Conditions: Endometriosis
Keywords: endometriosis gonadotropin-releasing hormone agonist healthy volunteers leuprolide oral tablet
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: yes

Brief summary:
This Phase 2a, pharmacokinetic/pharmacodynamic study will determine the safety and provide evaluation of the PK/PD metrics of three different oral doses selected upon the results of the study LOPDT-PH1-01 - 4 mg oral tablets administered over 28 days as QD and BID regimens and 10 mg oral tablets administered over 28 days as a BID regimen. The PK/PD profiles of the study drug will be compared to the leuprolide formulation approved for the treatment of endometriosis (a monthly intramuscular injection, Lupron Depot 3.75 mg). Major PK (e.g., a total exposure to leuprolide) and PD parameters (e.g., rates of the estradiol suppression and cessation of the menstrual period) will also be evaluated against the Lupron Depot historical data.

Detailed description:
Site initiation visit of the study site, InVentiv Health Clinique, Inc. by on-site visit and teleconference was done and the final report signed 21st July 2017.

For the demographic and baseline characteristics descriptive statistics consisting of mean, median, standard deviation, minimum, maximum and sample size is reported for continuous variables like age, body mass index, weight and height. categorical variables like ethnicity, gender and race is presented as frequency counts and percentages.

For PK analysis, Steady state concentration level of leuprolide calculated for oral tablets (Treatments A and B) at the end of the fourth treatment week (Treatment Days 28) as the 24-hour AUCs divided by the duration of the dosing interval i.e., 24 hours.

For PD analysis, subject incidence of estradiol level below 40 pg/mL was assessed. The ovulation rate determined by the extent of progesterone suppression is presented.

Only observed data is used in the data analysis except for concentration values below the lower limit of quantitation (BLQ) and samples with no reportable value occurring prior to dosing (on Day 1 only). No attempt is made to impute (i.e., extrapolate or interpolate) estimates for missing data.

For safety analysis, incidence of treatment emergent adverse events both during the dosing and post dosing period is presented.

The Medical Dictionary for Regulatory Activities (MedDRA®) Version 20.1 is used to classify all medical history findings and incidences of treatment emergent adverse events (TEAE) reported during the study by System Organ Class (SOC) and Preferred Term (PT).

Arms:
arm 1: Leuprolide Oral Tablet QD: 4 mg for 28 consecutive days. arm 2: Leuprolide Oral Tablet BID: 4 mg, 12 hours apart for 28 consecutive days. arm 3: Leuprolide Depot : intramuscular (IM) 3.75 mg depot injection administered for one month of therapy arm 4: Leuprolide Oral Tablet BID: 10 mg, 12 hours apart for 28 consecutive days

Interventions: intervention 1: Leuprolide Oral Tablet 4-mg QD intervention 2: Leuprolide Oral Tablet 4-mg BID intervention 3: Leuprolide Depot intervention 4: Leuprolide Oral Tablet 10-mg BID
Intervention descriptions: intervention 1: 4-mg Leuprolide oral tablet once daily for 28 consecutive days. intervention 2: 4-mg Leuprolide oral tablet twice daily for 28 consecutive days. intervention 3: 3.75 mg intramuscular depot injection intervention 4: 10-mg Leuprolide oral tablet twice daily for 28 consecutive days.

Protocol document:
Prot_000.pdf: 
Document Approval Date: February 1st, 2018 
Official Title: A randomized, open-label, parallel-group, active-control study to evaluate the 
pharmacokinetic (PK) and pharmacodynamic (PD) profiles of three doses of Leuprolide Oral 
Tablets (Ovarest™) in comparison to an intramuscular dose of leuprolide acetate (Lupron 
Depot® 3.75 mg) in healthy female volunteers. 
NCT number: NCT02807363 
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information 
(PPD) or company confidential information (CCI). 
LOPDT-ENDO-01-Leuprolide Oral Tablet vs. Lupron Depot
Enteris BioPharma Inc.


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1. TITLE PAGE 
 
TITLE: 
A randomized, open-label, parallel-group, active-control study to evaluate 
the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of three 
doses of Leuprolide Oral Tablets (Ovarest™) in comparison to an 
intramuscular dose of leuprolide  acetate  (Lupron Depot® 3.75 mg) in 
healthy female volunteers 
PROTOCOL NO. 
LOPDT-ENDO-01 
STUDY 
DRUGS: 
Treatment A: Leuprolide Oral Tablet (Ovarest™), 4 mg, administered daily 
(qd) for 28 consecutive days 
Treatment B: Leuprolide Oral Tablet (Ovarest™), 4 mg, administered twice 
daily (bid), 12 hours apart for 28 consecutive days 
Treatment C: Leuprolide Acetate intramuscular (IM) injection (Lupron 
Depot 3.75 mg) administered for one month of therapy 
Treatment D: Leuprolide Oral Tablet (Ovarest™), 10 mg, administered 
twice daily (bid), 12 hours apart for 28 consecutive days 
 
PRIMARY 
INVESTIGATOR: 
 
 
 
 
SPONSOR 
Enteris BioPharma, Inc. 
83 Fulton Street 
Boonton, New Jersey 07005 
Tel.: 973-453-3518 
Fax:  973-588-5966 
 
 
CRO 
 
inVentiv Health 
2500 rue Einstein 
Québec (Québec) G1P 0A2 
 
DATE OF ORIGINAL 
June 22, 2016 
 
DATE OF VERSION 
 
February 1, 2018 
 
 
VERSION 
 
Amendment 03 
 
CONFIDENTIAL 
 
This document is strictly confidential. It was developed by Enteris BioPharma Inc. and should not be 
disclosed to any party, with the exception of regulatory agencies and study audit personnel without the 
consent the Sponsor. 
 
Property of Enteris BioPharma Inc. 


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1. TABLE OF CONTENTS 
 
1. TITLE PAGE ............................................................................................................................... 1 
2. PROTOCOL SIGNATURE SHEET ........................................................................................... 4 
3. INVESTIGATOR SIGNATURE SHEET ................................................................................... 5 
4. PROTOCOL SYNOPSIS ............................................................................................................ 6 
5. BACKGROUND ....................................................................................................................... 17 
6. STUDY OBJECTIVES ............................................................................................................. 18 
7. STUDY DESIGN ...................................................................................................................... 19 
7.1 Overall Study Design and Plan – Description ................................................................... 19 
7.1.1 Discussion of the Study Design ............................................................................................ 22 
7.2 Study Procedures ............................................................................................................... 23 
8. ELIGIBILITY CRITERIA ........................................................................................................ 30 
8.1 Inclusion Criteria ............................................................................................................... 30 
8.2 Exclusion Criteria .............................................................................................................. 31 
8.3 Contraindications, Warnings and Other Notes .................................................................. 33 
8.4 Withdrawal of Subjects ..................................................................................................... 35 
9   STUDY TREATMENT ............................................................................................................ 36 
9.1 Description......................................................................................................................... 36 
9.1.1 Drug Administration and Return .......................................................................................... 37 
9.1.2 Dispensing ............................................................................................................................ 37 
9.1.3 Storage .................................................................................................................................. 37 
9.1.4 Method of Assigning Subjects to Treatments....................................................................... 38 
9.1.5 Restrictions ........................................................................................................................... 38 
9.1.6 Physical Activity................................................................................................................... 38 
9.2 Prior and Concomitant Medications .................................................................................. 38 
9.3 Drug Accountability .......................................................................................................... 39 
9.4 Treatment Compliance ...................................................................................................... 39 
10. PHARMACOKINETIC, PHARMACODYNAMIC AND SAFETY EVALUATIONS ........ 39 
10.1 Pharmacokinetic and Pharmacodynamic Evaluations ..................................................... 39 
10.2 Safety Evaluations ........................................................................................................... 41 
11. ADVERSE EVENT REPORTING ......................................................................................... 41 
11.1 Definition of Adverse Events .......................................................................................... 41 


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11.2 Routine Reporting of Adverse Events ............................................................................. 42 
11.3 Reporting of Serious Adverse Drug Experiences, Including Deaths .............................. 43 
11.4 Withdrawal from Study Treatment Due to Adverse Event ............................................. 43 
12. STATISTICAL METHODS .................................................................................................... 44 
12.1 Populations and General Considerations ......................................................................... 44 
12.2 Pharmacokinetic Parameters and Analyses ..................................................................... 44 
12.3 Pharmacodynamic Parameters and Analyses .................................................................. 45 
12.4 Safety Endpoints and Analyses ....................................................................................... 46 
12.5 Sample Size ..................................................................................................................... 46 
13.  ACCESS TO SOURCE DOCUMENTS ................................................................................ 46 
14. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 47 
15. ETHICS ................................................................................................................................... 47 
15.1 Declaration of Helsinki .................................................................................................... 47 
15.2 Institutional Review Board .............................................................................................. 47 
16. DATA HANDLING AND RECORDING .............................................................................. 48 
17. PUBLICATION POLICY ....................................................................................................... 48 
18. PROTOCOL AMENDMENTS AND MODIFICATIONS ..................................................... 48 
19. REFERENCES ........................................................................................................................ 49 
20. APPENDIX A: LIST OF ABBREVIATIONS ........................................................................ 50 
21. APPENDIX B: TIME AND EVENTS SCHEDULE .............................................................. 52 
22. APPENDIX C: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ... 54 
23. APPENDIX D: LUPRON DEPOT® 3.75 MG (FULL PRESCRIBING INFORMATION) .. 59 
23. APPENDIX E: CLINICAL LABORATORY TESTS ............................................................ 83 
24. APPENDIX F: SUBJECT DIARY CARD ............................................................................. 85 
25.  APPENDIX G:  ACCEPTABLE DAYS FOR INITIATION OF DOSING IN RELATION TO 
CYCLE LENGTH ................................................................................................................... 87 
 






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4. PROTOCOL SYNOPSIS 
 
Title of Study 
A randomized, open-label, parallel-group, active-control study to evaluate the 
pharmacokinetic (PK) and pharmacodynamic (PD) profiles of three doses of 
Leuprolide Oral Tablets (Ovarest™) in comparison to an intramuscular (IM) 
dose of leuprolide  acetate  (Lupron Depot 3.75 mg) in healthy female 
volunteers 
Protocol Number 
LOPDT-ENDO-01 
Phase 
2a 
Number of Study 
Centers  
One or two sites, Phase I clinical unit(s) in the North America (US and/or 
Canada) 
Investigational 
Product, Dosage,  
and Route of 
Administration 
Leuprolide Oral Tablets (Ovarest™) utilizing Enteris’ Oral Peptide Delivery 
Technology. The Ovarest™ dosing regimens are selected based upon the results 
of the PK study LOPD-PH1-01. 
The Ovarest™ dosing regimens are:            
Treatment “A”: Leuprolide Oral Tablet (Ovarest™), 4 mg, administered daily 
(qd) for 28 consecutive days                                                                              
Treatment “B”: Leuprolide Oral Tablet (Ovarest™), 4 mg, administered twice 
daily (bid), 12 hours apart for 28 consecutive days  
Treatment “D”: Leuprolide Oral Tablet (Ovarest™), 10 mg, administered twice 
daily (bid), 12 hours apart for 28 consecutive days 
Control Drug 
(Reference 
Product) 
 
Treatment C: Leuprolide Acetate intramuscular (IM) injection (Lupron Depot 
3.75 mg) administered for one month of therapy  
Study Design 
Randomized, Open-Label, Parallel-Group, Active-Control Study for Treatment 
“A”, Treatment “B” and “Treatment “C”. Treatment “D” will be evaluated in a 
Non-Randomized, Open-Label, Single-Group Study design setting.  
Study Objectives 
The objectives are to determine the safety, PK profile, and PD effects of the 
three doses of Ovarest™ in healthy female volunteers in comparison to a 
marketed dose of leuprolide acetate administered IM (Lupron Depot 3.75 mg). 
Note: For the third Ovarest dose (Treatment “D”), a complete PK profile will not 
be evaluated.  
This trial will serve as a bridging PK/PD study between the 4 mg Leuprolide 
Oral Tablet administered over 28 days as qd or bid regimens, the 10 mg 
Leuprolide Oral Tablet administered over 28 days as a bid regimen, and a 
marketed IM injection of leuprolide acetate (Lupron Depot 3.75 mg) designed 
for one month of therapy. This trial will also be a bridging study to historical 


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PK/PD data for Lupron Depot® 3.75-mg and Lupron Depot® 11.25-mg (3-
month) formulations. 
The most important objective of this study is to provide adequate PD 
assessments to support development of the Leuprolide Oral Tablet with estradiol 
(E2) suppression similar to those reported for the Lupron Depot® and other E2-
inhibiting hormonal therapies. Another reason for this trial is to describe the 
PK/PD dose-proportionality of the 4-mg and 10-mg Leuprolide Oral Tablet 
administered as qd and/or bid regimens.  
Thus, the Primary Study Objectives are: 
1) To determine the safety and to provide comparative evaluation of the PK 
and PD profiles of the 4-mg Leuprolide Oral Tablets following qd and bid 
administration and the 10-mg Leuprolide Oral Tablets following bid 
administration in healthy, premenopausal female volunteers over 28 days vs 
a marketed formulation of leuprolide acetate administered IM for one 
month of therapy.  
2) To evaluate the PK properties of Leuprolide Oral Tablets after multiple 
dosing (ie, 28 days of dosing)   
3) To assess the PK/PD dose-proportionality of the Leuprolide Oral Tablets 
administered as 4 mg qd, 4 mg bid and 10 mg bid dosing regimens  
4) To evaluate the PK and/or PD properties of the Leuprolide Oral Tablets (eg, 
E2 suppression rates) vs other hormonal therapies for the treatment of 
reproductive disorders, including endometriosis.  
Secondary Study Objective: 
 
To evaluate safety and tolerability of the long-term administration of leuprolide in 
healthy female volunteers. 
Number of 
Subjects 
Up to thirty-two (32) subjects (12 subjects in each of the two Ovarest™ treatment 
groups and 8 subjects in the Lupron Depot group) were to be enrolled in the 
study. Eligible subjects were to be randomly assigned to one of three treatment 
groups in a Treatment“A”:Treatment“B”:Treatment“C” ratio of 3:3:2. The 
randomization schedule was prepared prior to the study and will be balanced by 
using permuted blocks. The randomization schedule could be further stratified by 
the study site, if necessary. 
Twenty-three subjects were initially enrolled in this study (9 subjects in each of 
Ovarest treatment groups and 5 subjects in the Lupron Depot group). At the time 
of the current protocol Amendment, all initially enrolled subjects had completed 
the study, except for one subject who was withdrawn on post–dose Day 1 (due to 
vomiting). After interim PK and safety evaluations, it was decided not to enroll 
any new subjects in Treatment Groups “A”, “B” and “C”. Instead, up to twelve 
(12) subjects will be enrolled in a new Treatment Group D” (Leuprolide Oral 


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Tablet, Ovarest, 10 mg, administered twice daily (bid), 12 hours apart for 28 
consecutive days). 
Dose Justification 
of Treatment “D” 
Pharmacodynamic data, specifically the suppression of estradiol, showed that 
both the 4 mg QD and BID regimens (Treatments “A” and “B”) fell substantially 
short of the suppression demonstrated by Lupron Depot®. Interim safety results 
from this study were also evaluated.  Overall, Leuprolide Oral Tablets within a 4 
mg to 8 mg daily dosing range were safe and reasonably well tolerated. The study 
results support a further dose increase in planned clinical evaluations.   
Leuprolide Oral Tablets were shown to be safe and well tolerated in the Phase 1 
study LOPDT-PH1-01, at doses of 1 and 4 mg in normal healthy volunteers.  The 
absolute bioavailability was 2.2% and 3.0% for the 1 and 4 mg doses, 
respectively, compared to subcutaneous injection.  The 4-mg Leuprolide Oral 
Tablet generated an overall drug exposure (a 24-hour AUC=19338 h*pg/mL) that 
was less than 12% of the drug exposure (163021 h*pg/mL) reported for a 
marketed 1-mg SC injection. A projected AUC for the 10 mg tablet administered 
twice daily (Treatment “D”) will be less than 60% of the 1-mg SC drug exposure. 
Projected Cmax of Treatment “D” will also be lower than Cmax reported for the 
1-mg SC injection. These estimates clearly support the safety of the 10 mg tablet 
administered twice daily (Treatment “D”). 
There is a further safety margin for the Treatment “D” dose of 10 mg bid:  the 
Lupron Depot® 3.75 mg label contains the statement, “In early clinical trials 
using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses 
as high as 20 mg/day for up to two years caused no adverse effects differing from 
those observed with the 1 mg/day dose.”  Given the low bioavailability of the oral 
dose, about 3%, a substantial safety margin is assured. 
Inclusion Criteria 
Subjects enrolled in this study will be members of the community at large. The 
recruitment advertisements may use various media types (eg, radio, newspaper). 
Subjects must meet all of the following criteria to be included in the study: 
1) Healthy premenopausal female volunteers, aged 18 to 49 years  
2) Body mass index (BMI) 18 and 32 kg/m2, and weight ≥110 lb (≈50 kg) 
3) Regular menstrual cycles with a usual length ranging from 21 days to 35 
days. If subject has recently used hormonal birth control, historical data prior 
to use will be used to determine qualification and must also meet this 
criterion.  
4) If of childbearing potential and sexually active with a risk of pregnancy, 
willing to use one of the following acceptable methods of contraception 
throughout the study and for at least 30 days after the last drug administration: 
a) intrauterine contraceptive device without hormone release system placed 
at least 4 weeks prior to the first study drug administration with 


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simultaneous use of condom for the male partner 
b) simultaneous use of diaphragm with intravaginally applied spermicide and 
condom for the male partner starting at least 14 days prior to drug 
administration 
c) sterile male partner (vasectomized for at least 6 months) 
d) Note: Surgically sterile subjects who have had tubal ligation are 
considered of non-childbearing potential and are not required to use 
contraception 
5) Willing to refrain from excessive use of alcohol during the entire study and 
willing to refrain from use of alcohol 24 hours prior to any PK blood draw 
taken during the study  
6) Willing to refrain from use of prescription medications, over-the-counter 
medications and natural health products during the entire study  
7) Willing and capable to give informed consent to participate in study 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1) Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist 
analogs, similar nonapeptides or any of the excipients in LUPRON DEPOT. 
Note: This is a contraindication from the Lupron Depot label.   
2) Undiagnosed abnormal vaginal bleeding. Note: This is a contraindication 
from the Lupron Depot label.   
3) Known or suspected pregnancy, or subjects who are considering becoming 
pregnant prior to the conclusion of this study. Note: LUPRON DEPOT is 
contraindicated in women who are or may become pregnant while receiving 
the drug. LUPRON DEPOT may cause fetal harm when administered to a 
pregnant woman…. If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of 
the potential hazard to the fetus.  
4) Breastfeeding or within 2 months after stopping breastfeeding (relative to the 
screening visit). Note: Use of LUPRON DEPOT is contraindicated in 
women who are breastfeeding. 
5) Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past 
history of these conditions. Note: Per the LUPRON DEPOT label, a possible 
coadministration of norethindrone acetate is contraindicated in women with 
thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past 
history of these conditions. 
6) Markedly impaired liver function or liver disease. Note: Per the LUPRON 
DEPOT label, a possible coadministration of norethindrone acetate is 
contraindicated in women with markedly impaired liver function or liver 


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disease.  
7) Known or suspected carcinoma of the breast. Note: Per the LUPRON 
DEPOT label, a possible coadministration of norethindrone acetate is 
contraindicated in women with known or suspected carcinoma of the breast. 
8) Status postpartum or postabortion within a period of 2 months prior to the 
screening visit 
9) A cervical cytology smear of Papanicolaou (Pap) class III or greater or a 
Bethesda System report of low grade squamous intraepithelial lesions or 
greater (Pap smear results within last 12 months are acceptable if properly 
documented) 
10) Use of any tobacco products (including electronic cigarettes) in the 3 months 
preceding the screening visit or positive urine cotinine test at screening 
11) History of significant alcohol or drug abuse within one year prior to the 
screening visit 
12) Clinically significant vital sign abnormalities (systolic blood pressure lower 
than 90 or over 140 mm Hg, diastolic blood pressure lower than 50 or over 90 
mm Hg, or heart rate less than 50 or over 100 bpm) at screening 
13) Any clinically significant history or presence of neurologic, endocrinologic, 
pulmonary, hematologic, immunologic, or metabolic disease 
14) History of severe respiratory depression or pulmonary insufficiency 
15) Diabetes mellitus requiring insulin 
16) History of headaches with focal neurological symptoms 
17) Uncontrolled thyroid disorder 
18) Sickle cell anemia 
19) Current or history of clinically significant depression in the last year 
20) Known disturbance of lipid metabolism 
21) Hepatic adenoma or carcinoma 
22) Known or suspected endometrial carcinoma or estrogen-dependent neoplasia 
23) Clinically significant history or presence of any gastrointestinal pathology 
(eg, 
chronic 
diarrhea, 
inflammatory 
bowel 
diseases), 
unresolved 
gastrointestinal symptoms (eg, diarrhea, vomiting) or kidney disease, or other 
conditions known to interfere with the absorption, distribution, metabolism, 
or excretion of the drug 
24) Difficulty in swallowing study medication 
25) Any food allergy, intolerance, restriction or special diet that, in the opinion of 


