An Open-Label Study of Serum Testosterone and Nestorone in Females After Secondary Exposure to Nestorone ® (NES) + Testosterone (T) Combined Gel Applied to Shoulders and Upper Arms in Males: Effect of Washing or Clothing Barrier to the Application
Phase: PHASE1
Conditions: Healthy Men, Male Contraception, Healthy Women, Product Transference
Sponsor: Kimberly Myer

Protocol: CCN005B 
 
CONFIDENTIAL-PROPRIETARY INFORMATION 
Version 01.00 (FINAL) Date: 16-NOV-2016 
 
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Title:  
An Open-Label Study of Serum Testosterone and Nestorone in Females After 
Secondary Exposure to Nestorone ® (NES) + Testosterone (T) Combined Gel 
Applied to Shoulders and Upper Arms in Males: Effect of Washing or 
Clothing Barrier to the Application 
 
Protocol Number: 
CCN005B 
 
IND Number:  
105,079 
 
Clinical Phase:  
Ib 
 
Sponsors:  
 
National Institutes of Health  
Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) 
Contraceptive Clinical Trial Network (Male) 
6710B Rockledge Drive  
Bethesda, MD 20814 USA 
 
Population Council, Center for Biomedical Research 
1230 York Avenue 
New York, NY 10065 USA  
 
Program Director: 
Diana Blithe, PhD, NICHD 
 
Medical Monitor:  
Mark Payson, MD 
 
Safety Officer: 
Mohcine Alami, MD, Population Council  
 
Director: 
 
Régine Sitruk-Ware, MD, Population Council 
 
Original Protocol:  
Version 1.0 (16-NOV-2016) 
 
Investigators and Institutions: 
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center 
Principal Investigator: Christina Wang, MD 
Co-Investigators:  
Ronald S. Swerdloff, MD  
Peter Liu, MBBS FRACP PhD 
 
University of Washington 
Principal Investigator: Stephanie Page, MD, PhD 
Co-Investigators:  
William J. Bremner, MD, PhD 
 
 
 
Bradley Anawalt, MD 
 
Statistical & Clinical Coordinating Center: 
Clint Dart, MS 
Health Decisions 
2510 Meridian Parkway, Suite 100 
Durham, NC 27713, USA  
Telephone: (919) 967-1111 
Fax: (919) 967-1145 
www.healthdec.com  
 

Protocol: CCN005B 
 
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TABLE OF CONTENTS 
1. 
Introduction and Background ..................................................................................................... 14 
2. 
Objectives...................................................................................................................................... 15 
2.1 
Primary objective .......................................................................................................................... 15 
2.2 
Primary Endpoint .......................................................................................................................... 15 
2.3 
Secondary objectives .................................................................................................................. 15 
2.4 
Secondary Endpoints .................................................................................................................. 16 
3. 
Rationale, Benefits and Risks .................................................................................................... 16 
3.1 
Rationale ....................................................................................................................................... 16 
3.2 
Risks and Benefits ....................................................................................................................... 17 
3.3 
Dose Rationale ............................................................................................................................. 17 
4. 
Study Design ................................................................................................................................ 17 
5. 
Subject Compliance ..................................................................................................................... 18 
6. 
Principal Investigators and Research Centers ........................................................................ 18 
7. 
Subject Recruitment .................................................................................................................... 18 
8. 
Study Duration .............................................................................................................................. 19 
9. 
Number of Subjects ..................................................................................................................... 19 
10. 
Selection of Subjects ................................................................................................................... 19 
10.1 
Inclusion criteria: .......................................................................................................................... 19 
10.1.1 
Male Partner Inclusion Criteria: ................................................................................................. 19 
10.1.2 
Female Partner Inclusion Criteria: ............................................................................................. 20 
10.2 
Exclusion criteria: ......................................................................................................................... 20 
10.2.1 
Male Partner Exclusion Criteria: ................................................................................................ 20 
10.2.2 
Female Partner Exclusion Criteria: ........................................................................................... 21 
11. 
Concomitant Treatment .............................................................................................................. 21 
11.1 
Exclusionary Medications ........................................................................................................... 21 
12. 
Study Materials ............................................................................................................................. 22 
12.1 
Study Medication .......................................................................................................................... 22 
12.1.5 
Investigational Product Accountability ...................................................................................... 23 
12.1.6 
Storage .......................................................................................................................................... 24 
12.1.7 
Disposal/Return ............................................................................................................................ 24 
13. 
Study Procedures ........................................................................................................................ 24 
13.1 
Clinical Assessments .................................................................................................................. 24 
13.1.1 
Skin Exam ..................................................................................................................................... 24 
13.2 
Laboratory Tests and Evaluations ............................................................................................. 24 
13.2.1 
CBC, Clinical Chemistries, and PSA......................................................................................... 25 
13.2.2 
Hormone Testing .......................................................................................................................... 25 
13.2.2.1 
Screening Hormones ................................................................................................................... 25 
13.2.2.2 
Treatment Hormone Measurements ......................................................................................... 25 
13.2.2.3 
Testosterone Assays ................................................................................................................... 26 
13.2.2.4 
Nestorone Assays ........................................................................................................................ 26 
13.2.3 
Urine tests ..................................................................................................................................... 26 
13.2.4 
Safety Procedures ....................................................................................................................... 26 
14. 
Evaluations By Study Visit .......................................................................................................... 27 
14.1 
Screening Phase .......................................................................................................................... 27 
14.1.1 
Screening Visit 1 (Visit 1) ............................................................................................................ 28 
14.1.1.1 
Both Partners ................................................................................................................................ 28 
14.1.1.2 
Male Partner Only ........................................................................................................................ 28 
14.1.1.3 
Female Partner Only ................................................................................................................... 29 
14.1.2 
Screening Visit 2 (Visit 2) ............................................................................................................ 29 
14.2 
Treatment Phase (Visits 3-8) ..................................................................................................... 30 

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14.2.1 
Treatment Phase Visit 3 (Day 1), Visit 5 (Day 8), and Visit 7 (Day 15) (+7 day window) . 30 
14.2.1.1 
Pre- Gel Application ..................................................................................................................... 30 
14.2.1.1.1 Both Partners ................................................................................................................................ 30 
14.2.1.1.2 Male Partner Only ........................................................................................................................ 30 
14.2.1.1.3 Female Partner Only ................................................................................................................... 30 
14.2.1.2 
Gel Application ............................................................................................................................. 30 
14.2.1.2.1 Male Partner Only ........................................................................................................................ 30 
14.2.1.3 
Post- Gel Application ................................................................................................................... 30 
14.2.1.3.1 Male Partner Only ........................................................................................................................ 31 
14.2.1.3.2 Both Partners ................................................................................................................................ 31 
14.2.1.3.3 Female Partner Only ................................................................................................................... 31 
14.2.1.3.4 For Visit 3 (Day 1) Only – Post Application: ............................................................................. 31 
14.2.1.3.5 For Visit 5 (Day 8) Only – Post Application: ............................................................................. 31 
14.2.1.3.6 For Visit 7 (Day 15) Only – Post Application: .......................................................................... 31 
14.2.2 
Treatment Visit 4 (Day 3), Visit 6 (Day 10), and Visit 8 (Day 17) (no window) ................... 32 
14.2.2.1 
Female Partner ............................................................................................................................. 32 
14.3 
End of Study/Exit Visit – Visit 9 (Day 31) ( -12/+14 days) ..................................................... 32 
14.3.1 
Both Partners ................................................................................................................................ 32 
14.3.2 
Male Partner ................................................................................................................................. 32 
14.3.3 
Female Partner ............................................................................................................................. 32 
14.4 
Contacts Between Visits ............................................................................................................. 33 
14.5 
Early Discontinuation Visit .......................................................................................................... 33 
14.6 
Unscheduled Visits (UNS) .......................................................................................................... 33 
15. 
Adverse Events: Recording and Reporting .............................................................................. 33 
15.1 
Definition of Adverse Events ...................................................................................................... 33 
15.2 
Study Reporting Period for Adverse Events ............................................................................ 34 
15.3 
Recording of Adverse Events..................................................................................................... 34 
15.4 
Relationship to Study Product .................................................................................................... 35 
15.6 
Serious Adverse Events (SAEs) ................................................................................................ 36 
15.6.1 
Definition of a SAE ....................................................................................................................... 36 
15.6.2 
Study Reporting Period for SAEs .............................................................................................. 37 
15.6.3 
Notification to Sponsor of SAEs and Sponsor Reporting of SAEs ....................................... 37 
15.6.4 
Notification of IRB or Independent Ethics Committee of SAEs ............................................ 38 
15.6.5 
Pregnancy Determination and Follow-up ................................................................................. 39 
16. 
Medical Monitor ............................................................................................................................ 39 
17. 
Safety Desk ................................................................................................................................... 40 
18. 
Safety and Efficacy Monitoring (DSMB) ................................................................................... 40 
19. 
Study Conduct .............................................................................................................................. 40 
19.1 
Deviation from the Protocol ........................................................................................................ 40 
19.2 
Amendments to the Protocol ...................................................................................................... 41 
19.3 
Subject Confidentiality ................................................................................................................. 41 
19.4 
Discontinuing Subjects ................................................................................................................ 41 
19.5 
Withdrawals from Study .............................................................................................................. 42 
19.6 
Medication Errors ......................................................................................................................... 43 
20. 
Study Monitoring and Documentation ....................................................................................... 43 
20.1 
Clinical Monitoring, Quality Control, and Quality Assurance ................................................. 43 
20.2 
Administrative and Record Management ................................................................................. 43 
20.3 
Study Documentation .................................................................................................................. 43 
20.4 
Electronic Data Capture System/Data Transmission ............................................................. 43 
20.5 
Data Handling and Processing .................................................................................................. 44 
20.6 
Confidentiality and Reporting of Results .................................................................................. 44 
20.7 
Retention of Data ......................................................................................................................... 44 

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20.8 
Publication Policy ......................................................................................................................... 45 
20.9 
Financing and Insurance ............................................................................................................ 45 
21. 
Evaluations.................................................................................................................................... 45 
21.1 
PK Evaluations ............................................................................................................................. 45 
21.2 
Safety Evaluations ....................................................................................................................... 45 
21.2.1 
Safety Parameter Methods ......................................................................................................... 46 
22. 
Statistical and Analytical Methods ............................................................................................. 46 
22.1 
Sample Size .................................................................................................................................. 46 
22.2 
Analysis populations .................................................................................................................... 46 
22.2.1 
Primary Analysis .......................................................................................................................... 47 
22.2.2 
Secondary Analysis ..................................................................................................................... 47 
22.3 
CBC and Clinical Chemistry Parameters ................................................................................. 47 
22.4 
Hormones ...................................................................................................................................... 47 
22.5 
Adverse Events (AEs) ................................................................................................................. 47 
22.6 
Deaths............................................................................................................................................ 48 
22.7 
Other Safety Analyses ................................................................................................................ 48 
22.8 
Disposition of Subjects ................................................................................................................ 48 
22.9 
Demographic and Other Subject Characteristics .................................................................... 48 
23. 
Ethical Considerations ................................................................................................................ 48 
23.1 
Statement of Compliance ........................................................................................................... 48 
23.2 
Interactions with Ethics Committees ......................................................................................... 48 
23.3 
Informed Consent ........................................................................................................................ 49 
23.4 
Conflicts of Interest ...................................................................................................................... 49 
23.5 
Confidentiality ............................................................................................................................... 50 
References ........................................................................................................................................................ 51 
INVESTIGATOR OBLIGATIONS .................................................................................................................. 54 
Appendix 1: Schedule of Assessments ........................................................................................................ 55 
Appendix 2: List of Exclusionary Medications ............................................................................................. 57 
Appendix 3: Instructions for Gel Application – Male Contraceptive ......................................................... 60 
Appendix 4: Study Procedures for Male and Female Subjects ................................................................ 61 
Appendix 5: Outline of Timed NES and T sampling ................................................................................... 61 
Appendix 6: Preparation of Nestorone/Testosterone (NES/T) Combined Gel Investigational Product 
by the Investigational pharmacists at each site........................................................................................... 62 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
 
Adverse Event 
AIDS 
 
Acquired Immunodeficiency Syndrome 
ALPH  
Alkaline Phosphatase 
ALT 
 
Alanine Aminotransferase 
AST 
 
Aspartate Aminotransferase 
BMI 
 
Body Mass Index 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
C 
 
Celsius 
CAP 
 
College of American Pathologists 
CBC 
 
Complete Blood Count 
CCTN  
Contraceptive Clinical Trial Network  
CDC 
 
U.S. Centers for Disease Control and Prevention  
CFR 
 
Code of Federal Regulations  
CI 
 
Confidence Interval 
CLIA 
 
Clinical Laboratory Improvement Amendments 
CMC 
 
Chemistry and Manufacturing Controls  
CRB 
 
Contraceptive Research Branch 
CRF 
 
Case Report Form 
CRO 
 
Clinical Research Organization  
CSR 
 
Clinical Study Report 
CV 
 
Curriculum Vitae 
DBP 
 
Diastolic Blood Pressure 
DHHS  
Department of Health and Human Services 
DHT 
 
Dihydrotestosterone 
DMPA  
Depo-medroxyprogesterone acetate 
DSMB  
Data Safety Monitoring Board  
eCRF  
Electronic Case Report Form 
EDC 
 
Electronic Data Capture  
EudraCT 
European DataBase for Clinical Trials 
F 
 
Fahrenheit 
FDA 
 
Food and Drug Administration  
FSH 
 
Follicle-Stimulating Hormone  
GCP 
 
Good Clinical Practice  
GGT 
 
Gamma-Glutamyl Transpeptidase 
GMP 
 
Good Manufacturing Practice 
hCG 
 
Human Chorionic Gonadotropin 
HCO3  
Bicarbonate 
HD 
 
Health Decisions 
HDL 
 
High-Density Lipoprotein  
HIPAA  
Health Insurance Portability and Accountability Act  
HIV 
 
Human Immunodeficiency Virus 
hMG 
 
Human Menopausal Gonadotropin 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form  
ICH 
 
International Conference on Harmonisation  
ID 
 
Identification  
IEC 
 
Institutional Ethics Committee  
IM 
 
Intramuscular 
IMP 
 
Investigational Medicinal Product  

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IMPD  
Investigational Medicinal Product Dossier 
IND 
 
Investigational New Drug 
IP 
 
Investigational Product  
IPSS 
 
International Prostate Score System 
IRB 
 
Institutional Review Board  
IRP 
 
Intramural Research Program 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine System 
K+ 
 
Potassium 
LA 
 
Los Angeles 
LDL 
 
Low-Density Lipoprotein 
LH 
 
Luteinizing Hormone 
LTFU  
Lost To Follow-Up 
MedDRA® 
Medical Dictionary for Regulatory Activities  
Na+ 
 
Sodium 
NDA 
 
New Drug Application 
NES 
 
Nestorone® 
NICHD  
National Institute of Child Health and Human Development (NICHD)  
NIH 
 
National Institutes of Health  
PC 
 
Population Council 
PHQ-9  
Patient Health Questionnaire – 9 (Depression Module) 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetics 
PSA 
 
Prostate-Specific Antigen 
PSI 
 
Particle Science Inc 
Q 
 
Quarter 
RBC 
 
Red Blood Cells 
SBP 
 
Systolic Blood Pressure 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAS®  
Statistical Analysis System 
SCCC  
Statistical and Clinical Coordinating Center 
SD 
 
Standard Deviation 
SHBG  
Sex Hormone-Binding Globulin  
SOP 
 
Standard Operating Procedure 
STI 
 
Sexually Transmitted Infection 
T  
 
Testosterone 
TEAE  
Treatment-Emergent Adverse Event 
UCLA  
University of California Los Angeles 
WBC 
 
White Blood Cells 
WHO  
World Health Organization  
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title: 
An Open-Label Study of Serum Testosterone and Nestorone in Females After 
Secondary Exposure to Nestorone® (NES) + Testosterone (T) Combination Gel 
Applied to Shoulders and Upper Arms in Males: Effect of Washing or Clothing 
Barrier to the Application 
Protocol Number: 
CCN005B 
Clinical Phase: 
Phase Ib 
Sponsors: 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) Contraception Research Branch 
 
Population Council 
IND Number: 
105,079 
IND Holder: 
Population Council 
Primary Objective: The primary objective of the study is to determine the pharmacokinetics of 
testosterone (T) and Nestorone (NES) concentrations in female participants after a 
single exposure of skin contact with a male participant dosed with a gel containing T 
and NES applied to the shoulders and upper arms. The skin contact with non-dosed 
female participants occurs 2 hours after male gel application, and has 3 variations: 
 
With a 100% cotton T-shirt clothing barrier; 
 
After the application site is washed with soap and water in a shower then 
dried; 
 
Without washing or clothing barrier to the skin to skin contact.  
Secondary 
Objectives: 
The secondary objectives are: 
1. To determine the effects of showering on the pharmacokinetics of 
testosterone and Nestorone concentrations in male participants after 
application of testosterone and Nestorone combined gel on shoulders and 
upper arms in men.  
2. To determine the amount of testosterone and Nestorone that remained on 
the skin after application in men. 
3. To assess the safety and tolerability of the combined gel in men.  
4. To assess the safety in women possibly exposed to the gel after skin contact 
at the site of application of the gel in men. 
Primary 
Endpoints: 
The primary objective will be evaluated in female participants by assessing changes 
from baseline up to 48 hours for serum testosterone levels in Cavg, Cmax, and Cmin 
after secondary exposure to Nestorone + Testosterone Combination Gel (NES/T gel).  
Also, the Nestorone levels will be summarized after secondary exposure to NES/T gel 
by presenting Cavg, Cmax, and Cmin.  These endpoints will be summarized for each 
of the 3 types of skin contact between the man and woman. 
Secondary 
Endpoints: 
The secondary objectives will be evaluated using the following endpoint measures: 
1. The pharmacokinetic parameters of testosterone and Nestorone in males 
after wearing a T shirt and after washing will be compared to serum 
testosterone and Nestorone pharmacokinetics after application of the 
combined gel without washing. 
2. Serum testosterone pharmacokinetics in males after applying NES/T gel with 
or without T shirt and with washing will be compared to baseline 
pharmacokinetic parameters.  
3. Average testosterone and Nestorone levels 90 and 150 minutes after 
application in men as measured by adhesive D-square strips with and 
without showering. 

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4. Incidence of adverse events and serious adverse events for both partners. 
5. Changes from baseline in safety labs in both partners. 
6. Percentage of females with increased (relative to baseline) acne and 
hirsutism at each visit. 
These endpoints will be summarized for each of the 3 types of skin contact between 
the man and woman. 
Investigators and 
Institutions: 
Investigators and sites listed below will participate in this study. Detailed information 
(addresses, statement of qualifications, names of sub-investigators, and name and 
address of each reviewing Institutional Review Board) will be maintained in a separate 
file. 
 
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center 
Principal Investigator: Christina Wang, MD 
Co-Investigators:  
Ronald S. Swerdloff, MD  
Peter Liu, MBBS FRACP PhD 
 
University of Washington 
Principal Investigator: Stephanie Page, MD, PhD  
Co-Investigators:  
William J. Bremner, MD, PhD 
Bradley Anawalt, MD 
Rationale, 
Background, 
Risks and 
Benefits:  
A number of sporadic reports have shown the transfer of applied testosterone from 
the skin of men to women  (Merhi & Santoro, 2007) and children (Brachet, et al., 
2005; Kunz, et al., 2004) that may result in hirsutism, acne and virilization in the 
women and children. Previous studies have confirmed that testosterone may be 
transferred from men who applied transdermal testosterone gel to women upon 
close contact (Miller, et al., 2012; Rolf, et al., 2002; Stahlman, et al., 2012; 
Stahlman, et al., 2012). The transfer of testosterone to women is related to the dose 
of testosterone applied to men. In studies for testosterone transference, secondary 
exposure to women occurred after direct skin contact 2 hours after gel application. 
The studies showed that 2.5 g (40.5 mg) and 5 g (81 mg) of testosterone gel 
resulted in elevation of serum T in females with changes of all testosterone 
pharmacokinetics parameters as compared to baseline by 24-27% and 52 to 70% 
respectively. Transference of testosterone from the site where testosterone gel is 
applied in men to the female after close skin contact was prevented by men wearing 
a 100% cotton T-shirt covering the application area or by showering approximately 2 
hours after application of gel (Stahlman, et al., 2012; Stahlman, et al., 2012). 
Washing the skin 2 to 6 hours after applying 81 mg of Androgel 1.62 % on the skin 
of men resulted in 10-14 % decrease in the average concentration of serum 
testosterone.  Skin washing decreased the mean amount of testosterone remaining 
on the skin by at least 81% (Stahlman, et al., 2012). Showering within 30 minutes 
after application of testosterone gel may lower serum testosterone in men to levels 
below the adult reference range and is not recommended (de Ronde, et al., 2011).  
 
