history of prostate cancer, testis cancer, azoospermia, or genetic cause of hypogonadism will be excluded.

Number of subjects: 40 participants will be enrolled and receive treatment with Natesto.

Study Duration:Total participation in the study will be approximately 24-28 weeks.

Study Procedures: Participants will undergo a total of six study visits. At the first visit, subjects will undergo screening procedures which will include signing of the consent form, physical exam, assessment for inclusion and exclusion criteria, Sexual Health Inventory in Men (SHIM) and quality of life questionnaire, blood sample for clinical laboratory assessment, and a semen analysis. At visit 2, subjects will undergo a second semen analysis and blood analysis for T. After 12 weeks (90 days), Participants will return for a third visit for blood sample and semen analysis as well as safety monitoring. The Participants will also be given SHIM and quality of life questionnaires. This procedure will be repeated at week 24 to get a final blood and semen analysis.

Study Endpoints: The primary endpoint will be change in FSH, LH, Estradiol, T, and Semen Analysis after 12 weeks and 24 weeks of treatment with Natesto. The secondary endpoint will be monitoring for adverse events

Statistical Methods: Analyses will consist of summaries of the values and total change from baseline in each value (visit value versus baseline value) using descriptive statistics (sample size, mean, median, standard deviation, 95% confidence interval, minimum, and maximum). The change from baseline in each endpoint will compared using a two-sample t-test, or the Wilcoxon rank sum test if distributional assumptions are violated. The primary time point of interest for assessing hormone effects is the week 12 visit.

Arms: arm 1: Participants in this group will receive Natesto for a 24 consecutive weeks treatment course.
Interventions: intervention 1: Natesto
Intervention descriptions: intervention 1: 4.5% nasal testosterone. 11.0 mg testosterone administered per dose (2 pump actuations, 1 pump per nostril) applied intranasally three times a day.

Protocol documents:
Prot_SAP_000.pdf: 
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Date:  July 9th, 2019 
 
NCT03203681 
 IRB# 20170462 
Natesto TM Effects on Testosterone, Luteinizing Hormone, Follicle 
Stimulating Hormone and Semen Parameters 
______________________________________________________________________________ 
 
 
PRINCIPAL INVESTIGATOR  
Ranjith Ramasamy, M.D 
Assistant Professor 
Department of Urology 
1120 N.W. 14th st 
Miami, Florida 33136 
Phone: 305-243-6596 
Fax: 305-243-4562 
Email: Ramasamy@miami.edu 
          
 
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
 
Emad Ibrahim, MD 
305-932-9308 
 
 
 
 
 
 
Clinical Instructor 
eibrahim@miami.edu 
 
SPONSOR:  
 
 
 
Aytu Bioscience 
 
 


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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. PATIENT SELECTION/ELIGIBILITY CRITERIA .......................................................................... 9 
6.1 Inclusion (Eligibility) Criteria ....................................................................................................... 9 
6.2 Exclusion (Eligibility) Criteria ...................................................................................................... 9 
6.3 Study Population ...................................................................................................................... 11 
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 .............................................................................. 12 
7.4 Follow-Up Procedures and Evaluations: ................................................................................... 12 
8. ADVERSE EVENTS .............................................................................................................. 12 
8.1 Expected Adverse Events .......................................................................................................... 12 
8.2 Serious Adverse Events ............................................................................................................ 12 
9. DATA AND SAFETY MONITORING PLAN ............................................................................ 13 
10. STATISTICAL CONSIDERATIONS ....................................................................................... 13 
10.1 Primary Study Endpoints ........................................................................................................ 13 
10.2 Endpoint definitions ............................................................................................................... 13 
10.3 Sample size, accrual and study duration ................................................................................. 14 
10.4 Statistical Analysis and Power calculation .............................................................................. 14 
11. INVESTIGATORS RESPONSIBLITIES ................................................................................... 14 
11.1 Investigator Responsibility/Performance ............................................................................... 14 
11.3 Confidentiality ....................................................................................................................... 14 
11.4 Informed Consent and Permission to Use Protected Health Information ................................ 15 
11.5 Source Documentation and Investigator Files ......................................................................... 15 