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the Investigator, could contraindicate the subject’s participation in this study 
26) Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus at 
screening 
27) Administration of any investigational drug and/or experimental device within 
30 days prior to the screening visit 
28) Administration of any biologics within 90 days prior to the screening visit 
29) Clinically significant finding on the electrocardiogram (ECG) suggesting 
participation in the study could pose a risk to the subject 
30) A depot injection or an implant of any drug within 6 months prior to the 
screening visit 
31) Use of oral contraceptives or other sex steroid hormones within 3 months 
prior to the screening visit 
32) Any clinically significant physical or gynecological abnormality at the 
screening visit 
33) Any clinically significant abnormal laboratory test result at the screening visit  
34) Hemoglobin <115 g/L and/or hematocrit <0.32 L/L  
35) Use of prescription medication within 14 days prior to the first administration 
of study medication or over-the-counter products (including natural health 
products; eg, food supplements, vitamins, herbal supplements) within 7 days 
prior to the first administration of study medication, except for topical 
products without significant systemic absorption 
36) Donation of plasma within 7 days prior to dosing. Donation or loss of blood 
(excluding volume drawn at screening) of 50 mL to 499 mL of blood within 
30 days, or more than 499 mL within 56 days prior to the first dosing 
37) Deemed by the Investigator to have questionable ability to comply with the 
study protocol  
38) History of seizures, epilepsy, cerebrovascular disorders, central nervous 
system anomalies or tumors; 
39) Significant risk factors for decreased bone mineral content and/or bone mass, 
such as family history (in a first degree relative) of osteoporosis, personal 
history of chronic use of corticosteroids or anticonvulsants. 
Treatment and 
Duration 
Approximately one month of dosing ( either 28 consecutive days of daily oral 
dosing, or a single IM injection on day 1) and approximately 1 month (28 days) 
of post-dosing PK/PD evaluations. The total study duration, from screening to 
the final study visit will be up to approximately 3.5 months. 
Study 
Subjects meeting the eligibility criteria will be randomized to receive one of 
the two doses of Ovarest™ for 28 days or a monthly IM dose of Lupron 


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Methodology and 
Evaluations 
Depot. Newly enrolled subjects will receive the third Ovarest dose (Treatment 
“D”) that will be administered in the same fashion as Treatment “B”. 
Assessments of the PD profile of treatment “D” will also mimic evaluations of 
Treatment “B”. However, unlike other Ovarest groups, Treatment “D” will not 
have comprehensive assessments of the PK profile. The subjects that have 
already participated in this study may be invited to receive Treatment “D” if they 
are eligible per the study inclusion and exclusion criteria. The subjects in 
Treatments “A”, “B”, and “C” will start dosing (Treatment Day 1) on either Day 
1 up to Day 4 of their menstrual cycle, or within the last 11 days of their 
menstrual cycle.  (Note: onset of menstrual period is considered as day 1 of the 
menstrual cycle.) Please see Appendix G for a table of acceptable days for 
initiation of dosing in relation to cycle length.  Permissible time windows for the 
start of the dosing will be determined based on the onset of menstrual period 
prior to the screening visit or a projected start of the next menstrual cycle. The 
projected start of the next menstrual cycle will be based on the date of onset of 
menses during the screening period and the typical length of the normal 
menstrual cycle for each subject as reported by each subject during the 
screening visit. Subjects enrolled to the third oral dose (Treatment “D”) will have 
a dosing initiation visit scheduled 5-9 days before the anticipated start of their 
next menstrual cycle, based on their self-reported menstrual cycle length and the 
day the current menstrual cycle began. The 4-mg qd oral dose will be 
administered once daily, in the morning, on an empty stomach; the 4-mg and 
10-mg bid oral doses will be administered twice daily, in the morning and in the 
evening, 12 hours apart and on an empty stomach. Note: On an empty stomach 
means that the oral doses are administered at least 2 hours before or at least 2 
hours after the meal. Oral administration instructions are applicable to both on-
site and at-home dosing. For at-home dosing, each subject will take the oral 
dose with approximately 240 mL of water.   Subjects randomized to the two oral 
doses (Treatments “A” and “B”) will have twenty-four (24) serial serum 
samples drawn on Treatment Days 1 and 28 immediately prior to dosing (0 
time), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 
18, 20, and 24 hours following oral dosing. For the IM injection (Treatment 
“C”), serial serum samples will also be drawn on Treatment Day 1, prior to 
dosing (0 time), at 0.5, 1, 2, 6, 12, 18, and 24 hours postdosing. Blood samples 
for the IM injection will also be taken in the morning on Day 29. Additional 
blood samples for all subjects will be taken in the morning (in the oral 
groups, just prior to dosing) on Treatment Days 8, 15, and 22. Samples will be 
appropriately stored until they can be assayed for leuprolide and hormonal 
levels. Serum concentrations of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH), and plasma concentrations of E2 and 
progesterone will be measured (immediately prior to dosing) on Treatment 
Days 1, 8, 15, 22, and in the morning of Day 29. 
 
Subjects enrolled to the third oral dose (Treatment “D”) will have a dosing 


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initiation visit scheduled 5-9 days before the anticipated start of their next 
menstrual cycle, based on their self-reported menstrual cycle length and the day 
the current menstrual cycle began.   During the visit, just prior to the first 
dosing, baseline blood samples will be taken for leuprolide and hormonal levels. 
The same blood draws will be performed immediately prior to the first dose of 
the day on Treatment Days 8, 15, 22, and in the morning of Day 29. 
 
On Day 29, after the 24-hour blood draws in the oral groups (Treatments “A”, 
and “B”) and after the PK/PD blood draws in the Treatment “D” and the IM 
injection group (Treatment “C”), physical, gynecological, and safety laboratory 
evaluations will be performed. 
 
Note: Throughout the text, Treatment Day 29 may be used interchangeably with 
Postdosing Day 1. 
 
Four follow-up visits will be scheduled at 7, 14, 21 and 28 days after the last 
dose (Treatments “A”, “B”, and “D”)  or the last day of the 28-day dosing cycle 
(Treatment “C”). During each follow-up visit, blood samples will be drawn to 
assess leuprolide (via a single blood draw) and LH, FSH, E2, and progesterone 
concentrations. During each follow-up visit, subjects will be asked about onset 
(or absence) of menstrual period. 
 
Safety laboratory evaluations will also be performed during the 28-day 
postdosing visit. The 28-day postdosing visit will be considered the Final Study 
Visit. In addition, to the PK/PD and safety laboratory assessments, ECG, 
physical and gynecological examinations will also be performed.  
 
A total of 55 PK blood samples will be taken from subjects in the two oral 
groups (Treatments “A” and “B”) for the evaluation of the leuprolide serum 
concentrations. A total of 11 PD blood samples will also be taken for the 
determination of LH, FSH, E2, and progesterone levels. The blood volume for 
each PK sample is assumed to be approximately 3 mL for leuprolide analysis, 
and the volume for each PD sample is assumed to be approximately 16 mL (10 
mL for progesterone and estradiol analysis, and 6 mL for FSH and LH 
analysis).  The total amount of blood volume for all PK and PD draws is 341 
mL. Four safety blood draws will be performed during the study with a volume 
of 8 mL per draw. An additional 34 mL of blood may be drawn during the study 
to allow for repeat draws and/or additional safety tests and for the screening 
pregnancy test. The total amount of blood drawn should not exceed 407 mL 
over 3 months, including all samples collected for PK and PD analyses and 
eligibility and safety purposes. 
 
In the Treatment group “D” a total number of samples for PK evaluations will 
be reduced by 46 when compared to other oral groups. The total amount of 


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blood drawn will be reduced by 138 mL (46 x 3 mL) and should not exceed 269 
mL over 3 months, including all samples collected for PK and PD analyses and 
eligibility and safety purposes.  
 
A total of 16 PK blood samples will be taken from subjects in the Lupron group 
(Treatment “C”) for the evaluation of the leuprolide serum concentrations. A 
total of 10 PD blood samples will also be taken for the determination of LH, 
FSH, E2, and progesterone levels. The total amount of blood volume for all PK 
and PD draws is 208 mL. Four safety blood draws will be performed during the 
study with a volume of 8 mL per draw. An additional 34 mL of blood may be 
drawn during the study to allow for repeat draws and/or additional safety tests 
and for the screening pregnancy test. The total amount of blood drawn in the 
Lupron group should not exceed 274 mL over 3 months, including all samples 
collected for PK and PD analyses and eligibility and safety purposes. 
 
Serum concentrations of leuprolide and concentrations of PD parameters will be 
determined via validated bioanalytical methods. Sensitivity and specificity of the 
employed bioanalytical methods will be described in the study report.  
During both the 28-day dosing period and the post-dosing 28-day follow-up, 
subjects will record vaginal (menstrual) bleeding on diary cards. 
 
Pharmacokinetic 
(PK) Parameters  
The following PK parameters will be evaluated for each subject for each 
evaluation period (ie, Treatment Days 1 and 28 for the two oral groups 
(Treatments “A” and “B”) and day 1 for the Lupron Depot group): 
- Maximum concentration level (Cmax); 
- Time to maximum concentration level (Tmax); 
- Area under the concentration versus time curve from 0 hours to 24 hours 
(AUC0-24) 
- Area under the concentration versus time curve from 0 hours to last available 
observation (AUC0-t). 
- Area under the concentration versus time curve from 0 hours to infinity 
(AUC0-inf). 
 
In addition, in the two oral groups (Treatments “A” and “B”) steady-state 
concentration levels (Css) will be calculated at the end of the fourth 
treatment week (Days 28-29) as the 24-hour AUCs divided by the duration of the 
dosing interval. This parameter will be considered as the primary PK endpoint 
for Treatments “A” and “B.” A comparable primary endpoint for the Lupron 
group (Treatment “C”) will be an average concentration during the fourth 
treatment week (calculated as a mean of leuprolide concentration levels on Days 
22 and 29).   
 
Other PK parameters may be calculated if necessary. 


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Summaries of the leuprolide concentrations will also be reported for each follow-
up visit. 
Pharmaco-
dynamic (PD) 
Parameters 
As noted earlier, PD assessments include LH, FSH, E2, and progesterone.  
 
Blood draws for the PD assessments will be performed immediately prior to 
dosing on Treatment Days 1, 8, 15, 22, and Postdosing Day 1.  
 
Additional PD assessments will be performed during the follow-up visits 
(postdosing Days 7, 14, 21 and 28).  
 
The primary PD metric - suppression of E2 level - will be assessed at each on-
treatment evaluation timepoint. Treatment Day 22 and Treatment Day 28 
evaluations (separately and combined) will be considered as most important. In 
addition to a primary E2 suppression threshold (E2≤ 40pg/mL), a suppression 
of E2 below 20 pg/mL may also be assessed, if considered necessary. The 
suppression o f  ovulation (as evidenced by progesterone levels <3 ng/mL) 
will be evaluated with Treatment Day 22 and Postdosing Day 1 assessments 
positioned as primary. 
 
Similar summaries will be provided for the follow-up visits (postdosing Days 
7, 14, 21, and 28). In addition, time to return to prestudy baseline hormonal 
levels could be estimated.   
 
Number of vaginal (menstrual) bleeding days will be summarized by treatment 
group for 28 days of therapy and for 28 days of poststudy follow-up. The 
subject incidence of the onset of menstrual period after completion of therapy 
will be reported for each treatment group.  
 
Summaries of PD metrics may be further stratified by the cycle period (days) 
of the start of dosing. 
Safety Evaluations 
and Adverse 
Events 
Safety evaluations will be based on the discontinuations due to treatment-
emergent adverse events (TEAEs), changes from screening to last assessment 
(poststudy) in physical and gynecological examinations, clinical laboratory test 
results (hematology, serum chemistry, and urinalysis), treatment-induced 
changes in vital signs, and by the incidence and severity of TEAEs reported. 
TEAEs will be reported for the entire study and separately for the two study 
subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
Clinically notable events (including possible flare-up symptoms) may also be 
recorded on diary cards. 
Statistical 
Methods 
The primary statistical analyses of PK data (Treatments “A” and “B” only) will 
be conducted on the population of subjects completing 28 days of dosing. 
Supporting evaluations will be performed for the cohort of subjects who received 


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at least one dose of study medication and provided any PK data.  
Similarly, the primary statistical analyses of PD data (all Treatment groups) will 
be conducted on the population of subjects completing 28 days of dosing. 
Supporting evaluations will be performed for the cohort of subjects who received 
at least one dose of study medication and provided any PD data.  
The safety analysis will be performed on all subjects who received at least one 
dose of study medication.  
Incidence of subjects with suppressed E2 levels will be reported for each 
study period by treatment group. The incidence of subjects with suppressed E2 
levels for the fourth treatment week (Day 22 and Day 29 combined) will be 
considered as a primary efficacy endpoint. The incidence of suppressed 
ovulation during the same period will also be reported. The FSH, LH, E2 and 
progesterone levels will be reported by treatment group for each evaluation 
period by using summary statistics. Changes in these parameters from prestudy 
baseline will also be summarized by treatment group.  
 
The summaries will be provided for the PK parameters with a focus on steady-
state concentration levels. PD and PK parameters will be graphed by treatment 
group 
for 
each 
evaluation 
period. 
Correlations between leuprolide 
concentration levels and PD parameters will be assessed. 
Safety endpoints, study discontinuation information, changes in the physical and 
gynecological examination findings, and treatment-emergent changes in vital 
signs and clinical laboratory test results will be summarized. The subject 
incidence of TEAEs will be reported by the treatment received. 
A detailed Statistical Analysis Plan will be developed prior to the database lock. 
Sample Size  
The sample size for this study is not based on the statistical power considerations. 
This sample size is considered as adequate for a pilot PK/PD “proof-of-concept” 
study. Since a formal proof of the PK bioequivalence across the treatment arms 
and/or formal across-treatment statistical comparisons of the PD endpoints are 
not objectives of this proof-of-concept study, the sample size is not based on the 
power considerations. With the proposed sample size, we expect reliable 
estimates of the PK and PD parameters for leuprolide oral tablets and a general 
validation of related historical data for Lupron Depot therapy. The safety and 
tolerability assessments of the qd and bid regimens of the 4-mg oral tablet and bid 
regimen of the 10-mg oral tablet should also be robust enough to support the 
dosing selection and instructions in subsequent clinical studies.  
Manufacturer of 
the Investigational 
Product 
Enteris BioPharma Inc. 


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5. BACKGROUND 
Enteris BioPharma has developed a proprietary Oral Peptide Delivery Technology to enable, for the 
first time, the oral administration of the widely-prescribed gonadotropin-releasing hormone agonist 
leuprolide, a synthetic nonapeptide.  
Various formulations of leuprolide at several different dose levels have been previously approved by the 
FDA for treatment of prostate cancer, endometriosis, uterine fibroids, and central precocious puberty. 
Specifically, approval of leuprolide for the treatment of endometriosis has been granted for both 3.75 
mg q 1 month and 11.25 mg q 3 months as intramuscular (IM) injections (Lupron Depot® and 
Lupaneta®, the latter including co-packaging of leuprolide with daily oral norethindrone acetate 5 mg).   
Enteris now develops a daily oral form of leuprolide (Leuprolide Oral Tablet) for the treatment of 
endometriosis. The prospect of delivering this drug orally would allow the elimination of IM injections 
associated with disturbing side effects. In addition, an oral route of delivery may offer a number of other 
potential clinical benefits (eg, a possibility of immediate termination of therapy for medical or any other 
reasons). 
The name of the product (Leuprolide Oral Tablet) contains the name of the active moiety (Leuprolide), 
and not the name of the salt (Leuprolide Acetate), as stipulated by the USP Salt Policy and FDA 
Guidance for Industry titled, “Naming of Drug Products Containing Salt Drug Substances.”  The 
strength is also expressed in terms of the active moiety (e.g., “4 mg Leuprolide Oral Tablets”) rather 
than the salt strength equivalent (e.g., “4.46 mg Leuprolide Acetate Oral Tablets). 
 
Because of the well-documented pharmacology, clinical efficacy and safety of leuprolide for this and 
other indications, the clinical development of this new oral dosage form will be ultimately linked to 
pharmacokinetic (PK) and pharmacodynamic (PD) properties of marketed leuprolide formulations, 
including but not limited to IM depot form (“Lupron Depot”) which will serve as reference product(s) in 
the Enteris BioPharma’ 505(b)(2) NDA. Particularly, the PK exposure and safety profile of Leuprolide 
Oral Tablets will be evaluated against the marketed 1-mg subcutaneous (SC) injection. Extensive 
nonclinical safety data, and clinical safety and efficacy data exist from publicly available sources. 
 
Leuprolide Oral Tablets were shown to be safe and well tolerated in the Phase 1 study LOPDT-PH1-01, 
at doses of 1 and 4 mg in normal healthy volunteers.  The absolute bioavailability was 2.2% and 3.0% 
for the 1 and 4 mg doses, respectively, compared to subcutaneous injection.  The 4-mg Leuprolide Oral 
Tablet generated an overall drug exposure (a 24-hour AUC=19338 h*pg/mL) that was less than 12% of 
the drug exposure (163021 h*pg/mL) reported for a marketed 1-mg SC injection. A projected AUC for 
the 10 mg tablet administered twice daily (Treatment “D”) will be less than 60% of the 1-mg SC drug 
exposure. Projected Cmax of Treatment “D” will also be lower than Cmax reported for the 1-mg SC 
injection. These estimates clearly support the safety of the 10 mg tablet administered twice daily 
(Treatment “D”).   
 
Following the conclusion of LOPDT-PH1-01, Leuprolide Oral Tablets were reformulated in an effort to 
increase bioavailability.  Reformulated tablets were administered to beagle dogs and the bioavailability 
was compared to the 4 mg dose from LOPDT-PH1-01.  An increase in bioavailability was seen, from 
2.2% for the Phase 1 tablet to 7.3% for the reformulated tablet.  The reformulated 4 mg tablet (LEU-


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012-17002) was then tested in this study, with 28 days of dosing in QD and BID regimens (Treatments 
“A” and “B”, respectively), and Lupron Depot 3.75 mg as an active comparator (Treatment “C”).  
Interim PK/PD results from this study were recently evaluated, which showed that the bioavailability of 
the reformulated tablet, rather than increase as predicted by testing in the dog, actually decreased to 
approximately 1.5%.  Pharmacodynamic data, specifically the suppression of estradiol, showed that 
both the 4 mg QD and BID regimens fell substantially short of the suppression demonstrated by Lupron 
Depot®. Interim safety results from this study were also evaluated.  Overall, Leuprolide Oral Tablets 
within a 4 mg to 8 mg daily dosing range were safe and reasonably well tolerated. The study results 
support a further dose increase in planned clinical evaluations.   
This protocol amendment include a fourth arm, which will be a 10 mg Leuprolide Oral Tablet 
administered BID for 28 days (Treatment “D”).  As with the previous arms of the study, PD markers 
will be evaluated weekly during the 28 days of dosing and for a 28 day wash out period.  The tablet 
formulation will revert to the more successful formulation used in the Phase 1 study, where the 
bioavailability was 3.0%.  The amount of leuprolide projected to be absorbed into the circulation is 0.6 
mg per day (3% of 20 mg).  This is roughly equivalent to the 0.5 mg per day delivered by daily 
subcutaneous injection that was effective in treating uterine fibroids, and is approximately 60% of the 1 
mg approved SC dose administered in the Phase 1 study.  There is a further safety margin for the 
Treatment “D” dose of 10 mg bid:  the Lupron Depot® 3.75 mg label contains the statement, “In early 
clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high 
as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 
mg/day dose.”  Given the low bioavailability of the oral dose, about 3%, a substantial safety margin is 
assured. 
The comparative PK/PD evaluations will form important bridges between different routes of leuprolide 
administration using both the company’s proprietary data and relevant published findings.  
Additional information on Leuprolide Oral Tablet can be found in the Investigator's Brochure. 
 
6. STUDY OBJECTIVES 
The objectives are to determine the safety, PK profile, and PD effects of the three doses of Ovarest™ 
in healthy female volunteers in comparison to a marketed dose of leuprolide acetate administered IM 
(Lupron Depot 3.75 mg). Note: For the third Ovarest dose (Treatment “D”), a complete PK profile will 
not be evaluated. 
This trial will serve as a bridging PK/PD study between the 4 mg Leuprolide Oral Tablet administered 
over 28 days as qd or bid regimens and the 10 mg Leuprolide Oral Tablet administered over 28 days as 
a bid regimen and a marketed IM injection of leuprolide acetate (Lupron Depot 3.75 mg) designed for 
one month of therapy. This trial will also be a bridging study to historical PK/PD data for Lupron 
Depot® 3.75 mg and Lupron Depot® 11.25 mg (3-month) formulations. 
The most important objective of this study is to provide adequate PD assessments to support 
development of the Leuprolide Oral Tablet with E2 suppression similar to those reported for Lupron 
Depot® and other E2-inhibiting hormonal therapies. Another reason for this trial is to describe the 
PK/PD dose-proportionality of the 4-mg and 10-mg Leuprolide Oral Tablet administered as qd and/or 
bid regimens.  


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Thus, the Primary Study Objectives are: 
5) To determine the safety and to provide comparative evaluation of the PK and PD profiles of the 4 
mg Leuprolide Oral Tablets in healthy, premenopausal female volunteers following qd and bid 
administration and the 10-mg Leuprolide Oral Tablets following bid administration in healthy, 
premenopausal female volunteers over 28 days vs a marketed formulation of leuprolide acetate 
administered IM for one month of therapy 
1) To evaluate the PK properties of Leuprolide Oral Tablets after multiple dosing (ie, 28 days of 
dosing)   
2) To assess the PK/PD dose-proportionality of the Leuprolide Oral Tablets administered as 4 mg qd, 
4 mg bid and 10 mg bid dosing regimens  
3) To evaluate the PK and/or PD properties of the Leuprolide Oral Tablets (eg, E2 suppression rates) 
vs other hormonal therapies for the treatment of reproductive disorders, including endometriosis  
Secondary Study Objective: 
 
To evaluate safety and tolerability of the long-term administration of leuprolide in healthy female 
volunteers. 
 