Possible transfer of transdermal Nestorone from men to women upon close skin 
contact has not been studied. In our proposed study “Clinical Evaluation of 
Nestorone® (NES) and Testosterone (T) Combination Gel for Male Contraception 
(CCN017)”, adult men will apply a combined testosterone and Nestorone gel on their 
arms and shoulders for approximately 68 weeks. Their female partner may be 
exposed to transfer of testosterone and Nestorone inadvertently though close skin 
contact despite the male participant being asked to wear a 100% cotton T-shirt 
covering the area of gel application or washing with soap and water before close 
skin contact with his female partner or children. This proposed study will be 

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conducted to assess maximum testosterone and Nestorone transfer from the skin of 
the healthy male volunteers to non-dosed female participants after application of the 
combined testosterone and Nestorone gel over the shoulders and upper arms of the 
male participant. The study will assess the absorption and pharmacokinetics of 
testosterone and Nestorone in female healthy volunteers after single exposure of 
skin contact (her hands and arms) to the area where the   male participant had 
applied the gel (his shoulders and upper arms) approximately 2 hours earlier.  The 
study will assess the absorption and pharmacokinetics under three conditions: 1) 
indirect contact with the male participant wearing a 100% cotton T-shirt covering the 
area of application; 2) direct skin contact with male participant’s skin where the gel 
was applied after the male has washed the application area with soap and water 
then dried it; and 3) direct skin contact where the gel was applied without a T-shirt 
barrier or shower for the male participant. The effect of showering on the 
pharmacokinetics of Nestorone will also be assessed in the male and compared to 
that obtained when there is no shower.  
Study Design: 
This is a two-center, open-label study conducted in healthy male and female 
volunteers at two academic research centers. The study will consist of three single 
applications of the Nestorone (NES) + testosterone (T) combined gel on the 
shoulders/upper arms of male participants followed 2 hours later by supervised skin 
contact by the non-dosed female participants on the application site on days 1, 8, 
and 15.  
 
On day 1, the male participant will wear a 100% cotton T-shirt over the application 
area before skin contact with the female.   
 
On day 8, the male participant will shower approximately 1 hour and 45 minutes 
after gel application and engage in skin contact with the female participant (2 hours 
after gel application) after washing the area with soap and water then drying it.  A 
measurement of residual Nestorone and testosterone will be taken from the male’s 
skin on a single location of the application site using adhesive D-square strips 90 
minutes after application (30 minutes before shower/90 minutes after gel application) 
and 30 minutes after the shower and rubbing (150 minutes after application). 
 
On day 15, there will be no shower or clothing barrier for the male participant before 
skin contact with the female participant. A measurement of residual Nestorone and 
testosterone will be taken from a single location of the application using adhesive D-
square strips site 90 minutes and 150 minutes after the application. 
 
An end of study/exit visit will occur for both male and female participants two weeks 
after treatment completion.  
Compliance:  
As gel application and skin contact will occur under direct study staff supervision, no 
issues with compliance are anticipated. 
 
All aspects of this study will be performed according to CFR Title 21, CRF Title 45, 
Part 46, Good Clinical Practices  (GCP) and International Conference on 
Harmonisation (ICH) under an IND application. All principles of the Declaration of 
Helsinki will be followed. 
Number of 
Subjects: 
The protocol is expected to enroll a total of 12 healthy male subjects and their 
partners (i.e.12 female subjects), 6 male and 6 female subjects per site.   
Study Duration: 
The subjects will be evaluated for a period of about 2 months (screening up to 4 
weeks, treatment phase of 17 days, and post-treatment for 2 weeks).   

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Investigational 
Product: 
The investigation product is a combination gel with Nestorone® (NES) and 
Testosterone (T) applied transdermally.  
Dosage and 
Regimen: 
This will be a Phase Ib, open-label study with three single applications of the NES + 
T combined gel. The volume of gel to be applied will be approximately 5 mL. This gel 
volume will contain 62.5 mg of T that will deliver approximately 6 mg T to the body per 
day and will also contain 8.3 mg of NES that will deliver about 0.8 mg NES to the body 
per day (NES 8 mg/d + T 60 mg/d (NES8/T60) gel) in 5 ml of combined gel.  
Inclusion Criteria: 
Male participant – Inclusion Criteria 
 
Men who meet all the following criteria will be eligible for enrollment in the trial: 
1. Good health as confirmed by medical history, physical examination, and 
clinical laboratory tests of blood and urine at the time of screening; 
2. 18 to 50 years of age;  
3. BMI ≥ 18 and < 35 kg/m2;   
4. No history of androgen use prior to the first screening visit as follows: 
a. 1 month prior for oral or transdermal androgen, 
b. 3 months prior for Testosterone cypionate or enanthate injection, 
c. 6 months prior for Testosterone undecanoate injection; 
5. Agreement to use a recognized effective method of short acting contraception 
with his partner (i.e. at a minimum use double-barrier method such as a 
condom with spermicide) during the entire study;  
6. In the opinion of the investigator, male subject is willing and able to comply 
with the protocol; 
7. Provision of valid, written and informed consent. 
 
Female participant – Inclusion Criteria 
 
Women who meet all the following criteria will be eligible for enrollment in the trial: 
1. Good general health (BMI ≥18 and <30 kg/m2)with no chronic medical 
conditions that result in periodic exacerbations which require significant 
medical care; 
2. Aged between 18 and 40 years, at the enrollment visit;  
3. Not pregnant and not breastfeeding. 
4. Agreement to use a recognized effective method of contraception throughout 
the study  
5. Willingness and ability to provide valid, written and informed consent and to 
comply with the protocol; 
6. No desire for pregnancy within the next 6 months. 
Exclusion Criteria: Male participant – Exclusion Criteria 
 
Men who meet any of the following criteria are not eligible for enrollment in the trial: 
1. Men participating in another clinical trial involving an investigational drug within 
the last 30 days prior to the first screening visit. 
2. Men not living in the catchment area of the study site or within a reasonable 
travel time from the site. 
3. Any clinically significant abnormal findings at screening per the Investigator’s 
medical judgement. 
4. Elevated PSA (e.g. levels ≥ 4 ng/mL), according to study site’s local 
laboratory reference normal values for adult men. 
5. Abnormal serum chemistry values that may indicate clinically significant liver 
or kidney dysfunction. Other abnormal laboratory values may also be 
exclusionary, if so considered by the investigator to be clinically significant. 

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6. Use of androgens or other anabolic steroids that may affect testosterone 
measurements 
7. Diastolic  blood pressure (DBP) ≥ 85 and Systolic  blood pressure (SBP) ≥ 
135 mm Hg; (BP will be taken three times at approximately 5 minute intervals 
and the mean of the 3 measurements will be considered). 
8. History of hypertension (well-controlled treated hypertension (< 135/85) is 
allowed). 
9. Known history of primary testicular disease or disorders of the hypothalamic-
pituitary axis. 
10. Known hypersensitivity to progestins or testosterone. 
11. History of prostate or breast carcinoma  
12. Significant lower urinary obstructive symptoms (IPSS > 19). 
13. Known history of significant cardiac, renal, hepatic or prostatic disease. 
14. History of thromboembolic disease. 
15. A serious systemic disease such as diabetes mellitus (including diabetes 
controlled with treatment), HIV, or morbid obesity. 
16. Current active or ongoing Hepatitis infection 
17. Known or suspected current alcohol dependence syndrome, chronic 
marijuana use, or any illicit drug use that may affect 
metabolism/transformation of steroid hormones and study treatment 
compliance. 
18. Known active or chronic dermatitis or other severe skin disorder. 
19. Desiring fertility within 6 months of study participation. 
20. History of severe depression or other serious mental health disorder. 
21. Men participating in competitive sports where drug screening for prohibited 
substances (including anabolic steroids) is routine will be advised of the 
relative and temporary hazards that participating in this study may have for 
their sporting status. 
 
Female participant – Exclusion Criteria 
 
Women who meet any of the following criteria are not eligible for enrollment in the 
trial: 
1. Desire to become pregnant during the study. 
2. Breastfeeding 
3. Known or suspected current alcoholism or drug abuse. 
4.  History of thrombosis 
5. Serum testosterone outside normal reference ranges by local laboratory 
standards or evidence of hirsutism (modified Ferriman-Galwey score > 8) 
6. Participation in another clinical trial involving an investigational drug within 
the last 30 days prior to the first screening visit. 
7. Current pregnancy. 
8. Known hypersensitivity to progestins or testosterone. 
9. Any clinically significant abnormal findings at screening per the Investigator’s 
medical judgement.  
10. Use of androgens or other anabolic steroids that may affect testosterone 
measurements. 
11. Known active or chronic dermatitis or other severe skin disorder. 
12. Known or suspected current alcohol dependence syndrome, chronic 
marijuana use, or any illicit drug use that may affect 
metabolism/transformation of steroid hormones and study treatment 
compliance. 

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13. Not living in the catchment area of the study site or within a reasonable travel 
time from the site. 
Safety 
Parameters: 
Safety parameters include enumeration of all AEs and clinically significant safety 
labs abnormalities. 
 
Safety laboratory tests will be performed at each clinical site. Serum testosterone 
and Nestorone will be measured by liquid chromatography tandem mass 
spectrometry at the Endocrine and Metabolic Research Laboratory at Los Angeles 
Biomedical Research Institute, Harbor-UCLA Medical Center. 
Other 
Assessments: 
Demographic characteristics, including age, ethnicity and race will be collected. 
Statistical 
Analysis: 
An estimated sample size of 12 couples is based on the studies conducted 
assessing testosterone transference. Based on the published data, a sample size of 
12 female participants will give an 80% power to detect a change from baseline in 
serum testosterone of non-dosed females for a mean difference of 9 ng/dL with a 
standard deviation of 10 ng/dL (Stahlman, et al., 2012) (Stahlman, et al., 2012).  
 
The safety sample will be all subjects who had been exposed to one dose of the 
medication. 
 
The pharmacokinetic sample will consist of all subjects in the safety sample who had 
sufficient bioanalytical assessments to calculate a complete set of pharmacokinetic 
parameters. These are AUC 0-24, Cavg, Cmax, Cmin, Tmax, Tmin, Fluctuation 
(Cmax-Cmin/Cavg) for both serum testosterone and Nestorone.  
 
 
 

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Title:  
An Open-Label Study of Serum Testosterone and Nestorone in Females After 
Secondary Exposure to Nestorone ® (NES) + Testosterone (T) Combined Gel 
Applied to Shoulders and Upper Arms in Males: Effect of Washing or Clothing 
Barrier to the Application 
 
1. Introduction and Background  
 
Contraception options for men are limited to condoms and vasectomy, yet international surveys have 
shown that a large number of men would use a new contraceptive method if one were available 
(Heinemann et al., 2005; Dorman and Bishai, 2012; Martin et al., 2000). The goal is to develop a 
hormonal contraceptive method for men that proves to be effective, safe, reversible, self-delivered, user-
friendly and affordable.  Gonadotropins and testosterone (T) play a pivotal role in the maintenance of 
normal spermatogenesis, with suppression of gonadotropins by exogenous administration of androgens 
resulting in azoospermia/oligozoospermia in 50 – 70% of normal men (WHO Task Force, 1990; 
Cummings and Bremner, 1994).  Azoospermia may not be achieved until both gonadotropins and T are 
suppressed (Nieschlag, Zitzmann, and Kamischke, 2003). Therefore, in addition to the suppression of 
gonadotropins, intratesticular depletion of T is also required to achieve oligozoospermia. In order to 
maintain androgenicity (including libido, bone structure, mental effects, hematopoiesis), T should be 
substituted by an androgen preparation.   
 
The treatment with androgen alone has been shown to be highly effective in Asian men but less effective 
in non-Asian men enrolled in clinical trials  (World Health Organization Task Force on Methods for the 
Regulation of Male Fertility, 1990). In order to increase the contraceptive efficacy of androgen treatment 
in Caucasian men, several other combinations of testosterone preparations with different progestins or 
gonadotropin releasing hormone antagonists have been tested in clinical trials.  Depo-
medroxyprogesterone acetate (DMPA) in combination with T has been shown to result in suppression of 
gonadotropins and spermatogenesis (Knuth, Yeung, and Nieschlag, 1989; Handelsman et al., 1996). 
Adding a single intramuscular (IM) injection of DMPA 300mg in men receiving T pellets at 800mg 
increased suppression of spermatogenesis from 40% in men receiving T alone, to 90% in men receiving 
both T and DMPA.  This combination of T implants and DMPA by IM injection resulted in no significant 
changes in body weight or lipids (total, LDL- or HDL-cholesterol levels).  
 
Efficacy data using this combination of T pellets (800 mg/4 months) plus DMPA injections (300 mg/3 
months) was effective in preventing pregnancies in 55 couples with 36.4 person years of exposure 
(Turner et al., 2003).  Similar to DMPA, both levonorgestrel and norethistrone enanthate have been 
shown to suppress gonadotropins and sperm counts when added to T administration (Bebb et al., 1996; 
Kamischke et al., 2000; Kamischke et al., 2002).  However, all of these regimens have also been shown 
to decrease HDL cholesterol, possibly due to the inherent androgenic activity of 19-nortestosterone 
progestins (Anawalt et al., 1999; Wu FC et al., 1999; Wallace and Wu, 1990). 
 
Nestorone® (NES) is a synthetic, 19-nor-progesterone derived progestin, with selective pharmacological 
profile, with no binding to androgen receptors (Kumar et al., 2000).  NES is inactive when taken orally but 
very potent when given parenterally (Sitruk-Ware et al., 2003) and has shown no androgenic effects in 
animals, unlike 19-nortestosterone derived progestins such as norethisterone and levonorgestrel. The 
Population Council (PC) has been working on NES for use in female contraception.  NES has proven to 
be effective as a female contraceptive when administered via vaginal rings (Laurikka-Routti, Haukkamaa, 
and Heikinheimo, 1990), implants (Haukkamaa et al., 1992; Diaz et al., 1995; Brache et al., 2000) and 
transdermal systems (Fraser et al., 2007; Stiruk-Ware, 1989; Sitruk-Ware, 1995).   
 
We have previously shown the safety and efficacy of using separate NES and T gels as a strong 
suppressor of gonadotropins and spermatogenesis (CCN005 and CCN007) (Illani et al., 2012; Mahabadi 

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et al., 2009).  Gonadotropin suppression is marked after 3 to 4 weeks of gel application.  Severe 
oligozoospermia is observed in over 89 percent of men at 20 to 24 weeks after daily application of 8 mg 
NES gel and 100 mg T gel (Ilani et al., 2012).  Results of a recent study (CCN005A) showed the 
combined NES/T gel, in a small volume of 5mL per dose, applied to the arms and shoulders resulted in 
effective suppression of gonadotropins to below 1 IU/L and levels of serum NES were comparable to 
those observed in the previous studies (CCN005 and CCN007) (Roth et al., (unpublished)).  
 
In another proposed study “Clinical Evaluation of Nestorone® (NES) and Testosterone (T) Combination 
Gel for Male Contraception (CCN017)”, adult men will apply a combined testosterone and Nestorone gel 
on their arms and shoulders for approximately 68 weeks. Possible transfer of transdermal Nestorone 
from men to women upon close skin contact has not been studied.  Their female participant may be 
exposed to transfer of testosterone and Nestorone inadvertently through close skin contact despite the 
male participant being asked to wear a 100% cotton T-shirt covering the area of gel application or 
washing with soap and water before close skin contact with his female participant or children.  
 
This proposed study will be conducted to assess maximum testosterone and Nestorone transfer from the 
skin of the healthy male volunteers to non-dosed female participants after application of the combined 
testosterone and Nestorone gel over the shoulders and upper arms of the male participant.  
 
2. Objectives 
 
2.1 Primary objective  
 
The primary objective of the study is to determine the pharmacokinetics of testosterone (T) and 
Nestorone (NES) concentrations in female participants after a single exposure of skin contact with a 
male participant dosed with a gel containing T and NES applied to the shoulders and upper arms. The 
skin contact with non-dosed female participants occurs 2 hours after male gel application, and has 3 
variations: 
 
With a 100% cotton T-shirt clothing barrier; 
 
After the application site is washed with soap and water in a shower and dried; 
 
Without washing or clothing barrier to the skin to skin contact.  
 
This will be evaluated by assessing differences between average serum testosterone and Nestorone 
levels at baseline compared to Cavg, Cmax, Cmin after secondary exposure to Nestorone + 
Testosterone Combination Gel (NES/T gel). 
 
2.2 Primary Endpoint 
 
The primary objective will be evaluated in female participants by assessing changes from baseline up to 
48 hours for serum testosterone levels in Cavg, Cmax, and Cmin after secondary exposure to Nestorone 
+ Testosterone Combination Gel (NES/T gel).  Also, the Nestorone levels will be summarized after 
secondary exposure to NES/T gel by presenting Cavg, Cmax, and Cmin. These endpoints will be 
summarized for each of the 3 types of skin contact between the man and woman. 
 
2.3 Secondary objectives   
 
The secondary objectives are: 
1. To determine the effects of showering on the pharmacokinetics of testosterone and Nestorone 
concentrations in male participants after application of testosterone and Nestorone combined gel 
on shoulders and upper arms in men.  
2. To determine the amount of testosterone and Nestorone that remained on the skin after 
application in men. 

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3. To assess the safety and tolerability of the combined gel in men.  
4. To assess the safety in women possibly exposed to the gel after skin contact at the site of 
application of the gel in men. 
 
2.4 Secondary Endpoints 
 
The secondary objectives will be evaluated using the following endpoint measures: 
1. The pharmacokinetic parameters of testosterone and Nestorone in males after wearing a T shirt 
and after washing will be compared to serum testosterone and Nestorone pharmacokinetics after 
application of the combined gel without washing. 
2. Serum testosterone pharmacokinetics in males after applying NES/T gel with or without T shirt 
and with washing will be compared to baseline pharmacokinetic parameters.  
3. Average testosterone and Nestorone levels 90 and 150 minutes after application in men as 
measured by adhesive D-square strips with and without showering. 
4. Incidence of adverse events and serious adverse events for both partners. 
5. Changes from baseline in safety labs in both partners. 
6. Percentage of females with increased (relative to baseline) acne and hirsutism at each visit. 
These endpoints will be summarized for each of the 3 types of skin contact between the man and the 
woman. 
 