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11.6 Recording and Processing of Data ........................................................................................... 16 
11.7 Non-Protocol Research ........................................................................................................... 16 
11.8 Ethics ..................................................................................................................................... 16 
11.9 Essential Documents for the conduct of a clinical trial ............................................................ 16 
12. STUDY CALENDAR ........................................................................................................... 17 
13 REFERENCES ..................................................................................................................... 18 
 


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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 
 
 
 
  
 
 
 
 
March 4, 2019 
 
Physician’s Signature 
Date 
 
 


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1.BACKGROUND 
 
1.1 Study Disease 
 
Testosterone is an anabolic steroid and the primary male sex hormone promoting development of 
male reproductive tissues such as prostate and testis. It can activate androgen receptors in its 
unchanged form or it can be converted to 5α-dihydrotestosterone (DHT) by the enzyme 5 α 
reductase before binding to the androgen receptor. Once bound, the receptor-hormone complex 
moves into the cell nucleus altering specific gene sequences on the cellular DNA and modifying 
its transcription, therefore promoting protein synthesis and thus growth of tissues that are sensible 
to its action.1 Spermatogenesis is a process that relies on testosterone levels in order to produce 
good quality sperm cells. This process starts with a primitive germ cell known as spermatogonia; 
which divides to produce spermatocytes that ultimately form young sperm cells known as 
spermatids. These last cells then mature and are transformed into spermatozoa or sperm cells. Is 
in this maturation process where testosterone is crucial. Normal sperm count for a healthy male is 
higher than 20 million per milliliter.2     
 
Hypogonadism, or low testosterone (Low T), is the deficiency in producing testosterone by the 
testes. Low T affects more than 10% of men worldwide, with high incidence in the elderly (Haring, 
et al., 2010). It occurs in association with aging, chronic disease, or other modifiable risk factors 
such as obesity and diabetes.1 Testosterone deficiencies have been shown to associated with less 
muscle mass3, lower bone mineral density4, lower hematocrit and hemoglobin concentrations5, 
smaller prostate glands6, and diminished energy and sexual function than normal men.7,8 
 
 
 
1.2 Study Interventions 
 
Testosterone replacement therapy (TRT) is becoming more widely available and has seen a greater 
than three-fold increase in use men 40 years and older.9 Current delivery systems of TRT include 
transdermal gels and patches10, injection therapy11, and long acting subcutaneous pellets.12 TRT 
has been shown to improve bone mineral density, prostate volume, energy, and sexual function.8 
Natesto TM is a relatively new form of TRT that is delivered intranasal to men diagnosed with low 
T and that has the potential to avoid side effects related to TRT that are commonly seen with other 
delivery methods. A recent study showed that this medication was well tolerated with very low 
adverse events and discontinuation rates among patients. 11 
 
 
1.3 Study Rationale  
 
 
Current advantages to Natesto TM include ease of delivery and decreased risk of the medication 
being transfer upon skin contact to woman or children.11 Recently Natesto 4.5% NTG (125 
uL/nostril, 11.0mg testosterone/dose) TID dosing was shown to also increase serum testosterone 
while maintaining normal, though decreased, serum levels of LH and FSH.16 This has the 


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theoretical benefit of maintaining normal semen parameters while on TRT with Natesto- to date, 
this theoretical benefit has not been evaluated.  
 