7. STUDY DESIGN 
 
7.1 Overall Study Design and Plan – Description 
This study will evaluate the safety, PK profile and PD effects of the three Ovarest™ dosing regimens: 
Leuprolide Oral Tablet, 4 mg, administered qd for 28 consecutive days (Treatment “A”), Leuprolide 
Oral Tablet, 4 mg, administered bid for 28 consecutive days (Treatment “B”), and Leuprolide Oral 
Tablet, 10 mg, administered bid for 28 consecutive days (Treatment “D”), in comparison to leuprolide 
acetate administered IM, Lupron Depot 3.75 mg (Treatment “C”). 
The study was originally designed as a randomized, open-label, parallel-group active-control trial. Up to 
thirty-two (32) subjects (12 subjects in each Ovarest™ treatment group and 8 subjects in the Lupron 
Depot 
group) 
were 
to 
be 
randomly 
assigned 
to 
the 
study 
drug 
in 
a 
Treatment 
“A”:Treatment“B”:Treatment“C” ratio of 3:3:2. The randomization schedule was to be balanced by 
using permuted blocks. The randomization schedule could be further stratified by the study site, if 
necessary. 
Twenty-three subjects were initially enrolled in this study (9 subjects in each of Ovarest treatment 
groups and 5 subjects in the Lupron Depot group). At the time of the current protocol Amendment, all 
initially enrolled subjects had completed the study, except for one subject who was withdrawn on post–
dose Day 1 (due to vomiting). After interim PK and safety evaluations, it was decided not to enroll any 
new subjects in Treatment Groups “A”, “B” and “C”. Instead, up to twelve (12) subjects will be 
enrolled in a new Treatment Group D” (Leuprolide Oral Tablet, Ovarest, 10 mg, administered twice 
daily (bid), 12 hours apart for 28 consecutive days). 
The study consists of two major periods: approximately one month of dosing ( either 28 consecutive 
days of daily oral dosing, or a single IM injection on Treatment Day 1) and approximately 1 month (28 


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days) of postdosing PK/PD evaluations. The total study duration from screening to the final study visit 
will be up to approximately 3.5 months. 
Study design schematic is displayed in Figure 1 below. A detailed “Times and Events Schedule” is 
presented in APPENDIX B. 
 
Figure 1 Study Design Schematic 
 
 
 
 
 
 
 
 
 
_ 
 
 
 
 
 
 
 
 
 
Subjects meeting the eligibility criteria will be randomized to receive one of the two doses of 
Ovarest™ for 28 days or a monthly IM dose of Lupron Depot. Newly enrolled subjects will receive 
the third Ovarest dose (Treatment “D”) that will be administered in the same fashion as Treatment “B”. 
Assessments of the PD profile of treatment “D” will also mimic evaluations of Treatment “B”. 
However, unlike other Ovarest groups, Treatment “D” will not have comprehensive assessments of the 
PK profile. The subjects that have already participated in this study may be invited to receive Treatment 
“D” if they are eligible per the study inclusion and exclusion criteria  The subjects in Treatments “A”, 
“B”, and “C” will start dosing (Treatment Day 1) on either days 1-4 or days 18-28 of their menstrual 
cycle. (Note: onset of menstrual period is considered as day 1 of the menstrual cycle.)  Permissible 
time windows for the start of the dosing will be determined based on the onset of menstrual period 
prior to the screening visit or a projected start of the next menstrual cycle. The projected start of the 
next menstrual cycle will be based on the date of onset of menses during the screening period and the 
typical length of the normal menstrual cycle for each subject as reported by each subject during the 
screening visit. Subjects enrolled to the third oral dose (Treatment “D”) will have a dosing initiation 
visit scheduled 5-9 days before the anticipated start of their next menstrual cycle, based on their self-
reported menstrual cycle length and the day the current menstrual cycle began. The 4-mg qd oral dose 
will be administered once daily, in the morning, on an empty stomach; the 4-mg and 10-mg bid oral 
doses will be administered twice daily, in the morning and in the evening, 12 hours apart and on an 
Post-Dosing Assessments: 
- Duration: ≈ 1 Month (28 days) 
- Four Follow-up visits (7, 14, 21, 
and 28 days after the last dose)  
-  During each Follow-up visit: 
   a) a single PK blood draw  
   b) PD (E2, FSH, LH, 
Progesterone) blood draws  
   c) Confirmed onset/absence of 
menstrual period. 
- Safety Labs (28-day Follow-up 
visit) 
- Final Study Visit (28-day Follow-
up visit): In addition to evaluations 
above,  ECG, physical and 
gynecological exams performed          
Screening 
Visit  
Treatment Period: 
- Total N=32 
- 4-mg Ovarest™ qd (Treatment “A”): 
N =12  
- 4-mg Ovarest™, bid (Treatment 
“B”): N =12 
- 10-mg Ovarest™, bid (Treatment 
“D”): N =12 
- Lupron Depot (3.75 mg)  
  Treatment “C”): N =8 
- PK blood draws (Days 1-2*, 8,   
  15, 22, 28-29*)  Note:  For Treatment 
“D”, a complete PK profile (Days 1-2 
and Days 28-29) will not be evaluated.      
- PD (E2, FSH, LH, Progesterone)   
  blood draws (Days 1, 8, 15,    
  22, 29)      


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empty stomach. Note: On an empty stomach means that the oral doses are administered at least 2 hours 
before and at least 2 hours after the meal. For clarity, all oral doses have to be taken on an empty 
stomach except for the morning doses of Days 1 and 28, for which the fasting period is -10h to +4h.  
Subjects randomized to the two oral doses (Treatments “A” and “B”) will have twenty-four (24) serial 
serum samples drawn on Treatment Days 1 and 28 immediately prior to dosing (0 time), and at 0.5, 1, 
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 20, and 24 hours following oral 
dosing. For Treatment “B”, the PK blood draws will be drawn for the morning dose.  For the IM 
injection (Treatment “C”), serial serum samples will also be drawn on Treatment Day 1, prior to 
dosing (0 time), at 0.5, 1, 2, 6, 12, 18, and 24 hours postdosing. Blood samples for the IM injection 
will also be taken in the morning on Postdosing Day 1. Additional blood samples for all subjects will 
be taken in the morning (in the oral groups, just prior to dosing) on Treatment Days 8, 15, and 22. 
Samples will be appropriately stored until they can be assayed for leuprolide and hormonal levels. 
Serum concentrations of LH, FSH, E2, and progesterone will be measured (immediately prior to 
dosing) on Treatment Days 1, 8, 15, 22, and in the morning of Day 29. 
 
Subjects enrolled to the third oral dose (Treatment “D”) will have a dosing initiation visit scheduled 5-
9 days before the anticipated start of their next menstrual cycle, based on their self-reported menstrual 
cycle length and the day the current menstrual cycle began.   During the visit, just prior to the first 
dosing, baseline blood samples will be taken for leuprolide and hormonal levels. The same blood 
draws will be performed immediately prior to the first dose of the day on Treatment Days 8, 15, 22, 
and in the morning of Day 29. 
 
On Day 29, after the 24-hour blood draws in the oral groups (Treatments “A” and “B”) and after the 
PK/PD blood draws in the Treatment “D” and the IM injection group (Treatment “C”), physical, 
gynecological, and safety laboratory evaluations will be performed. 
 
Note:  throughout the text, Treatment Day 29 may be used interchangeably with Postdosing Day 1. 
 
After the 28-day dosing period, four follow-up visits will be scheduled at 7, 14, 21, and 28 days after 
the last dose. During each follow-up visit, blood samples will be drawn to assess leuprolide (via a 
single blood draw) and LH, FSH, E2, and progesterone concentrations. During each follow-up visit, 
subjects will be asked about onset (or absence) of menstrual period. 
 
Safety laboratory evaluations will also be performed during the 28-day postdosing visit. The 28-day 
postdosing visit will be considered the Final Study Visit. In addition to the PK/PD and safety 
laboratory assessments, ECG, physical and gynecological examinations will also be performed.  
 
A total of 55 PK blood samples will be taken from subjects in the oral groups (Treatments “A”,and 
“B”) for the evaluation of the leuprolide serum concentrations. A total of 11 PD blood samples will 
also be taken for the determination of LH, FSH, E2, and progesterone levels. The blood volume for 
each PK sample is assumed to be approximately 3 mL for leuprolide analysis, and the volume for each 
PD sample is assumed to be approximately 16 mL (10 mL for progesterone and estradiol analysis, and 
6 mL for FSH and LH analysis).  The total amount of blood volume for all PK and PD draws is 341 
mL. Four safety blood draws will be performed during the study with a volume of 8 mL per draw. An 


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additional 34 mL of blood may be drawn during the study to allow for repeat draws and/or additional 
safety tests and for the screening pregnancy test. The total amount of blood drawn should not exceed 
407 mL over 3 months, including all samples collected for PK and PD analyses and eligibility and 
safety purposes. 
 
In the Treatment group “D” the total number of samples for PK evaluations will be reduced by 46 
when compared to other oral groups. The total amount of blood drawn will be reduced by 138 mL (46 
x 3 mL) and should not exceed 269 mL over 3 months, including all samples collected for PK and PD 
analyses and eligibility and safety purposes.  
 
A total of 16 PK blood samples will be taken from subjects in the Lupron group (Treatment “C”) for 
the evaluation of the leuprolide serum concentrations. A total of 10 PD blood samples will also be 
taken for the determination of LH, FSH, E2, and progesterone levels. The total amount of blood 
volume for all PK and PD draws is 208 mL. Four safety blood draws will be performed during the 
study with a volume of 8 mL per draw. An additional 34 mL of blood may be drawn during the study 
to allow for repeat draws and/or additional safety tests and for the screening pregnancy test. The total 
amount of blood drawn in the Lupron group should not exceed 274 mL over 3 months, including all 
samples collected for PK and PD analyses and eligibility and safety purposes. 
 
Serum concentrations of leuprolide and concentrations of PD parameters will be determined via 
validated bioanalytical methods. Sensitivity and specificity of the employed bioanalytical methods will 
be described in the study report.  
 
A number of PK parameters will be evaluated for each subject for each evaluation period (ie, Treatment 
Days 1 and 28 for the two oral groups (Treatments “A” and “B”) and day 1 for the Lupron Depot group 
(eg, Cmax, Tmax, AUC0-24, AUC0-t, Css, etc). PD parameters will include values of the hormones 
measured (LH, FSH, E2, and progesterone) in relation to the baseline values and/or prespecified 
thresholds). See Section 12.2 and Section 12.3 for the detailed description of the PK and PD parameters 
and planned statistical analyses.  
 
During both the 28-day dosing period and postdosing 28-day follow-up, subjects will record vaginal 
(menstrual) bleeding on diary cards. Clinically notable events (including possible flare-up symptoms) 
may also be recorded. See APPENDIX F for a sample diary card. 
 
The evaluation of safety will be based on the incidence of TEAEs, discontinuations due to TEAEs, 
treatment-induced changes in vital signs, body weight, physical and gynecological examinations, and 
laboratory test results.  
 
7.1.1 Discussion of the Study Design 
With the weekly measurements of leuprolide and hormonal concentration levels, the study design is 
generally consistent with published PK/PD studies of Lupron Depot (Enteris BioPharma. Data on file).  
Interim analysis of the PK portion of this study for Treatments “A” and “B” showed that the leuprolide 
exposure was approximately 6% and 12% of the exposure of a marketed 1 mg subcutaneous injection of 


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leuprolide.  By returning to the formulation used in the phase 1 study (LOPDT-PH1-01), and by 
increasing the dose to 10 mg bid (Treatment “D”), the projected systemic exposure will is still less 60%  
of the exposure of a marketed 1-mg subcutaneous injection of leuprolide.  These estimates clearly 
support the safety of the 10 mg tablet administered twice daily (Treatment “D”).  Further support for the 
safety of the 10 mg tablet administered twice daily is found in the Lupron Depot® 3.75 mg label, which 
contains the statement, “In early clinical trials using daily subcutaneous leuprolide acetate in patients 
with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing 
from those observed with the 1 mg/day dose.”   
Additional information on PK properties of Leuprolide Oral Tablet can be found in the Investigator's 
Brochure. 
The blood PK sampling schedule in this study for oral tablets is generally similar to that implemented in 
the study LOPDT-PH1-01. Since leuprolide oral tablets have a “peak-and-trough” PK pattern, their 
sampling schedule will be different from that of the Lupron Depot with its continuous drug release.  
A once-weekly schedule of PD evaluations mimics a number of published E2 inhibition and ovulation 
suppression trials. 
The following precautions are incorporated into the study to minimize bias: 
 Subjects are sequentially assigned to randomly ordered treatment arm. 
 Subject enrollment is dependent on satisfactory fulfillment of the inclusion/exclusion criteria with 
particular attention to contraindications to the leuprolide therapy as noted in (LUPRON DEPOT 
3.75 mg, leuprolide  for depot suspension. Full prescribing information). 
 The person performing the PK/PD assays will be blinded to the oral treatment arms. 
Since a formal proof of the PK bioequivalence across the treatment arms and/or formal across-treatment 
statistical comparisons of the PD endpoints are not objectives of this proof-of-concept study, the sample 
size is not based on the power considerations. With the proposed sample size, we expect reliable 
estimates of the PK and PD parameters for leuprolide oral tablets and a general validation of related 
historical data for Lupron Depot therapy. The safety and tolerability assessments of the qd and bid 
regimens of the 4-mg oral tablet and a bid regimen of the 10-mg oral tablet should also be robust 
enough to support the dosing selection and instructions in subsequent clinical studies.  
 
7.2 Study Procedures 
 
Unless otherwise specified, procedures, data collection, and evaluation will be conducted as per the 
clinical site Standard Operating Procedures. 
 
Screening Visit 
Subjects will be assessed for eligibility within 40 days prior to the start of study medication. Written 
informed consent must be obtained prior to the performance of any study procedures. For eligibility 
purposes, abnormal laboratory or vital signs results may be repeated once if abnormal result is observed 
at the initial reading. Moreover, abnormalities found in the ECG may need to be confirmed by repeated 
measurements. 


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The following procedures will be performed and information collected at the Screening Visit: 
 Informed Consent Form signed. Demographic data (race, age), information regarding smoking 
habits and alcohol consumption 
 Baseline characteristics and vital signs (height, body weight, body mass index [BMI], temperature, 
pulse rate, respiratory rate, systolic and diastolic blood pressure)      
 Relevant medical history with focus on reproductive history (number of pregnancies and deliveries), 
gynecological history, menstrual pattern (typical duration of a menstrual cycle and typical duration 
of a menstrual period), and use of contraceptives.  
 Date of onset of the last menstrual period (LMP) 
 Cervical cytology Papanicolaou (Pap) smear. The cervical smear may be waived if done within last 
12 months and a report is available. 
 Clinical laboratory tests (hematology, clinical chemistry, serology and urinalysis – see APPENDIX 
E for details) 
 Serum pregnancy test (-human chorionic gonadotropin [-hCG]). Subjects with positive results are 
not eligible for the study. 
 Alcohol breath test 
 Obtain baseline PD blood sample (LH, FSH, E2, and progesterone) 
 Urine drug screen and urine cotinine. Subjects with positive results are not eligible for the study. 
 Physical examination 
 Gynecological examination (including manual breast exam)  
 12-lead ECG 
 Check of inclusion/exclusion criteria 
 
Treatment Period (28-Day Dosing Cycle)  
Treatment Day – 1 (Check-in) – Treatments “A”, “B” and “C” 
This visit will take place within 40 days of the Screening Visit. 
Subjects will report to the investigational clinic at least 11 hours before next-day dosing and will remain 
domiciled until the completion of all study procedures on Treatment Day 2.    
 Collect information on changes in medical history/current medical conditions and concomitant 
medication since the Screening Visit, to confirm that excluded medications have not been taken or 
have appropriately been discontinued and washed out. 
 Collect information on the date of onset of the LMP if it took place after the Screening Visit. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure).   
 Collect samples for urine drug screen and urine cotinine tests.  


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 Perform serum pregnancy test (-hCG) for all subjects; subjects with positive results are not eligible 
for the study. 
 Perform alcohol breath test. 
 Review inclusion and exclusion criteria to confirm eligibility. 
 The subjects will undergo a supervised overnight fast of at least 10 hours in duration. A light snack 
will be served on the evening of admission the clinical facility. No liquid or food intake is allowed 
during the fast, except water, which is permitted up until 1 hour prior to study drug administration. 
Treatment Day 1 – Treatments “A”, “B”,  and “C” 
 Verify no change in subject’s health status before dosing. 
 Assign randomization number. 
 Obtain baseline PK blood sample immediately (within 10 minutes) prior to dosing. 
 Obtain baseline PD blood sample (LH, FSH, E2, and progesterone) immediately (within 30 minutes) 
prior to dosing. 
 Do not allow any food or liquid during the fasting period, except water, which is permitted up until 
1 hour prior to study drug administration.  
 Administer study drug in the morning according to the randomization schedule. Oral tablets will be 
administered with 240 mL of water. Perform mouth check following oral tablet dosing to ensure 
compliance.   
 Subjects will remain seated or semireclined and will be required to avoid lying down or sleeping 
(unless medically necessary or procedurally required) for the first 1 hour after drug administration.  
 Obtain serial blood samples for the PK evaluations at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 
12, 13, 14, and 15 hours following single oral dosing in Treatment group “A” or the first oral dosing 
in Treatment group “B” (16, 17, 18, 20, and 24 hour samples to be obtained on Treatment Day 2). 
Note: A 12-hour sample in Treatment group “B” will be obtained within 10 minutes before the 
second oral dose. 
 Obtain serial blood samples for the PK evaluations at 0.5, 1, 2, 6, and 12 hours following an IM 
injection (Treatment “C”) (18 and 24 hour samples to be obtained on Treatment Day 2).  
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) predose (within 2 hours prior to dosing). Note: The vital signs will be assessed prior 
to the single oral dosing in Treatment group “A”, prior to the first oral dosing in Treatment group 
“B” and prior to the IM injection in Treatment group “C”. 
 Record adverse events (AEs) and concomitant medication use. 
 The fasting period will be -10h to +4h for Treatment groups “A” and “C.”, and -10h to +4h for the 
first dose in Treatment group “B”, and -2h to +2h for the second dose in Treatment “B”. All meal 
times will be recorded and entered into the clinical database. 
 Water will not be permitted until 1 hour after dosing. 


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Treatment Day 1 – Treatment “D” 
This visit will take place within 40 days of the Screening Visit. Subjects enrolled to the third oral dose 
(Treatment “D”) will have a dosing initiation visit scheduled 5-9 days before the anticipated start of 
their next menstrual cycle, based on their self-reported menstrual cycle length and the day the current 
menstrual cycle began.  
• 
Verify no change in subject’s health status before dosing. 
• 
Perform urine pregnancy test; subjects with positive results cannot be enrolled in the study. 
• 
Collect samples for urine drug screen and urine cotinine tests.  
• 
Perform alcohol breath test. 
• 
Assign randomization number. 
• 
Obtain baseline PK blood sample immediately (within 10 minutes) prior to dosing. 
• 
The fasting period will be -2h to +2h for the first administered dose. 
• 
Obtain baseline PD blood sample (LH, FSH, E2, and progesterone) immediately (within 30 minutes) 
prior to dosing. 
• 
Administer study drug in the morning. Oral tablets will be administered with 240 mL of water. 
Perform mouth check following oral tablet dosing to ensure compliance.    
• 
Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) predose (within 2 hours prior to dosing). Note: The vital signs will be assessed prior 
to the first oral dosing  
• 
Record adverse events (AEs) and concomitant medication use. 
• 
Release subject from the clinical site 2 hours after dosing.   
Treatment Day 2– Treatments “A”, “B”,  and “C” 
 Obtain PK blood samples at 16, 17, 18, 20, and 24 hours following single oral dosing in Treatment 
group “A” or the first oral dosing in Treatment groups “B” and “D”. Obtain PK blood samples at 18 
and 24 hours following an IM injection (Treatment group “C”).  
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) at approximately 24 hours after the previous dose (just prior to the Day 2 single oral 
dosing in Treatment group “A” and prior to the first oral dosing in Day 2 in Treatment groups “B” 
and”D”). 
 Record AEs and concomitant medication use. 
 Release subject from the clinical site after the 24-hour blood draw.  Provide diary before check-out.   
Treatment Days 8, 15, 22– Treatments “A”, “B”, “C” and “D” 
 Verify no change in subject’s health status before the scheduled oral dosing (single oral dosing in 
Treatment group “A” or the first oral dosing in Treatment groups “B” and “D”). 


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 Collect samples for urine drug screen and urine cotinine tests. Potential cases of subjects with 
positive drug screen, cotinine or alcohol results will be evaluated on a case-by-case basis for 
discontinuation in the study. 
 On Treatment Day 15 only: Perform urine pregnancy test; subjects with positive results must be 
discontinued from study. 
 Perform alcohol breath test. 
 Obtain PK blood sample immediately (within 10 minutes) prior to scheduled oral dosing or any time 
for Treatment group “C.” 
 Obtain PD blood sample (LH, FSH, E2, and progesterone) immediately (within 30 minutes) prior to 
scheduled oral dosing or any time for Treatment group “C.” 
 Oral dosing will be done in the clinic 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) within 1 hour prior to schedule oral dosing or any time for Treatment group “C.” 
 Record AEs and concomitant medication use. 
 Review subject’s diaries. 
 Subjects will be asked to take their breakfast at least 2 hours before dosing time (for example, at 
6AM if dosing time is 8AM), and to verify upon arrival at the clinic if they respected the 
requirement.   
 Release subject from the clinical site after dosing. 
 