3. Rationale, Benefits and Risks 
3.1 Rationale 
 
A number of sporadic reports have shown the transfer of applied testosterone from the skin of men to 
women  (Merhi & Santoro, 2007) and children (Brachet, et al., 2005; Kunz, et al., 2004) that may result in 
hirsutism, acne and virilization in the women and children. Previous studies have confirmed that 
testosterone may be transferred from men who applied transdermal testosterone gel to women upon 
close contact (Miller, et al., 2012; Rolf, et al., 2002; Stahlman, et al., 2012; Stahlman, et al., 2012).The 
transfer of testosterone to women is related to the dose of testosterone applied to men. In studies for 
testosterone transference, secondary exposure to women occurred after direct skin contact 2 hours after 
gel application. The studies showed that 2.5 g (40.5 mg) and 5 g (81 mg) of testosterone gel resulted in 
elevation of serum T in females with changes of all testosterone pharmacokinetics parameters as 
compared to baseline by 24-27% and 52 to 70% respectively. Transference of testosterone from the site 
where testosterone gel is applied in men to the female after close skin contact was prevented by men 
wearing a 100% cotton T-shirt covering the application area or by showering approximately 2 hours after 
application of gel (Stahlman, et al., 2012; Stahlman, et al., 2012). Washing the skin 2 to 6 hours after 
applying 81 mg of Androgel 1.62 % on the skin of men resulted in 10-14 % decrease in the average 
concentration of serum testosterone.  Skin washing decreased the mean amount of testosterone 
remaining on the skin by at least 81% (Stahlman, et al., 2012). Showering within 30 minutes after 
application of testosterone gel may lower serum testosterone in men to levels below the adult reference 
range and is not recommended ( (de Ronde, et al., 2011). 
 
Possible transfer of transdermal Nestorone from men to women upon close skin contact has not been 
studied. In another proposed study “Clinical Evaluation of Nestorone® (NES) and Testosterone (T) 
Combination Gel for Male Contraception (CCN017)”, adult men will apply a combined testosterone and 
Nestorone gel on their arms and shoulders for approximately 68 weeks. Their female partner may be 
exposed to transfer of testosterone and Nestorone inadvertently through close skin contact despite the 
male participant being asked to wear a 100% cotton T-shirt covering the area of gel application or 
washing with soap and water before close skin contact with his female partner or children. This proposed 
study will be conducted to assess maximum testosterone and Nestorone transfer from the skin of the 
healthy male volunteers to non-dosed female participants after application of the combined testosterone 
and Nestorone gel over the shoulders and upper arms of the male participant. The study will assess the 

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absorption and pharmacokinetics of testosterone and Nestorone in female healthy volunteers after single 
exposure of skin contact (her hands and arms) to the area where the male participant had applied the gel 
(his shoulders and upper arms) approximately 2 hours earlier.  The study will assess the absorption and 
pharmacokinetics under three conditions: 1) indirect contact with the male participant wearing a 100% 
cotton T-shirt covering the area of application; 2) direct skin contact with male participant’s skin where 
the gel was applied after the male has washed the application area with soap and water; and 3) direct 
skin contact where the gel was applied without a T-shirt barrier or shower for the male participant. The 
effect of showering on the pharmacokinetics of Nestorone will also be assessed in the male and 
compared to that obtained when there is no shower. 
 
3.2 Risks and Benefits 
 
There is no immediate benefit to the participating couples. The benefits would be in the future 
development of a reversible and effective male contraceptive. 
 
Previous experience with study preparations of NES and T gel suggests that serious adverse events are 
unlikely.  The risks of participation in this study are expected to be minimal.  T gel has been FDA 
approved for clinical use in hypogonadal men, produces minimal skin irritation, and has long-term safety 
data. In the United States, transdermal testosterone preparations are the popular and well accepted form 
of testosterone replacement therapy. Testosterone in men may produce reversible androgen related side 
effects such as: mild breast enlargement, acne, oiliness of skin, slight weight gain, mild increases in 
hematocrit, decrease in HDL cholesterol, and slight increase in the size of the prostate.  In a prior study 
for men of NES and T gel for 24 weeks, no serious adverse events were reported.  Common minor side 
effects included skin symptoms, including acne and dry skin, weight gain, and some mood changes 
including depressed mood, changes in libido, mood swings, fatigue or irritability.  Transfer of applied 
testosterone from the skin of men to women may result in hirsutism, acne and virilization in women.   
 
3.3 Dose Rationale 
 
In a prior 6-month study of NES and T gel applied separately on two sites of the body daily, two doses of 
NES gel were evaluated, 8mg and 12 mg (Ilani et al., 2012).  There was no significant difference in the 
number of men who achieved a sperm concentration <1 million/mL; therefore, the 8 mg dose was 
selected for a future study. In addition, previous studies tested lower than 8mg doses which showed 
lower doses were not effective in suppressing gonadotropins (Mahabadi, et al., 2009). 
 
Based upon long-term use of T gel for treatment of male hypogonadism and the prior studies of NES and 
testosterone gels (CCN005 and CCN007), the dose of 62.5 mg T was selected to deliver the appropriate 
amount of T (approximately 60 mg) within the combination gel in a volume of about 5 mL in order to 
maximize the number of treated men with a serum T in the mid-normal range, without supraphysiologic 
levels of T. 
 
Based on results of a 4 week study (CCN005A) applying a combined NES + T gel delivering 
approximately 62.5 mg T and 8.3 mg NES per day in 5 mL volume, a larger efficacy trial of the combined 
gel (CCN017) is proposed.  This study will test the transference effects of the combined product 
proposed for the larger efficacy study. 
 
4. Study Design 
 
This is a two-center, open-label study conducted in healthy male and female volunteers at two academic 
research centers. The study will consist of three single applications of the Nestorone (NES) + 
testosterone (T) combined gel on the shoulders/upper arms of male participants followed 2 hours later by 

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supervised skin contact by the non-dosed female participants on the application site on days 1, 8, and 
15. 
 
The protocol is expected to enroll a total of 12 healthy male subjects and their partners (i.e.12 female 
subjects), 6 male and 6 female subjects per site.  The couple will be instructed to use another highly 
effective method of contraception for the duration of the study (i.e. at a minimum use double barrier 
method such as a condom with spermicide).  
 
Screening will take approximately 2 to 4 weeks to ensure the participants meet inclusion criteria.  
Couples who meet the eligibility requirements will begin the treatment phase, which includes three 
overnight visits on days 1, 8, and 15. Within two weeks after the completion of the day 15 treatment 
application, a telephone call will be made to the male participants as their end of study/exit visit. At the 
same time, the female participants will return to the clinic for a blood draw and AE assessment for their 
end of study/exit visit. 
 
A study design table outlining the schedule of assessments is provided in Appendix 1. 
 
Participating clinical sites will transmit male and female subject data to the statistical and clinical 
coordinating center (SCCC) on a weekly basis.  
 
5. Subject Compliance 
 
As gel application and skin contact will occur under direct study staff supervision, no issues with 
compliance are anticipated. 
 
All aspects of this study will be performed according to CFR Title 21, CRF Title 45, Part 46, Good Clinical 
Practices  (GCP) and International Conference on Harmonisation (ICH) under an IND application. All 
principles of the Declaration of Helsinki will be followed. 
 
6. Principal Investigators and Research Centers 
 
Two investigational research centers will conduct the study. A complete list of investigators, sub-
investigators and coordinators will be maintained with trial documentation. 
 
Listed here are the investigational research centers conducting this study: 
 
Christina Wang, MD, PI: Harbor-UCLA Medical Center and Los Angeles Biomedical Research 
Institute 
 
Stephanie Page, MD, PhD PI: University of Washington 
 
7. Subject Recruitment 
 
This study will be conducted by the National Institute of Child Health and Human Development (NICHD) 
in its Contraceptive Clinical Trials Network (CCTN) (Male Group) at two sites in the US (Los Angeles and 
Seattle).  This study will be listed on the website ClinicalTrials.gov and the websites of the respective 
institutions. Study couples will be recruited from the general population and reproductive health services 
affiliated with each site.  Referrals from previous participants in male contraceptive clinical trials are 
accepted.    Sites will obtain IRB approval for all recruitment materials used as part of the study.  
Subjects will be asked to contact one of the study sites by telephone or email. The coordinator will 
screen potential male subjects over the phone or email by inquiring about their age and medical history. 
Potential male subjects who qualify by initial screen will be scheduled with their partner for an 
appointment to consult with the investigator about further eligibility requirements for the study. Both the 
male and female subjects will sign an informed consent prior to initiation of any study screening 

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procedures. Couples will be selected for the study according to the selection criteria detailed in Section 
10.   
 
8. Study Duration 
 
The total duration of the study for each couple is expected to be approximately 2 months.  Both members 
of the couple will be enrolled in the study throughout this period. The study will be divided into 3 phases: 
 
a screening phase of 2 to 4 weeks  
 
a treatment phase of 17 days  
 
and a post-treatment phase of 2 weeks  
 
This protocol will involve a start-up period including the time to initiate the study and begin recruitment of 
couples. The recruitment period for sites to enroll subjects, including the site start-up period will be about 
2 months with the treatment phase for some subjects starting during this period. After Informed Consent 
is obtained, the couple should use a reliable method of contraception until the study exit visit occurs. 
 
Subject recruitment is expected to begin and complete during Q1 2017. If this enrollment timeline is met, 
all male subjects should finish treatment by approximately the end of Q1 2017 and the study should end 
by approximately Q2 2017.  Therefore, the total duration of the study will be approximately 6 months for 
each study site including pre- and post- study activities.  The end of the study will occur when the last 
couple to be enrolled has completed their end of study/exit visits.   
 
Results of the study are expected to be available Q3 2017. 
 
9. Number of Subjects 
 
The protocol is expected to enroll a total of 12 healthy male subjects and their partners (i.e.12 female 
subjects), 6 male and 6 female subjects per site.   
 
Couples who do not complete the study will be replaced.  Couples who discontinue will not be re-enrolled 
into this study. 
 
10. Selection of Subjects 
 
Healthy men ages 18 – 50 years with an 18 –40 year old female will be enrolled in the study according to 
the inclusion and exclusion criteria. Couples will be informed about the nature, aims and objectives of the 
study and both male and female subjects will be required to give their written consent prior to 
participation in the study. 
 
Couples will be enrolled after providing informed consent and completing screening examinations, which 
include, but are not limited to, clinical evaluation of general and reproductive history, a detailed physical 
examination and analyses of blood.  Screening results should be within reference ranges or assessed by 
the Investigator to be not clinically significant if out of normal ranges prior to couple enrollment.   
 
The couple will be instructed to use a highly effective method of contraception for the duration of the 
study (i.e. at a minimum use double barrier method such as a condom with spermicide).  
 
10.1 Inclusion criteria: 
 
10.1.1 Male Partner Inclusion Criteria: 
 
Men who meet all the following criteria will be eligible for enrollment in the trial: 

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1. Good health as confirmed by medical history, physical examination, and clinical laboratory tests of 
blood and urine at the time of screening; 
2. 18 to 50 years of age;  
3. BMI ≥18 and < 35 kg/m2;   
4. No history of androgen use prior to the first screening visit as follows 
a. 1 month prior for oral or transdermal androgen, 
b. 3 months prior for Testosterone cypionate or enanthate injection, 
c. 6 months prior for Testosterone undecanoate injection; 
5. Agreement to use a recognized effective method of short acting contraception with his partner (i.e. 
at a minimum use double barrier method such as a condom with spermicide) during the entire 
study;   
6. ;  
7. In the opinion of the investigator, male subject is willing and able to comply with the protocol; 
8. Provision of valid, written and informed consent. 
 
10.1.2 Female Partner Inclusion Criteria: 
 
Women who meet all the following criteria will be eligible for enrollment in the trial: 
1. Good general health (BMI ≥18 and <30 kg/m2) with no chronic medical conditions that result in 
periodic exacerbations which require significant medical care; 
2. Aged between 18 and 40 years, at the enrollment visit;  
3. Not pregnant and not breastfeeding. 
4. Agreement to use a recognized effective method of contraception throughout the study.   
5. Willingness and ability to provide valid, written and informed consent and to comply with the 
protocol; 
6. No desire for pregnancy within the next 6 months. 
 
10.2 Exclusion criteria: 
 
10.2.1 Male Partner Exclusion Criteria: 
 
Men who meet any of the following criteria are not eligible for enrollment in the trial: 
1. Men participating in another clinical trial involving an investigational drug within the last 30 days 
prior to the first screening visit. 
2. Men not living in the catchment’s area of the study site or within a reasonable travel time from the 
site. 
3. Any clinically significant abnormal findings at screening per the Investigator’s medical judgement. 
4. Elevated PSA (e.g. levels ≥ 4 ng/mL), according to study site’s local laboratory reference normal 
values for adult men. 
5. Abnormal serum chemistry values that may indicate clinically significant liver or kidney 
dysfunction. Other abnormal laboratory values may also be exclusionary, if so considered by the 
investigator to be clinically significant. 
6. Use of androgens or other anabolic steroids that may affect testosterone measurements 
7. Diastolic  blood pressure (DBP) ≥ 85 and Systolic  blood pressure (SBP) ≥ 135 mm Hg; (BP will 
be taken three times at approximately 5 minute intervals and the mean of the 3 measurements 
will be considered). 
8. History of hypertension (well –controlled treated hypertension (< 135/85) is allowed). 
9. Known history of primary testicular disease or disorders of the hypothalamic-pituitary axis. 
10. Known hypersensitivity to progestins or testosterone. 
11. History of prostate or breast carcinoma  
12. Significant lower urinary obstructive symptoms (IPSS > 19). 
13. Known history of significant cardiac, renal, hepatic or prostatic disease. 

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14. History of thromboembolic disease. 
15. A serious systemic disease such as diabetes mellitus (including diabetes controlled with 
treatment), HIV, or morbid obesity. 
16. Current active or ongoing Hepatitis infection 
17. Known or suspected current alcohol dependence syndrome, chronic marijuana use, or any illicit 
drug use that may affect metabolism/transformation of steroid hormones and study treatment 
compliance. 
18. Known active or chronic dermatitis or other severe skin disorder. 
19. Desiring fertility within 6 months of study participation. 
20. History of severe depression or other serious mental health disorder. 
21. Men participating in competitive sports where drug screening for prohibited substances (including 
anabolic steroids) is routine will be advised of the relative and temporary hazards that 
participating in this study may have for their sporting status. 
 
10.2.2 Female Partner Exclusion Criteria: 
 
Women who meet any of the following criteria are not eligible for enrollment in the trial: 
1. Desire to become pregnant during the study. 
2. Breastfeeding 
3. Known or suspected current alcoholism or drug abuse.  
4. History of thrombosis 
5. Serum testosterone outside normal reference range by local laboratory standards or evidence 
hirsutism (modified Ferriman-Galwey score > 8) 
6. Participation in another clinical trial involving an investigational drug within the last 30 days prior 
to the first screening visit. 
7. Current pregnancy. 
8. Known hypersensitivity to progestins or testosterone. 
9. Any clinically significant abnormal findings at screening per the Investigator’s medical judgement.  
10. Use of androgens or other anabolic steroids that may affect testosterone measurements. 
11. Known active or chronic dermatitis or other severe skin disorder. 
12. Known or suspected current alcohol dependence syndrome, chronic marijuana use, or any illicit 
drug use that may affect metabolism/transformation of steroid hormones and study treatment 
compliance. 
13. Not living in the catchment area of the study site or within a reasonable travel time from the site. 
 
11. Concomitant Treatment 
 
Any other investigational medication should be stopped 30 days before the first screening visit.  
Concomitant and over the counter medications are discouraged except as prescribed for the treatment of 
concurrent medical conditions that are not exclusionary.  All prior medications taken within 30 days of 
screening and concomitant treatments while participating on the study for both male and female subjects 
will be recorded on the subject’s case report form (eCRF), including the name of the drug (preferably the 
generic drug name), start and stop dates, dose, and reason for use from the time of informed consent 
signing through the end of study/exit visit.  
 
Male and female subjects will be instructed to limit alcohol consumption while on the study to a total of 14 
and 7 drinks respectively per week with no more than 2 drinks per night. Asking about concomitant 
medications at each visit will include asking about alcohol and recreational drug use. 
 
11.1 Exclusionary Medications 
 
Concomitant medications that are exclusionary for the couple include: 

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 
Use of sex hormones/steroids  
 
Use of androgens or other anabolic compounds for medical purposes or for body building 
including hCG, FSH, clomiphene, anastrazole/letrozole, finasteride and dutasteride, 
 
Anticoagulants 
 
Antihypertensives 
 
Use of medications that will interfere or interact with Nestorone or Testosterone  
 
Use of oily cosmetic skin gels/products that would prevent absorption of steroids 
 
Refer to Appendix 2 for a detailed list of exclusionary medications. 
 
Subjects who begin taking an exclusionary medication after study enrollment will require a waiver from 
the Medical Monitor to continue in the study.  Waiver will be assessed on dose and amount of time 
medication will be taken against the potential effects the medication may have on the subjects. 
 
12. Study Materials 
 
12.1 Study Medication 
 
The combined gel jars will be manufactured by Particle Science International supplied through the 
NICHD under the supervision of the Population Council. The combined gel is a transdermal treatment 
that will be applied as three single applications to a male subject’s arms and shoulders on three different 
treatment days. The formulation will be a hydro alcoholic gel containing about 1.43% T (14.3 mg T/g gel).  
About 9 to 14% of the steroid (T or NES) in the gel applied is available to the body. The amount of gel to 
be applied each application will be approximately 5 mL in volume.  The gel application volume will 
contain 62.5 mg of T that will deliver approximately 6 mg T to the body per day (Swerdloff et al., 2000; 
Wang et al., 2000). This gel volume will also contain 8.3 mg of NES that will deliver about 0.8 mg of NES 
to the body per day (NES 8 mg/d + T 60 mg/d (NES8/T60) gel). The dose of T that is delivered to the 
body per day is at the middle range of what is produced by the body per day in a healthy man (Ilani et al., 
2012).  
 
The progestin Nestorone (NES) has been tested in men as a transdermal gel with T gel in three prior 
studies and has an excellent safety profile (Mahabadi et al., 2009; Illani et al., 2012; Roth et al., 
(unpublished). Nestorone® (NES) is a synthetic, 19-nor-progesterone derived progestin, with selective 
binding to the progesterone receptors and with no binding to androgen receptors (Kumar et al., 2000).  
NES is inactive when taken orally but very potent when given parenterally (Sitruk-Ware et al., 2003) and 
has shown no androgenic effects in animals, unlike 19-nortestosterone derived progestins such as 
norethisterone and levonorgestrel. The Population Council has an IND for the use of NES8/T60 gel and 
this study will be conducted under this IND.  
 
The current formulation tested in CCN005A will be provided for this study and was produced by Particle 
Science (PSI) (Bethlehem, PA), a Good Manufacturing Practice (GMP) contract manufacturing 
organization under the supervision of Population Council and sponsored by NICHD. NES is obtained 
from Population Council (New York, NY). The CMC documentation is included in the IND submission. 
The preparation of the investigation product to be delivered to the study subjects by the investigational 
pharmacists at each site is described in Appendix 6. 
 
The summary of findings from preclinical studies and previous clinical trials is presented in the separate 
Investigator’s Brochure. 
 
12.1.1 Target Population 
 

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Healthy men ages 18 – 50 years, involved in a relationship with an 18 – 40 year old female partner will 
be enrolled in the study according to the inclusion and exclusion criteria. Approximately 12 couples will 
participate in the study.   
 
12.1.2 Packaging 
 
All packaging and labeling of the study medication will be prepared in accordance with 21CFR Section 210 
and 211.  The combination NES8/T60 gel study treatment will be prepared by site pharmacists in a single 
syringe which is placed in a bag and delivered to the clinic for each day of application (1, 8 or 15) that a 
couple is in clinic for transference assessment.  The NES8/T60 combined gel has been formulated to 
deliver a total of 5 mL of the combined gel containing 8.3 mg NES and 62.5 mg T per daily dose, the 
formulation tested in the current CCN005A study.   
 
Each bag will be labeled with a 2-part label which will be applied by the pharmacist. The part of the label 
remaining on the bag will have NICHD/PC, product identification, number of syringes of IP within the bag, 
subject ID, date dispensed and the FDA caution statement for an investigational new drug required by 
law. The detachable part of the label contains a place to enter the subject ID and date dispensed. The 
pharmacist will place a 1-part label on the individual syringes with the FDA caution statement, product 
identification and subject number. Prior to dispensing, the site pharmacist will label the bags, removing 
the detachable section of the label and paste it into their pharmacy dispensing log. The 1-part labels on 
the individual syringes will also be applied prior to dispensing.  
 
As bags and syringes are used, they should be retained by the site for later monitor accountability.   
 