While Natesto has been shown to have positive effects on Testosterone while maintaining LH and 
FSH, the impact on sperm count has not yet been proven. Past research has shown a marked 
reduction in spermatogenesis in topical testosterone gel treatment. 17  Natesto TM has the potential 
to maintain normal spermatogenesis levels via maintenance of FSH and LH levels in the normal 
range. Our hypothesis is that Natesto TM will significantly increase Testosterone while having no 
significant impact on FSH, LH, and serum parameters in men with Low testosterone.  A proposed 
mechanism for this is that the TID dosing of Natesto will maintain pulsatile release of GnRH, 
preventing marked decreases in serum FSH and LH. 
 
2. HYPOTHESIS 
 
2.1 Alternate hypothesis 
 
Natesto TM will not change sperm count by ± 10% from baseline. 
 
2.2 Null Hypothesis 
Natesto TM will  change sperm count by ± 10% from baseline. 
 
 
3. OBJECTIVES 
 
3.1 Primary Efficacy Objective 
 
Primary outcomes will be changes in LH, FSH, testosterone, estrogen, and quality of life from 
baseline, 14 weeks +/- 7 days and 26 weeks +/- 7 days.  
 
3.2 Secondary Efficacy Objective 
 
Secondary outcomes will be changes in sperm count from baseline, 14 weeks+/- 7 days, and 26 
weeks+/- 7 days after treatment, as well as monitoring for adverse effects throughout the duration 
of our study.  
4. STUDY DESIGN 
 
4.1 Accrual goal 
 
A total of 40 patients with a diagnosis of idiopathic hypogonadism (testosterone <350 on two 
consecutive T samples collected 1-4 weeks apart. meeting the eligibility criteria will be recruited 
from the Department of Urology clinic.  


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4.2 Duration of Study Participation 
 
Total study duration will be 6 months and subjects will be provided with Natesto for the duration 
of the study (24 weeks treatment course).  
 
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.  
 
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.  
 


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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. PATIENT 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 55 years of age, inclusive, with documented onset of 
hypogonadism prior to age 55.  
 
3. Documented diagnosis of primary hypogonadism (congenital or acquired) or 
hypogonadotropic hypogonadism (congenital or acquired). 
 
4. Serum total testosterone < 350 ng/dL based on 2 consecutive blood samples obtained 1-
4 weeks apart between 6 and 10 AM following an appropriate washout of current 
androgen replacement therapy; with clinical symptoms of hypogonadism such as 
diminished energy and sexual function; and/or a decreased sperm count (<20 million 
sperm/mL semen).  
 
5. Naïve to androgen replacement or has discontinued current treatment and completed a 
washout of 4 weeks following androgen treatment (excluding Testopel TM). Washout 
must be completed prior to collection of baseline serum testosterone samples to 
determine study eligibility.  
 
6. Judged to be in good general health as determined by the principal investigator based 
upon the results of a medical history, physical examination, vital signs, and laboratory 
profile and a 12-lead electrocardiogram (ECG) performed at the time of enrolment of 
within the previous 6 months. 
 
6.2 Exclusion (Eligibility) Criteria 
 
Subjects meeting any of the following criteria will be excluded from the study: 
 
 
1. History of significant sensitivity or allergy to androgens, castor oil or product excipients. 
 
2. Clinically significant findings in the pre-study examinations including abnormal breast 
examination requiring follow-up.  
 


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3. Abnormal prostate digital rectal examination (DRE) with palpable nodule(s) or I-PSS 
score > 19 points.  
 
4. Body mass index (BMI) ≥ 35 kg/m2. 
 
5. Azoospermia or severe oligospermia (<1 million sperm/cc) on screening semen 
analysis: no sperm found in direct nor centrifuged semen sample or previous history of 
vasectomy. 
 
6. 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  
 
b. Hematocrit < 35% or > 50%  
 
c. PSA > 4 ng/mL and age >40 
 
7. History of seizures or convulsions, including febrile, alcohol or drug withdrawal 
seizures.  
 
8. History of any clinically significant illness, infection, or surgical procedure within 4 
weeks prior to study drug administration. 
 