Treatment Day 27 (Check-in): Treatment “A” and Treatment “B” groups only 
Subjects from Treatment groups “A” and “B” will report to the investigational clinic at least 11 hours 
before next-day morning oral dosing and will remain domiciled until the completion of all study 
procedures on Postdosing Day 1.   
 Verify no change in subject’s health status. 
 Record AEs and concomitant medication use. 
 Review subject’s diaries. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure).   
 Collect samples for urine drug screen and urine cotinine tests.  
 Perform urine pregnancy test; subjects with positive results must be discontinued from study. 
 Perform alcohol breath test. 


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 The subjects will undergo a supervised overnight fast of at least 10 hours in duration. A light snack 
will be served on the evening of admission the clinical facility. No liquid or food intake is allowed 
during the fast, except water, which is permitted up until 1 hour prior to study drug administration. 
 Oral dosing will be done in the clinic for the evening dose in Treatment group “B”. 
Treatment Day 28: Treatment “A” and Treatment “B” groups only 
 Verify no change in subject’s health status before dosing. 
 Obtain baseline PK blood sample immediately (within 10 minutes) prior to scheduled oral dosing 
(single oral dosing in Treatment group “A” or first oral dosing in Treatment group “B”). 
 Obtain baseline PD blood sample (LH, FSH, E2, and progesterone) immediately (within 30 minutes) 
prior to the scheduled oral dosing. 
 Do not allow any food or liquid during the fasting period except water, which is permitted up until 1 
hour prior to study drug administration.  
 Administer oral tablets in the morning with 240 mL of water. Perform mouth check following oral 
tablet dosing to ensure compliance.   
 Subjects will remain seated or semireclined and will be required to avoid lying down or sleeping 
(unless medically necessary or procedurally required) for the first 1 hour after drug administration.  
 Obtain serial blood samples for the PK evaluations at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 
12, 13, 14, and 15 hours following single oral dosing in Treatment group “A” or the first oral dosing 
in Treatment group “B” (16, 17, 18, 20, and 24 hour samples to be obtained on Postdosing Day 1). 
Note: A 12-hour sample in Treatment group “B” will be obtained just prior to the second oral dose. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) predose (within 1 hour prior to dosing). Note: The vital signs will be assessed prior 
to the single oral dosing in Treatment group “A” and prior to the first oral dosing in Treatment 
group “B.” 
 Record AEs and concomitant medication use. 
 The fasting period will be -10h to +4h for Treatment group “A”, and -10h to +4h for the first dose in 
Treatment group “B”, and -2h to +2h for the second dose in Treatment “B”. All meal times will be 
recorded and entered into the clinical database. 
 Water will not be permitted until 1 hour after dosing (Treatment “A” and both doses of Treatment 
“B”). 
 
Postdosing Period  


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Postdosing Day 1:  
Treatment “A” and Treatment “B” groups only 
 
 Obtain PK blood sample at 16, 17, 18, 20, and 24 hours following single oral dosing in Treatment 
group “A” or the first oral dosing in Treatment group “B.”  
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) at approximately 24 hours after the last dose for Treatment group “A: and 12 hours 
after the last dose for Treatment group “B”. 
Treatment “C” and Treatment “D” groups only 
 Treatment “C” and Treatment “D” volunteers are not confined on day 28, but rather shall be present 
in the morning of postdosing day 1 only following on overnight fast for 12h because of the lipid 
panel clinical laboratory test. 
 Obtain PK blood sample any time in the morning. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) any time in the morning. 
 Review subject’s diaries. 
 Collect samples for urine drug screen and urine cotinine tests.  
 Perform urine pregnancy test; subjects with positive results must be discontinued from study. 
 Perform alcohol breath test. 
All Treatment groups 
 Obtain PD blood sample (LH, FSH, E2, and progesterone) any time in the morning. 
 Record AEs and concomitant medication use. 
 Clinical laboratory tests (hematology and clinical chemistry – see – See APPENDIX E for details). 
 Physical examination 
 Gynecological examination (including manual breast exam)  
 Release subject from the clinical site after all scheduled evaluations. 
Postdosing Days 7, 14, 21 
 Collect samples for urine drug screen and urine cotinine tests.  
 Perform alcohol breath test. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) any time in the morning. 
 Obtain PK blood sample any time in the morning. 
 Obtain PD blood sample (LH, FSH, E2, and progesterone) any time in the morning. 


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 Record AEs and concomitant medication use. 
 Review subject’s diaries. 
 Release subject from the clinical site after the PK and PD blood samples. 
Final Study Visit (Postdosing Day 28) 
 Obtain PK blood sample any time in the morning. 
 Obtain PD blood sample (LH, FSH, E2, and progesterone) any time in the morning. 
 Assess body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic 
blood pressure) any time in the morning. 
 Perform urine pregnancy test. 
 Record AEs and concomitant medication use. 
 Review subject’s diaries. 
 Clinical laboratory tests (hematology, clinical chemistry and urinalysis - see– See APPENDIX E for 
details). 
 Physical examination 
 Gynecological examination (including manual breast exam)  
 12-lead ECG 
 Release subject from the clinical site after all scheduled evaluations. 
Note: the same procedures will be performed for subjects who prematurely discontinue from the study. 
Throughout the study, abnormal safety measurements will be repeated as per the clinical site SOPs or 
upon physician request. Any abnormal repeated measurement will be evaluated by a physician and 
repeated again if judged necessary 
 
8. ELIGIBILITY CRITERIA 
 
8.1 Inclusion Criteria 
Subjects enrolled in this study will be members of the community at large. The recruitment 
advertisements may use various media types (eg, radio, newspaper). Subjects must meet all of the 
following criteria to be included in the study: 
1) Healthy premenopausal female volunteers, aged 18 to 49 years  
2) BMI 18 and 32 kg/m2, and weight ≥110 lb (≈50 kg). 
3) Regular menstrual cycles with a usual length ranging from 21 days to 35 days. If subject has 
recently used hormonal birth control, historical data prior to use will be used to determine 
qualification and must also meet this criterion.  


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4) If of childbearing potential and sexually active with a risk of pregnancy, willing to use one of the 
following acceptable methods of contraception throughout the study and for at least 30 days after 
the last drug administration: 
a) intrauterine contraceptive device without hormone release system placed at least 4 weeks prior 
to the first study drug administration with simultaneous use of condom for the male partner 
b) simultaneous use of diaphragm with intravaginally applied spermicide and condom for the male 
partner starting at least 14 days prior to drug administration. 
c) sterile male partner (vasectomized for at least 6 months) 
d) Note: Surgically sterile subjects who have had a tubal ligation are considered of non-
childbearing potential and are not required to use contraception 
5) Willing to refrain from excessive use of alcohol during the entire study and willing to refrain from 
use of alcohol 24 hours prior to any PK blood draw taken during the study  
6) Willing to refrain from use of prescription medications, over-the-counter medications and natural 
health products during the entire study  
7) Willing and capable to give informed consent to participate in study 
 
8.2 Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1) Hypersensitivity to GnRH, GnRH agonist analogs, similar nonapeptides, or any of the excipients in 
LUPRON DEPOT. Note: This is a contraindication from the Lupron Depot label.   
2) Undiagnosed abnormal vaginal bleeding. Note: This is a contraindication from the Lupron Depot 
label.   
3) Known or suspected pregnancy, or subjects who are considering becoming pregnant prior to the 
conclusion of this study. Note: LUPRON DEPOT is contraindicated in women who are or may 
become pregnant while receiving the drug. LUPRON DEPOT may cause fetal harm when 
administered to a pregnant woman…. If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 
the fetus.  
4) Breastfeeding or within 2 months after stopping breastfeeding (relative to the screening visit). Note: 
Use of LUPRON DEPOT is contraindicated in women who are breastfeeding. 
5) Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these 
conditions. Note: Per the LUPRON DEPOT label, a possible coadministration of norethindrone 
acetate is contraindicated in women with thrombophlebitis, thromboembolic disorders, cerebral 
apoplexy, or a past history of these conditions. 
6) Markedly impaired liver function or liver disease. Note: Per the LUPRON DEPOT label, a possible 
coadministration of norethindrone acetate is contraindicated in women with markedly impaired 
liver function or liver disease.  


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7) Known or suspected carcinoma of the breast. Note: Per the LUPRON DEPOT label, a possible 
coadministration of norethindrone acetate is contraindicated in women with known or suspected 
carcinoma of the breast. 
8) Status postpartum or postabortion within a period of 2 months prior to the screening visit 
9) A cervical cytology smear of Papanicolaou (Pap) class III or greater or a Bethesda System report of 
low grade squamous intraepithelial lesions (SIL) or greater (Pap smear results within last 12 months 
are acceptable if properly documented) 
10) Use of any tobacco products (including electronic cigarettes) in the 3 months preceding the 
screening visit or positive urine cotinine test at screening 
11) History of significant alcohol or drug abuse within one year prior to the screening visit 
12) Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mm 
Hg, diastolic blood pressure lower than 50 or over 90 mm Hg, or heart rate less than 50 or over 100 
bpm) at screening 
13) Any clinically significant history or presence of neurologic, endocrinologic, pulmonary, 
hematologic, immunologic, or metabolic disease 
14) History of severe respiratory depression or pulmonary insufficiency. 
15) Diabetes mellitus requiring insulin 
16) History of headaches with focal neurological symptoms 
17) Uncontrolled thyroid disorder 
18) Sickle cell anemia 
19) Current or history of clinically significant depression in the last year 
20) Known disturbance of lipid metabolism 
21) Hepatic adenoma or carcinoma 
22) Known or suspected endometrial carcinoma or estrogen-dependent neoplasia 
23) Clinically significant history or presence of any gastrointestinal pathology (eg, chronic diarrhea, 
inflammatory bowel diseases), unresolved gastrointestinal symptoms (eg, diarrhea, vomiting) or 
kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, 
or excretion of the drug. 
24) Difficulty in swallowing study medication 
25) Any food allergy, intolerance, restriction or special diet that, in the opinion of the Investigator, could 
contraindicate the subject’s participation in this study 
26) Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening 
27) Administration of any investigational drug and/or experimental device within 30 days prior to the 
screening visit 
28) Administration of any biologics within 90 days prior to the screening visit 


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29) Clinically significant finding on the ECG suggesting participation in the study could pose a risk to 
the subject 
30) A depot injection or an implant of any drug within 6 months prior to the screening visit 
31) Use of oral contraceptives or other sex steroid hormones within 3 months prior to the screening visit 
32) Any clinically significant physical or gynecological abnormality at the screening visit 
33) Any clinically significant abnormal laboratory test result at the screening visit 
34)  Hemoglobin <115 g/L and/or hematocrit <0.32 L/L 
35)  Use of prescription medication within 14 days prior to the first administration of study medication 
or over-the-counter products (including natural health products; eg, food supplements, vitamins, 
herbal supplements) within 7 days prior to the first administration of study medication, except for 
topical products without significant systemic absorption 
36) Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding volume 
drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 
days prior to the first dosing 
37) Deemed by the Investigator to have questionable ability to comply with the study protocol 
38) History of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or 
tumors; 
39) Significant risk factors for decreased bone mineral content and/or bone mass, such as family history 
(in a first degree relative) of osteoporosis, personal history of chronic use of corticosteroids or 
anticonvulsants. 
 
8.3 Contraindications, Warnings and Other Notes 
Leuprolide is contraindicated in:  
1) Women with hypersensitivity to GnRH and GnRH agonist analogs. 
2) Women with undiagnosed abnormal vaginal bleeding. 
3) Women who are or may become pregnant while receiving the drug. Leuprolide may cause fetal 
harm when administered to a pregnant woman. Major fetal abnormalities were observed in rabbits 
but not in rats after administration of leuprolide. There was increased fetal mortality and decreased 
fetal weights in rats and rabbits. The effects on fetal mortality are expected consequences of the 
alterations in hormonal levels brought about by the drug. If this drug is used during pregnancy, or if 
the patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to the fetus. 
4) Women who are breastfeeding  
The following are warnings from the approved product label of a marketed formulation of leuprolide 
(Lupron Depot®, 3.75 mg) 


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 Safe use of leuprolide in pregnancy has not been established clinically. Before starting treatment 
with LUPRON DEPOT, pregnancy must be excluded. 
 When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and 
stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. 
 Therefore, patients should use nonhormonal methods of contraception. 
 Patients should be advised to see their physician if they believe they may be pregnant. If a patient 
becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised 
of the potential risk to the fetus. 
 During the early phase of therapy, sex steroids temporarily rise above baseline because of the 
      physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be 
      observed during the initial days of therapy, but these will dissipate with continued therapy. 
 Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post 
marketing. 
Per leuprolide (Lupron Depot®, 3.75 mg) prescribing information, patients should be aware of the 
following information: 
1) Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient should notify 
her physician if regular menstruation persists. Patients missing successive doses of LUPRON DEPOT 
may experience breakthrough bleeding. 
2) Patients should not use LUPRON DEPOT if they are pregnant, breastfeeding, have undiagnosed 
abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON DEPOT. 
3) Safe use of the drug in pregnancy has not been established clinically. Therefore, a nonhormonal 
method of contraception should be used during treatment. Patients should be advised that if they miss 
successive doses of LUPRON DEPOT, breakthrough bleeding or ovulation may occur with the 
potential for conception. If a patient becomes pregnant during treatment, she should discontinue 
treatment and consult her physician. 
4) Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with 
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, 
reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was 
discontinued. 
5) Patients should be counseled on the possibility of the development or worsening of depression and 
the occurrence of memory disorders. 
6) The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, 
some of which may not be reversible. Clinical studies show that concurrent hormonal therapy with 
norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with 
LUPRON. (All patients received calcium supplementation with 1000 mg elemental calcium.)  
7) If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course 
of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered. Retreatment beyond 
this one six-month course cannot be recommended. It is recommended that bone density be assessed 


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before retreatment begins to ensure that values are within normal limits. Retreatment with LUPRON 
DEPOT alone is not recommended. 
8) In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or 
tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass 
such as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may pose an additional risk. In 
these patients, the risks and benefits must be weighed carefully before therapy with LUPRON 
DEPOT alone is instituted, and concomitant treatment with norethindrone acetate 5 mg daily should 
be considered. Retreatment with gonadotropin releasing hormone analogs, including LUPRON is not 
advisable in patients with major risk factors for loss of bone mineral content. 
 
8.4 Withdrawal of Subjects 
Every subject has the right to refuse further participation in the study at any time and without providing 
reasons for this decision and without prejudice to further treatment. A subject’s participation is to be 
terminated immediately upon their request. The Investigator should record the appropriate reason in the 
case report form (CRF) and in the source document.  
The subject may be withdrawn from the study at any time at the discretion of the Investigator; the 
reason should be fully documented in the CRF. Should the subject, during the course of the study, 
develop conditions that would prevent the subject from being dosed as per Investigator’s judgment (eg, 
absolute contraindications, prohibited concomitant medications) or would be considered as potentially 
dangerous AEs, they must be withdrawn immediately. The reasons are to be fully documented in the 
CRF.  
A positive alcohol breath test, urine drug screen, or cotinine test will also be grounds for subject 
withdrawal, to be handled on a case-by-case basis. If pregnancy occurs or is suspected during study 
drug treatment, the subject must be discontinued immediately. The outcome of the pregnancy must be 
followed and a Pregnancy Follow-up form completed.  
The termination of an individual’s participation should be considered in case of a serious adverse event 
(SAE) (see Section 11.3 for details) or considerable worsening of the subject’s clinical conditions.  
At the discretion of Enteris BioPharma, the entire study or part of the study may be canceled for 
medical or other reasons. In case of premature termination or suspension of the study or part of the 
study, the Sponsor will promptly inform the Investigator/institutions, regulatory authorities and 
Institutional Review Boards (IRBs) of the termination or suspension and the reason for the measure. 
In addition, Enteris BioPharma retains the right to end the study at any time if the study cannot be 
carried out as agreed upon in the protocol. 
The reasons for discontinuation include: 
- 
AE 
- 
Death 
- 
Pregnancy 
- 
Protocol violation 


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- 
Lost to follow-up 
- 
Study terminated by Sponsor  
- 
Noncompliance with study drug (to be handled on a case-by-case basis) 
- 
Withdrawal by subject decision (appropriate details must be provided on the CRF) 
- 
Physician decision (appropriate details must be provided on the CRF) 
- 
Other 
If, by the time of discontinuation, a dose of the investigational product has been administered, the 
subject must be advised to agree to the study evaluation described for the Early Discontinuation Visit. 
If a randomized subject misses a scheduled appointment, she should be immediately contacted by phone 
to reschedule office visit. After waiting 2 weeks for the subject to respond, a certified letter with request 
for an end-of-study visit must be sent. The certified letter receipt will be filed with the Investigator’s 
copy of the subject’s case record form. If the subject fails to return after use of these methods, they will 
be considered lost to follow-up. 
Subjects discontinued early after having received at least one dose of study drug will not be replaced. 
Study drug assigned to the withdrawn subject may not be given to another subject.  
Data generated from screening failures (subjects not admitted to the study after the screening phase and 
not assigned a randomization number) may be listed according to main reason for not being admitted 
into the treatment phase. 
9   STUDY TREATMENT 
 
9.1 Description  
The active ingredient in both Leuprolide Oral Tablet and LUPRON DEPOT is leuprolide acetate [5-
oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-
prolinamide, acetate salt], which has the following molecular formula: C59H84N16O12 · 1-2C2H4O2.  
Enteris BioPharma will supply the Leuprolide Oral Tablet study drug.  Each 4 mg tablet contains 4 mg 
of leuprolide active moiety as the acetate salt (4.46 mg of leuprolide acetate salt), plus inactive 
ingredients as follows: 
 
 
 
 
 
 
  
 
 
 
 
, 


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. 
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized 
microspheres which, when mixed with diluent, become a suspension intended as a monthly IM 
injection. The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains 
leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 
mg), and D-mannitol (6.6 mg). The second chamber of diluent contains carboxymethylcellulose sodium 
(5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, 
USP to control pH. During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving 
the peptide. 
 
9.1.1 Drug Administration and Return 
Oral Tablet. Leuprolide Oral Tablet will be administered to each subject with 240 mL of water. The 4-
mg qd oral dose (Treatment “A”) will be administered once daily, in the morning, on an empty stomach; 
the 4-mg and 10-mg bid oral doses (Treatments “B” and “D”) will be administered twice daily, in the 
morning and in the evening, 12 hours apart and on an empty stomach. Note: On an empty stomach 
means that the oral doses are administered at least 2 hours before and at least 2 hours after the meal. 
Oral administration instructions are applicable to both on-site and at-home dosing. For at-home dosing, 
each subject will take the oral dose with approximately 240 mL of water.  
Intramuscular Injection. As is noted earlier, LUPRON DEPOT is available in a prefilled dual-
chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a 
suspension intended as a monthly IM injection. The dual-chamber syringe contains leuprolide acetate 
(3.75 mg), See APPENDIX D. “Lupron Depot® 3.75 mg” for additional details. 
9.1.2 Dispensing 
Study drug will be shipped directly to the study site. Each oral medication kit is labeled with the 
following information: drug description (leuprolide, lot number, protocol number, route of 
administration, storage conditions, Sponsor’s identification and address, and the statement, 
“Investigational Drug”.  The subject number and the date of study drug administration will be recorded 
in the CRF. As this study is an open-label study, study drug will not be blinded. 
The composition and pharmaceutical quality of the investigational products can be traced back via the 
lot number. Further details of the investigational product can be found in the Investigator’s Brochure. 
9.1.3 Storage 
Leuprolide Oral Tablet must be stored refrigerated between 2° and 8°C (36° and 46°F). The container 
must be kept tightly closed and protected from light and moisture. 
Leuprolide acetate IM injection must be stored at 25°C (77°F); excursions permitted to 15-30°C (59-
86°F) [See USP Controlled Room Temperature]. 
A clinical site will be required to keep a temperature log to establish a record of compliance with these 
storage conditions. 
 


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9.1.4 Method of Assigning Subjects to Treatments  
Eligible subjects were to be given study drug according to the randomization schedule. Initially enrolled 
subjects 
were 
randomly 
assigned 
to 
one 
of 
three 
treatment 
groups 
in 
a 
Treatment“A”:Treatment“B”:Treatment“C” ratio of 3:3:2. The randomization schedule was prepared 
prior to the study and was to be balanced by using permuted blocks (SAS®, PROC PLAN will be 
employed). Subjects will be assigned a subject number (randomization number) with 2 digits (e.g., 01-
32). The subject numbers was to be linked to a specific treatment (Treatment “A,” Treatment “B,” or 
Treatment “C”). The randomization schedule could be further stratified by the study site, if necessary. 
Newly enrolled subjects will also receive a number linked to a specific treatment (Treatment “D”).  
Subjects that have already participated in this study will receive a new unique subject number that will 
be linked exclusively to protocol-specified procedures for Treatment “D”. 
9.1.5 Restrictions 
Subjects will be required to abstain from: 
 use of prescription medications, over-the-counter medications, and natural health products during 
the entire study  
 using soft or hard drugs or any tobacco products during the study 
 excessive use of alcohol during the entire study and willing to refrain from use of alcohol for 24 
hours prior to any PK blood draw taken during the study  
 products containing xanthines, energy drinks, and grapefruit for 24 hours prior to any PK blood 
draw taken during the study 
 food containing poppy seeds prior to any PK blood draw taken during the study 
A urine drug screen, a urine cotinine test, and an alcohol breath test will be performed for all subjects at 
scheduled study visits.  
9.1.6 Physical Activity 
For safety reasons, subjects will be required to remain seated or semireclined and will be required to 
avoid lying down or sleeping (unless medically necessary, procedurally required, or to go to the 
bathroom) for the first 1 hour after on-site drug administration. When subjects will be ambulated during 
this interval, they will be accompanied by the study site personnel. Vigorous physical activity will be 
prohibited at all times during the confinements. These restrictions are not applicable to subjects 
receiving Treatment “D”. 
 