12.1.3 Dosage and Administration 
 
The investigational product will be provided to the male subjects as a transdermal gel in single 
application syringes.    All male subjects will apply NES 8 mg/d + T 60 mg/d (NES8/T60) combined gel to 
the right and left shoulders and area of the upper arms to the top of the bicep muscle (i.e., to shoulder 
and arm skin area that would typically be covered by a short sleeve T-shirt) on the three treatment days.  
Male subject instructions regarding gel application is located in Appendix 3.  Male subjects will push the 
plunger of the syringe to deliver the gel onto the palm of their hand and then gently rub gel on the skin of 
the upper arms and shoulders. The gel dries within a few minutes.  The dose of the gel application will be 
done at the study visit under the direct observation of the study staff.  The day and time of the treatment 
applications will be recorded in the source.  
 
12.1.4 Duration of Subject Participation 
 
Male and female subjects will be evaluated for a period of approximately 2 months and both members of 
the couples will be enrolled in the study throughout this period.  The study will be divided into a screening 
phase of 2 to 4 weeks, a 17-day treatment phase, and then a 2 week post-treatment phase (see 
Appendix 1).  
 
12.1.5 Investigational Product Accountability 
 
Each study site is required to maintain records of administration of the test product, including dates and 
quantities, by subject ID number and initials of the research center personnel distributing study product. 
Study gel accountability logs will be provided for this purpose. 
 
Investigational product will be shipped to each research center after the receipt and acceptance of all 
necessary regulatory documents. Upon receipt of investigational product, an inventory of the 
investigational product must be completed by the Investigator or Investigator's designee.  All 

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investigational product administered must be recorded for each male subject. All dosing records must be 
consistent with the master dispensing and return records. 
 
The site will be responsible for maintaining adequate inventory of investigational product supply at the 
research center(s). In order to receive additional shipments of investigational product, a request from the 
research centers must be emailed or faxed to their study monitor or the designated contact. 
 
12.1.6 Storage 
 
NES8/T60 combined gel jars will be stored at room temperature (20 °C/68 °F – 25°C/77 °F) in a dry 
place under controlled and secured conditions (i.e. locked storage area away from sunlight) at the study 
site.  The investigational product will be accessible only to study personnel designated to handle the 
product by the Principal Investigator. While at the study site, the gel must be stored within the 
appropriate temperature range and secured in a limited-access area. A temperature log for the 
investigational product storage area must be maintained for the duration of the study.   
 
12.1.7 Disposal/Return 
 
Empty used syringes will be retained at the site with their dispensing bags in ziplock biohazard bags.   All 
empty syringes will be destroyed at each study site following site and local regulatory specific drug 
destruction standard operating procedures once final drug accountability has been performed by the 
study monitor and they have authorized drug destruction. If necessary, destruction will also be performed 
during the study in accordance with site and local regulatory specific drug destruction standard operating 
procedures after accountability has been completed by the monitor and they have authorized destruction. 
Procedures for remaining unused study product return or disposal will be provided by the Sponsors at 
the end of the study. 
  
13. Study Procedures 
 
13.1 Clinical Assessments  
13.1.1 Skin Exam 
Skin Exams will be performed on female subjects at Screening and various points throughout the study 
using the Ferriman-Gallwey scale to assess changes in acne and hirsutism in female subjects exposed 
to the combination Nes/T gel.  A score between 1 and 4 is assessed for nine different areas of the female 
body then a total score tallied.  A total score of 0 on the scale indicates the absence of terminal hair. If 
the total score is less than 8 it is considered normal.  If the total score is between 8 and 15 it is 
considered mild hirsutism.  If the score is greater than 15 it is considered moderate or severe hirsutism. 
 
13.2 Laboratory Tests and Evaluations 
 
Blood samples for laboratory analyses will be collected at visits throughout each phase of the study for 
processing at both the central and local labs as outlined below. Venipuncture for blood sampling should 
be in the antecubital fossa or lower on the arm for male participants.  Venipuncture for blood sampling for 
female participants should be in the antecubital fossa to prevent issues of her rubbing her hands and 
arms.   
 
For any labs processed by the study site’s local lab, the investigator must review and sign all 
laboratory reports and file a copy with each subject’s chart.  All out-of-range laboratory results 
must be assessed by the investigator for clinical significance. Any reports required from the screening 
assessment must be reviewed, signed and dated on or before the date/time of enrollment in order to 
properly document the determination of eligibility.  

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13.2.1 CBC, Clinical Chemistries, and PSA 
Blood samples for laboratory analyses will be collected for analysis at the local certified laboratories at 
each center for the following: 
 
Complete Blood Counts (CBC): RBC, WBC, Hemoglobin, Hematocrit, Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Platelet Count 
 
Clinical chemistries: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, calcium.  
 
Liver function tests:  total bilirubin, alkaline phosphatase (ALPH), alanine aminotransferase (ALT), 
aspartate transaminase (AST), BUN, and albumin 
 
Prostate Specific Antigen (PSA) (male subjects only) 
 
All local laboratory values will be recorded on case report forms (CRFs). 
 
 
13.2.2 Hormone Testing 
 
13.2.2.1 
Screening Hormones 
 
At screening, a urinary beta HCG level will be tested in females, processed by the study site’s local lab 
and reported in the electronic Case Report Forms to confirm that the subject is not pregnant.  
Additionally, if at any time a urine pregnancy test on the study comes back positive after screening, then 
a confirmatory serum quantitative beta HCG test will be performed. 
 
Screening serum total testosterone measurements will be done locally at both sites for male and female 
subjects to assess for total testosterone outside normal reference ranges by local laboratory standards.  
Results will be reported in the EDC system. If abnormal, the sample will be repeated with free 
testosterone, sex-hormone binding globulin, luteinizing hormone and follicle-stimulating hormone 
measurements at Visit 2 with results assessed prior to the couple being enrolled. 
 
13.2.2.2 
Treatment Hormone Measurements 
 
All serum hormone measurements except for screening testosterone will be measured centrally at the 
Endocrine and Metabolic Research Laboratory at Los Angeles Biomedical Research Institute at Harbor-
UCLA Medical Center (LA BioMed/Harbor-UCLA). All sites will ship samples in batches throughout the 
study to the Endocrine and Metabolic Research Laboratory at LA BioMed/Harbor-UCLA Medical Center. 
This laboratory is licensed both by CLIA and the state of California and participates in CAP external quality 
control program and the CDC steroid assay harmonization program. The laboratory has extensive 
experience serving as a central laboratory for international multicenter studies and has served as the 
central hormone laboratory for the past five studies of the male CCTN (see Sections 13.2.2.2 and 13.2.2.3 
below).  
 
Blood samples for hormone are collected in red top plain tubes, allowed to clot and then centrifuged within 
an hour before serum samples are stored.  Samples that will be tested by the central lab will be frozen and 
stored at the local site at -20°C for later transport to the central laboratory, which will perform subject-
batched analysis. A detailed description of the procedures to follow when processing, handling, and 
transporting hormone samples to the Endocrine and Metabolic Research Laboratory at LA BioMed will be 
distributed to each site prior to first subject enrollment (CCN005B Laboratory Manual).  A freezer 
temperature log should be maintained for stored frozen samples. 
 

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When processing samples that will be measured by the central lab, 1 aliquot for central lab processing 
and 1 aliquot for back-up will be processed from collected samples.  After shipment of aliquot 1 to the lab 
for processing, aliquot 2 will remain at the site as a backup in case of sample issues during 
transportation or testing at the lab.  Further information related to back-up samples will be outlined in the 
Lab Manual mentioned above.  Subjects will be asked to consent for any lab samples remaining at the 
end of the study to be stored long term for possible future studies.  Otherwise, the extra samples will be 
destroyed once all lab testing and analysis has been completed for this study. 
 
13.2.2.3 
Testosterone Assays  
 
Serum T samples from all sites will be measured centrally by validated methods using Liquid 
Chromatography Tandem Mass Spectrometry developed at the LA Biomed at Harbor – UCLA and 
Endocrine Research Laboratory (Shiraishi et al., 2008; Wang et al., 2008). The lower limit of 
quantification is 2 ng/dL. These methods have been established in the Harbor – UCLA Medical Center 
Endocrine Research Laboratory and is specific and sensitive, allowing for measurements of levels below 
the normal male range. 
 
13.2.2.4 
Nestorone Assays 
 
The serum samples for NES measurements will be measured centrally by =methods validated following 
FDA/EMEA guidelines for a bioanalytical laboratory using Liquid Chromatography Tandem Mass 
Spectrometry developed at the Endocrine and Metabolic Laboratory at LA Biomed/ at Harbor – UCLA. The 
specifications of this method and the sample requirement will be detailed in the CCN005B Laboratory 
Manual.  
 
13.2.3 Urine tests 
 
Urine will be obtained from both the male and female subject as a clean-catch specimen for routine 
urinalysis and toxicology at the screening visit.  Testing for drug screening, dipstick urinalysis will be 
performed locally by the research centers under usual procedures for such tests.  For male subjects with 
abnormal results, clinical significance and need for treatment prior to approval for enrollment will be 
determined. All routine urinalysis and toxicology results done locally will be recorded on study case report 
forms (CRFs). 
 
Urine pregnancy testing will be done for female subjects at each treatment visit before rubbing occurs and 
whenever there is any question about whether a woman might be pregnant at any time during the study.  
The urine pregnancy test kits will be supplied centrally by NICHD through a single source.     
 
13.2.4 Safety Procedures 
 
Efforts to reduce safety events from occurring will be completed through the following methods: 
 
The side effects of venipuncture and blood sampling will be minimized by having blood drawn by an 
experienced nurse or physician with the subject in a recumbent position.  
 
The effects of NES8/T60 gel in the male subjects will be minimized by applying the strict inclusion and 
exclusion criteria and carefully monitoring the indices of possible side effects such as hematocrit, and 
PSA. 
 
The side effects of gynecomastia, acne and oiliness of skin in the male should be minimal with the 
dose of testosterone used. 
 
The effects of NES8/T60 gel in the female subjects will be minimized by close observation of the 
transference amounts for careful monitoring of possible side effects such as hirsutism, acne and 
virilization.   
 

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14. Evaluations By Study Visit  
 
The study will include three phases: 
 
a screening phase of 2 to 4 weeks  
 
a treatment phase of 17 days  
 
and a post-treatment phase of 2 weeks  
 
Male and female subjects will be screened for study eligibility and interest in participating in this study 
(Screening Visit 1).  All subjects will have the study explained to them and sign the informed consent prior 
to beginning any study procedures. Both male and female subjects must meet the inclusion criteria and 
have no exclusions in order for a couple to participate. Screening evaluations will continue for subjects for 
at least 1 additional visit in order to complete all screening assessments and to perform a testosterone 
assessment over 24 hours before the start of treatment.  The definition of a couple for this study is a male 
and female subject that will participate in the entire study together.  There are no obligatory relationship 
requirements of the two participants other than the same male and female subjects should participate for 
the duration of the study. 
 
The treatment phase will be initiated once eligibility is confirmed.  At least 6 visits are anticipated for both 
male and female subjects during the treatment phase (Visits 3-8).   
 
The post-treatment phase will begin after the 48 hour female blood draw following the last treatment 
application on day 15.  Two weeks after the completion of the final application a telephone call will be made 
to the male participants as their end of study/exit visit (Visit 9). At the same time, the female participants 
will return to the clinic for a blood draw and AE assessment for their end of study/exit visit (Visit 9). 
 
Throughout the study, both male and female subjects will be encouraged to contact their study site and 
report by phone or visit any unusual event(s) including medical problems.  Extra visits will be arranged if 
indicated.  If necessary, the investigator or study site staff member will contact the subject more frequently 
in order to retain subjects.  (E-mail, phone or text message communication may be used based on subject 
preference and study site assessment regarding this mode of communication with individual subjects).  
 
All subject data will be recorded on electronic case report forms (eCRFs). Subject names will not be 
recorded on the eCRFs; instead, unique subject identifiers will be assigned to the couples per directions 
provided by Health Decisions.  
 
A summary of study procedures are located in the Study Schedule of Assessments (see Appendix 1).  
Missed visits or assessments should be completed as soon as possible prior to the next scheduled visit 
and then the subjects will continue with their regular visit schedule.  The schedule should not be updated 
based on a change in visit days due to the missed visit or assessment.  If a missed visit or assessment 
cannot occur prior to the next regularly scheduled visit, the visit or assessment will just be a completely 
missed visit or assessment without pushing the regularly scheduled visits. 
 
14.1 Screening Phase 
 
The Screening Phase is expected to take 2 to 4 weeks to complete across multiple visits and occurs prior 
to treatment with study product.  If for any reason, more than 28 days elapse between screening visit 1 
and treatment day 1, repeat safety labs (CBC with differential and clinical chemistries) will be performed 
and results reviewed prior to treatment. 
 
The purpose of the pre-treatment screening evaluations is to obtain baseline history, physical exam 
characteristics, and laboratory evaluations to determine if the couple meets eligibility criteria.  
 

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Prior to screening, potential participants will receive information about the study including potential risks 
and a written informed consent form.  Subjects will sign the informed consent form and a copy will be 
given to the subject. Couples will be entered into the EDC system at time of consent. 
 
14.1.1 Screening Visit 1 (Visit 1)  
 
14.1.1.1 
Both Partners 
Both male and female partners will attend the screening visit.  The following screening procedures will be 
performed at Screening Visit 1 for both male and female subjects: 
 
Undergo the informed consent process and sign the informed consent form prior to any study-
specific procedures. The original signed informed consent form will be kept on file with the 
subject's records and a copy will be given to each subject. 
 
A unique subject identification number will be assigned by the site after the couple signs the 
informed consent form and prior to the initiation of screening assessments.  Dr. Wang’s UCLA 
site will start with subject number 31XX.  Dr. Page’s UW site will start with subject number 41XX.  
Subsequent subject numbers will be assigned in sequential order. The subject numbers will not 
be reused (i.e. used more than once) regardless of whether the subject is enrolled or becomes a 
screen failure. To differentiate the male and female participant when labeling lab samples, they 
will be numbered as 31XXM versus 31XXF and so on for lab samples only and by the single 
31XX number for the entire couple when completing eCRF data within the EDC system. 
 
Determine eligibility. 
 
Collect demographic information including age, gender, and ethnicity/race. 
 
Obtain medical, reproductive and contraceptive histories.  
 
Vital signs will be taken including height, weight, pulse, blood pressure and respiratory rate. Blood 
pressure will be taken three times at approximately 5 minute intervals with a rest period in 
between and the three values averaged.  BMI will be calculated in kg/m ² using the formula 
weight (kg)/height(m)2 for determining eligibility but will be automatically calculated by the EDC 
system upon data entry. 
 
Blood samples will be obtained for the following measurements:  
o Complete blood count (CBC): hemoglobin, red blood cell count (RBC), red cell distribution 
width (RDW), packed cell volume (PCV), mean cell volume (MCV), mean cell hemoglobin 
concentration (MCHC), hematocrit, platelets, white cell count, neutrophils, lymphocytes, 
monocytes, eosinophils and basophils 
o Clinical chemistries: sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium.  
o Liver function tests:  total bilirubin, alkaline phosphatase (ALPH), alanine 
aminotransferase (ALT), aspartate transaminase (AST), BUN, and albumin 
o Full lipid panel: total cholesterol, HDL, LDL, and triglycerides 
o Hormone assessments: Total testosterone concentration. Should this be abnormal, then 
this will be repeated at screening visit 2.  
o Serum pregnancy test for females only. 
 
Participants will be questioned regarding prior and concomitant medications.  Concomitant 
medications taken from time of consent will be reported, in addition to indications for the 
medications and reasons for discontinuing. Asking about concomitant medications will include 
asking about alcohol and recreational drug use. 
 
14.1.1.2 
Male Partner Only 
 
The following screening procedures will be performed for the male subject at Screening Visit 1:  
 
Obtain andrological history. 

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 
Complete physical exam, including detailed andrological examination. 
 
PSA will be drawn. 
 
Urinalysis will be done to evaluate the subject’s health and screen for illicit or illegal drugs. 
  
14.1.1.3 
Female Partner Only 
 
The following screening procedures will be performed for the female subject at Screening Visit 1: 
 
Obtain gynecological and menstrual history. 
 
The female partner will undergo a serum pregnancy test and serum T (screening serum T in the 
female should be within the referenc range of the local laboratory). 
 
Assess any kind of body acne or hirsutism (using Ferriman-Gallwey score).   
 
REMINDER: To assure that Good Clinical Practices (GCP) guidelines for documenting subject study data are 
followed, physicians and site staff will record subject histories and study specific examinations in the subject’s 
medical record.  Physicians and site staff will review source documents prior to study enrollment to ensure that all 
subject histories and examinations are appropriately captured in the subject’s medical record.  Original medical 
records will be made accessible to the study auditor during any audit visit that occurs.  This includes allowing 
review of Electronic Medical Records [EMR] when it is the original medical record entry for a given assessment 
related to the study.  
 
Once lab results are obtained and considered normal or not clinically significant (if out of normal ranges) 
by the investigator as per the inclusion/ exclusion criteria for enrollment, the participants will be informed 
of the lab results. If conformance to the inclusion/exclusion is confirmed, the couple will be scheduled to 
return to the study site for the second screening visit (Visit 2).   
 
Subjects will be advised to refrain from taking medications and excessive amounts of grapefruit juice, 
recreational drugs and alcoholic beverages during the study. 
 
Subjects and their partners will also be required to use a reliable method of contraception throughout the 
study as this is not a contraceptive efficacy study. 
 
If any results are abnormal, according to local laboratory standards, and are clinically significant in the 
clinical judgment of the investigator, the subject will be informed and excluded from the study and 
referred to their primary health care provider. At the discretion of the investigator, abnormal laboratory 
assessments may be repeated before a final determination of exclusion is made.  
 
Subjects will be entered into the EDC system at time of consent. 
 
If for any reason, more than 28 days elapse between screening visit 1 and treatment day 1, repeat safety 
labs (CBC with differential and clinical chemistries) will be performed and results reviewed prior to 
treatment. 
 
 
14.1.2 Screening Visit 2 (Visit 2) 
 
Once couples have passed all screening assessments and eligibility is confirmed, both partners will return 
to the clinic for a 24-hour in-patient clinic stay to obtain baseline 24 hour T PK samples.  The couple should 
report to the clinic by 7 am on the day the draws are to begin. Samples will be collected at 1, 2, 4, 8, 12, 
16, 20 and 24 hours.  Concomitant medications and adverse events will be assessed. Asking about 
concomitant medications will include asking about alcohol and recreational drug use. 
 

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Visit 3 can occur as quickly as completion of Visit 2 (i.e. couple would come for their baseline 24 hour PK 
draws (Visit 2) and then continue directly into starting Visit 3, thus staying for 48 hours in the clinical 
research unit). 
 
14.2 Treatment Phase (Visits 3-8) 
 
If both partners qualify for the study and have completed the baseline 24-hour PK draws, they will return 
to the study clinic and the male partner begins treatment using the NES8/T60 combination gel (Visit 3).  
This will be the start of the couple’s treatment phase of the study.  Only the female subject is required to 
come in for Visit 4 (Day 3), Visit 6 (Day 10), and Visit 8 (Day 17). 
 
The Treatment Phase is expected to take 17 days.  In this phase, the study gel will be applied as three 
single applications to a male subject’s shoulders and area of the upper arm to the top of the biceps 
muscle (i.e., to shoulder and arm skin that would be covered by a short sleeve T-shirt) on three different 
treatment days (1, 8, and 15).  Approximately two hours following the gel application, the male subject 
will have supervised skin contact with the female subject. Venipuncture for blood sampling should be in 
the antecubital fossa or lower on the arm for male participants. Venipuncture for blood sampling for 
female participants should be in the antecubital fossa to prevent issues of her rubbing her hands and 
arms.   
 