9. History of stroke or myocardial infarction within the past 5 years.  
 
10. History of, or current or suspected, prostate or breast cancer.  
 
11. History of diagnosed, severe, untreated, obstructive sleep apnea.  
 
12. History of abuse of alcohol or any drug substance in the opinion of the investigator 
within the previous 2 years.  
 
13. History of nasal disorders such as nasal polyps; nasal septal perforation; nasal surgery; 
nasal trauma resulting in nasal fracture within the previous 6 months or nasal fracture 
that caused a deviated anterior nasal septum; sinus surgery or sinus disease 
 
14. 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.  
 
15. Inadequate venous access for collection of serial blood samples required for 
pharmacokinetic profiles.  
 
16. Receipt of any investigational product within 4 weeks or within 5 half-lives prior to the 
start of treatment.  
 


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17. Inability to understand and provide written informed consent for the study.  
 
18. Considered by the investigator or the sponsor-designated physician, for any reason, that 
the subject is an unsuitable candidate to receive Natesto. 
 
19. History of treatment with clomiphene citrate within the last 12 months. 
 
 
20. History of varicocele repair. 
 
21. Actively seeking conception unless agreeing on sperm cryopreservation for a minimum 
of 12 months from enrollment in the study.  
 
6.3 Study Population 
 
The study will consist of 80 males suffering from idiopathic hypogonadism. 
 
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 patients will receive an explanation of the study. Patients 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 prospective clinical study aimed to evaluate the safety and efficacy of Natesto TM on 
patients with idiopathic hypogonadism. Clinical signs and symptoms of hypogonadism, i.e. 
diminished energy and sexual function; and/or a decreased sperm count constitute the clinical 
indication for TRT in our study population.   
 
7.2 Screening Evaluations and Procedures 
 
The first visit of the patients will be for screening and medical evaluation. Patient’s medical co-
medication history will be collected and documented and a physical examination will be 
performed.  
 


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Previous month’s blood test results will be reviewed including a general chemistry panel, a lipid 
profile, and Testosterone levels during chart review. 
 
Patients 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 Evaluations  
 
Upon evaluating the inclusion/exclusion criteria, patients will be recruited to the study. Patients 
will be instructed to stop any use of androgen replacement for 4 weeks prior to first treatment 
session and refrain from using any other androgen replacement therapy option during the study. 
After the washout period and before the first treatment session, patients will answer the IIEF-EF 
and SF-36 questionnaires for baseline evaluation.  
 
7.4 Follow-Up Procedures and Evaluations: 
 
Follow-up visits will be conducted at week 14+/- 7 days and 26+/- 7 days, these visits shall include:  
 
• Measuring IIEF-EF and SF-36 scores of patients at the clinic  
 
• Taking serum FSH, LH, E, and total Testosterone levels 
 
• Semen analysis 
 
• Reporting and recording adverse events at every follow-up visit. 
 
Additional determinations of total serum testosterone will be performed periodically at every 
follow up visit, beginning one month after initiation of therapy. Additional semen analysis will be 
performed at weeks 15+/- 7 days and 27+/- 7 days.  
 
8. ADVERSE EVENTS 
 
8.1 Expected Adverse Events  
 
In a 90-day clinical study, the most commonly reported adverse reactions to Natesto TM were 
“prostate specific antigen (PSA) increased, headache, rhinorrhea, epistaxis, nasal discomfort, 
nasopharyngitis, upper respiratory tract infection (URI), sinusitis, bronchitis and nasal scab”2 
Natesto TM  in large doses may lower sperm count and occasionally lead to azoospermia.    
 
8.2 Serious Adverse Events  
 
Serious injury or death  
 


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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. Patients 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.  
 
For Reporting of adverse events see section 9  
 
9. DATA AND SAFETY MONITORING PLAN 
 
The study investigators will report to a surgeon monitor Dr. Satyanarayana Ramgopal 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) , will be entered into study database and reviewed at research committee meetings. 
In addition, all adverse reactions considered “serious” will be entered into research database and 
reviewed by the Surgeon monitor on an ongoing basis. If a death occurs within 30 days of  
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 FSH, LH, Testosterone, and Semen Analysis after 6 
months of treatment of Natesto. 
 