9.2 Prior and Concomitant Medications 
With the exception of concomitant drug therapy required for the medical management of an AE, there 
will be no other scheduled prior or concomitant therapy permitted during this study.  
Seasonal flu vaccine will be allowed during the study; however, subjects will be advised that receiving 
vaccination within 3 days prior to admission to the clinic could result in vaccine-related side effects that 
could appear while on study. Any subject presenting with side effects associated with vaccination or 


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who has been vaccinated within 3 days prior to the admission will be evaluated by the study physician 
and could be judged ineligible or withdrawn from the study. 
All concomitant medications, whether prescription or nonprescription (including pharmacological doses 
of vitamins), are to be recorded in the CRF using the brand name and stating dosage, indication, and 
duration of intake.  
 
9.3 Drug Accountability 
Accurate records must be kept regarding administration of study drug to each individual participant in 
the study. Reasons for departure from the expected drug administration must be recorded.  
In accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP), 
the Investigator will be responsible for monitoring the receipt, storage, dispensing and accounting of all 
study drugs according to accepted medical and pharmaceutical practice. All details of study drug 
receipt, storage, administration, and return will be recorded and the records must be retained in the 
Investigator’s site file. Accurate site records of drug inventory and dispensing must be maintained. All 
records must be made available to Enteris BioPharma, the clinical research organization, and 
appropriate regulatory agencies upon request. Study drug must be administered exclusively to study 
participants during the course of the study.  
At the end of the study or as directed during the course of the study, all leuprolide study supplies 
(including partial and empty containers) will be returned to drug supplier, Sponsor or to the local 
warehouses for future destruction. A final reconciliation statement will be completed at the end of the 
study.  
9.4 Treatment Compliance 
For the on-site dosing days, measurements of treatment compliance will be performed by the study site 
personnel. The subject identification will be verified and cross-checked with the predispensed 
medication and a mouth (using a tongue depressor and a flash light) and hand check will be performed 
to ensure subjects have swallowed the study medication (applicable to oral leuprolide tablets only). 
During off-site dosing days, subjects will record the oral tablets intake on their diary cards. Proper 
instructions will be given to subjects when compliance issues are identified.  
 
10. PHARMACOKINETIC, PHARMACODYNAMIC AND SAFETY EVALUATIONS 
 
10.1 Pharmacokinetic and Pharmacodynamic Evaluations 
 
Subjects randomized to the the two oral doses (Treatments “A” and “B”) will have twenty-four (24) 
serial blood samples drawn on Treatment Days 1 and 28 immediately prior to dosing (0 time), and at 
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 20, and 24 hours following 
oral dosing. For the IM injection (Treatment “C”), serial blood samples will also be drawn on 
Treatment Day 1, prior to dosing (0 time), at 0.5, 1, 2, 6, 12, 18, and 24 hours postdosing. Blood 
samples for the IM injection will also be taken in the morning on Postdosing Day 1. Additional blood 
samples for all subjects will be taken in the morning (in the oral groups, just prior to dosing) on 
Treatment Days 8, 15, and 22. Samples will be appropriately stored until they can be assayed for 


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leuprolide 
and hormonal levels. Serum concentrations of LH and  FSH, and plasma 
concentrations of E2 and progesterone, will be measured (immediately prior to dosing) on 
Treatment Days 1, 8, 15, 22, and in the morning of Day 29 (postdosing day 1). 
 
After the 28-day dosing period, four follow-up visits will be scheduled at 7, 14, 21, and 28 days after 
the last dose. During each follow-up visit, blood samples will be drawn to assess leuprolide (via a 
single blood draw) and LH, FSH, E2, and progesterone concentrations. During each follow-up visit, 
subjects will be asked about onset (or absence) of menstrual period. 
 
A total of 55 PK blood samples will be taken from subjects in the oral groups (Treatments “A” and 
“B”) for the evaluation of the leuprolide serum concentrations. A total of 11 PD blood samples will 
also be taken for the determination of LH, FSH, E2, and progesterone levels. The blood volume for 
each PK sample is assumed to be approximately 3 mL for leuprolide analysis, and the volume for each 
PD sample is assumed to be approximately 16 mL (10 mL for progesterone and estradiol analysis, and 
6 mL for FSH and LH analysis).  The total amount of blood volume for all PK and PD draws is 341 
mL. Four safety blood draws will be performed during the study with a volume of 8 mL per draw. An 
additional 34 mL of blood may be drawn during the study to allow for repeat draws and/or additional 
safety tests and for the screening pregnancy test. The total amount of blood drawn should not exceed 
407 mL over 3 months, including all samples collected for PK and PD analyses and eligibility and 
safety purposes. 
 
In the Treatment group “D” a total number of samples for PK evaluations will be reduced by 46 when 
compared to other oral groups. The total amount of blood drawn will be reduced by 138 mL (46 x 3 
mL) and should not exceed 269 mL over 3 months, including all samples collected for PK and PD 
analyses and eligibility and safety purposes.  
 
A total of 16 PK blood samples will be taken from subjects in the Lupron group (Treatment “C”) for 
the evaluation of the leuprolide serum concentrations. A total of 10 PD blood samples will also be 
taken for the determination of LH, FSH, E2, and progesterone levels. The total amount of blood 
volume for all PK and PD draws is 208 mL. Four safety blood draws will be performed during the 
study with a volume of 8 mL per draw. An additional 34 mL of blood may be drawn during the study 
to allow for repeat draws and/or additional safety tests and for the screening pregnancy test. The total 
amount of blood drawn in the Lupron group should not exceed 274 mL over 3 months, including all 
samples collected for PK and PD analyses and eligibility and safety purposes. 
 
Serum concentrations of leuprolide and concentrations of PD parameters will be determined via 
validated bioanalytical methods. Sensitivity and specificity of the employed bioanalytical methods will 
be described in the study report.  
During the both 28-day dosing period and post-dosing 28-day follow-up, subjects will record vaginal 
(menstrual) bleeding on diary cards. Clinically notable events (including possible flare-up symptoms) 
may also be recorded on diary cards. 
See Section 12.2 and Section 12.3 for the detailed description of the PK and PD parameters and planned 
statistical analyses.  


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10.2 Safety Evaluations 
AEs and concomitant therapies will be reported during the scheduled office visits. At each treatment 
office visit, the body weight and vital signs (temperature, pulse rate, respiratory rate, systolic and 
diastolic blood pressure) will be assessed.  
Complete physical and gynecological examinations and routine laboratory evaluations will be repeated 
at the end of dosing period (Postdosing Day 1) and at the Final Visit and also in case of early 
discontinuation.  
Safety evaluations will be based on the discontinuations due to TEAEs, treatment-induced changes in 
physical and gynecological examinations, in clinical laboratory test results, in body weight and vital 
signs, as well as by the incidence and severity of TEAEs reported. TEAEs will be evaluated for the 
entire study and separately for the two study subperiods (a 28-day dosing cycle and a 28-day postdosing 
evaluation period). 
 
11. ADVERSE EVENT REPORTING 
The most important part of the safety evaluations is analysis of TEAEs and SAEs as well 
discontinuations due to AEs. The following sections describe procedures related to AEs monitoring and 
reporting.  
11.1 Definition of Adverse Events 
AEs or adverse experiences are defined in the (ICH) Guidance for Industry E6: Good Clinical Practice 
as follows: 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product (ICH April 1996). 
Any medical condition or clinically significant laboratory abnormality with an onset date before the first 
date of study drug administration is considered to be preexisting, and should be documented in the CRF.  
Any AE (ie, a new event or an exacerbation of a preexisting condition) with an onset date after study 
drug administration up to the last day on study (including the follow-up, off-study medication period of 
the study), should be recorded as an AE on the appropriate CRF page(s) (see Section 11.2 for details).  
An AE does not include: 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); the condition 
leading to the procedure is an AE 
 Preexisting diseases or conditions present or detected prior to start of study drug administration if 
they do not worsen 
 Situations where an untoward medical occurrence has not occurred (eg, hospitalization for elective 
surgery, social and/or convenience admissions) 


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 Overdose of either study drug or concomitant medication without any signs or symptoms unless the 
patient is hospitalized for observation 
The period of observation for AEs starts at first dose of study drug and continues until the subject 
undergoes a final examination as part of the study. The period will also include 30 days following the 
final examination during which time SAEs must be reported. AEs occurring after the completion of the 
study must be reported if the Investigator considers that there is a causal relationship with the study 
medication. 
All patients experiencing AEs – whether the events are considered to be associated with any study 
procedure and/or study medication and/or devices or not – must be monitored as much as possible at 
least until symptoms subside, any abnormal laboratory values have returned to baseline, or until there is 
a satisfactory explanation for the changes observed, or until death. In the latter instance, a full 
pathologist’s report must be supplied as soon as possible. All findings must be reported in the Adverse 
Event CRF and documented in the patient’s medical records. The Sponsor will provide Investigators 
involved in this clinical study with periodic updates on clinically relevant AEs according to legal 
requirements.  
 
11.2 Routine Reporting of Adverse Events 
AEs, whether or not associated with study drug administration, will be recorded electronically and will 
be submitted to the Sponsor at regularly scheduled intervals. 
The information to be collected in the source data and populated in the CRF will include: 
 The date of onset of any new AE or the worsening of a previously observed AE. 
 The specific type of reaction in standard medical terminology 
 The resolution status of the AE (“Resolved” or “Ongoing”) 
 For the resolved AEs, stop date 
 The severity of the adverse categorized using the following definitions: 
Mild: discomfort noted, but no disruption of normal daily activity 
Moderate: discomfort noted of sufficient severity to reduce or adversely affect normal activity 
Severe: incapacitating, with inability to work or perform normal daily activity 
 The relationship of the AE to the study drug, according to the following definitions:  
Unrelated: There is evidence that the AE definitely has an etiology other than the assigned 
study drug. 
Possibly Related: The AE has a temporal relationship to study drug administration. However, 
an alternative etiology may be responsible for the AE. Information on drug/product withdrawal 
may be lacking or unclear. 
Probably Related: The AE has a temporal relationship to study drug administration. The event 
is unlikely to be related to an alternative etiology. There is a reasonable response on withdrawal. 
Rechallenge information is not required. 


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Definitely Related: The AE has a temporal relationship to study drug administration and 
resolves when the drug is discontinued. An alternative etiology is not apparent. If the subject is 
rechallenged with the assigned study drug, the AE recurs. Rechallenge is not necessarily 
required. 
 Description of action taken in treating the AE (“Dose not Changed” and “Drug Withdrawn” – to 
be specified on the CRF) 
 
11.3 Reporting of Serious Adverse Drug Experiences, Including Deaths 
A serious adverse drug experience (SAE), as defined in 21 CFR 312.32 is: 
Any adverse drug experience occurring at any dose that results in any of the following outcomes:  
 
Death 
 
A life threatening adverse drug experience  
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasia or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
Serious adverse experiences, including death due to any cause, which occur during this study or within 
30 days following the final examination, whether or not related to the administration of study drug, must 
be reported immediately (within 24 hours of learning of the event) to the Medical Monitor.  
Contact: 
 
Dr. Paul Shields 
Phone:                        973-453-3520 
Back up phone:           973-641-5807 
Fax: 
 
            973-588-5966 
 
11.4 Withdrawal from Study Treatment Due to Adverse Event 
Subjects withdrawn from receiving additional study drug due to an AE will be followed by the 
Investigator until the outcome is determined. Additional reports will be provided to the Sponsor or 
regulatory authorities when requested. Every effort will be made to follow the subject for the full study 
period as per the schedule of study visits. 
 


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12. STATISTICAL METHODS 
 
12.1 Populations and General Considerations 
The primary statistical analyses of PK data will be conducted on the population of subjects completing 
28 days of dosing. Supporting evaluations will be performed for the cohort of subjects who received at 
least one dose of study medication and provided any PK data.  
Similarly, the primary statistical analyses of PD data will be conducted on the population of subjects 
completing 28 days of dosing. Supporting evaluations will be performed for the cohort of subjects who 
received at least one dose of study medication and provided any PD data.  
The safety analysis will be performed on all subjects who received at least one dose of study 
medication.  
Compliance with the oral dosing regimens will be assessed, and criteria for the subject’s evaluability 
for PK and/or PD analyses will be specified in the Statistical Analysis Plan (SAP).  
Unless otherwise noted, the summaries for quantitative variables (eg, continuous PK and PD 
parameters) will include the sample size, mean, median, standard deviation, coefficient of variation, 
minimum, and maximum. For qualitative (categorical) variables (eg,, suppression of E2 below a 
specified threshold), the summaries will include the number and percent of subjects in each category. 
A detailed SAP will be developed prior to the database lock. 
12.2 Pharmacokinetic Parameters and Analyses 
The following PK parameters will be calculated from the individual serum drug concentration versus 
time profiles for each subject from Treatment groups “A”, “B” and “C” and for each treatment period: 
 
Table 1 Description of the Pharmacokinetic Parameters 
Parameter 
Description 
Cmax 
Maximum concentration level 
Tmax 
Time to maximum concentration level 
AUC0 – 24 
Area under the drug concentration versus time curve calculated using the 
linear trapezoidal method from 0 hours to 24 hours  
AUC0 – t 
Area under the drug concentration versus time curve calculated using the 
linear trapezoidal method from 0 hours to t, where t is the time of the last 
available observation (Ct)                                   
AUC0 – inf 
Area under the drug concentration versus time curve from 0 hours to infinity, 
AUC0-inf = AUC0-t + Ct/Kel 
Css_oral 
Steady state concentration level calculated for oral tablets at the end of 
the fourth treatment week (Treatment Days 28-29) as the 24-hour AUCs 
divided by the duration of the dosing interval. 
Css_im 
Steady state concentration level calculated for IM injection at the fourth 
treatment week (a mean of leuprolide levels on Days 22 and 29).   


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Kel 
The apparent elimination rate constant, calculated by linear regression of log 
concentration vs time during the elimination phase 
T1/2 
Terminal half-life calculated as ln(2)/ Kel 
PK parameters will be derived using a non-compartmental PK model. Scheduled sampling time points 
will be used for the calculations. To derive the PK parameters, the serum concentrations below limit of 
quantification in early timepoints will be treated as zero and serum levels below limit of quantification 
appearing in the elimination phase will be omitted from the calculations of Kel. 
The summaries will be provided for all PK parameters with steady-state concentration levels (Css) 
considered as most important. No formal statistical between-treatment comparisons will be conducted. 
PK parameters will be graphed by treatment group for each evaluation period.  
 
12.3 Pharmacodynamic Parameters and Analyses 
 
As noted earlier, PD assessments (LH, FSH, E2, and progesterone) will be performed during the 
Screening Visit and immediately prior to dosing on Treatment Days 1, 8, 15, 22, and 29. Additional PD 
assessments will be performed during the follow-up visits (postdosing Days 7, 14, 21 and 28).  
 
The primary PD metric - suppression of E2 level - will be assessed at each on-treatment evaluation 
timepoint. Treatment Day 22 and Treatment Day 28 evaluations (separately and combined) will be 
considered as most important. The summaries will also be provided across the entire dosing period and 
the entire postdosing period, separately and combined. The summaries of PD metrics may be further 
stratified by the cycle period (days) of the start of dosing. 
 
In addition to a primary E2 suppression threshold (E2 ≤40 pg/mL), a suppression of E2 below 20 pg/mL 
may also be assessed, if considered necessary. The suppression o f  ovulation (as evidenced by 
progesterone levels <3 ng/mL) will be evaluated with Treatment Day 22 and Postdosing Day 1 
assessments positioned as primary. Changes from predosing baseline in E2 and progesterone levels will 
also be summarized at each on-treatment evaluation timepoint. Predosing baseline for all PD metrics is 
the highest value across two observations: (a) screening measurement and (b) measurement taken just 
prior to the first dose of the study drug. Similar summaries will be provided for the follow-up visits 
(postdosing Days 7, 14, 21, and 28). In addition, time to return to prestudy baseline hormonal levels 
could be estimated.   
 
PD parameters will be graphed by treatment group for each evaluation period.  
 
Additionally, correlations between leuprolide concentration levels and PD parameters will be examined. 
 
Number of vaginal (menstrual) bleeding days will be summarized by treatment group for 28 days of 
therapy and for 28 days of poststudy follow-up. The subject incidence of the onset of menstrual period 
after completion of therapy will be reported for each treatment group.  
Further details of the PD data analysis will be disclosed in the SAP.   
 


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12.4 Safety Endpoints and Analyses 
Safety summaries will be provided for the discontinuations due to TEAEs, treatment-induced changes in 
physical and gynecological examinations, in clinical laboratory test results (hematology, serum 
chemistry, and urinalysis), in vital signs and body weight, and by the incidence and severity of TEAEs 
reported. The TEAEs will be summarized for the entire study and separately for the two study 
subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). Clinically notable events 
(recorded on diary cards) may also be summarized by treatment group. A listing of SAEs will be 
compiled. 
 
12.5 Sample Size  
The sample size for this study is not based on the statistical power considerations. This sample size is 
considered as adequate for a pilot PK/PD “proof-of-concept” study. Since a formal proof of the PK 
bioequivalence across the treatment arms and/or formal across-treatment statistical comparisons of the 
PD endpoints are not objectives of this proof-of-concept study, the sample size is not based on the 
power considerations. With the proposed sample size, we expect reliable estimates of the PK and PD 
parameters for leuprolide oral tablets and a general validation of related historical data for Lupron 
Depot therapy. The safety and tolerability assessments of the qd and bid regimens of the 4-mg oral 
tablet and a bid regimens of the 10-mg oral tablet should also be robust enough to support the dosing 
selection and instructions in subsequent clinical studies.  
 
13.  ACCESS TO SOURCE DOCUMENTS 
The Investigator will make the source documents for this trial available to the Sponsor or its 
representatives, or to the regulatory authority or health authority inspectors. 
Subject medical information obtained as a result of this study is considered confidential and disclosure 
to third parties other than those noted below is prohibited. All reports and communications relating to 
subjects in this study will identify each subject only by their initials and number. Medical information 
resulting from a subject’s participation in this study may be given to the subject’s personal physician or 
to the appropriate medical personnel responsible for the subject’s welfare. Data generated as a result of 
this study are to be available for inspection on request by FDA or other government regulatory agency 
auditors, the Sponsor (or designee), and the IRB. 
The information developed in this clinical study will be used by the Sponsor in the clinical development 
of the study medication and therefore may be disclosed by the Sponsor as required for disclosure as a 
public company to other clinical investigators, to other pharmaceutical companies, to the FDA and to 
other government agencies. 
Any information, inventions, or discoveries (whether patentable or not), innovations, suggestions, ideas, 
and reports, made or developed by the Investigator(s) as a result of conducting this study shall be 
promptly disclosed to the Sponsor and shall be the sole property of the Sponsor. The Investigator 
agrees, upon the Sponsor’s request and at the Sponsor’s expense, to execute such documents and to take 
such other actions, as the Sponsor deems necessary or appropriate to obtain patents in the Sponsor’s 
name covering any of the foregoing. 


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The Investigator will retain all study documents for at least 2 years after the last approval of a marketing 
application in an ICH region (ie, United States, Europe, or Japan), and until there are no pending or 
contemplated marketing applications in an ICH region. If no application is filed or if the application is 
not approved for such indication, the Investigator will retain all study documents for at least 2 years 
after the investigation is discontinued and regulatory authorities have been notified.  
The Investigator will notify the Sponsor prior to destroying any study records. Should the Investigator 
wish to assign the study records to another party or move them to another location, the Sponsor must be 
notified in writing in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of the 
documents, special arrangements will be made between the Investigator and the Sponsor for storage. If 
source documents are required for continued care of the subject, appropriate copies for storage off site 
will be made. 
 