14.2.1 Treatment Phase Visit 3 (Day 1), Visit 5 (Day 8), and Visit 7 (Day 15) (+7 day window) 
 
14.2.1.1 
Pre- Gel Application 
14.2.1.1.1 Both Partners 
The following procedures will be performed for both male and female subjects prior to the study gel 
administration: 
 
Both subjects will arrive at the clinic by 7 am for the 24-hour in-patient clinic stay 
 
Vital signs will be taken including weight, pulse, blood pressure and respiratory rate. Blood 
pressure will be taken three times at approximately 5 minute intervals with a rest period in 
between and the three values averaged.  BMI will be calculated in kg/m ². 
 
Concomitant medications and adverse events will be assessed. Asking about concomitant 
medications will include asking about alcohol and recreational drug use. 
14.2.1.1.2 Male Partner Only 
 
Serial blood draws for Nestorone and testosterone measurements will be collected from the male 
partner only at -15 and -5 minutes before gel application. 
14.2.1.1.3 Female Partner Only 
The following procedures will be performed for female subjects: 
 
The female subject will wear a sleeveless top to the clinic visit. 
 
The current contraception method and last menstrual bleeding date will be recorded. 
 
Urine pregnancy test will be administered prior to the male’s NES/T gel application to reconfirm a 
negative test. If urine comes back positive, a confirmatory serum beta hcg test should be performed.  
If serum test is positive, the couple will be discontinued form the study.  
 
14.2.1.2 
Gel Application 
14.2.1.2.1 Male Partner Only 
 
At about 8 am (± 30 min), the male participant will apply 2.5 mL of the testosterone/Nestorone gel 
over a wide area over one shoulder and upper arm above the elbow and then 2.5 mL gel to the 
other shoulder and upper arm again on a large surface area (see Appendix 3) under supervision. 
The gel should dry in less than 5 minutes and the male participant will wash his hands with soap 
and water.  
 
14.2.1.3 
Post- Gel Application 

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14.2.1.3.1 Male Partner Only 
 
Serial blood draws for Nestorone and testosterone measurements will be collected from the male 
partner only at 1, 2, 4, 8, 12, 16, 20 and 24 hours (± 15 min) after gel application.  
14.2.1.3.2 Both Partners 
 
After the blood draw at 2 hours post treatment (+15 min), the female participant will engage in 
close skin contact with the male participant’s area of NES8/T60 gel application. Under direct 
observation, the female participant, using her hands, wrists, and arms, will rub up and down the 
arms and shoulders of the male partner during a contact period of 15 minutes. After 2 minutes of 
rubbing, the female participant may take a rest period of 1 minute before continuing rubbing, 
repeating the 2 minute rubbing to 1 minute break process until the 15 minute time period is 
reached. Study staff will witness the entire rubbing process. 
 
14.2.1.3.3 Female Partner Only 
 
The female participant will wash her hands with soap and water after skin contact is complete. 
The female participant will not shower for 24 hours after the contact period. The antecubital area 
of the female’s arm where the intravenous catheter has been placed will be covered during the 
contact period to prevent potential blood sample contamination.  
 
Blood samples will be collected for measurement of testosterone and Nestorone at 2, 3, 4, 5, 6, 8, 
10, 14, 18, 22 and 26 hours (±15 minutes) post male participant’s gel application.  
 
 
14.2.1.3.4 For Visit 3 (Day 1) Only – Post Application: 
 
After the gel is dry, the male subject will don a 100% cotton T-shirt (provided by the investigators) 
immediately after the applied gel has been allowed to dry.  The male subject will continue to wear 
the T-shirt until female participant rubs the area of the T-shirt covering the gel application site at 
approximately 2 hours (±15 minutes) post male participant gel application. 
 
14.2.1.3.5 For Visit 5 (Day 8) Only – Post Application: 
 
The male subject will don a 100% cotton T-shirt (provided by the investigators) immediately after 
the applied gel has been allowed to dry.  The male subject will continue to wear the T-shirt until 
he showers (and washes the gel application site with soap and water) one hour 45 minutes after 
the gel application.  The female participant will rub the gel application site 2 hours (±15 minutes) 
after gel application and just after male subject has showered and dried skin. 
 
At 90 minutes/1.5 hours (±15 minutes) after application and again at 30 minutes after shower and 
rubbing (150minutes/2.5 hours (±15 minutes) after application), using adhesive D-square strips 
(Cuderm Corporation, Dallas TX) a single location on the application site will be stripped on the 
male participant a total of ten times and the strips will then be analyzed for testosterone and 
Nestorone.  
 
14.2.1.3.6 For Visit 7 (Day 15) Only – Post Application: 
 
The male subject will don a 100% cotton T-shirt (provided by the investigators) immediately after 
the applied gel has been allowed to dry.  The male participant will remove the T-shirt immediately 
prior to the female subject rubbing the gel application site 2 hours (±15 minutes) after gel 
application.  
 
At 90 and 150 minutes (1.5 and 2.5 hours) (±15 minutes) after application, using adhesive D-
square strips (Cuderm Corporation, Dallas TX) a single location on the application site will be 
stripped on the male participant a total of ten times and the strips will then be analyzed for 
testosterone and Nestorone. 
 
Blood samples will be obtained for the following measurements on day 16 for both male and 
female subjects prior to leaving the in-patient clinic: 

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o Complete blood count (CBC): hemoglobin, red blood cell count (RBC), red cell distribution 
width (RDW), packed cell volume (PCV), mean cell volume (MCV), mean cell hemoglobin 
concentration (MCHC), hematocrit, platelets, white cell count, neutrophils, lymphocytes, 
monocytes, eosinophils and basophils 
o Clinical chemistries: sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium.  
o Liver function tests:  total bilirubin, alkaline phosphatase (ALPH), alanine 
aminotransferase (ALT), aspartate transaminase (AST), BUN, and albumin 
 
14.2.2 Treatment Visit 4 (Day 3), Visit 6 (Day 10), and Visit 8 (Day 17) (no window) 
 
Only the female partner is required to come to the clinic for these visits.  These visits will occur the next 
day after the female subject has finished each in-patient treatment clinic visit. No day visit window is 
allowed for these visits to be pushed out from the day of treatment as these visits are required for timed 
PK draws.  As a result, treatment day visits should be planned accordingly within their window to ensure 
the female subject is able to return for blood sampling after exiting the in-patient visit. 
 
14.2.2.1 
Female Partner 
 
The following procedures will be performed for female subjects: 
 
The female participants will return at around 10 am (± 2 hour) on the day after finishing the in-
patient clinic visit. 
 
Vital signs will be taken including weight, pulse, blood pressure and respiratory rate. Blood 
pressure will be taken three times at approximately 5 minute intervals with a rest period in 
between and the three values averaged.  BMI will be calculated in kg/m ². 
 
Concomitant medications and adverse events will be assessed. Asking about concomitant 
medications will include asking about alcohol and recreational drug use. 
 
Blood samples will be collected for measurement of testosterone and Nestorone at 50 hours post  
male participant’s gel application (or hour 48 post female exposure) at visits 3, 5, and 7.  
Assess any kind of body acne or hirsutism (using Ferriman-Gallwey score)  
14.3 End of Study/Exit Visit – Visit 9 (Day 31) ( -12/+14 days) 
 
The End of Study/Exit Visit will occur two weeks after the completion of the final gel application.  This 
visit will be conducted via telephone call for the male participants.  At the same time, the female 
participants will return to the clinic for their end of study/exit visit (Visit 9). 
 
14.3.1 Both Partners 
 
During this visit, the following procedures will be performed for both male and female subjects:  
 
Concomitant medications and adverse events will be assessed. Asking about concomitant 
medications will include asking about alcohol and recreational drug use.  
 
14.3.2 Male Partner 
There are no other assessments specific to the male subject only at this visit. 
 
14.3.3 Female Partner 
 
During this visit, the following procedures will be performed for the female subject:  
 
Vital signs will be taken including weight, pulse, blood pressure and respiratory rate. Blood 
pressure will be taken three times at approximately 5 minute intervals with a rest period in 
between and the three values averaged.  BMI will be calculated in kg/m ². 

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 
Blood samples will be collected once for measurement of testosterone and Nestorone to assess 
residual levels. 
 
Assess any kind of body acne or hirsutism (using Ferriman-Gallwey score) The current 
contraception method and last menstrual bleeding date will be recorded. 
 
14.4 Contacts Between Visits 
 
Subjects may, at the discretion of the Principal Investigator or Designee, be contacted between study 
visits to ensure subject retention and compliance with study requirements. This contact may be via text, 
phone or email. If the subject does not respond when text or email contacts are attempted, the study 
clinic staff should contact the subject by phone. 
 
In addition, the female subject may also be contacted at the discretion of the Principal Investigator or 
Designee to evaluate for pregnancy as indicated by clinical symptoms.  
 
All such contacts and attempts should be documented in the subject's source file. It is suggested that 
testing of any cell phone number provided by both male and female subjects prior to enrollment be 
completed to ensure number correctly connects to the subject. 
 
14.5 Early Discontinuation Visit  
 
At any time a subject decides to discontinue his/her participation in the study (or is discontinued from the 
study for any other reason), the female will be advised to return to the clinic to complete the end of 
study/exit visit Visit 9).  This visit will be conducted via telephone call for the male participants. 
 
Every effort must be made to follow-up with subjects who discontinue with adverse experiences, in order 
to determine the final outcome of adverse events.  
 
14.6 Unscheduled Visits (UNS) 
 
Unscheduled visits can occur any time that an Investigator feels additional assessment is warranted. 
During unscheduled visits, the investigator will perform vital signs, physical exams, appropriate laboratory 
tests and provide appropriate treatment, as necessary.  Male subjects should be discouraged from any 
self-medication; rather they should visit the research center for assessment and treatment.  Similarly, male 
subjects should be discouraged, but not prohibited, from seeking treatment at facilities other than the 
research center for a non-serious event. For serious events, subjects should always obtain appropriate 
immediate medical care and the site should request release of medical records by the subject upon 
notification of the event. 
 
Based on the results of the unscheduled visit assessments, if the investigator determines that the subject 
should be discontinued, the Early Discontinuation Visit procedures (as detailed in Section 14.5) will be 
performed and the subject will be discontinued from the trial.   
 
15. Adverse Events: Recording and Reporting 
 
15.1 Definition of Adverse Events 
 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An adverse event can therefore be any unfavorable or unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational product, whether or not considered related to the product. 
 

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Any adverse change from the study subject’s baseline condition that occurs following the signing of the 
Informed Consent is an adverse event for both male and female participants.  This includes the occurrence 
of a new adverse event or the worsening of a baseline condition, whether or not considered related to the 
study product.   
 
Adverse events include but are not limited to: adverse changes in the general condition of the study subject; 
signs and symptoms noted by the study subject or his/her care giver; concomitant disease with onset or 
increased severity after the signing of the Informed Consent and clinically meaningful adverse changes in 
laboratory safety parameters occurring after the signing of the Informed Consent.  Day-to-day fluctuations 
in pre-existing conditions that represent a clinically significant change in the subject’s status should be 
reported as adverse events. 
 
15.2 Study Reporting Period for Adverse Events 
 
Adverse events (AEs) will be reported on this study.  All AEs will be carefully monitored and categorized 
by severity and causality and time. AEs will be documented in an AE form that is included as part of the 
study eCRFs. All events including illnesses with onset during the study, or exacerbation of pre-existing 
illnesses should be reported as AEs. The reporting period for adverse events is the period immediately 
after informed consent has been obtained and lasts through the end of study/exit visit.  AEs will not need 
to be submitted for screen failed subjects unless the subject experiences a SAE. Those events that occur 
between the screening and the enrollment visits will be analyzed as pre-treatment signs and symptoms 
and not as treatment-emergent adverse events.  
 
At every visit/contact study staff will ask each subject how they felt since their last visit/contact and indirectly 
ask if they have experienced any adverse events.  
 
For all AEs, the Investigator must pursue and obtain information adequate to determine the outcome of 
the adverse event and to assess whether it meets the criteria for classification as a serious adverse event. 
Resolution of an AE is defined as the return to baseline status or stabilization of the condition with the 
expectation that it may remain chronic.  Follow-up of the AE, even after the date of IP discontinuation, is 
required if the AE persists.  For the purpose of study analysis, if a non-serious AE has not resolved at the 
end of the study-reporting period, it will be documented as still ongoing on the AE eCRF. However, the 
Investigator must make every effort to follow events to stabilization or resolution and report the 
findings/outcome to HD as soon as possible. A minimum of three follow-up attempts with different methods 
of communication (i.e. telephone, certified mail, email) should be documented. Male participants who 
exhibit persistent or severe AEs or concomitant illnesses will be removed from the study based on the 
Investigator’s medical judgment and will no longer use the study product nor will the study product be re-
applied. The monitor will be notified if such an event occurs. 
 
Please refer to Sections 15.6.2 and 15.6.3 regarding the reporting of SAEs for this study.   
 
15.3 Recording of Adverse Events 
 
Adverse events will be reported on the AE eCRF using a recognized medical term or diagnosis that 
accurately reflects the event.  Information recorded on the Adverse Event Case Report Form must be 
substantiated in the source documents.  All adverse events must be recorded in the subject’s CRF and 
must include the following information (when applicable): 
 
Specific condition or event 
 
Possible etiologies and whether the event meets criteria as a serious adverse event and therefore 
requires immediate notification to the sponsor.  See guidelines below for assessment of severity 
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 
Indication of whether the condition was preexisting prior to study entry or not and if yes, whether it 
has worsened in severity or frequency in which case it is reported as an AE.  Conditions present 
prior to study entry that do not worsen in severity are not considered AEs.  Conditions identified 
and treated at screening, i.e. laboratory abnormalities are included in medical history and are not 
reported as AEs. 
 
Date of occurrence 
 
Date of resolution.  If the event has not resolved at the end of the study-reporting period, it will be 
documented as still present on the case report form.  However, every effort should be made to 
obtain outcome. 
 
Severity.  AEs that change in intensity are recorded at the intensity level that is the most severe 
reported by the subject over consecutive days. If the intensity category changes over a non-
consecutive period of time, then these changes should be recorded separately (with distinct onset 
dates). 
 
Relationship to study drug as evaluated by the investigator (causality assessment) 
 
Action taken with the study drug per the investigator medical judgment (study drug continued, 
interrupted or discontinued)  
 
AE outcome (recovered, ongoing, etc.) 
 
Seriousness according to the approved regulatory classification {i.e. any event that is fatal, life-
threatening, disabling, incapacitating, results in or prolongs hospitalization, or is a medically 
significant event, e.g., an intervention to prevent one of the above outcomes, or any other serious 
criteria (cancer, congenital anomaly, overdose, other significant criteria) is considered serious. 
 
The severity of the AE will be characterized as mild, moderate, or severe using the following criteria: 
 
Mild: Participant was aware of the event, but was still able to do all activities. 
 
Moderate: Participant had to discontinue some activities due to the event.  
 
Severe: Participant was incapacitated by the event and unable to perform normal activities. 
 
15.4 Relationship to Study Product 
 
The site investigator is responsible for assessing the relationship between the AE and the study product. 
Site investigator must determine whether there is a reasonable possibility that the study product caused 
or contributed to an AE. The relationship assessment, based on clinical judgment, often relies on the 
following: 
 
A temporal relationship between the event and administration of study product, 
 
A plausible biological mechanism for the study product to cause the AE, 
 
Another possible etiology of the AE, 
 
Previous report of similar AEs associated with the study product or other agents in the same 
class. 
 
The terms used to assess the relationship of an event to the study product are: 
 
Causality 
Assessment 
Criteria for Assessment (note that re-challenge will not be done in 
this study) 
Highly Probable 
The experience occurs immediately following trial drug administration, 
related pharmacologically (not related to underlying condition/concurrent 
disease or other drugs or chemicals) and follows a known response 
pattern to the study drug. 
Probably Related 
The experience follows a reasonable temporal sequence from the time 
of drug administration and follows a known response pattern to the 
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factors such as the participant’s clinical state, therapeutic intervention or 
concomitant therapy. 
Possibly Related 
The experience follows a reasonable temporal sequence from the time 
of drug administration and/or follows a known response pattern to the 
trial drug but could have been produced by other factors such as the 
participant’s clinical state, therapeutic intervention or concomitant 
therapy.   
Unlikely Related 
Improbable temporal relationship. The experience was most probably 
produced by other factors such as the participant’s clinical state, 
therapeutic intervention or concomitant therapy and does not follow a 
known response pattern to the study drug. 
Not Related 
There is not a reasonable possibility that the AE is related to the study 
product; when an AE is assessed as not related to the study product, an 
alternative etiology, diagnosis or explanation for the AE should be 
documented.  If new information becomes available, the relationship of 
any AE should be reviewed again and updated, as required. 
Insufficient data to 
assess 
Selection of this rating should usually not occur in a clinical trial because 
the Investigators have an obligation to obtain and provide this 
information. In exceptional instances, this rating may be used in order to 
avoid delay in initial reporting of fatal or life-threatening SAEs from 
clinical trials. Such cases should include documentation in the source 
with rationale for why an assessment could not be made. 
 
15.5 Adverse Event Follow-Up 
 
Investigator must make every effort to follow events to stabilization or resolution.  Exceptions to this are 
cases where the subject is lost to follow-up or the adverse event is otherwise explained.  Unresolved SAEs 
at the conclusion of the study will be assessed by the investigator with a follow-up plan documented and 
approved by the Medical Monitor on a case-by case basis. 
 
15.6 Serious Adverse Events (SAEs) 
 
15.6.1 Definition of a SAE 
 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it: 
 
Results in death; 
 
Is life-threatening; 
o This term refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event that hypothetically might have caused death if it were 
more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
o In general, hospitalization signifies that the subject has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting.  Complications that occur during hospitalization are AEs or SAEs as defined 
above.  If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.  Hospitalization for elective treatment of 
a pre-existing condition that did not worsen from baseline is not considered an AE.  
 
Results in persistent or significant disability/incapacity; or 
o The term disability means a substantial disruption of a person’s ability to conduct normal 
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medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect. 
 
Medical or scientific judgment should be exercised in deciding whether (expedited) reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  These events should also be considered 
serious.  Examples of medically important events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that result in hospitalizations; or development 
of drug dependency or drug abuse.  In addition, cancer and drug overdose are included in the classification 
of an SAE for this study. 
 
15.6.2 Study Reporting Period for SAEs 
 
The reporting period for SAEs is the period immediately after Informed Consent has been obtained and 
lasts through the end of study/exit visit.  Individual SAEs must be followed until resolution, even if this 
extends beyond the study-reporting period.  Resolution of a serious adverse event is defined as the return 
to baseline status or stabilization of the condition with the expectation that it may remain chronic. 
 
Serious adverse events (SAEs) as defined by ICH and Code of Federal regulations will be reported within 
the 24 hours that the site is informed of the SAE as outlined in this section and Section 15.6.3  
 
15.6.3 Notification to Sponsor of SAEs and Sponsor Reporting of SAEs 
 
All Serious Adverse Events (SAEs) will be reported promptly in accordance with the FDA regulations and 
recorded on the appropriate forms.  As the Sponsor of this IND, the Population Council is responsible for 
complying with the reporting requirements of SAEs to the FDA in accordance with 21 CFR 312.50. 
Health Decisions will serve as the third party monitoring body of SAEs and will notify the NICHD Medical 
Monitor and the Safety Desk of Population Council upon occurrence. If warranted, the NICHD Medical 
Monitor will recommend to the NIH Project Officer and discuss with the Safety Desk of the Population 
Council, if action is required to convene the DSMB or if the trial should be stopped prematurely, undergo 
modification, or be placed on hold. Both PC and Health Decisions may also recommend to the NICHD 
Medical Monitor if any of these actions are warranted based on the SAE reports.  The Population Council 
will be responsible for the appropriate recording, review and compliance with regulatory reporting 
requirements to the FDA of the SAE.   
 