10.2 Endpoint definitions 
 
In the semen analysis, we will include changes in the following parameters: Semen volume (ml), 
sperm concentration (x106), sperm motility (% progressive), sperm morphology (% normal forms) 
and sperm viability (% viable); as exploratory endpoints. 
 
Total testosterone will be expressed in ng/dL, and FSH and LH in mIU/mL. Hormone 
determinations will be done by peripheral venous puncture blood draw.  
 


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10.3 Sample size, accrual and study duration 
 
TOTAL SAMPLE SIZE: 80 
TOTAL ACCRUAL: 80 
ACCURAL DURATION: 6 months 
STUDY DURATION: 27 weeks 
 
10.4 Statistical Analysis and Power calculation   
 
The average and standard deviation of all relevant variables and baseline characteristics, primary 
and secondary outcomes will be calculated.  
 
Change in sperm count will be analyzed using the ANOVA and MANOVA. A change in < ± 10% 
will be reject the null hypothesis. 
 
LH, FSH, E and Testosterone levels will be analyzed using one-same t-test with repeated measures 
throughout the study. 
 
IIEF-EF and SF-36 questionnaires will be analyzed and compared between the groups according 
to Fisher's exact test in each of the endpoints. The statistical significance will be set at P<0.05.    
  
Demographic characteristics such as age and testosterone level will be compared between groups 
A and B using student's test. Other demographic characteristics, such as medical background and 
risk factors will be compared between these groups using Fisher's exact test. 
 
11. INVESTIGATORS RESPONSIBLITIES 
 
11.1 Investigator Responsibility/Performance 
 
The investigator (or a person designated by the investigator) should inform the patient of all 
pertinent aspects of the study, including the written information. 
 
The investigator should provide the patient ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study.  All questions about the study 
should be answered to the satisfaction of the patient. Neither the investigator, nor the study staff, 
should coerce or unduly influence a patient to participate or to continue to participate in a study. 
 
11.3 Confidentiality 
 
The identity of the patients in this study will be treated as confidential. Patients eligible to 
participate in the study following the pre-treatment visit will be assigned a unique patient code. 
The results of the study, including any other data, may be published for scientific purposes but will 
not give the patients' name or include any identifiable references to them. 


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However, any records or data obtained as a result of the patient 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 in so far 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 patient records; physician's and nurse's notes; original laboratory, radiology, 
pathology, and special assessment reports; QOL forms, signed informed consent forms.  When the 
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 including semen analysis. 


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16 
• Condition and response of subject upon completion of or early termination from 
the study. 
• IIEF-EF and SF-36 Surveys. 
 
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 patient 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. 
• IRB documentation/correspondence. 
• Documentation of IRB certification. 
 
 
 
 
 
 
 
 
 


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17 
12. STUDY CALENDAR 
 
          Visit #, Time 
 
 
 
 
Activity 
Visit 1 (Week 1) 
Screening 
Visit 2  
(Week 2) 
 
Visit 3  
 (Week 6) 
Visit 4  
 (Week 14) 
 
Visit 5  
(Week 15)  
 
Visit 6  
(Week 26) 
Visit 7  
(Week 27) 
Medical 
& 
Urological History 
● 
 
 
 
 
 
 
Physical 
Examination 
& 
Questionnaire 
● 
 
 
● 
 
 
● 
 
Informed Consent 
● 
 
 
 
 
 
 
Inclusion 
& 
Exclusion Criteria 
● 
 
 
 
 
 
 
Blood 
Analysis 
(FSH, LH, T, E) 
● 
 
●  
(Only 
T) 
●  
 
● 
(Only 
T) 
● 
●  
(Only 
T) 
Semen Analysis 
● 
● 
 
● 
● 
● 
● 
Drug dispensing 
 
● 
 
● 
 
 
 


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18 
13 REFERENCES 
 
 
1. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late-onset hypogonadism: 
Systematic review and meta-analysis of TRT outcomes. Best Practice & Research 
Clinical Endocrinology & Metabolism. 2013; 27(4):557-579. 
 