14. QUALITY CONTROL AND QUALITY ASSURANCE 
Study monitors will periodically audit, at mutually convenient times during and after the study, all 
electronic source data and corresponding office and clinical laboratory records for each subject. The 
monitoring visits provide the Sponsor with the opportunity to evaluate the progress of the study, to 
verify the accuracy and completeness of the source data, to resolve any inconsistencies in the study 
records, and to assure that all protocol requirements, applicable FDA regulations, other requirements, 
and Investigator’s obligations are being fulfilled. 
15. ETHICS 
 
15.1 Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki (1964) including all 
amendments up to and including the Scotland revision (2000) and notes of clarification added in 2002 
and 2004 as described in APPENDIX C.  
15.2 Institutional Review Board 
The protocol, informed consent form, and any materials (such as advertisements, subject information 
sheets, or descriptions of the study used to obtain informed consent) for this study will be reviewed and 
approved by a duly constituted IRB/ethical committee. 
The Investigator will ensure that all aspects of the IRB review are conducted in accordance with current 
institutional, local, and national regulations. A letter documenting the IRB approval will be provided to 
the Sponsor prior to initiation of the study. Amendments to the protocol will be subject to the same 
requirements as the original protocol. The Investigator will submit all periodic reports and updates that 
the IRB may require, including any final close out reports. The Investigator will inform the IRB of any 
reportable adverse events. 
15.3 Informed Consent 
Each subject will be provided with oral and written information describing the nature and duration of 
the study, in a language they can understand, and must consent in writing to participate before 
undergoing screening. The date of the consent shall be entered by the subject. The original signed 


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consent form will be retained with the study center’s records. Each subject will also be given a copy of 
his/her signed consent form.  
16. DATA HANDLING AND RECORDING 
The Investigator is responsible for the completeness and accuracy of information collected in the CRFs 
for each individual enrolled. The CRFs will be signed and dated by the Investigator.  
All clinical raw data will be recorded promptly, accurately, and legibly; either directly into the 
Initiator™ Clinical Trial Management System as e-source data or indelibly on paper (eg, ECG 
readings). A detailed list of the type (electronic or paper) and location for all source data will be 
included in the Trial Master File. When recorded electronically using Initiator™, CRFs will be 
electronically generated afterwards. All raw data will be conserved in order to maintain data integrity. A 
physician and/or the clinical staff will assume the responsibility of ensuring the completeness and 
accuracy of the clinical data. 
The sponsor or designee will conduct data processing. Source data will be reviewed carefully for 
accuracy and completeness. If necessary, the study site will be contacted for corrections and/or 
clarifications. All data will be entered into a study database for analysis and reporting. Any data 
captured electronically (such as laboratory data) will be transferred electronically to the database. Upon 
completion of data entry, the database will receive a quality assurance check to ensure acceptable 
accuracy and completeness. 
 
17. PUBLICATION POLICY 
The result of this study will be published under the direction of the Sponsor. Results will not be 
published without prior review and approval by the Sponsor. 
 
18. PROTOCOL AMENDMENTS AND MODIFICATIONS 
The Investigator will ensure that the study is conducted in accordance with the procedures and 
evaluations described in this protocol. The Sponsor is responsible for all protocol amendments and 
modifications, except those intended to reduce immediate risk to subjects. The Sponsor is responsible 
for submitting protocol amendments to the appropriate government regulatory authorities. The 
Investigator is responsible for submitting protocol amendments to the appropriate IRB or ethical 
committee. Approval by the IRB will be obtained before changes are implemented. 
As per the Canadian regulatory agency, a Clinical Trial Application will be submitted before the 
beginning of the study and a No Objection Letter must be received prior to dosing. 
 


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19. REFERENCES 
 
1. Sennello LT et al. Single-dose pharmacokinetics of leuprolide in humans following intravenous and 
subcutaneous administration. J Pharm Sci 1986; 75(2): 158-160.  
2. LUPRON DEPOT 3.75 mg (leuprolide  for depot suspension). Full prescribing information. 
Available at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019943s032,020011s039lbl.pdf 
 (last accessed 23 May 2016). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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20. APPENDIX A: LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
area under the serum concentration-time curve 
ß-HCG 
beta-human chorionic gonadotropin 
bid 
twice daily 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
Blood Urea Nitrogen 
Cmax 
maximum observed concentration 
CRF 
case report form 
CRO 
clinical research organization 
E2 
estradiol 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Conference on Harmonization 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IM 
intramuscular 
Inc 
incorporated 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram(s) 
L 
liter(s) 
lb 
pound(s) 
LH 
luteinizing hormone 
LMP 
last menstrual period 
m 
meter 
mg 
milligram(s) 
MD 
medical doctor 
mL 
milliliter(s) 
mm Hg 
millimeters of mercury 
NDA 
New Drug Application 
PD 
pharmacodynamic 
pg 
picogram(s) 
pH 
negative logarithm of the activity of H+  
PK 
pharmacokinetic 


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QA 
quality assurance 
qd 
daily 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
T1/2 
elimination half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
time to maximum concentration 
WBC 
white blood cells 
 


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21. APPENDIX B: TIME AND EVENTS SCHEDULE 
Evaluation/Event 
 
Screening 
Visit a 
Treatment Period (28-Day Dosing Cycle) 
Post-Dosing Period 
Final Study Visit    
(PD Dayd 28)   
(or Early 
Discontinuation Visit)  
Dayb, n 
-1 
Dayb  
1 
Dayb, n 
2 
Dayb  
8 
Dayb 
15 
Dayb 
22 
Dayb,c 
27 
Dayb,c 
28 
PD 
Dayd  
1 
PD 
Dayd  
7 
PD 
Dayd 
14 
PD 
Dayd 
21 
Treatment Groups 
ABCD 
ABC 
ABCD 
ABC 
ABCD 
ABCD 
ABCD 
AB 
AB 
ABCD 
ABCD 
ABCD 
ABCD 
ABCD 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
X 
Xn 
Xo 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic and 
baseline characteristics  
Xe 
Xe,n 
Xe 
Xe,,n 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Physical examination 
X 
 
 
 
 
 
 
 
 
Xf 
 
 
 
Xf 
Gynecological 
examination 
X 
 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
Vital signs 
Xg 
Xg,n 
Xg 
Xg,n 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Evaluations 
(chemistry, hematology) 
X 
 
 
 
 
 
 
 
 
Xf 
 
 
 
X 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pap smear 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (-hCG) 
pregnancy test 
Xi 
Xi,n 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test  
 
 
Xo 
 
 
X 
 
Xf 
 
Xf 
 
 
 
X 
Urine drug screen/ Urine 
cotinine Test 
X 
Xn 
Xo 
 
X 
X 
X 
X 
 
X  
X 
X 
X 
 
Serology tests  
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
Xn 
Xo 
 
X 
X 
X 
X 
 
X  
X 
X 
X 
 
Confinement 
 
Xn 
Xn 
Xn 
 
 
 
Xc 
Xc 
Xc 
 
 
 
 
Drug administration by 
site personnel  
 
 
X k 
 
Xk 
Xk 
Xk 
Xk 
Xk 
 
 
 
 
 
Leuprolide (PK) Blood 
Draws 
 
 
Xl 
Xl,n 
Xl 
Xl 
Xl 
 
Xl 
Xl 
Xl 
Xl 
Xl 
               Xl 
(PD) blood draws (LH, 
FSH, E2,  progesterone)  
Xm 
 
Xm 
 
Xm 
Xm 
Xm 
 
Xm 
Xm 
Xm 
Xm 
Xm 
              Xm 
Review of AEs, 
concomitant meds, diaries 
 
 
X 
X,n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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a Screening visit may take place up to 40 days prior to start of the study drug administration 
b Days relative to the start of the study drug administration   
c Day 27 Confinement is for Ovarest groups (Treatment “A” and Treatment “B”) only  
d PD (Postdosing) days relative to the last day of the study drug administration (the last day of the 
28-day dosing cycle).  PD Day 1 is used interchangeably with Treatment Day 29 throughout the 
text.   
e Demographic information (eg, race, age) will be recorded at Screening Visit only. Height, body 
weight, BMI (Screening Visit), body weight (Treatment Days -1, 1, 2, 8, 15, 22, 27, 28 and 29; 
PD Days 7, 14, 21 and 28 (Final Visit)) or Early Discontinuation Visit. 
f Post-dosing evaluations on Day 29, after the PD blood draws: Physical and gynecological 
examinations, laboratory evaluations (chemistry, hematology), urine pregnancy test (Treatment 
groups “C” and “D”), Urine drug and cotinine Test (Treatments “C” and “D”), alcohol breath 
test (Treatment “C” and “D”). Note: For Treatment Groups “A”, and “B”, urine pregnancy test, 
urine drug and cotinine test, and alcohol breath test are performed on Treatment Day 27. 
g Temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure: Taken in the 
morning (in the Ovarest groups, just prior to oral dosing on Treatment Days 1, 2, 8, 15, 22) 
h Pap smear taken within 12 months prior to the screening will be acceptable if properly 
documented 
i Serum (-hCG) pregnancy test at Screening Visit and on Day - 1. Negative results must be 
obtained prior to randomization and dosing.  
j Serology tests at Screening visit only (include HIV antibody test, hepatitis B and C tests).  
k Day 1 - Treatment “A”, both doses of Treatment  “B”, first dose of Treatment  “D”, and 
Treatment “C”; Days 8, 15 and 22 – Treatment “A” and first dose of Treatments “B” and “D”; 
Day 27 – second dose of Treatments “B”; Day 28 – Treatment “A” and both doses of 
Treatment “B”. 
l PK blood draws: Subjects randomized to the Ovarest doses (Treatments “A”, and  “B”) will 
have twenty-four (24) serial blood samples drawn on Treatment Days 1 and 28 immediately 
prior to dosing (0 time), and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 13, 14, 15, 16, 
17, 18, 20, and 24 hours following oral dosing. For the IM injection (Treatment “C”), serial 
blood samples will also be drawn on Treatment Day 1, prior to dosing (0 time), at 0.5, 1, 2, 6, 
12, 18, and 24 hours post-dosing. Subjects from Treatment group “D will have PK sample 
drawn on Day 1, just prior to the first dosing. Additional blood samples for all subjects will be 
taken in the morning (in the oral groups, just prior to dosing) on Treatment Days 8, 15 and 22, 
and postdosing day 1, as well as during four follow-up visits (PD Days 7, 14, 21, and 28). 
m PD blood draws: Taken at screening and in the morning (in the Ovarest groups, just prior to 
oral dosing) on Treatment Days 1, 8, 15, 22 and 28 (Day 28 - for Treatments “A” and “B” only, 
and in the morning of Postdosing Days 1, 7, 14, 21 and 28.  
n Treatments “A”, “B” and “C” only 
o Treatment “D” only 
 
 
 
 
 
 
 


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22. APPENDIX C: WORLD MEDICAL ASSOCIATION DECLARATION 
OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
And amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, 
Tokyo 2004 
 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as 
a statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the 
people. The physician's knowledge and conscience are dedicated to the 
fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the 
physician with the words, "The health of my patient will be my first 
consideration," and the International Code of Medical Ethics declares that, "A 
physician shall act only in the patient's interest when providing medical care 
which might have the effect of weakening the physical and mental condition 
of the patient.". 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-
being of the human subject should take precedence over the interests of 
science and society. 
6. The primary purpose of medical research involving human subjects is to 
improve prophylactic, diagnostic and therapeutic procedures and the 
understanding of the aetiology and pathogenesis of disease. Even the best 


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proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility 
and quality. 
7. In current medical practice and in medical research, most prophylactic, 
diagnostic and therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all 
human beings and protect their health and rights. Some research populations 
are vulnerable and need special protection. The particular needs of the 
economically and medically disadvantaged must be recognized. Special 
attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for 
whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections 
for human subjects set forth in this Declaration. 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. It is the duty of the physician in medical research to protect the life, health, 
privacy, and dignity of the human subject. 
11. Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and on adequate 
laboratory and, where appropriate, animal experimentation. 
12. Appropriate caution must be exercised in the conduct of research which may 
affect the environment, and the welfare of animals used for research must be 
respected. 
13. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol. This 
protocol should be submitted for consideration, comment, guidance, and 
where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the Investigator, the sponsor or any 
other kind of undue influence. This independent committee should be in 
conformity with the laws and regulations of the country in which the research 
experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to 
the committee, especially any serious adverse events. The researcher should 
also submit to the committee, for review, information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest and 
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14 The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration. 
15. Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically 
competent medical person. The responsibility for the human subject must 
always rest with a medically qualified person and never rest on the subject of 
the research, even though the subject has given consent.  
16. Every medical research project involving human subjects should be preceded 
by careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others. This does not preclude the 
participation of healthy volunteers in medical research. The design of all 
studies should be publicly available. 
17. Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any 
investigation if the risks are found to outweigh the potential benefits or if 
there is conclusive proof of positive and beneficial results. 
18. Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject. This is especially important when the human subjects are healthy 
volunteers. 
19. Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the 
results of the research. 
20. The subjects must be volunteers and informed participants in the research 
project. 
21. The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the 
subject, the confidentiality of the patient's information and to minimize the 
impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
22. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail. The subject 
should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal. After ensuring 
that the subject has understood the information, the physician should then 
obtain the subject's freely-given informed consent, preferably in writing. If the 


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consent cannot be obtained in writing, the non-written consent must be 
formally documented and witnessed. 
23. When obtaining informed consent for the research project the physician 
should be particularly cautious if the subject is in a dependent relationship 
with the physician or may consent under duress. In that case the informed 
consent should be obtained by a well-informed physician who is not engaged 
in the investigation and who is completely independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the Investigator 
must obtain informed consent from the legally authorized representative in 
accordance with applicable law. These groups should not be included in 
research unless the research is necessary to promote the health of the 
population represented and this research cannot instead be performed on 
legally competent persons. 
25. When a subject deemed legally incompetent, such as a minor child, is able to 
give assent to decisions about participation in research, the Investigator must 
obtain that assent in addition to the consent of the legally authorized 
representative. 
26. Research on individuals from whom it is not possible to obtain consent, 
including proxy or advance consent, should be done only if the 
physical/mental condition that prevents obtaining informed consent is a 
necessary characteristic of the research population. The specific reasons for 
involving research subjects with a condition that renders them unable to give 
informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state 
that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate. 
27. Both authors and publishers have ethical obligations. In publication of the 
results of research, the Investigators are obliged to preserve the accuracy of 
the results. Negative as well as positive results should be published or 
otherwise publicly available. Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication. 
Reports of experimentation not in accordance with the principles laid down in 
this Declaration should not be accepted for publication. 
C.  ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE 
28. The physician may combine medical research with medical care, only to the 
extent that the research is justified by its potential prophylactic, diagnostic or 
therapeutic value. When medical research is combined with medical care, 
additional standards apply to protect the patients who are research subjects. 
29. The benefits, risks, burdens and effectiveness of a new method should be 
tested against those of the best current prophylactic, diagnostic and 


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therapeutic methods. This does not exclude the use of placebo, or no 
treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists.1 
30. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best proven prophylactic, diagnostic and therapeutic 
methods identified by the study.2 
31. The physician should fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study must 
never interfere with the patient-physician relationship. 
32. In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with 
informed consent from the patient, must be free to use unproven or new 
prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy. In all cases, new 
information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 
 
 
 
 
                                                 
1 Note: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a 
placebo-controlled trial and that in general this methodology should only be used in the absence of 
existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if 
proven therapy is available, under the following circumstances: 
  - Where for compelling and scientifically sound methodological reasons its use is necessary to 
determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or  
  - Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor 
condition and the patients who receive placebo will not be subject to any additional risk of serious 
or irreversible harm.  
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for 
appropriate ethical and scientific review. 
 
2 Note: Note of clarification on paragraph 30 of the WMA Declaration of Helsinki 
 
The WMA hereby reaffirms its position that it is necessary during the study planning process to 
identify post-trial access by study participants to prophylactic, diagnostic and therapeutic 
procedures identified as beneficial in the study or access to other appropriate care. Post-trial access 
arrangements or other care must be described in the study protocol so the ethical review 
committee may consider such arrangements during its review. 


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23. APPENDIX D: LUPRON DEPOT® 3.75 mg (Full Prescribing Information) 
 
 
 
 


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23. APPENDIX E: CLINICAL LABORATORY TESTS 
CLINICAL CHEMISTRY 
HEMATOLOGY 
The following clinical chemistry tests will 
be performed at the Screening Visit, at 
Postdosing Days 1, and at the Final Visit  
The following hematology tests will be 
performed 
at 
the Screening 
Visit, 
at 
Postdosing Day 1, and at the Final Visit  
Calcium 
Hemoglobin 
Chloride 
Hematocrit 
Creatinine 
RBC count 
Glucose 
WBC count with differential 
Alkaline phosphatase 
Platelet count 
Potassium 
URINALYSIS 
Sodium 
The following urinalysis tests will be 
performed at the Screening Visit and the 
Final Visit  
Aspartate aminotransferase (AST) 
pH 
Alanine aminotransferase (ALT) 
Specific gravity 
Blood urea nitrogen (BUN) 
Glucose 
Phosphorus 
Protein 
Protein total 
RBC 
Albumin 
WBC 
Bilirubin total 
Ketones  
LIPID PANEL 
Bilirubin  
Cholesterol 
Nitrite  
Triglycerides 
Urobilinogen  
LDL 
Microscopic 
examination 
(performed 
on 
abnormal findings unless otherwise specified)  
HDL 
Macroscopic examination  
SEROLOGY 
 
The following serology tests will be 
performed at the Screening Visit  
 
HIV antibody test 
 
HbsAg Hepatitis B test 
 
Hepatitis C (HCV) antibody test 
The following test will be performed at 
Screening Visit and at Treatment Day -1  
The following tests will be performed at 
the Screening Visit, at Treatment Days        
-1*, 8, 15, 22, 27** (Treatments “A”, 
“B”, and “D”), Treatment Day 29 
(Treatments “C” and “D”), and at Post-
Treatment Days 7, 14, 21. 
*Day – 1 for Treatments “A”, “B” and “C”, 
Day 1 for Treatment “D” 
** Day 27 for Treatments “A” and” B”only 
Serum pregnancy (β-hCG) test (Treament 
“A”, “B” and “C”) 
Urine drug screen test  
The following test will be performed at 


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Treatment Days 1* (*Treatment D) 15, 27** 
(**Treatments “A”, and, “B”), Postdosing Day 
1*** 
(***Treatment 
“C” 
and 
“D”) 
and 
Postdosing Day 28 (Final Visit) 
Urine cotinine test 
Urine pregnancy test 


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24. APPENDIX F: SUBJECT DIARY CARD 
 
Subject Number:_______ Subject initials: ______________  
 
PART 1:  28-Day Treatment (Dosing) Period  
 
Date (MM/DD)2 
Treatment Day → 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
Pills Taken1  
Time of first dose 
Fasting rules followed (1st dose) 
Time of second dose 
Fasting rules followed (2nd dose) 
Bleeding Diary 
Check if NO BLEEDING/SPOTTING 
Check if SPOTTING 
Check if LIGHT bleeding 
Check if NORMAL bleeding 
Check if HEAVY bleeding 
 
Principal Investigator or Designee Signature: ____________________________________  Date: ___________________ 
 
1This section is shown for Treatment Groups “B” and “D” subjects; for Treatment Group “A” subjects, remove reference to second 
dose; For Treatment Group “C” subjects, remove entire “Pills Taken” section. 


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Subject Number:_______ Subject initials: ______________  
 
PART 2:  28-Day Post-Dosing Evaluation Period  
 
Date (MM/DD) 
Post-dosing  Day → 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
Bleeding Diary 
Check if NO BLEEDING/SPOTTING 
Check if SPOTTING 
Check if LIGHT bleeding 
Check if NORMAL bleeding 
Check if HEAVY bleeding 
 
Principal Investigator or Designee Signature: _______________________________________  Date: ___________________ 
 
 


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25.  APPENDIX G:  ACCEPTABLE DAYS FOR INITIATION OF DOSING IN RELATION TO CYCLE LENGTH 
 
Cycle Length (days) 
Acceptable days for initiation of dosing 
21 
Day 1 – Day 4 
-or- 
Day 11 to Day 21 
22 
Day 1 – Day 4 
-or- 
Day 12 to Day 22 
23 
Day 1 – Day 4 
-or- 
Day 13 to Day 23 
24 
Day 1 – Day 4 
-or- 
Day 14 to Day 24 
25 
Day 1 – Day 4 
-or- 
Day 15 to Day 25 
26 
Day 1 – Day 4 
-or- 
Day 16 to Day 26 
27 
Day 1 – Day 4 
-or- 
Day 17 to Day 27 
28 
Day 1 – Day 4 
-or- 
Day 18 to Day 28 
29 
Day 1 – Day 4 
-or- 
Day 19 to Day 29 
30 
Day 1 – Day 4 
-or- 
Day 20 to Day 30 
31 
Day 1 – Day 4 
-or- 
Day 21 to Day 31 
32 
Day 1 – Day 4 
-or- 
Day 22 to Day 32 
33 
Day 1 – Day 4 
-or- 
Day 23 to Day 33 
34 
Day 1 – Day 4 
-or- 
Day 24 to Day 34 
35 
Day 1 – Day 4 
-or- 
Day 25 to Day 35 
 
Note: Subjects enrolled to the third oral dose (Treatment “D”) will have a dosing initiation visit scheduled 5-9 days before the 
anticipated start of their next menstrual cycle, based on their self-reported menstrual cycle length and the day the current 
menstrual cycle began. 

SAP_001.pdf: 
Document Approval Date: May 29th, 2018 
Official Title: A randomized, open-label, parallel-group, active-control study to evaluate the 
pharmacokinetic (PK) and pharmacodynamic (PD) profiles of three doses of Leuprolide Oral 
Tablets (Ovarest™) in comparison to an intramuscular dose of leuprolide acetate (Lupron 
Depot® 3.75 mg) in healthy female volunteers 
NCT number: NCT02807363 
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information (PPD) or 
company confidential information (CCI). 
LOPDT-ENDO-01-Leuprolide Oral Tablet vs. Lupron Depot 
Enteris BioPharma Inc.