WHEN ANY SAE, REGARDLESS OF RELATIONSHIP TO THE STUDY PRODUCT, IS ENCOUNTERED 
DURING THIS CLINICAL TRIAL AT AN INVESTIGATOR’S SITE, THE INVESTIGATOR, IN 
ACCORDANCE WITH 21 CFR 312.64(b), MUST NOTIFY BOTH PC AND HEALTH DECISIONS WITHIN 
24 HOURS OF IDENTIFICATION/AWARENESS OF THE SAE BY REPORTING THE EVENT VIA THE 
ELECTRONIC DATA CAPTURE SYSTEM. SAE SUBMISSION SHOULD BE COMPLETED FOR ANY 
SAE THAT IS EXPERIENCED AFTER THE SUBJECT HAS SIGNED THE INFORMED CONSENT 
FORM, EVEN IF INVESTIGATIONAL PRODUCT HAS NOT YET BE ADMINISTERED. 
 
The investigator should complete the SAE eCRF within the EDC system which will send the appropriate 
notifications to the Medical Monitor as well as the appropriate HD, NICHD, PC staff and PC Safety Desk.  
In the event of a system outage or other complication, notification may be made to the Population 
Council’s Safety Desk at: +1-212-237-9410 (telephone). Immediately following phone communication, 
the clinical investigator is to follow up with an SAE Report submission by email to both PC at 

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safety@popcouncil.org (email) and by fax or email to Health Decisions at +1-919-967-1145 
(fax)/nichd@healthdec.com (email). HD will then notify the NICHD Medical Monitor by facsimile or email.  
 
In the event that serious adverse events occur in the course of the study, participants will be referred to a 
specialist. Treatment or laboratory tests will be conducted at the discretion of the Investigator.  If the 
event causality assessment is probably or highly probably related with the investigational product, the 
Investigator must discontinue the couple from the study immediately.  
 
Additional supporting documentation for SAEs (i.e. hospital discharge summary, lab report, etc.) which 
should be provided whenever possible (with participant name redacted) to verify the medical diagnosis 
includes hospital discharge summaries and death certificates/autopsy reports (where applicable), 
surgical procedure summaries, histology reports, and imaging reports should be uploaded to the study 
document repository or Health Decisions EDC page as outlined in the Study Procedures Manual within 3 
days of receipt at the site. HD will ensure appropriate copies of supporting document are provided to the 
Medical Monitor and Population Council. 
 
NOTE: Investigators should not wait to collect the additional information needed to fully document the 
event before submission of an SAE.  An SAE report should be completed for any SAE that is 
experienced after the subject has signed the Informed Consent Form, even if investigational product has 
not yet been administered. 
 
For system outages, or other complication, which prevents reporting of the SAE information through the 
HD electronic systems, when sending follow up information after phone notification, please email the 
following documents to the Population Council Safety Desk (Email: Safety@popcouncil.org) if available 
at time of report.  
 
Serious Adverse Event Report Form 
 
Medical History Case Report Form 
 
Concomitant Medication Case Report Form or a list of concomitant medications 
 
Relevant laboratory/diagnostic test results and medical record progress notes 
 
Under 21 CFR 312.32 and 312.33, Pop Council, in consultation with the Medical Monitor, is responsible 
for notifying the FDA and all participating investigators of: (1) any unexpected fatal or life-threatening 
adverse experience associated with the use of the study drug by telephone or fax as soon as possible, 
but no later than 7 calendar days after the sponsor’s initial receipt of the information about the event, and 
(2) any adverse experience associated with use of the drug that is both serious and unexpected. 
Notification should occur in writing no later than 15 calendar days after the sponsor’s initial receipt of the 
information. Pop Council, as the IND holder, is also responsible for submitting annual study progress 
reports to the FDA. 
 
 
15.6.4 Notification of IRB or Independent Ethics Committee of SAEs 
 
All IND Safety reports (expedited SAEs) that occur at each site must be directly reported to the local IRB 
or Ethics Committee and to the local health/regulatory authorities (other than the FDA) by the 
Investigator or designee after case adjudication by the Population Council Safety Desk staff and the 
Medical Monitor. The Population Council as IND holder will report SAEs to the FDA if appropriate 
according to expectedness and causality assessment. The site should report non-expedited SAEs for 
their own site per their IRBs reporting guidelines.  
 
The investigator must comply with the applicable regulatory requirements related to the reporting of 
SAEs to the Institutional Review Board (IRB) or Independent Ethics Committee (IEC). The IRB or IEC 
must be informed in a timely manner by the investigator of SAEs occurring during the study. Investigators 

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must also submit applicable safety information provided by Population Council to their IRB or IEC. The 
final adjudication of an SAE will be conducted by the Population Council Safety Desk and the final 
CIOMS form will be sent to all sites for submission to their respective IRBs/IECs for applicable events. 
 
15.6.5 Pregnancy Determination and Follow-up 
 
The couple should agree to use an effective contraceptive method during the study. However, if despite 
this, a pregnancy would occur, information on pregnancy will be recorded on all couples becoming 
pregnant during the treatment phase of the study through study exit. 
 
If a female subject becomes pregnant during the trial, the Investigator must inform Health Decisions, 
NICHD and the Population Council of the pregnancy within 24 hours of determination.  
If a female subject is found to be pregnant during the study, the treatment of the male partner will be 
stopped.  Study participation will be terminated for the couple and all procedures scheduled for the Early 
Discontinuation Visit as detailed in Section 14.5 should be performed.  The site will submit a Pregnancy 
Notification eCRF to Health Decisions with 24 hours of determination, who will notify the Medical Monitor, 
NICHD, and PC immediately.  Additional pregnancy data will be submitted as it becomes available.  
 
The estimated date of conception will be made by the Investigator based upon results of the following 
pregnancy determination criteria, listed in ascending order of accuracy: 
 
Transvaginal ultrasound. 
 
Estimate based on pelvic and/or abdominal examination or pregnancy outcome. 
 
Coital diary information (e.g. last menstrual period and sexual activity). 
 
Quantitative β-hCG determination.  
 
Investigator estimation in the absence of the above criteria. 
 
Female subjects who become pregnant during the study will be informed of pregnancy options and 
referred for appropriate care. All pregnancies will be monitored until outcome (i.e., 9 months follow-up or 
until outcome information is obtained). Information will also be collected on any maternal or fetal 
complications.  A pregnancy will not be considered an adverse event for this study.  Congenital 
anomalies or birth defects will be classified as serious adverse events (SAEs).  Pregnancy outcome data 
will be collected for analysis.  Reports of pregnancy outcome and examinations during the pregnancy will 
be requested from the attending physician/outside clinic, if applicable. Every attempt should be made to 
obtain outcome data, including hospital and/or physician records. Pregnancy outcome data will include 
the rates of spontaneous abortion, stillbirth and live preterm and full-term births. If a female subject has a 
spontaneous abortion or ectopic pregnancy this will not be considered as a SAE unless it meets one of 
the SAE criteria indicated Section 15.6.1 or per the Investigator’s medical judgment it should be 
recorded as an SAE. In addition, congenital malformations and anomalies will be recorded and 
summarized.  If a female subject continues with her pregnancy through childbirth, every effort will be 
made to maintain contact with her so that her health and the health of the baby can be evaluated at 6 
months and 12 months following birth.  A clinical summary of the prenatal and postnatal events will be 
reported in a narrative format as part of or separate from the Clinical Study Report (CSR) at the end of 
the study. Any outstanding data at the end of the study that is collected will be submitted to the FDA as a 
Safety Update to the NDA submission. A clinical summary of the prenatal and postnatal events will be 
reported separately from the case report form in narrative format in the clinical study report. 
 
16. Medical Monitor 
 

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Mark Payson, MD, is the Medical Monitor for the protocol.  Dr. Payson has experience with NIH 
research. He is board certified in obstetrics & gynecology and reproductive endocrinology & infertility.  
Dr. Payson will be responsible for evaluating requests for waivers, reviewing protocol safety information 
and providing the NIH Project Director with a final recommendation based on the input from the Data and 
Safety Monitoring Board (DSMB) should one occur.   
 
Medical Monitor Contact Information: 
Mark Payson, MD  
Telephone: 240-463-9115 
Email: markpayson@gmail.com 
 
17. Safety Desk 
 
Population Council will maintain a Safety Desk.  Mohcine Alami, MD, at PC, is the Safety Expert manning 
the Safety Desk for the study.  Contact information for the Safety Desk is as follows:  
 
Mohcine Alami, MD 
Director, Global Medical Safety & Medical Affairs 
Population Council 
4301 Connecticut Avenue, NW Suite 280 
Washington, D.C. 20008 
Direct: +1 202-237-9410 
Switchboard: +1 202-237-9400 
Toll Free: +1 877-237-9400 
Facsimile: +1 202-237-8410 
 
18. Safety and Efficacy Monitoring (DSMB) 
 
All SAEs will be reported within 24 hours to the NICHD Project Director and Medical Monitor (see Section 
15.6.3).  An independent, autonomous Data Safety and Monitoring Board (DSMB) has been established 
by the NICHD. The Medical Monitor will be tasked to review the adverse events and safety considerations 
at routine intervals during the study.  The CCTN DSMB will be charted by NICHD to review the adverse 
events and safety considerations on an ad hoc basis if required by an unexpected serious adverse event 
that could be attributable to the treatment regimen.  If more than one unexpected serious adverse event 
occurs with causality assessment of probably or highly probably related the study will be stopped. 
Recommendations from the DSMB will be forwarded by the NICHD Project Officer to the Central IRB and 
the CCTN Principal Investigators in this Protocol. If the DSMB reviews the trial, they will make 
recommendations if the trial should be stopped prematurely, undergo modification, or continue.   
 
19. Study Conduct 
 
19.1 Deviation from the Protocol 
 
The Investigator should not deviate from the protocol without prior approval issued in a protocol waiver 
sent from HD and approved by the NICHD Medical Monitor, with the exception of minor visit window 
deviations, unless it is necessary to protect the subject’s immediate safety and welfare. In the event that 
the investigator or the subject deviates from the protocol without a protocol waiver, notification should be 
provided to HD as soon as possible detailing the circumstances who will assess the deviation for expedited 
reporting criteria to the NICHD. Certain protocol violations may require the couple to be terminated early 
from the study. It is the responsibility of the research centers to report all protocol waivers and protocol 
violations to their IRB/IEC according to IRB/IEC policy.  
 

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19.2 Amendments to the Protocol 
 
Any change of the clinical trial must be written and filed as an amendment to this protocol. Such 
amendments will be made jointly by the NICHD and the investigator(s) upon NICHD final approval. The 
investigator(s) must submit the protocol amendment for review by their IRB/IEC and shall obtain the 
approval of their IRB/IEC before it is implemented. 
 
In cases of emergency, when the protocol change or deviation is to eliminate or reduce an immediate 
hazard or risk to human subjects, the amendment may be implemented before review or approval by their 
IRB. In such cases, the investigator shall notify their IRB/IEC of the change or deviation in writing within 
10 working days after implementation. Any protocol-related issues that pose an immediate or significant 
hazard to subjects must be reported to NICHD and HD immediately.  If the protocol amendment is an 
administrative change, it will be sent to their IRB/IEC for information (updating of file). 
 
All modifications of the clinical trial will be written and filed with FDA by PC as an amendment to this 
protocol, maintaining original section identification. Such modifications will be made jointly by the NICHD, 
HD, PC, and all the investigators with the approval of all the IRBs/IECs. 
 
19.3 Subject Confidentiality 
 
Information on individual subjects arising from this study will be considered confidential and transmitted 
to the sponsor and Clinical Research Organization (CRO) in a form that will not permit identification of 
individuals. Subject confidentiality will be maintained by the use of coded subject ID numbers. All study 
records will be kept in a secure storage area with limited access. Coded subject numbers will identify all 
laboratory specimens and evaluation forms in order to maintain subject confidentiality. Clinical 
information will not be released without the written permission of the participant, except as necessary for 
monitoring by the FDA, NICHD, the Population Council, Health Decisions, local Clinical Research 
Organizations (CROs) contracted to monitor the study, or local regulatory authorities. 
 
19.4 Discontinuing Subjects 
 
Subjects will be considered to have completed the clinical trial after they have completed 2 weeks of using 
the study product followed by an end of study/exit visit plus the final set of data has been collected and 
entered on the appropriate CRF pages.  
 
Discontinuation of one participant (male or female) automatically results in discontinuation of their partner. 
The Principal Investigator can discontinue a given participant if, in her/his opinion, either member of the 
couple no longer meets the inclusion/exclusion criteria or the clinical observations during the study suggest 
that it might be unsafe for the participant/couple to continue.   
 
A subject (male or female) may be discontinued prematurely for any of the following reasons: 
 
Emergence of adverse or serious adverse event that, in the judgment of the investigator, 
continuation in the trial would negatively impact the health of the subject. 
 
Emergence of adverse effects such as symptoms (e.g. severe skin irritation, changes in libido or 
weight, acne, or non-specific symptoms) or biochemical changes (new or persistent abnormalities 
in clinical chemistry or hematological tests) that are considered medically hazardous by the 
supervising physician 
 
Inter-current illness that, in the judgment of the investigator, should result in premature 
discontinuation. 
 
Poor compliance or co-operation of the participant as judged by the Investigator. 
 
Use of prohibited medications/products, including any outlined in the Inclusion/Exclusion criteria 
(see Section 11.1). 

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 
Pathologically changed laboratory values. 
 
Suspected drug interaction. 
 
Knowledge of new risks necessitating new benefit/risk evaluation. 
 
Other non-study related reasons: change of address that makes participation unfeasible, 
termination of participant-partner relationship; no need of contraception. 
 
Not using another method of contraception. 
 
Major protocol violation. 
 
Subject lost to follow-up. 
 
Trial closed-out. 
 
A subject (male or female) must be discontinued for any of the following reasons: 
 
Failure to attend more than one study visit. 
 
Emergence of a serious adverse event that is probably or highly probable related to study product. 
 
Pregnancy of the female subject (see above section on pregnancies).  
 
Either participant (male or female) withdraws his/her consent to the study (e.g. due to personal 
reasons). 
 
All subjects/couples who terminate early from the trial will undergo an Early Discontinuation Visit/Exit Visit 
as outlined in Section 14.5 regardless of the reason for discontinuation with the exception of those couples 
who have lost contact with the research center. The necessary clinical and laboratory examinations 
planned at the last visit should be performed whenever it occurs. The Investigators will document the 
discontinuations in detail within the source files for the subject. The reasons for premature discontinuation 
will be recorded on the End of Trial eCRF. If discontinuation from the study is due to an adverse event, 
this information will also be recorded on the Adverse Event form. It is required that, throughout the study, 
the CCTN site study coordinators be informed with respect to enrolment and withdrawals from the study 
for their site’s subjects.  If the sponsor determines that the study must be stopped, all subjects will be 
required to end participation at that time.  
 
A couple cannot be considered lost to follow-up (LTFU) until the research center performs and documents 
at least three (3) attempts to contact him/her. Documentation must include a letter sent with a return receipt 
requested to the subject/couple instructing him/her/them to call the research center. Every effort must be 
made to follow-up with subjects who terminate with adverse experiences, in order to determine the final 
outcome of adverse events.  
 
Subjects (male or female) may withdraw from the study at any time or be dropped from the study at the 
discretion of the investigator should any untoward effects occur. In addition, a subject may be discontinued 
by the investigator or the sponsor if he/she violated the protocol (i.e. he is non-compliant) or for other safety 
reasons. 
 
Couples discontinuing from the study will be replaced, regardless of the reason for discontinuation, such 
that 6 couples at each site complete the study.  
 
19.5 Withdrawals from Study 
 
Any study participant (male or female) has the right to withdraw from the study at any stage and for any 
reason without giving reasons. Withdrawal of one participant automatically results in withdrawal of their 
partner.     
 
All efforts should be made to contact the study participant when they decide to withdraw so that 
appropriate discontinuation safety and efficacy data can be obtained from both the male and female 

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participants. Such contact will never be used to dissuade any subject (male or female) who wishes to 
terminate the study. 
 
19.6  Medication Errors 
 
As gel application will occur under direct study staff supervision, no issues with compliance are 
anticipated.  However, if one occurs the site should inform Health Decisions immediately upon 
determination. 
 
20. Study Monitoring and Documentation 
 
20.1 Clinical Monitoring, Quality Control, and Quality Assurance 
 
The Principal Investigator and sub-investigators will allow representatives from HD, PC and NICHD direct 
access to all eCRFs, source documents, and corresponding portions of the medical records for each 
participant at mutually convenient times for periodic review during the study and after the study has been 
completed. The monitoring visits provide HD with the opportunity to: 
 
 
Initiate the research center. 
 
Evaluate the progress of the study. 
 
Verify the accuracy and completeness of the eCRFs. 
 
Ensure that all protocol requirements, applicable FDA and other health authority regulations, and 
investigators’ obligations are being fulfilled. 
 
Resolve any inconsistencies in the study records. 
 
Close out the trial at the research center.  
 
In addition to routine monitoring, NICHD or its designee may, at its discretion, perform site audits. The 
purpose of such audits will be to evaluate site trial conduct and compliance with the protocol, SOPs, GCP, 
and the applicable regulatory requirements. If an audit is performed, a site must provide the auditors with 
direct access to all relevant records and documentation related to the study. 
 
20.2 Administrative and Record Management 
 
All investigative site records will be kept in a secure and hazard free storage area with limited access.  
Access will be restricted to personnel authorized to handle research documents. These records are to be 
retained for at least 2 years after approval of the marketing application or at least 2 years have elapsed 
since formal discontinuation of clinical development for this investigational product.  NICHD should be 
notified before destruction of any site records. 
 
 
20.3 Study Documentation 
 
Sites will maintain source documentation of all study visits assessments completed for each subject.  
Source documentation data will be transcribed into the eCRFs. 
 
Health Decisions is responsible for assuring that the essential documents maintained in the trial master 
file at the research center are accurate and complete. Essential documents in the trial master files at 
Health Decisions will be maintained according to written SOPs. 
 
20.4 Electronic Data Capture System/Data Transmission 
 

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Electronic Data Capture will be used to transmit data electronically from the site to the Data Coordinating 
Center (HD).  All requested information should be entered in the Electronic Data Capture (EDC) system.  
Prior to the start of the clinical trial, the investigator will complete an authorized signature sheet showing 
the signatures and handwritten initials of all individuals who are authorized to maintain study records and 
submit data using the EDC system. More detailed instructions regarding the EDC system will be provided 
by Health Decisions in training and the instructions documents.  The data in the database including any 
updates as a result of data cleaning will be compared to the source documents at subsequent monitoring 
visits. 
 
20.5 Data Handling and Processing 
 
Health Decisions’ Electronic Data Capture (EDC) will be used to create, modify, maintain, archive, 
retrieve and transmit study data generated for the clinical trial. The research centers will record clinical 
trial data (except for the central hormone laboratory data) on an electronic web-based CRF (eCRF). 
Laboratory data from the central laboratory will be sent electronically to HD and imported into a SAS 
database maintained by the HD Biometrics Department. HD Data Management will follow written 
standard operating procedures for processing EDC data.  Archiving of the EDC data will be done by the 
EDC vendor. 
 
20.6 Confidentiality and Reporting of Results 
 
The information on individual subjects arising from this study is to be considered confidential and 
transmitted to the sponsor only in a form that will not permit identification of the individual.  Regulatory 
and sponsoring agencies may request access to the study records and related medical records of each 
participating subject, and if requested, the subject’s identity will remain confidential to the extent 
permitted by the applicable laws and regulations.  All records will be kept in a secure storage area with 
limited access. 
 
The information obtained from the subjects that can be identified with the subject will remain confidential 
within the research team.  Subject names will not be entered into the EDC system; instead, unique 
subject identifiers will be assigned to the couple. The results of the research will be released to public 
agencies including regulatory agencies, clinical investigators, and research organizations without 
reference to items identifiable to a particular subject.  Medical records will be kept at the research center 
and will be available to study staff and the NICHD, Health Decisions, PC, or the FDA only while at the 
study site.  The results will be published such that the identity of the subjects will not be disclosed and 
cannot be ascertained. All data will only be used for the purpose for which it has been approved.  Data 
collected during this study and any analyses of that data will not be used in any way other than those 
ways already approved without further approval from the NICHD and/or PC. 
 