2. Walker WH. Testosterone signaling and the regulation of spermatogenesis. 
Spermatogenesis. 2011; 1(2): 116-120.  
 
3. Katznelson L, Finkelstein J, Schoenfeld D, Rosenthal D, Anderson E, Klibanski A. 
Increase in bone density and lean body mass during testosterone administration in men 
with acquired hypogonadism. The Journal of Clinical Endocrinology & Metabolism. 
1996; 81(12):4358-4365. 
 
4. Finkelstein J, Klibanski A, Neer R, et al: Osteoporosis in Men with Idiopathic 
Hypogonadotropic Hypogonadism. Annals of Internal Medicine. 1987;106(3):354 
 
5. Jockenhovel F, Vogel E, Reinhardt W, Reinwein D: Effects of various modes of 
androgen substitution therapy on erythropoiesis. Eur J Med Res. 1997; 2: 293-298.  
 
6. Behre H, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated 
hypogonadal men in comparison to age-matched normal controls. Clinical 
Endocrinology. 2010; 40(3):341-349. 
 
7. Davidson J, Camargo C, Smith E: Effects of Androgen on Sexual Behavior in 
Hypogonadal Men. The Journal of Clinical Endocrinology & Metabolism. 1979; 
48(6):955-958. 
 
8. Snyder P, Peachey H, Berlin J, et al: Effects of Testosterone Replacement in 
Hypogonadal Men. Journal of Clinical Endocrinology & Metabolism. 2000; 85(8):2670-
2677. 
 
9. Baillargeon J, Urban R, Ottenbacher K, Pierson K, Goodwin J. Trends in Androgen 
Prescribing in the United States, 2001 to 2011. JAMA Internal Medicine. 2013; 
173(15):1465. 
 
10. Koch C, Ullah M, Riche D. Transdermal testosterone replacement therapy in men. Drug 
Design, Development and Therapy. 2014; 101. 
 
11. Rogol AD, Tkachenko N, Bryson N. Netesto TM, a novel testosterone nasal gel, 
normalizes androgen levels in hypogonadal men. Andrology. 2016; 4(1): 46-54. 
12. Seal L. Testosterone replacement therapy. Medicine. 2009; 37(9):445-449. 


Version 2.1 
Date:  July 9th, 2019 
 
 
19 
 
 
13. Amory J, Anawalt B, Blaskovich P, Gilchriest J, Nuwayser E, Matsumoto A. 
Testosterone Release From a Subcutaneous, Biodegradable Microcapsule Formulation 
(Viatrel) in Hypogonadal Men. Journal of Andrology. 2002; 23(1):84-91. 
 
 
14.  Rhoden E, Morgentaler A. Risks of Testosterone-Replacement Therapy and 
Recommendations for Monitoring. New England Journal of Medicine. 2004; 350(5): 482-
492. 
 
15. Conners, W., Morgentaler, A., Guidry, M., Westfield, G., Bryson, N., & Goldstein, I. 
(2016) Preservation of Normal Concentrations of Pituitary Gonadotropins Despite 
Achievement of Normal Serum Testosterone Levels in Hypogonadal Men Treated with a 
4.5% Nasal Testosterone Gel. Poster Presented at American Urological Assoication 
Annual Meeting. 
 
16. Kim E, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and 
preserves sperm counts in obese hypogonadal men, unlike topical testosterone: 
restoration instead of replacement. BJU International. 2015; 117(4):677-685. 
 
17.  FDA. Natesto Full Prescribing Information. May 2014.  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205488s000lbl.pdf