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
Statistical Analysis Plan 
A RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP, ACTIVE-CONTROL STUDY 
TO EVALUATE THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) 
PROFILES OF THREE DOSES OF LEUPROLIDE ORAL TABLETS (OVAREST™) IN 
COMPARISON TO AN INTRAMUSCULAR DOSE OF LEUPROLIDE ACETATE 
(LUPRON DEPOT® 3.75 MG) IN HEALTHY FEMALE VOLUNTEERS 
Sponsor Protocol No. LOPDT-ENDO-01 
inVentiv Health Clinique Inc. Project No. 160218 
Final Version: 2.0 
Date: 29-MAY-2018 
Contract Research Organization: 
inVentiv Health Clinique Inc. (“inVentiv”), 
A Syneos Health Company 
2500, rue Einstein 
Québec (Québec) 
Canada, G1P 0A2 
Sponsor: 
Enteris BioPharma Inc. 
83 Fulton Street 
Boonton, New Jersey  
07005 
CONFIDENTIAL 


1 
Statisticnl A11alysis Plan 
Entcris BioPhnrmn lnc. 
Project No. 1 60218 (Sponsor Protocol No. LOPDT-ENDO·O 1} 
SIGNATURES 
Sponsor Protocol No.: LOPDT-END0-0 1 
inVentiv Project No.: 160218 
Study Titlc: A Randomized, Open-label, Parallel-group, Active-control Study to Evaluate the 
Pharmacokinetic (PK) and Pharmacodynamie (PD) Profiles ofThrce Doses of Leuprolide Oral 
Tablets (Ovarest"') in Comparison to an Jntramusculnr Dose of Leuprolide Acetate (Lupron 
Depot
00 3.75 mg) in Healthy Fcmalc Volunteers. 
Au thor: 
Senior 
 
 
Statisticinn 
inVcmiv 
Reviewer: 
 
Sponsor's 
Principal Statistician 
inVcntiv 
Rcp resentnt~ve: 
 
Sponsor's 
ChiefOpcrnting Officer 
Enteris Biopharmn lnc. 
Representative: 
 
Biostntistical and Projccl 
Consultant 
29-MA Y -2018 (f'innl 2.0) 
Signature:
  
  
Date: -~ \ - H 1\'1- ';10 1 Y 
s;gnature' 
--­
Dote: v9 MY ,Jo/ K 
1 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 3 of 23 
TABLE OF CONTENTS 
SIGNATURES ....................................................................................................................... 2 
TABLE OF CONTENTS ....................................................................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................ 5 
1.
Introduction ................................................................................................................. 7 
2.
Study Objectives .......................................................................................................... 7 
2.1 
Primary Objectives .................................................................................................. 8 
2.2 
Secondary Objectives .............................................................................................. 8 
3.
Study Design ............................................................................................................... 8 
3.1 
General Design ........................................................................................................ 8 
3.2 
Study Procedures ................................................................................................... 10 
3.3 
Treatment Description ........................................................................................... 10 
3.4 
Subject Withdrawal and Replacement ................................................................... 10 
4.
Changes from the Protocol ........................................................................................ 11 
5.
Primary and Secondary Parameters ........................................................................... 12 
6.
Analysis Populations ................................................................................................. 12 
6.1 
Safety Population ................................................................................................... 12 
6.2 
Pharmacokinetic Populations ................................................................................ 12 
6.3 
Pharmacodynamic Populations .............................................................................. 13 
7.
Interim Analyses ........................................................................................................ 13 
8.
Study Population and Exposure ................................................................................ 13 
8.1 
Subject Disposition ................................................................................................ 14 
8.2 
Protocol Deviations ............................................................................................... 14 
8.3 
Demographics and Baseline Characteristics .......................................................... 14 
8.4 
Medical History ..................................................................................................... 14 
8.5 
Prior and Concomitant Medications ...................................................................... 14 
8.6 
Study Drug Administration ................................................................................... 14 
9.
Safety Analyses ......................................................................................................... 15 
9.1 
Physical Examination Findings ............................................................................. 15 
9.2 
Adverse Events ...................................................................................................... 15 
9.3 
Laboratory Parameters ........................................................................................... 17 
9.4 
Vital Signs and Body Weight ................................................................................ 17 
9.5 
Electrocardiogram.................................................................................................. 18 
10.
Pharmacokinetic Analyses......................................................................................... 18 
10.1 Handling of the BLQ and the No Reportable Concentration Values .................... 18 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 4 of 23 
10.2 Handling of the Difference between the Scheduled and the Actual Sampling 
Times ..................................................................................................................... 19 
10.3 Pharmacokinetic Concentration and Parameters ................................................... 19 
10.4 Statistical Analyses ................................................................................................ 20 
11.
Pharmacodynamics Analyses .................................................................................... 21 
11.1 Pharmacodynamic Concentration and Parameters ................................................ 21 
11.2 Statistical Analyses ................................................................................................ 22 
12.
Datasets Handling ...................................................................................................... 23 
13.
Handling of Missing Data ......................................................................................... 23 
14.
Software to be Used .................................................................................................. 23 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 5 of 23 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
AUC0-24 
Area under the drug concentration versus time curve from 0 hour to 24 hours 
AUC0-t 
Area under the drug concentration versus time curve from 0 hour to t (time of the 
last observed non-zero concentration) 
AUC0-inf 
Area under the drug concentration versus time curve from 0 hour to infinity 
bid 
Twice daily 
BLQ 
Below the lower limit of quantitation 
BMI 
Body mass index 
Cmax 
Maximum concentration level 
Css_oral 
Steady state concentration level calculated for oral tablets  
Css_im 
Steady state concentration level calculated for IM injection  
CSR 
Clinical study report 
Ct 
The last observed non-zero concentration 
CV 
Coefficient of variation (equivalent to C.V.) 
df 
Degree of freedom 
E2 
Estradiol 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
g 
Gram 
ICF 
Informed consent form 
IM 
Intramuscular 
Inc. 
Incorporated 
IV 
Intravenous  
Kel 
The apparent elimination rate constant,  
Kel Lower 
The time point where Kel calculation begins 
Kel Upper 
The sampling time of the last non-zero concentration used to estimate the Kel 
LH 
Luteinizing Hormone 
LMP 
Last menstrual period 
ln 
Natural logarithm  
Max 
Maximum (equivalent to max.) 
MedDRA® Medical Dictionary for Regulatory Activities 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 6 of 23 
mg 
Milligram 
Min 
Minimum (equivalent to min.) 
mL 
Milliliter 
n 
Number of observations 
No. 
Number 
PD 
Pharmacodynamic; Postdosing 
pH 
Negative logarithm of the activity of H+ 
PK 
Pharmacokinetic 
PT 
MedDRA® Preferred Term 
qd 
Once a day 
QRS 
The QRS complex is a structure on the ECG that corresponds to the depolarization 
of the ventricles 
QT 
Time from electrocardiogram Q wave to the end of the T wave corresponding to 
electrical systole 
QTcB 
QT corrected with Bazett formula 
QTcF 
QT corrected with Fridericia formula 
RR 
Duration of ventricular cardiac cycle 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical analysis system 
SD 
Standard deviation 
SOC 
MedDRA® System Organ Class 
SOP 
Standard Operating Procedure 
T1/2 el 
Terminal elimination half-life  
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration level 
vs 
Versus 
WHO DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 7 of 23 
1.
Introduction
This statistical analysis plan (SAP) is intended to give a detailed description of the summaries 
and the analyses that will be generated for the present study by inVentiv. Analyses specified in 
this plan are based on (and/or consistent with) Enteris BioPharma study protocol No. LOPDT-
ENDO-01 Amendment 03 dated February 01, 2018 (inVentiv Project No. 160218). Safety, 
tolerability, pharmacokinetic (PK), and pharmacodynamics (PD) analyses will all be described. 
The plan may be revised due to unforeseen circumstances and any changes or modifications 
made after the plan has been finalized will be documented. If additional or revised analyses are 
required to supplement the planned analyses described in the SAP, the changes and justification 
for the changes will be outlined in the clinical study report (CSR). No changes will be made 
without prior approval of the study sponsor. No formal justifications are required for changes to 
the SAP which do not affect the statistical analysis methods, definitions, or rules defined in this 
document. 
When applicable, all analyses and related processes will be conducted according to inVentiv’s 
Standard Operating Procedures (SOPs). Protocol deviations occurring during the study will be 
listed. 
2.
Study Objectives
The objectives are to determine the safety, PK profile, and PD effects of the three doses of 
Ovarest™ in healthy female volunteers in comparison to a marketed dose of leuprolide acetate 
administered intramuscular (IM) (Lupron Depot® 3.75 mg). Note: For the third Ovarest™ dose 
(Treatment “D”), a complete PK profile will not be evaluated. 
This trial will serve as a bridging PK/PD study between the 4 mg Leuprolide Oral Tablet 
administered over 28 days as daily (qd) or twice daily (bid) regimens and the 10 mg Leuprolide 
Oral Tablet administered over 28 days as a bid regimen and a marketed IM injection of 
leuprolide acetate (Lupron Depot® 3.75 mg) designed for one month of therapy. This trial will 
also be a bridging study to historical PK/PD data for Lupron Depot® 3.75 mg and Lupron Depot® 
11.25 mg (3-month) formulations. 
The most important objective of this study is to provide adequate PD assessments to support 
development of the Leuprolide Oral Tablet with E2 suppression similar to those reported for 
Lupron Depot® and other E2-inhibiting hormonal therapies. Another reason for this trial is to 
describe the PK/PD dose-proportionality of the 4 mg and 10 mg Leuprolide Oral Tablet 
administered as qd and bid regimens. 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
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2.1 
Primary Objectives 
• To determine the safety and to provide comparative evaluation of the PK and PD profiles of
the 4 mg Leuprolide Oral Tablets in healthy, premenopausal female volunteers following qd
and bid administration and the 10 mg Leuprolide Oral Tablets following bid administration in
healthy, premenopausal female volunteers over 28 days vs a marketed formulation of
leuprolide acetate administered IM for one month of therapy.
• To evaluate the PK properties of Leuprolide Oral Tablets after multiple dosing (i.e., 28 days
of dosing)
• To assess the PK/PD dose-proportionality of the Leuprolide Oral Tablets administered as 4
mg qd, 4 mg bid and 10 mg bid dosing regimens
• To evaluate the PK and/or PD properties of the Leuprolide Oral Tablets (eg, E2 suppression
rates) vs other hormonal therapies for the treatment of reproductive disorders, including
endometriosis
2.2 
Secondary Objectives 
• To evaluate safety and tolerability of the long-term administration of leuprolide in healthy
female volunteers.
3.
Study Design
3.1 
General Design 
This study will evaluate the safety, PK profile and PD effects of the three Ovarest™ dosing 
regimens: Leuprolide Oral Tablet, 4 mg, administered qd for 28 consecutive days (Treatment 
“A”), Leuprolide Oral Tablet, 4 mg, administered bid for 28 consecutive days (Treatment “B”), 
and Leuprolide Oral Tablet, 10 mg, administered bid for 28 consecutive days (Treatment “D”), 
in comparison to leuprolide acetate administered IM, Lupron Depot® 3.75 mg (Treatment “C”). 
This study was originally designed as a randomized, open-label, parallel-group active-control 
trial. Up to thirty-two (32) subjects (12 subjects in each Ovarest™ treatment group and 8 subjects 
in the Lupron Depot group) were planned to be randomly assigned to the study drug in a A:B:C 
ratio of 3:3:2. The randomization schedule was to be balanced by using permuted blocks.  
Twenty-three subjects were initially enrolled in this study (9 subjects in each of Ovarest™ 
treatment groups and 5 subjects in the Lupron Depot group). At the time of the current protocol 
Amendment, all initially enrolled subjects had completed the study, except for one subject who 
was withdrawn on post–dose Day 1 (due to vomiting). After interim PK and safety evaluations, it 
was decided not to enroll any new subjects in Treatment Groups “A”, “B” and “C”. Instead, up 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 9 of 23 
to twelve (12) subjects will be enrolled in a new Treatment Group “D” (Leuprolide Oral Tablet, 
Ovarest™, 10 mg, administered twice daily (bid), 12 hours apart for 28 consecutive days). 
Subjects assigned to the third Ovarest™ dose (Treatment “D”) had study drug administered in the 
same fashion as Treatment “B”. Assessments of the PD profile of treatment “D” had to mimic 
evaluations of Treatment “B”. However, unlike other Ovarest™ groups, Treatment “D” does not 
have comprehensive assessments of the PK profile. The subjects that have already participated in 
this study could be invited to receive Treatment “D” if they were eligible per the study inclusion 
and exclusion criteria.  
The study consists of two major periods: approximately one month of dosing (either 28 
consecutive days of daily oral dosing, or a single IM injection on Treatment Day 1) and 
approximately 1 month (28 days) of post-dosing PK/PD evaluations. The total study duration 
from screening to the final study visit will be up to approximately 3.5 months. 
Study design schematic is displayed in Figure 1 below. 
Figure 1 Study Design Schematic 
 
Post-Dosing Assessments: 
- Duration: ≈ 1 Month (28 days) 
- Four Follow-up visits (7, 14, 21, and
28 days after the last dose)
- During each Follow-up visit: 
a) a single PK blood draw 
b) PD (E2, FSH, LH, Progesterone)
blood draws
c) Confirmed onset/absence of
menstrual period.
- Safety Labs (28-day Follow-up visit) 
- Final Study Visit (28-day Follow-up
visit): In addition to evaluations
above, ECG, physical and 
gynecological exams performed
Screening 
Visit  
Treatment Period: 
- Total N=32
- 4-mg Ovarest™ qd (Treatment “A”): N 
=12 
- 4-mg Ovarest™, bid (Treatment “B”): N 
=12
- 10-mg Ovarest™, bid (Treatment “D”): 
N =12
- Lupron Depot (3.75 mg)
Treatment “C”): N =8
- PK blood draws (Days 1-2, 8,
15, 22, 28-29)  Note:  For Treatment
“D”, a complete PK profile (Days 1-2 and
Days 28-29) will not be evaluated.
- PD (E2, FSH, LH, Progesterone)
blood draws (Days 1, 8, 15,  22, 29)


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 10 of 23 
3.2 
Study Procedures 
The overall schedule of procedures and assessments is provided in the protocol. 
3.3 
Treatment Description 
The treatments administered in this study are presented in Table 3-1. 
Table 3-1 Treatment Description 
Treatment 
Description 
A 
Leuprolide Oral Tablet,  Ovarest™ 4 mg, administered qd for 28 consecutive days 
B 
Leuprolide Oral Tablet, Ovarest™ 4 mg, administered bid for 28 consecutive days 
C 
Leuprolide Acetate IM, Lupron Depot® 3.75 mg, administered for one month of 
therapy 
D 
Leuprolide Oral Tablet, Ovarest™ 10 mg, administered bid for 28 consecutive 
days 
Subjects meeting the eligibility criteria were to be initially randomized to receive one of the two 
doses of Ovarest™ for 28 days or a monthly IM dose of Lupron Depot®. After the protocol 
amendment, subjects meeting the eligibility criteria were to be enrolled in Treatment “D” The 
initially randomized subjects had to start dosing (Treatment Day 1) on either days 1-4 or days 
18-28 of their menstrual cycle. Subjects enrolled to the third oral dose (Treatment “D”) had to
start dosing 5-9 days before the anticipated start of their next menstrual cycle, based on their self-
reported menstrual cycle length and the day the current menstrual cycle began.
3.4 
Subject Withdrawal and Replacement 
Every subject has the right to refuse further participation in the study at any time and without 
providing reasons for this decision and without prejudice to further treatment. A subject’s 
participation is to be terminated immediately upon their request.  
The subject may be withdrawn from the study at any time at the discretion of the Investigator. 
Should the subject, during the course of the study, develop conditions that would prevent the 
subject from being dosed as per Investigator’s judgment (e.g., absolute contraindications, 
prohibited concomitant medications) or would be considered as potentially dangerous AEs, they 
must be withdrawn immediately.  
A positive alcohol breath test, urine drug screen, or cotinine test will also be grounds for subject 
withdrawal. If pregnancy occurs or is suspected during study drug treatment, the subject must be 
discontinued immediately. 


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0)
Page 11 of 23 
The termination of an individual’s participation should be considered in case of a serious adverse 
event (SAE) or considerable worsening of the subject’s clinical conditions.  
At the discretion of Enteris BioPharma, the entire study or part of the study may be canceled for 
medical or other reasons. In case of premature termination or suspension of the study or part of 
the study, the Sponsor will promptly inform the Investigator/institutions, regulatory authorities 
and IRBs of the termination or suspension and the reason for the measure. 
In addition, Enteris BioPharma retains the right to end the study at any time if the study cannot 
be carried out as agreed upon in the protocol. 
The reasons for discontinuation include: 
- AE
- Death
- Pregnancy
- Protocol violation
- Lost to follow-up
- Study terminated by Sponsor
- Noncompliance with study drug (to be handled on a case-by-case basis)
- Withdrawal by subject decision (appropriate details must be provided on the CRF)
- Physician decision (appropriate details must be provided on the CRF)
- Other
Subjects discontinued early after having received at least one dose of study drug will not be 
replaced. Study drug assigned to the withdrawn subject may not be given to another subject. 
Data generated from screening failures (subjects not admitted to the study after the screening 
phase and not assigned a randomization number) may be listed according to main reason for not 
being admitted into the treatment phase. 
4.
Changes from the Protocol
Any changes in planned analyses compared to the protocol will be noted in this section. 
Primary statistical analyses of the PD endpoints will utilize measurements for Treatment Day 22 
and Treatment Day 29 (not Treatment Day 28 as noted in the protocol). This change will ensure 
consistent methodology across all treatment groups some of which (Treatments “C” and “D”) did 
not have scheduled PD assessments on Treatment Day 28.   


Statistical Analysis Plan 
Enteris BioPharma Inc. 
Project No. 160218 (Sponsor Protocol No. LOPDT-ENDO-01) 
29-MAY-2018 (Final 2.0) 
 
Page 12 of 23 
Suppression of E2 ≤50 pg/mL, ≤60 pg/mL, and ≤70 pg/mL may also be assessed, if considered 
necessary. 
The determination of the suppression of E2 or other PD endpoints across evaluation intervals was 
clarified. 
An additional analysis for the adverse drug reactions (ADR) (excluding the PT “Menstrual 
Disorder)” was described. 
5.
Primary and Secondary Parameters
Primary Parameters
•
Comparative evaluation of safety and tolerability variables, by treatments (refer to
Section 9).
•
PK parameters as Cmax, Tmax, AUC0-24, AUC0-t, AUC0-inf, Css_oral, Css_im, Kel, Kel Lower,
Kel Upper, and T1/2el for leuprolide (refer to Section 10).
•
PD parameters derived from LH, FSH, E2, and Progesterone levels (refer to Section 11).
Secondary Parameters 
•
Safety and tolerability variables for long-term administration of leuprolide in healthy
female volunteers (refer to Section 9)
6.
Analysis Populations
6.1 
Safety Population 
All subjects who received at least one dose of study medication will be included in the safety 
population. Subjects will be analyzed based on the actual treatment received. 
In addition to the overall safety population, separate safety populations will be identified for the 
two study subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
The subjects in Treatment “D” that have already participated in this study (have received 
Treatments “A”, “B”, or “C”), will be considered in all listings and summaries as completely new 
study participants with subject identifiers for the study (SUBJID) unrelated to their previous  
numbers. Unless otherwise noted, these subjects will not be flagged as previous study participants 
in any statistical summaries and/or individual data listings.   
6.2 
Pharmacokinetic Populations 
6.2.1 
Primary PK Population 
The primary PK population is defined as the group of randomized subjects who completed 28 
days of dosing without major protocol violations and for whom the PK profile can be adequately 
16.1.9 - 16


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characterized. For Treatment “D”, primary PK population is defined as a population of subjects 
who completed 28 days of dosing without major protocol violations.  
6.2.2 
Supportive PK Population 
The supporting PK population is defined as the group of randomized subjects who received at 
least one dose of study medication and provided any PK data. 
Here are some aspects to be considered (but not to be limited to) when determining subject 
eligibility for PK population: inclusion and exclusion criteria, acceptable times for visit dates and 
measurements, compliance with treatment, the nature and quality of the data, withdrawal and any 
protocol deviation. The final responsibility of deciding which subjects are to be included or 
excluded lies with the principal investigator and the sponsor. 
In addition to the overall PK population, separate PK populations will be identified for the two 
study subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
6.3 
Pharmacodynamic Populations 
6.3.1 
Primary PD Population 
The primary PD population is defined as the group of randomized subjects who completed 28 
days of dosing without major protocol violation. 
6.3.2 
Supportive PD Population 
The supporting PD population is defined as the group of randomized subjects who received at 
least one dose of study medication and provided any PD data. 
In addition to the overall PD population, separate PD populations will be identified for the two 
study subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
7.
Interim Analyses
No formal interim analysis was planned. 
However, there was a preliminary evaluation of the PK and PD results for administrative 
purposes. The results of the preliminary evaluations triggered a protocol amendment and an 
introduction of Treatment “D”. See section 3.1 for additional details. 
8.
Study Population and Exposure
Shells for all summary descriptive statistic tables, figures and listings referred to in this section 
are displayed in separate mock shells document. The shells may be revised as they are presented 


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to illustrate the general layout of data to be included in the final report. No inferential analyses 
are planned. No data imputation methods will be utilized i.e. only observed data will be used. 
8.1 
Subject Disposition 
Subject disposition will be summarized by treatment group (frequency and the percentage of 
subjects). The reason for discontinuation will be also listed. 
The subject disposition summaries will be presented for the entire study and separately for the 
two study subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
8.2 
Protocol Deviations 
The protocol deviations will be listed by subject. The protocol deviation criteria have to be 
endorsed by the sponsor prior to the database lock. 
8.3 
Demographics and Baseline Characteristics 
The descriptive statistics (mean, median, standard deviation [SD], minimum [Min], maximum 
[Max], and sample size as n) will be reported for continuous variables (age, body mass index 
[BMI], height, and weight). Frequency counts and percentages will be tabulated for categorical 
variables (age group, gender, ethnicity, and race). Results will be presented by treatment group. 
All demographic and baseline characteristics will be listed by subject. 
8.4 
Medical History 
Medical history records will be listed by subject. The Medical Dictionary for Regulatory 
Activities (MedDRA®) Version 20.1 will be used to classify all medical history findings by 
System Organ Class (SOC) and Preferred Term (PT). 
8.5 
Prior and Concomitant Medications 
The use of concomitant medications will be monitored throughout the study. The World Health 
Organization Drug Dictionary (WHO DD) Version Sep2017, format B will be used to classify all 
medication reported before and during the study. 
The prior and concomitant medication summaries will be presented for the entire study and 
separately for the two study subperiods (a 28-day dosing cycle and a 28-day postdosing 
evaluation period). 
Prior and concomitant medications (with a study subperiod noted) will be listed by subject. 
8.6 
Study Drug Administration 
The study drug administration details (including duration of dosing period, compliance with the 
dosing regimen, etc.) will be summarized by treatment group. The compliance rates will be 


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evaluated for the Ovarest™ groups only as a percentage of days with the protocol-specified 
dosing during the scheduled 28-dosing interval. 
The study drug administration details (including treatment or dose received, date and time of 
administration, number of pills administered daily, and compliance with the fasting 
requirements) will be listed by subject. 
9.
Safety Analyses
Safety data evaluations will be based on adverse events (AEs), laboratory test results, clinical 
signs and symptoms from physical and gynecological examinations, electrocardiogram (ECG) 
and vital signs assessments.  
Safety parameters will be summarized by treatment group for the entire study and separately for 
the two study subperiods (a 28-day dosing cycle and a 28-day postdosing evaluation period). 
Shells for all summary descriptive statistic tables and listing referred to in this section are 
displayed in the document containing the TFL shells; the shells may be revised as they are 
presented to illustrate the general layout of data to be included in the final report. 
9.1 
Physical Examination Findings 
Physical examinations and gynecological examinations will be performed at screening, end of 
dosing period (Post-dosing Day 1) and at the Final Visit and also in case of early discontinuation 
Any abnormal findings judged to be clinically significant prior to first dose will be documented 
as medical history and those after first dose will be captures as an AE (treatment emergent AE; 
[TEAE). Any physical or gynecological examination findings documented as AEs will be 
included in the AE summaries (overall summaries and summaries for study subperiods). 
9.2 
Adverse Events 
Treatment-emergent AEs (TEAEs) and non-TEAEs (those occurring prior to administration of 
study medication or those first occurred prior to study drug administration and did not worsen in 
frequency or severity) will be listed. TEAEs will be defined as AEs that occur on or after the 
date and time of study drug administration, or those that first occur pre-dose but worsen in 
frequency or severity after study drug administration. TEAEs will be captured through the end of 
the entire study including two study sub-periods (a 28-day dosing cycle and a 28-day post-dosing 
evaluation period) or which occur within 30 days following the final examination. In addition, 
TEAEs with a start date and time during a particular study sub-period will be attributed to the 
corresponding subperiod.   
Serious adverse events (SAEs), which occur during this study or within 30 days following the 
final examination, will also be listed separately and described in the study report.  