20.7 Retention of Data 
 
The Investigator will maintain adequate records of the study including subjects’ CRFs, medical records, 
laboratory reports, consent form, drug disposition records, safety reports, information regarding 
participants who discontinued, and other pertinent data.  All records are to be retained by the Investigator 
for a period of at least 2 years after the last approval of a marketing application or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product (per FDA 
CFR 312.62, “2 years after the investigation is discontinued and FDA is notified.”).  These documents 
should be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.  The Investigator will 
contact NICHD, the Population Council and Health Decisions for authorization prior to destruction of any 
such records or in the event of accidental loss or destruction of any study records. 

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20.8 Publication Policy 
 
Data on the use of the study medication and results of all clinical and laboratory studies are considered 
private and confidential. NICHD will encourage publication of the results of the study. Any publications or 
presentations that result from this study will maintain participant confidentiality. The IND and proprietary 
information about the investigational drug, Nestorone, are under the supervision of the Population 
Council. Institutions and/or the Principal Investigators agree to submit all proposed publications, papers, 
abstracts, manuscripts, posters or other written materials which include data relating to the Study or the 
use of the Product supplied under this Agreement, and all outlines of any proposed oral presentations 
with respect thereto, to NICHD and PC at least thirty (30) days prior to either (a) submission of such 
written materials for publication or (b) any proposed oral disclosure to a third party outside of the NICHD 
CCTN. NICHD and PC shall have the right to comment on such written material or outline within (30) 
days of receipt, and such comments shall be considered in good faith by the Principal Investigators in 
determining the final form of disclosure. PC shall also have the right to eliminate any reference to 
confidential or proprietary information provided to Institutions and/or the Principal Investigators or the 
Staff pursuant to this Agreement.  Institutions and the Principal Investigators agree to acknowledge the 
NICHD and PC’s contribution to Institution’s and/or the Principal Investigator’s work in any publication or 
public disclosure unless requested by the Council not to do so. 
 
20.9 Financing and Insurance 
 
Financing and insurance are addressed in separate documentation. 
 
21. Evaluations 
 
This is a single dose, open label study designed to assess the secondary exposure in females after male 
application of NES + T combination gel to shoulders and upper arms. The effect of washing or clothing 
barrier to application will also be assessed.  
 
21.1 PK Evaluations 
 
The pharmacokinetics (PK) evaluations will be evaluated by assessing differences between average 
serum testosterone and Nestorone levels at baseline comparted to Cavg, Cmax, and Cmin after 
secondary exposure to NES/T gel.  PK differences in exposure will be assessed with a 100% T-shirt 
clothing barrier, after washing the application site with soap and water and without washing or a T-shirt 
barrier to skin to skin contact.  
 
PK evaluations relative to the level of testosterone and Nestorone remaining on the skin 2 hours after 
application with and without washing will also be completed.  
 
21.2 Safety Evaluations 
 
Each subject’s health status will be monitored carefully throughout the trial. Safety evaluations completed 
during the study will include: 
 
Adverse event reports  
 
Vital signs  
 
Safety lab tests including CBC, blood chemistries, and liver panel 
 
Monitoring of pregnancies that occur during study participation 
 
Facial acne and hirsutism assessment (in females) 
 
 

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21.2.1 Safety Parameter Methods 
 
Each subject’s health status will be monitored carefully throughout the trial.  Baseline data collected at 
the screening visit will consist of the medical history and vitals. Baseline data obtained from clinical 
chemistries and a complete blood count (CBC) will be used to monitor liver and renal function and 
hematologic status.   
 
Adverse event reports will be collected and assessed at each visit. The results of the CBC and blood 
chemistries, will be reviewed by the investigators when results are available.  If there is any clinically 
significant abnormal finding, the test will be repeated and the results reviewed and discussed with the 
medical monitor.  If the subject has persistent abnormal parameters, the subject will be discontinued from 
the study and reassessed in a month.  If the parameter does not return to normal after drug withdrawal at 
the end of the study/exit visit, the subject will be referred for appropriate assessment and treatment, if 
necessary. The outcome will be followed in 3 months by contacting the subjects. 
 
Subjects who withdraw from the study will have all safety assessments repeated with the exception of 
medical history and STI screening.  Interviews with subjects will include a review of any AE recorded on 
the log or otherwise reported in order to obtain as much information as possible. The AEs will be recorded 
at each visit on the CRF and on the appropriate forms. The principal investigator (or designated medical 
designee) will review each study event, assess severity, causality, seriousness, and report it in accordance 
with established procedures. There will be strict adherence to SAE reporting (see Sections 15.6.2 and 
15.6.3). The site IRB/IEC will be notified of any serious, unexpected adverse events in compliance with 
IRB/IEC research requirements.  PC, as the sponsor of the IND for Nestorone, will make the final 
adjudication and submit IND safety reports as required to FDA.  
 
Safety evaluations will be based primarily on the incidence of AEs, including study product reactions, study 
discontinuation information, changes from screening to the last assessment in vital signs and clinical 
laboratory tests, including hematology and blood chemistry.   
 
22. Statistical and Analytical Methods 
 
A detailed statistical analysis plan will be developed prior to performing the statistical analysis for this 
trial.  Further details of the statistical methodology in addition to the below will be described in the 
statistical analysis plan (SAP). Statistical methods in the statistical analysis plan that are different than 
the methods presented in the protocol will be discussed in the analysis plan.  The final study report will 
discuss any deviations from the final statistical analysis plan. 
 
22.1 Sample Size 
 
An estimated sample size of 12 couples is based on the studies conducted assessing testosterone 
transference. Based on the published data, a sample size of 12 female participants will give an 80% 
power to detect a change from baseline in serum testosterone of non-dosed females for a mean 
difference of 9 ng/dL with a standard deviation of 10 ng/dL (Stahlman, et al., 2012).  
 
22.2 Analysis populations  
 
The following analysis populations will be created: 
1. All Enrolled: All couples that are enrolled into the study. 
2. All Treated: All enrolled couples where the man applied at least one dose of study drug. 
 
Overview of analyses to be performed for each analysis population: 
 

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Analysis 
Population 
Demographics 
and Subject 
Characteristics 
Exposure AEs PK/Hormones 
All Enrolled 
 
 
 
 
All Treated 
(Safety) 
 
 
 
 
 
22.2.1 Primary Analysis 
The primary analysis will be evaluated in female participants by assessing changes from baseline up to 
48 hours for serum testosterone levels in Cavg, Cmax and Cmin after secondary exposure to Nestorone 
+ Testosterone Combination Gel (NES/T gel).  Also, the Nestorone levels will be analyzed after 
secondary exposure to NES/T gel by presenting Cavg, Cmax, and Cmin. These endpoints will be 
summarized for each of the 3 types of skin contact between the man and woman. 
 
22.2.2 Secondary Analysis 
Secondary analysis will include:  
 
Pharmacokinetic parameters of testosterone and Nestorone in men will be compared with and 
without wearing a T shirt and washing.  
 
Serum T pharmacokinetics parameters in males with and without T shirt and washing will also be 
compared with baseline pharmacokinetic parameters.  
 
Average Testosterone and Nestorone levels on male skin 90 and 150 minutes after application as 
measured by adhesive D-square strips. 
 
. 
 
Change from baseline in safety lab parameters for all who received or were exposed to study 
drug. 
 
Incidence of adverse events and serious adverse events for both partners. 
 
Percentage of females with increased (relative to baseline) acne and hirsutism at each visit. 
These endpoints will be summarized for each of the 3 types of skin contact between the man and 
woman. 
 
22.3 CBC and Clinical Chemistry Parameters 
 
CBC and Chemistry mean changes from baseline to final evaluation will be summarized in both partners.  
The summary will present data for the screening visit and the mean change from screening to final 
evaluation. The sample size, mean, SD, median, minimum, and maximum values will be presented for 
each parameter at each time measured. A summary of shifts from screening to final evaluation will be 
given for each parameter.  The normal range for each parameter will be used to create categories of low, 
normal, or high.  Any result that is higher (lower) than the upper (lower) limit of normal will be categorized 
as high (low) and any result within the lower and upper limits of normal will be categorized as normal.  
The number of subjects in each shift category from screening to final evaluation will be shown for each 
parameter. 
 
22.4 Hormones 
 
Percentage changes from baseline for Testosterone will be summarized for the All Treated population.  
Nestorone levels at each time point after dosing will also be summarized. 
 
22.5 Adverse Events (AEs) 
 

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Treatment-Emergent Adverse Events (TEAEs) are defined as AEs that began on or after first use of the 
investigational gel and up to 14 days after final investigational gel use, and pre-existing conditions that 
worsened during the same timeframe. 
 
The number (percentage) of subjects with at least one treatment-emergent AE will be presented in a 
frequency table by MedDRA® system-organ class and per MedDRA® “preferred” term. A similar 
summary will be created for SAEs and AEs leading to discontinuation. Summaries will also be presented 
by relationship to investigational product (“drug related” is defined as possibly, probably, or highly 
probable related to investigational product) and intensity of AE. Adverse event summaries will be done 
for the All Treated population in order to look at AE rates in all subjects combined as well as looking at 
the subset of subjects that did not enter the efficacy phase and the subset of subjects that did enter the 
efficacy phase. 
 
22.6 Deaths 
 
Subjects who died during the clinical trial will be listed and the following variables will be included: main 
reason(s) for death (as reported by the investigator), diagnosis of the SAE contributing to the death, date 
of death relative to the first day and last day of product use, and relationship to investigational product 
according to the investigator and NICHD. Subject SAE narratives, including information regarding the 
death (Certificate of death, autopsy report, etc.), will be part of the final clinical study report. 
 
22.7 Other Safety Analyses 
 
Changes from baseline in other safety parameters (e.g., vital signs, physical exam, etc.) will be 
summarized. 
 
22.8 Disposition of Subjects 
 
The number of subjects, who are enrolled, treated, attended the various assessments and who complete 
the clinical trial will be tabulated. 
 
22.9 Demographic and Other Subject Characteristics 
 
Baseline demographics and characteristics will be summarized. 
 
23. Ethical Considerations 
 
23.1 Statement of Compliance 
 
All aspects of this study will be performed according to CFR Title 21, CFR Title 45, Part 46, Good Clinical 
Practices (GCP) and International Conference on Harmonisation (ICH) under an active U.S. IND 
Application of the Population Council and equivalent health authority permission in other countries.  All 
principles of the Declaration of Helsinki will be followed. Conduct of the trial will be monitored by NICHD’s 
designated CCTN Statistical and Clinical Coordinating Center (SCCC).  The trial will be registered at 
ClinicalTrials.gov. Investigators from all sites have been trained in human research subject protection 
and the privacy of protected health information. 
 
23.2 Interactions with Ethics Committees 
 
The protocol will be reviewed by the FDA and the Central IRB designated by NICHD and the Statistical 
and Clinical Coordinating Center (SCCC).  This protocol and any protocol amendments, together with the 
required documents will be submitted by the study site to the responsible ethics committees according to 

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the applicable requirements at the site. The study will commence at each participating site only after their 
relevant ethics committees (IRB/IEC) has granted full approval. Investigators/institutions will permit trial 
related monitoring, audits, IRB/IEC review and regulatory inspection(s) providing direct access to source 
data/documents. 
 
23.3 Informed Consent 
 
The principles of informed consent will be implemented according to the 1996 revision of the Declaration 
of Helsinki, ICH Consolidated Good Clinical Practice (E6), and current FDA regulations. 
 
Principal investigators must provide the NICHD and the Population Council with a copy of the Informed 
Consent approved for both male and female subjects by their local Institutional Review Board (IRB).  It is 
the investigator's responsibility to assure that each subject is provided an explanation of the details 
contained in the informed consent statement and other locally required documents prior to the individual 
signing the informed consent form certifying voluntary participation in the trial and prior to study 
participation. If required by the IRB/IEC or local regulations, a witness (impartial observer to the informed 
consent process) must also sign the informed consent form. The subject is to receive a copy of this consent 
form after signatures of the investigator or his/her designees are obtained. Under this consent, the subject 
shall understand that he/she is authorizing access to medical records as required for monitors, auditors, 
IRBs and regulatory authorities. To expedite collection of supporting documentation in the event of a 
serious adverse event, the subject should also be asked to provide a release of medical records 
authorization at the enrollment/treatment day 1 visit. 
 
Subjects, male and female, that agree to participate in the study must sign the informed consent form (ICF) 
prior to study-specific procedures. The principles of informed consent will be implemented according to the 
1996 revision of the Declaration of Helsinki and current NIH, DHHS, and FDA regulations. The informed 
consent form will be HIPAA compliant. 
 
The subjects will be informed of their right to privacy and the fact that personal information will be treated 
as strictly confidential and will not be publicly available in accordance with HIPAA regulations. They will 
also be informed that the NICHD and the FDA have the right to inspect and possibly photocopy their 
medical records to verify the accuracy and completeness of the clinical trial results. The subject is to 
receive a copy of this consent form. 
 
Prior to study participation, all study candidates will: 
 
Be informed of the nature and purpose of the study. 
 
Be given an explanation of the procedures to be followed in the study. 
 
Be given a description of any attendant discomforts and risks reasonably to be expected from the 
study, as well as from the study product. 
 
Be given an opportunity to ask any questions concerning the study. 
 
Be instructed that consent to participate in the study may be withdrawn at any time; and that the 
participant may discontinue participation in the study without prejudice. 
 
Be given a copy of an informed consent form. 
 
Be given the opportunity to decide to consent or not to consent to the study without coercion. 
 
Be informed of alternative contraceptive methods available. 
 
Be given information for whom to contact if there are questions about the research, participant 
rights, or to report research-related injury.  
 
23.4 Conflicts of Interest 
 
Investigators will be affiliated with their study sites.  They will receive support for this clinical trial from the 
NICHD/NIH, which is a sponsor of this study, but will not profit from results, either positive or negative, 

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with regard to the product being evaluated. Population Council, a sponsor for this study and the IND 
holder, which is a not for profit organization, could profit from the successful development of this product. 
 
23.5 Confidentiality 
 
The information on individual subjects arising from this study is to be considered confidential and 
transmitted to the sponsor only in a form that will not permit identification of the individual.  The information 
obtained from the subjects that can be identified with the subject will remain confidential within the research 
team. Regulatory and sponsoring agencies may request access to the study records and related medical 
records of each participating subject; the subject’s identity will remain confidential to the extent permitted 
by the applicable laws and regulations.  The results of the research will be released to public agencies 
including regulatory agencies, clinical investigators, and research organizations without reference to items 
identifiable to a particular subject.  The results will be published such that the identity of the subjects will 
not be disclosed and cannot be ascertained. National and international agencies and sponsoring agencies 
may request access to the medical records of each participating subject, and if requested, the subject’s 
identity will remain confidential. All records will be kept in a secure storage area with limited access. 
 
 

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References 
 
Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. (1999) A lower dosage levonorgestrel and 
testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin 
levels with fewer metabolic effects than higher dosage combinations. J Androl. 20(3), 407-414. 
Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. (1996) Combined 
administration of levonorgestrel and testosterone induces more rapid and effective suppression of 
spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin 
Endocrinol Metab. 81(2), 757-762. 
Brachet C, Vermeulen J & Heinrichs C. (2005) Children's virilization and the use of a testosterone gel by 
their fathers. Eur. J. Pediatr. 164, 646-647. 
Brache V, Massai R, Mishell DR, Moo-Young AJ, Alvarez F, Salvatierra AM, Cochon L, Croxatto H, 
Robbins A, Faundes A. (2000) Ovarian function during use of Nestorone(R) subdermal implants. 
Contraception. 61(3), 199-204. 
Cummings DE, Bremner WJ. (1994) Prospects for new hormonal male contraceptives. Endocrinol Metab 
Clin North Am. 23(4), 893-922. 
de Ronde W, Vogel S, Bui H N & Heijboer A C. (2011) Reduction in 24-hour plasma testosterone levels in 
subjects who showered 15 or 30 minutes after application of testosterone gel. Pharmacotherapy 
31, 248-252. 
Díaz S, Schiappacasse V, Pavez M, Zepeda A, Moo-Young AJ, Brandeis A, Lähteenmäki P, Croxatto HB. 
(1995) Clinical trial with Nestorone subdermal contraceptive implants. Contraception. 51(1), 33-38. 
Dorman E and Bishai D. (2012) Demand for male contraception. Expert Rev Pharmacoecon Outcomes 
Res. 12(5), 605-613. 
Fraser IS, Weisberg E, Kumar N, Kumar S, Humberstone AJ, McCrossin L, Shaw D, Tsong YY,  Sitruk-
Ware R. (2007) An initial pharmacokinetic study with a metered dose transdermal systemfor 
delivery of the progestogen nestorone as a possible future contraceptive. Contraception. 76(6), 
432-438. 
Handelsman DJ, Conway AJ, Howe CJ, Turner L, Mackey MA. (1996) Establishing the minimum effective 
dose and additive effects of depot progestin in suppression of human spermatogenesis by a 
testosterone depot. J Clin Endocrinol Metab. 81(11), 4113-4121. 
Haukkamaa M, Laurikka-Routti M, Heikinheimo O, Moo-Young A. (1992) Contraception with subdermal 
implants releasing the progestin ST-1435: a dose-finding study. Contraception. 45(1), 49-55. 
Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. (2005) Attitudes toward male fertility control: 
results of a multinational survey on four continents. Hum Reprod. 20(2), 549-556. 
Ilani N, Liu PY, Swerdloff RS, Wang C (2011) Does ethnicity matter in male hormonal contraceptive 
efficacy? Asian J Androl. 13(4), 579-584. 
Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, Bremner WJ, Siturk-Ware R, Kumar N, Blithe DL, 
Wang C. (2012) A New Combination of Testosterone and Nestorone Transdermal Gels for Male 
Hormonal Contraception. J Clin Endocrinol Metab. 97(10), 3476-3486. 
Kamischke A, Plöger D, Venherm S, von Eckardstein S, von Eckardstein A, Nieschlag E. (2000) 
Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-
controlled feasibility study for male contraception. Clin Endocrinol (Oxf). 53(1), 43-52. 
 
Knuth UA, Yeung CH, Nieschlag E. (1989) Combination of 19-nortestosterone-hexyloxyphenylpropionate 
(Anadur) and depot-medroxyprogesterone-acetate (Clinovir) for male contraception. Fertil Steril 
51(6), 1011-1018. 
Kumar N, Koide SS, Tsong Y, Sundaram K. (2000) Nestorone: a progestin with a unique pharmacological 
profile. Steroids. 65(10-11), 629-636. 
Kunz G J, Klein K O, Clemons R D, Gottschalk M E & Jones K L. (2004) Virilization of young children after 
topical androgen use by their parents. Pediatrics 114, 282-284. 