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The incidence of TEAEs will be summarized for entire study and separately for the two study 
sub-periods (a 28-day dosing cycle and a 28-day post-dosing evaluation period) using the safety 
populations for any particular study subperiods. The MedDRA® dictionary Version 20.1 will be 
used to classify all TEAEs reported during the study by SOC and PT.  
Incidence of subjects who experienced TEAEs will be presented by treatment group, by SOC, 
PT, by investigator-assessed causality (relationship to study drug) and severity. Each subject may 
only contribute once to each of the incidence rates, for a TEAE following a given treatment, 
regardless of the number of occurrences; the highest severity or highest causality will be 
presented, as appropriate. In each summary table, SOC will be presented in descending order of 
overall incidence rate in terms of frequency of subjects and then in frequency of events 
(alphabetical order will be used in case of equal rates). For each SOC, PT will be presented the 
same way. Incidence of TEAEs (number of events) will also be presented by treatment, SOC, 
and PT, by investigator-assessed causality and severity.  
The causality of TEAEs will be classified according to the study protocol as Unrelated, Possibly 
Related, Probably Related, or Definitely Related. The severity of TEAEs will be rated as per the 
protocol as mild, moderate, or severe.  
Adverse drug reactions (ADR) are defined in the ICH Guidance for Industry E2A: clinical safety 
data management: definitions and standards for expedited reporting as follows: “All noxious and 
unintended responses to a medicinal product related to any dose should be considered adverse 
drug reactions (ADR).” An ADR can therefore be any TEAE judged related to the medicinal 
product (causal relationship between a medicinal product and an AE is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out). 
In accordance with the prescribing information for Lupron Depot and other amenorrhea-inducing 
drugs, one category of ADR (represented by the PT “Menstrual Disorder”), may be analyzed as 
both TEAE and a metric of the menstrual bleeding pattern (e.g., a number of bleeding days 
during the dosing interval). 
As an additional ADR analysis, incidence of subjects who experienced ADR will be presented 
by treatment group, by SOC, and PT, excluding the PT “Menstrual Disorder”.  
The incidence of ADRs will be summarized for entire study and separately for the two study sub-
periods (a 28-day dosing cycle and a 28-day post-dosing evaluation period) using the safety 
populations for any particular study subperiods. Each subject may only contribute once to each 
of the incidence rates, for an ADR following a given treatment, regardless of the number of 
occurrences. In summary table, SOC will be presented in descending order of overall incidence 
rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be 
used in case of equal rates). For each SOC, PT will be presented the same way. Incidence of 
ADR (number of events) will also be presented by treatment, SOC, and PT. 


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9.3 
Laboratory Parameters 
Clinical laboratory (hematology and serum chemistry) results will be obtained at screening, end 
of dosing period (Post-dosing Day 1) and at the Final Visit and also in case of early 
discontinuation. Urinalysis results will be obtained only at screening and final visit (or early 
discontinuation).  
Listings of all clinical laboratory results will be provided with the abnormal values flagged with 
"L" for low and "H" for high for continuous parameters, and “A” for abnormal for categorical 
parameters.  
Descriptive statistics (mean, median, SD, Min, Max, and sample size “n”) for each clinical 
laboratory test (continuous variables) will be presented for screening and final visit, and by 
treatment for Post-dosing Day 1 timepoint. Change from screening will also be presented. For 
categorical variable (urinalysis test), the number of subjects (frequency and percentage) will be 
tabulated by results (e.g. negative, positive, trace). A summary table of shifts from screening to 
final visit will be provided. The shift tables will include normal, low, and high values relative to 
the laboratory reference ranges (or normal-abnormal for categorical variables). Results from 
repeat tests will not be included in the summary statistics unless the repeat was required (and 
documented as such) due to technical reasons or an invalid initial result.  
Note: all analyses described above will be performed by treatment group for the entire study and 
separately for the two study subperiods (a 28-day dosing cycle and a 28-day postdosing 
evaluation period). 
In the analyses for the entire study duration, laboratory results from pre-study screening and final 
study visits will be used.  In the analyses for the 28-day dosing cycle, laboratory results from 
pre-study screening and end-of-dosing study visits will be used.  In the analyses for the 28-day 
postdosing evaluation period, laboratory results from end-of-dosing and final study visits will be 
used. 
9.4 
Vital Signs and Body Weight 
Vital signs measurements (temperature, heart rate, respiratory rate, systolic and diastolic blood 
pressure) and body weight will be performed at screening, Days -1, 1, 2, 8, 15, 22, 27, 28 ; PD 
Days 1, 7, 14, 21 and 28 (Final Visit)) or Early Discontinuation Visit. Note: No evaluations on 
Days -1, 2, 27, and 28 will be performed for Treatment “D”. 
A listing of all vital signs and body weight results will be provided. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) will be presented for 
screening and final visit (or early discontinuation visit), and by the associated current treatment 
for other evaluation timepoints, for each vital sign measurement and body weight.  


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Note: all analyses described above will be performed by treatment group for the entire study and 
separately for the two study subperiods (a 28-day dosing cycle and a 28-day postdosing 
evaluation period). 
In the analyses for the entire study duration, vital sign and body weight results from pre-study 
screening and final study visits will be used.  In the analyses for the 28-day dosing cycle, vital 
sign and body weight results from pre-study screening through end-of-dosing study visits will be 
used.  In the analyses for the 28-day postdosing evaluation period, vital sign and body weight 
results from end-of-dosing through final study visits will be used. 
Change from baseline (or change from screening for the final visit) will also be presented. 
Baseline will be defined as the last results (scheduled or unscheduled) obtained prior to first 
study drug administration. Results from post-dose repeat tests will not be included in the 
summary statistics unless the repeat was required (and documented as such) due to technical 
reasons or an invalid initial result. 
9.5 
Electrocardiogram 
Twelve-lead ECGs will be performed at screening and final visit (or early discontinuation). 
A listing of all ECG results will be provided. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size “n”) will be presented for 
each timepoint for each ECG measurement as per data availability. Also, change from screening 
descriptive statistics for final visit will be presented. Results from repeat tests will not be 
included in the summary statistics unless the repeat was required (and documented as such) due 
to technical reasons or an invalid initial result. 
10.
Pharmacokinetic Analyses
Shells for all summary descriptive statistic tables and listings referred to in this section are 
displayed in the document containing the TFL shells; the shells may be revised as they are 
presented to illustrate the general layout of data to be included in the final report. 
The primary statistical analyses of PK data will be conducted on the primary PK population. 
Supportive statistical analyses of PK data will be conducted on the supportive PK population. 
10.1 Handling of the BLQ and the No Reportable Concentration Values 
All concentration values below the lower limit of quantitation (BLQ) and samples with no 
reportable value occurring prior to dosing (on Day 1 only) will be replaced by “0”. For 
tabulation, graphical representation and calculation purposes, all samples with no reportable 
value observed after administration of the first dosing will be set to missing.  


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10.2 Handling of the Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK 
samples will be recorded using the electronic data capture. For all sampling times, the actual 
sampling times will be calculated as the difference between the sample collection actual clock 
time and the actual clock time of dosing. The actual post-dose sampling times expressed in hours 
and rounded off to three decimal digits will be presented, except for pre-dose samples occurring 
prior to dosing, which will always be reported as zero (0.000), regardless of the time difference. 
A listing of the actual times will be provided for PK samples. However, the scheduled sampling 
times will be used for calculation of the PK parameters. In the PK section of the report, 
scheduled sampling times will be presented in concentration tables, mean graphs, and the 
individual graphs.  
10.3 Pharmacokinetic Concentration and Parameters 
A total of 55 PK blood samples will be taken from subjects in the oral groups (Treatments “A” 
and “B”) for the evaluation of the leuprolide serum concentrations at Dosing period Day 1 and 
Day 28  immediately prior to dosing (0 time), and at 0.500, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 
4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 20.0, and 24.0 
hours following oral dosing and also in morning prior to dosing on Days 8, 15, and 22. There 
will be samples taken in Post-dosing Evaluation Period Day 7, 14, 21 and 28. 
A total of 16 PK blood samples will be taken from subjects in the Lupron group (Treatment “C”) 
for the evaluation of the leuprolide serum concentrations at Dosing period Day 1 prior to dosing 
(0 time), at 0.500, 1.00, 2.00, 6.00, 12.0, 18.0, and 24.0 hours post-dosing, Day 8, 15, 22 and 
Post-dosing Evaluation Period Day 1, 7, 14, 21 and 28. 
Subjects enrolled to the third oral dose (Treatment “D”) will have a very few PK samples: just 
prior to the first study drug administration and immediately prior to the first dose of the day on 
Treatment Days 8, 15, 22, and in the morning of Day 29. The PK samples will also be taken in 
Post-dosing Evaluation Period Day 7, 14, 21 and 28. 
PK parameters will be calculated using the scheduled sample collection timepoints. For each 
evaluation period (i.e.: Treatment Days 1 and 28 for the oral groups and day 1 for the Lupron 
Depot group), where applicable, serum concentrations from leuprolide acetate will be used to 
calculate the following parameters by standard non-compartmental methods: Note: these PK 
parameters will be calculated for each treatment period for Treatment groups “A”, “B” and “C 
only.  
AUC0-24 
Area under the drug concentration versus time curve calculated using the linear 
trapezoidal method from 0 hours to 24 hours. In the case where the 24 hours 
concentration value is missing, AUC0-24 will not be calculated. 
AUC0-t 
Area under the drug concentration versus time curve calculated using the linear 


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trapezoidal method from 0 hours to t, where t is the time of the last available 
observation (Ct) 
AUC0-inf 
Area under the drug concentration versus time curve from 0 hours to infinity, 
AUC0-inf = AUC0-t + Ct/Kel 
Cmax 
Maximum concentration level 
Css_oral 
Steady state concentration level calculated for oral tablets at the end of the fourth 
treatment week (Treatment Days 28-29) as the 24-hour AUCs divided by the 
duration of the dosing interval i.e. 24 hours. 
Css_im 
Steady state concentration level calculated for IM injection at the fourth treatment 
week (a mean of leuprolide levels on Days 22 and 29). 
Tmax 
Time to maximum concentration level 
T½ el 
Terminal half-life calculated as ln(2)/ Kel 
Kel
The apparent elimination rate constant, calculated by linear regression of log 
concentration vs time during the elimination phase 
To derive the PK parameters, the serum concentrations below limit of quantification in early 
timepoints will be treated as zero and serum levels below limit of quantification appearing in the 
elimination phase will be omitted from the calculations of Kel. 
Some PK parameters may not be calculated for all or some subjects, at the discretion of the 
inVentiv pharmacokineticist, if the concentration data is not deemed to be amenable to 
evaluation. Explanations for PK parameters that could not be estimated will be provided in the 
CSR report.  
10.4 Statistical Analyses  
Individual and mean concentration versus time curves will be presented using linear and semi-
log scales for leuprolide acetate. Descriptive statistics (mean, standard deviation, coefficient of 
variation, median, minimum value, maximum value and geometric mean) of the serum 
concentrations versus time will be presented. Summaries of the leuprolide concentrations will 
also be reported for each intermediate (within the 28-day dosing interval) and for each follow-up 
(post-dosing period) visit. 
The summaries will be provided for all PK parameters listed above. The most important PK 
endpoint for the oral groups is Css_oral. A related primary endpoint for the Lupron group is Css_im. 
No formal statistical between-treatment comparisons are planned.   
For Treatment “D” leuprolide concentration levels will be summarized for individual sampling 
timepoints. 


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11.
Pharmacodynamics Analyses
Shells for all summary descriptive statistic tables and listings referred to in this section are 
displayed in the document containing the TFL shells; the shells may be revised as they are 
presented to illustrate the general layout of data to be included in the final report. 
The primary statistical analyses of PD data will be conducted on the primary PD population. 
Supportive statistical analyses of PD data will be conducted on the supportive PD population. 
11.1 Pharmacodynamic Concentration and Parameters 
A total of 11 PD blood samples for Treatments “A” and “B” and 10 PD blood samples for 
Treatment “C” will be taken for the determination of LH, FSH, E2, and progesterone levels. 
Serum concentrations of PD endpoints will be measured at screening and in the morning (in the 
Ovarest™ groups, just prior to oral dosing) on Dosing period Treatment Days 1, 8, 15, 22 and 28 
(except for Treatment “C”), and in the morning of Evaluation Period Days 1 (or Day 29), 7, 14, 
21 and 28. 
A total of 10 PD blood samples for Treatment “D” will be taken for the determination of LH, 
FSH, E2, and progesterone levels. Serum concentrations of PD endpoints will be measured at 
screening and in the morning just prior to oral dosing) on Dosing period Treatment Days 1, 8, 15, 
22, and in the morning of Evaluation Period Days 1 (or Day 29), 7, 14, 21 and 28. 
The primary PD metric - suppression of E2 level - will be assessed at each on-treatment (28-day 
dosing) and 28-day post-dosing evaluation timepoint. Treatment dosing Day 22 and Treatment 
dosing Day 29 evaluations (separately and combined) will be considered as most important 
primary evaluations.  
For the purposes of the statistical analyses, PD measurements for Day 29 will be considered as 
the last measurements of the 28-day dosing interval. This Day 29 measurement will NOT be 
included in the post-dosing PD evaluations. The post-dosing PD evaluations will utilize 
measurements collected on post-dosing days 7, 14, 21, and 28.   
Suppression of E2 levels across various evaluation intervals (e.g., Days 22-29 of the dosing 
period, entire 28-day dosing period, and 28-day postdosing period) will be evaluated in two 
ways: 
(1) E2 level is considered suppressed during the evaluation period if a value below pre-
specified threshold was reported at least once during that period. For example, if a
subject had E2 ≤40 pg/mL at Day 29 and E2 > 40 pg/mL at Day 22, she will be
categorized as a subject with a supressed E2 level during the 22-29 Day evaluation
period;
(2) E2 level is considered suppressed during the evaluation period if a value below pre-
specified threshold was reported at each timepoint of that period. For example, if a


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subject had E2 ≤40 pg/mL at Day 29 and E2 > 40 pg/mL at Day 22, she will not be 
categorized as a subject with a supressed E2 level during the 22-29 Day evaluation 
period; To be considered as a subject with a suppressed E2 level during that period, E2 
must be ≤40 pg/mL on both Days 22 and 29. 
The former definition, (1) will be considered as primary. 
Note: For Treatments “A” and “B” additional protocol-specified evaluations will be performed 
for Days 22 and 28 of the dosing period  
Similar approach will be utilized for other PD endpoints (e.g., a suppression of ovulation as 
evidence by progesterone level – see below). 
In addition to a primary E2 suppression threshold (E2 ≤40 pg/mL), a suppression of E2 ≤20 
pg/mL, ≤50 pg/mL, ≤60 pg/mL, and ≤70 pg/mL may also be assessed, if considered necessary. . 
The suppression of ovulation (as evidenced by progesterone levels <3 ng/mL) will be assessed at 
each on-treatment (28-day dosing) and 28-day post-dosing evaluation timepoint. Treatment 
dosing Day 22 and Treatment dosing Day 28 (Day 29 for Treatments “C” and “D”) evaluations 
(separately and combined) will be considered as most important (primary) evaluations. 
11.2 Statistical Analyses  
Individual and mean concentration of hormonal levels versus nominal time curves will be 
presented by treatment group for each evaluation timepoint. Descriptive statistics (sample size 
“n”, mean, standard deviation, coefficient of variation, median, minimum value and maximum 
value) of hormonal levels will be presented for each timepoint. 
Summaries of the LH, FSH, E2, and progesterone levels will be reported for each dosing and 
post-dosing  evaluation timepoint, for the dosing days 22 and 28 (Day 29 for Treatments “C” and 
“D”) (combined: i.e. the maximum among the 2 values) and, optionally, for the entire 28-day 
dosing period and the entire post-dosing Evaluation Period. Changes from pre-dosing baseline in 
LH, FSH, E2 and progesterone levels will also be summarized (sample size “n”, mean, standard 
deviation, median, minimum value and maximum value) at each on-treatment evaluation 
timepoint. Pre-dosing baseline for all PD metrics is the highest value across two observations: (a) 
screening measurement and (b) measurement taken just prior to the first dose of the study drug. 
Similar summaries will be provided for the follow-up visits (postdosing Days 7, 14, 21, and 28). 
In addition, time to return to pre-study baseline hormonal levels could be estimated. 
Summaries of PD metrics may be further stratified by the cycle period (days) of the start of 
dosing. Categorical variables will be summarized by using frequency counts and percentages for 
each treatment by visits involved. In addition, the number of patients with missing values will be 
displayed. 


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Additionally, correlations between leuprolide concentration levels and PD parameters will be 
examined graphically. PD parameters may include LS, FSH, E2 and progesterone levels. These 
evaluations will not be performed for Treatment “D”. 
Number of vaginal (menstrual) bleeding days will be summarized by treatment group for 28 days 
of therapy and for 28 days of post-study follow-up. The subject incidence of the onset of 
menstrual period after completion of therapy will be reported for each treatment group. 
The onset of menstrual period is defined as at least three consecutive bleeding/spotting days 
during the 28-day postdosing period. 
Additional PD analyses could be performed if necessary. 
12.
Datasets Handling
The PK, PD, safety and tolerability data will be received as SAS® datasets from the data 
management facility. It should be noted that, in the datasets, the subjects in Treatment “D” that 
have already participated in this study (have received Treatments “A”, “B”, or “C”) will have the 
same unique subject identifier (USUBJID). However, the link with the different subject identifiers 
for the study (SUBJID) for those who participated more than once in the study will be provided in 
a separate dataset (e.g. suppdm).  
13.
Handling of Missing Data
Only observed data will be used in the data analysis except for concentration values BLQ and 
samples with no reportable value occurring prior to dosing (on Day 1 only) as described in 
section 10.1. No attempt will be made to impute (i.e., extrapolate or interpolate) estimates for 
missing data. 
14.
Software to be Used
Calculation of the PK parameters for Treatments “A”, “B” and “C” will be performed using 
Phoenix WinNonlin® version 6.4, which are validated for bioequivalence/bioavailability studies 
by inVentiv. The descriptive statistical analyses, the safety data tables and listings, PK tables and 
listings, as well as PD tables and listings will be done using SAS®, release 9.2 or a higher 
version. PK and PD figures will be created using R version 3.2.2 (or higher) or SAS®, release 9.2 
or a higher version. The CSR text will be created using Microsoft® Office Word 2010, or a 
higher version.