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Laurikka-Routti M, Haukkamaa M, Heikinheimo O. (1990) A contraceptive vaginal ring releasing ethinyl 
estradiol and the progestin ST-1435: bleeding control, serum steroid concentrations, serum lipids 
and serum chemistry. Contraception. 42(1), 111-120. 
Mahabadi V, Amory JK, Swerdloff RS, Bremner WJ, Page ST, Sitruk-Ware R, Christensen PD, Kumar N, Tsong 
YY, Blithe D, Wang C. (2009) Combined transdermal testosterone gel and the progestin nestorone 
suppresses serum gonadotropins in men. J Clin Endocrinol Metab. 94(7):2313-2320.  
Martin CW, Anderson RA, Cheng L, Ho PC, van der Spuy Z, Smith KB, Glasier AF, Everington D, Baird DT. 
(2000) Potential impact of hormonal male contraception: cross-cultural implications for development of 
novel preparations. Hum Reprod.15(3):637-645. 
Merhi Z O & Santoro N. (2007) Postmenopausal virilization after spousal use of topical androgens. Fertil. 
Steril. 87, 976.e913-975. 
Miller M G, Rogol A D & Zumbrunnen T L. (2012) Secondary exposure to testosterone from patients 
receiving replacement therapy with transdermal testosterone gels. Curr. Med. Res. Opin. 28, 267-
269. 
Nieschlag E, Zitzmann M, Kamischke A. (2003) Use of progestins in male contraception. Steroids. 68(10-
13), 965-972. 
Rolf C, Knie U, Lemmnitz G & Nieschlag E. (2002) Interpersonal testosterone transfer after topical 
application of a newly developed testosterone gel preparation. Clin. Endocrinol. (Oxf). 56, 637-641. 
Shiraishi S, Lee PW, Leung A, Goh VH, Swerdloff RS, Wang C. (2008) Simultaneous measurement of serum 
testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clin Chem.  
54(11), 1855-1863. 
Sitruk-Ware R. (1989) Transdermal delivery of steroids. Contraception.39(1), 1-20. 
Sitruk-Ware R. (1995) Transdermal application of steroid hormones for contraception. J Steroid Biochem 
Mol Biol. 53(1-6), 247-251. 
Sitruk-Ware R, Small M, Kumar N, Tsong YY, Sundaram K, Jackanicz T. (2003) Nestorone: clinical applications 
for contraception and HRT. Steroids. 68(10-13), 907-913. 
Stahlman J, Britto M, Fitzpatrick S, McWhirter C, Testino S A, Brennan J J & Zumbrunnen T L. (2012) 
Effect of application site, clothing barrier, and application site washing on testosterone transfer with 
a 1.62% testosterone gel. Curr. Med. Res. Opin. 28, 281-290. 
Stahlman J, Britto M, Fitzpatrick S, McWhirter C, Testino S A, Brennan J J & Zumbrunnen T L. (2012) 
Effects of skin washing on systemic absorption of testosterone in hypogonadal males after 
administration of 1.62% testosterone gel. Curr. Med. Res. Opin. 28, 271-279. 
Stahlman J, Britto M, Fitzpatrick S, McWhirter C, Testino S A, Brennan J J & Zumbrunnen T L. (2012) 
Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone 
gel: effects of clothing barrier on testosterone absorption. Curr. Med. Res. Opin. 28, 291-301. 
Swerdloff R S, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto A M, Snyder P J, Weber T, 
Longstreth J & Berman N. (2000) Long-term pharmacokinetics of transdermal testosterone gel in 
hypogonadal men. J. Clin. Endocrinol. Metab. 85(12), 4500-4510. 
Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI, Handelsman DJ. (2003) Contraceptive 
efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab. 88(10):4659-
4667. 
Wallace EM, Wu FC. (1990) Effect of depot medroxyprogesterone acetate and testosterone oenanthate 
on serum lipoproteins in man. Contraception. 41(1), 63-71. 
Wang C, Berman N, Longstreth JA, Chuapoco B, Hull L, Steiner B, Faulkner S, Dudley RE, Swerdloff RS. 
(2000) Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one 
site versus four sites: a General Clinical Research Center Study. J Clin Endocrinol Metab. 85(3), 964-
969. 
Wang,C, Wang XH, Nelson AL, Lee KK, Cui YG, Tong JS, Berman N, Lumbreras L, Leung A, Hull L, Desai S, 
Swerdloff RS. (2006) Levonorgestrel implants enhanced the suppression of spermatogenesis by 
testosterone implants: comparison between Chinese and non-Chinese men. J. Clin. Endocrinol. Metab. 
91(2) 460-470. 

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Wang C, Shiraishi S, Leung A, Baravarian S, Hull L, Goh V, Lee PW & Swerdloff RS. (2008) Validation of a 
testosterone and dihydrotestosterone liquid chromatography tandem mass spectrometry assay: 
Interference and comparison with established methods. Steroids. 73(13) 1345-1352. 
Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, 
Berman N, Testosterone Gel Study Group. (2000) Transdermal testosterone gel improves sexual 
function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin 
Endocrinol Metab. 85(8) 2839-2853. 
World Health Organization (WHO) Task Force on methods for the regulation of male fertility. (1990) 
Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet. 336(8721), 955-
956. 
Wu FC, Balasubramanian R, Mulders TM, Coelingh-Bennink HJ. (1999) Oral progestogen combined with 
testosterone as a potential male contraceptive: additive effects between desogestrel and 
testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid 
metabolism. J Clin Endocrinol Metab. 84(1), 112-122. 
 
 
 
 
   
 
 
 
 
 
 
 

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INVESTIGATOR OBLIGATIONS 
Clinical research studies are subject to the regulations of the FDA. Prior to beginning the study, the 
investigator will be asked to demonstrate compliance with ICH E6, 8.2 and 21 CFR 312 by providing the 
signed essential documents required for the clinical trial. The responsibilities imposed upon investigators 
by the FDA are summarized in the “Statement of Investigator Form” (Form FDA-1572) which documents 
that he or she will follow the FDA regulations with respect to this study. 
The investigator agrees to assume the responsibilities stated on the Form FDA-1572, and signifies his or 
her agreement by signing the Form FDA-1572, these responsibilities include: 
 
- 
To conduct the study in accordance with the Study Protocol, Investigator Brochure, GCPs, ICH, and 
Declaration of Helsinki. 
- 
To secure prior approval of the study by an appropriate Institutional Review Board (IRB). This board 
should be constituted in conformity with FDA regulations. 
- 
To report on the progress of the study to the IRB and to submit a final report within three (3) months of 
the conclusion of data collection. 
- 
To maintain current records of the receipt, dispensing, and disposition of study product and to return 
(or destroy as recommended when appropriate) all unused product to the sponsor or the sponsor’s 
designated agent. 
- 
To obtain a valid, fully informed, freely given written consent from each subject who participates in the 
study. 
- 
To maintain adequate study documentation including web-based electronic case report forms (eCRFs), 
hospital records, and lab results, and to store these case histories for a minimum of two years following 
notification by the sponsor that all investigations have been discontinued or that the FDA has approved 
the drug application. 
- 
To identify all sub-investigators who will also supervise drug administration. 
- 
To report all Adverse Events to the sponsor or designated agent promptly. 
- 
To notify the Population Council Safety Desk and HD within 24 hours of identifying a serious adverse 
event, regardless of the presumed relationship to the study product. 
- 
To allow inspection or copying by the FDA, sponsor, or sponsor’s designated agent of case histories 
and records of drug distribution. 
Investigator Documentation required:  
Prior to beginning the study, the investigator will be asked to comply with ICH E6, 8.2 and 21 CFR 312 by 
providing the following essential documents, including but not limited to: 
(a) An original signed Investigator Agreement page of the protocol.  
(b) An original signed acknowledgement of receipt of the Investigator’s Brochure.  
(c) An IRB/IEC-approved Informed Consent (as described in Section 23.3) in the local language.  
(d) Local IRB/IEC approval of protocol and informed consent.  
(e) Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572.  
(f) Current Curriculum Vitae (CV) for the investigator and each sub investigator listed on Form FDA 1572. 
(g) Financial disclosure information to attest to the absence of financial interests and arrangements, 
including any equity interests in the sponsor or proprietary interest in the tested product, which could 
introduce bias in the study conduct. 

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Appendix 1: Schedule of Assessments 
 
Assessment 
Screening 
Phase 
 
Treatment Phasea 
 
End of 
Studya 
UNS 
Visit Number 
1 
2j 
 
3 
4 
5 
6 
7 
8 
 
9 
 
Study Day^  
-28 to 0 
 
1 
3 
8 
10 
15 
17 
 
31 
 
Both Partners 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Assign Subject Number 
X 
 
 
 
 
 
 
 
 
 
 
 
Determine/Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical, Reproductive, and Contraceptive History 
X 
 
 
 
 
 
 
 
 
 
 
 
Questions on Contraceptive and Pregnancy Planning 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
X 
 
 
X 
Xl 
X 
Xl 
X 
Xl 
 
Xl 
X 
CBC and Clinical Chemistryb 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
X 
Hormone assessment (total testosterone only)c 
X 
 
 
 
 
 
 
 
 
 
 
 
24-hour T PK samplingk 
 
X 
 
 
 
 
 
 
 
 
 
 
Overnight Stay 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Supervised Skin Contact 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Adverse Events 
 
X 
 
X 
Xl 
X 
Xl 
X 
Xl 
 
X 
X 
Concomitant Medications 
X 
X 
 
X 
Xl 
X 
Xl 
X 
Xl 
 
X 
X 
Male Partner 
Andrological History 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exame 
X 
 
 
 
 
 
 
 
 
 
 
X 
PSA 
X 
 
 
 
 
 
 
 
 
 
 
X 
Gel Application 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Wear 100% Cotton T-shirt 
 
 
 
X 
 
 
 
 
 
 
 
X 
Shower 
 
 
 
 
 
X 
 
 
 
 
 
X 
NES and T samplingf 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Residual Nestorone and testosterone Measurementsg 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Phone Contact 
 
 
 
 
 
 
 
 
 
 
X 
X 
Female Partner 
Gynecological and Menstrual History 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 

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Assessment 
Screening 
Phase 
 
Treatment Phasea 
 
End of 
Studya 
UNS 
Visit Number 
1 
2j 
 
3 
4 
5 
6 
7 
8 
 
9 
 
Study Day^  
-28 to 0 
 
1 
3 
8 
10 
15 
17 
 
31 
 
Urine Pregnancy Test 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Skin exam for Acne and Hirsutism Assessment i 
(Ferriman-Gallwey) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Contraception and Menstrual Bleeding Questions 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
Post Skin Contact Washing 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
NES and T samplingh 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Footnotes: 
^ A 28 day window is allowed for the screening period before safety labs must be repeated. Treatment Visits 3, 5 and 7 have a +7 day window. Treatment Visits 4, 
6 and 8 must occur the day after the female subject has finished each in-patient treatment visit (Visits 3, 5, and 7) (i.e. no day visit window is allowed for these visits). 
End of Study Visit should occur on day 31 (-12 days/+14 days). 
a Only the female partner is required to come in for visits on days 3, 10, 17 and 30. 
b CBC (complete blood counts ) and Clinical Chemistry panel (glucose, liver and renal function tests including urea, creatinine, albumin, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, bilirubin) will be done for both men and women at screening and then again on day 16 prior to leaving the in-
patient clinic.  If a couple discontinues early, a CBC and Clinical Chemistry draw will occur for the female subjects only at the early discontinuation visit. 
c  If total testosterone is abnormal, this will be repeated with free testosterone, sex-hormone binding globulin, luteinizing hormone and follicle-stimulating hormone 
measurements at the Visit 2 with results assessed prior to the couple being enrolled. 
d Vitals includes weight, pulse, blood pressure and respiratory rate. Height will also be collected at screening in order to calculate BMI. Three blood pressure 
measurements will be taken with 5-minute rest period in between readings and the mean of the three measurements will be documented.   
e Complete physical exam should include a detailed andrological exam 
f For the male partner, serial blood draws for Nestorone and testosterone measurements will be collected at -15 and -5 minutes before gel application and at 1, 2, 
4, 8, 12, 16, 20 and 24 hours after gel application. 
g Using adhesive D-square strips a single location on the application site will be stripped on the male partner a total of ten times and the strips will then be analyzed 
for testosterone and Nestorone. 
h For the female partner, serial blood draws for Nestorone and testosterone measurements will be collected at 2, 3, 4, 5, 6, 8, 10, 14, 18, 22, 26 and 50 hours after 
male participant gel application. She will also return at around 10 am on days 3, 10 and 17 for a single 50 hour post male participant gel application blood draw. A 
single blood draw at Visit 9 (Day 31) will occur to assess residual levels of testosterone and Nestorone. 
I For the female partner, an examination should be done to assess any kind of facial acne or hirsutism. j Screening Visit 2 can occur one day prior to Visit 3/Day 1 
(i.e. couple would come for their baseline 24 hour PK draws (Visit 2) and then continue directly into Visit 3/Day 1, thus staying for 48 hours straight. 
k 24-hour Testosterone PK assessment before the first dose. 
l Vitals signs will only be collected for female subjects. 
 

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Appendix 2: List of Exclusionary Medications 
The following list includes some of the common drugs that contraindicate study participation. Please note 
that this list is NOT exhaustive; drugs not on the list should be researched by the study center staff and 
approval granted from the Medical Monitor if a site is uncertain about contraindication. 
 
Subjects who begin taking an exclusionary medication (i.e. antibiotic) after study enrollment will require a 
waiver to continue in the study.  
 
Certain antibiotics can interfere with metabolism of hormone contraceptives. 
Please request an approval from Medical Monitor for specific antibiotics you are 
unsure of 
Accutane 
Isotretinoin 
Azathioprine 
Lithium 
Cytotec 
Misoprostol 
Diethylstilbestrol (DES) 
Phenylbutazone 
High dose Vitamin A 
Prednisone  
human growth hormone 
Ritonavir 
Immuoprin 
somatotropin 
Imuran 
Thalidomide 
Sex Hormones/Steroids 
Androgens/Anabolic Compounds 
anastrazole/letrozole 
finasteride 
clomiphene 
FSH 
dutasteride 
hCG 
All Androgens, Estrogens and Progestins not specified 
Androgen Receptor Blocker 
flutamide 
Anticoagulants 
Anticonvulsant 
alprazolam 
Klonopin 
benzodiazepines 
Neurontin 
clonazepam 
Restoril 
clorazepate 
temazepam 
Depakote 
Tranxene 
diazepam 
triazolam 
divalproex sodium 
Valium 
gabapentin 
Xanax 
Halcion 
Antihypertensives 
Interfere/Interact with Nestorone or Testosterone 
anisindione 
Kynamro 
Arava 
leflumomide 

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Aubagio 
lomitapide 
Coumadin 
mipomersen 
dicumarol 
Miradon 
Jantoven 
teriflunomide 
Juxtapid 
warfarin 
Interfere with the metabolism of hormone contraceptives: 
barbiturates 
Oxcarbazepine 
Griseofulvin 
Primidone 
Isoretinoin 
Topiramate 
Modafinil 
Liver enzyme inducers: 
carbamazepine 
Phenytoin 
Carbatrol 
Rifampin 
Dilantin 
Rifabutin 
Lansoprazole 
St. John's Wort 
phenobarbital 
Tegretol 
FDA List of CYP3A4 Inhibitors 
STRONG: 
Boceprevir 
(12) nefazodone 
Biaxin 
nelfinavir 
clarithromycin 
posaconazole 
conivaptan 
ritonavir 
(11) indinavir 
saquinavir 
itraconazole 
telaprevir 
ketoconazole 
telithromycin 
lopinavir/ritonavir 
voriconazole 
mibefradil 
  
MODERATE: 
Amprenavir 
erythromycin 
aprepitant 
fluconazole 
atazanavir 
fosamprenavir 
ciprofloxacin 
(11) imatinib 
darunavir/ritonavir 
verapamil 
diltiazem 
  
Lipid-lowering Statin Drugs 
  
Atorvastatin 
Pravastatin 
Lipitor 
Provachol 
lovastatin 
simvastatin 
Mevacor 
Zocar 
 spironolactone 
  
Aceon 
Mavik 
Accupril 
Moexipril  

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Altace 
Monopril 
benazepril 
Perindopril  
Capoten 
Prinivil 
captopril 
Quinapril  
Enalapril 
Ramipril  
Fosinopril  
Trandolapril  
Lisinopril  
Univasc 
Lotensin 
Zestril 
Chemotherapeutic agents 
Vaccinations within 3 months of study treatment 
Measles 
Rubella 
Mumps 
Varicella 
Oily Cosmetic Skin Gels/Products that would prevent absorption of steroids 
 
 
 

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Appendix 3: Instructions for Gel Application – Male Contraceptive 
 
 
 
Gel should be applied to clean dry skin at approximately 8am under study staff supervision. 
 
The syringe cap should not be removed until the male participant is ready to use the gel. 
 
The male participant should wash his hands and then push the plunger of the syringe to deliver 
the gel to his hand. 
 
Using his palms, the male participant will apply the prescribed daily dose of the gel to the right 
and left shoulders and area of the upper arms to the top of the bicep muscle (i.e., to shoulder and 
arm skin that would be covered by a short sleeve T-shirt)as shown in the shaded areas in Figure 1 
below.  
 
 
Figure 1: Application sites for the study gel 
 
 
Once the application site is dry, the site should be covered with clothing until time of rubbing with 
female participant, at which time specific visit rubbing non/coverage requirements will be 
followed.  Treatment and contact variations are as followed for each specific treatment day: 
o Day 1/Visit 3 - “Shirt” PK day: Apply gel and don shirt (provided by the investigators) 
immediately after applied gel has been allowed to dry. Continue to wear the T-shirt until 
female participant rubs the area of the T-shirt covering the gel application site at 
approximately 2 hours (±15 minutes) post gel application; 
o Day 8/Visit 5 - “Shower” PK day: Apply gel and don shirt (provided by the investigators) 
immediately after applied gel has been allowed to dry. Continue to wear the T-shirt until 
showering occurs (washing the gel application site with soap and water) one hour 45 
minutes after the gel application.  The female participant will rub the gel application site 2 
hours (±15 minutes) after gel application and just after showing once skin has been dried.; 
o Day 15/Visit 7 - “Bare, unshowered” PK day: Apply gel and don shirt (provided by the 
investigators) immediately after applied gel has been allowed to dry. Remove the T-shirt 
immediately prior to the female subject rubbing the gel application site 2 hours (±15 
minutes) after gel application. 
 
Wash hands thoroughly with soap and water after gel application. Avoid fire, flames or smoking 
until the gel has dried since alcohol based products, including the study gel, are flammable. 
 
Clothing should be worn over the gel application area or a shower should be taken prior to close 
skin contact with women or children outside of supervised study procedures outlined within the 
study protocol. 
 
 

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Appendix 4: Study Procedures for Male and Female Subjects 
Apply gel at 8 am                                  Apply gel at 8 am               
Apply gel at 8 am               
T shirt on during rubbing       
Shower 2 h after Gel application   
No T-shirt/shower
Day  1                                                     Day 8                                                    Day 15   
Female
•
Supervised close skin contact by rubbing male gel application site 2h 
after male gel application on day 1, 8, 15
•
Blood draws for T and NES 2, 3, 4, 5, 6, 8, 10, 14, 18, 22, 26 and 50 h after 
male participant gel application 
Male
•
Blood draws for NES at -15, -5 minutes and at 1, 2, 4, 8, 12, 16, 20,and 24 h after 
gel application each treatment day (days 1, 8 and 15).
 
 
 
Appendix 5: Outline of Timed NES and T sampling  
 
Hour for 
draw time 
-15 
min 
-5 
min 
0/gel 
applied 1 2 3 4 5 6 8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
50 
Men 
X 
X 
 
X X  
X  
 
X  
X 
 
X 
 
X 
 
X 
 
 
Women 
 
 
 
 
X X X X X X X 
 
X 
 
X 
 
X 
 
X 
X 
  
 

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Appendix 6: Preparation of Nestorone/Testosterone (NES/T) Combined Gel Investigational Product 
by the Investigational pharmacists at each site 
 
• The combined NES/T gel will be shipped in glass jars from Particle Science to the Investigational Pharmacy 
of each site. Each jar will be used only for one participant. 
• In advance of a day that the male participant will be coming to administer the gel (day 1, 8, and 15), the 
pharmacist will aspirate the gel from the glass jar using 6 mL plastic syringes. Precaution should be taken to 
avoid excess periods that would allow for evaporation of gel. 
• Air bubbles and excess gel will be displaced from the syringe using the plunger until 5 mL of the combined 
gel is in the syringe. A syringe cap will then be placed on the tip of the syringe 
• The pharmacist will place a label on the individual syringes to identify the study product. Refer to Section 
12.1.2 regarding label information. 
• The pharmacist will prepare a single syringe for each subject visit and store them at room temperature and 
then place the syringe into a bag, sealed, and delivered to the clinic for the participant. The opaque bag will 
have a two part label that will be applied by the pharmacist. Refer to Section 12.1.2 regarding label 
information. 
 
 

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Appendix 7: Ferriman-Gallwey Scale for Skin Exam