Clinical trial NCT02817841
Conditions: Contraception
Keywords: Estetrol Drospirenone Prevention of pregnancy Oral contraception
Sponsor: Estetra
Start date: 2016-08-30; Completion date: 2018-11-16
Enrollment: 2148 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objectives of this study are to evaluate the contraceptive efficacy, vaginal bleeding pattern (cycle control), and the general safety and acceptability of the 15 mg estetrol (E4)/3 mg drospirenone (DRSP) combination in healthy women aged 16 to 50 years.

Detailed description:

Arms: arm 1: 15 mg estetrol (E4)/3 mg drospirenone (DRSP) combined oral contraceptive
Interventions: intervention 1: 15 mg E4/3 mg DRSP
Intervention descriptions: intervention 1: 15 mg estetrol and 3 mg drospirenone tablets administered once daily for 13 consecutive cycles following a 24/4-day regimen, i.e. one 15 mg E4/3 mg DRSP active tablet per day for 24 consecutive days followed by one placebo tablet per day for 4 consecutive days.

Protocol documents:
Prot_001.pdf: 
 
 
  
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1 
TITLE PAGE 
Clinical Trial Protocol: MIT-Es0001-C302 
Study Title: 
A Multicenter, Open-label, Single-Arm Study to Evaluate the 
Contraceptive Efficacy and Safety of a Combined Oral 
Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone 
Study Short Title: 
E4 FREEDOM (Female Response concerning Efficacy and safety of 
Estetrol/Drospirenone as Oral contraceptive in a Multicenter study) 
Study Number: 
MIT-Es0001-C302 
ClinicatTrials.gov 
registration No. 
NCT02817841 
IND Number: 
110,682 
Investigational 
Product: 
15 mg Estetrol/3 mg Drospirenone 
Indication: 
Prevention of pregnancy 
Sponsor: 
Estetra SPRL 
Rue Saint Georges 5-7 
4000 Liège 
Belgium 
Telephone: +32 4 349 28 22 
Fax: +32 4 349 28 21 
Safety Monitor: 
PRA Health Sciences  
PRA Pharmacovigilance Department  
Telephone: +1 (800) 772-2215 
Fax: +1 (888) 772-6919 
Email: CHOSafety@prahs.com 
Original Protocol Date: 
07 June 2016 
 
Final Version 1.1 
Amendment 1.0 
 
Date 
14 December 2016 
Amendment 1.1 
 
Date 
10 July 2017 
 
 
Confidentiality Statement 
This document is a confidential communication of the Sponsor.  Acceptance of this document signifies agreement 
by the recipient that no unpublished information contained within will be published or disclosed to a third party 


 
 
  
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without prior written approval, except that this document may be disclosed to an Institutional Review Board or 
Ethics Committee under the same confidentiality conditions.  


 
 
  
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2 
SYNOPSIS 
Sponsor: 
Estetra SPRL 
Investigational Product: 
15 mg Estetrol (E4)/3 mg Drospirenone (DRSP)  
Study Title: 
A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and 
Safety of a Combined Oral Contraceptive (COC) Containing 15 mg E4 and 3 mg DRSP. 
Study Number: 
MIT-Es0001-C302 
Study Phase:  
Phase 3 
Primary Objective – Efficacy:  
To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index in 
subjects aged 16 to 35 years, inclusive, at the time of screening. 
 
Primary efficacy endpoint:   
The number of on-treatment pregnancies as assessed by the Pearl Index in subjects aged 16 
to 35 years, inclusive, at the time of screening.  
Secondary Efficacy Objectives: 
1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method 
failure Pearl Index and  life-table analysis in subjects aged 16 to 35 years, inclusive, 
at the time of screening. 
2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl 
Index, the method failure Pearl Index and life-table analysis in the overall study 
population. 
Secondary efficacy endpoints: 
1. The number of on-treatment pregnancies as assessed by the method failure Pearl 
Index and the cumulative pregnancy rate in subjects aged 16 to 35 years, inclusive, 
at the time of screening. 
2. The number of on-treatment pregnancies as assessed by the Pearl Index, the method 
failure Pearl Index and the cumulative pregnancy rate in the overall study population.  
Other Secondary Objectives: 
1. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg 
DRSP.  
2. To evaluate general safety of 15 mg E4/3 mg DRSP. 


 
 
  
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3. To evaluate the impact of 15 mg E4/3 mg DRSP on physical, psychological, and 
social functioning and well-being. 
4. To assess the effect of various individual characteristics/ covariates (body weight, 
race, smoking, and fed/fasted condition) on the pharmacokinetics (PKs) of 15 mg 
E4/3 mg DRSP (Population PK Substudy). 
Other secondary endpoints: 
1. Cycle control and bleeding patterns based on vaginal bleeding information recorded 
daily by the subjects in the diaries. 
2. Safety data in the overall study population obtained from routine laboratory 
parameters, vital signs, and physical, gynecological and breast examinations, 
evaluated as the number, frequency, type and intensity of adverse events (AEs) and 
serious adverse events (SAEs). 
3. Change from baseline to end of treatment in the different items of well-established 
questionnaires. 
4. Plasma E4 and DRSP concentration data from a subset of approximately 500 subjects 
for the development of a population PK model (Population PK Substudy). 
Study Design: 
Multicenter, open-label, single-arm study. 
Study Population:  
Approximately 2000 healthy female subjects at risk for pregnancy, between 16 and 50 years 
old, inclusive (at the time of screening), and requesting contraception will be enrolled in the 
study and initiate the investigational product. In total 1800 subjects will be 16 to 35 years 
old, inclusive (at the time of screening). Recruitment may be stopped when 2000 subjects 
have initiated the investigational product if the required number of subjects for the primary 
analysis (1800 subjects in the age group up to and including 35 years) has been reached. 
Recruitment in the age group > 35 years will be stopped when 200 subjects have initiated 
the investigational product. Approximately 500 of these subjects will be included in the 
Population PK Substudy. 
Study Locations:  
This clinical study will be conducted in up to approximately 80 centers in North America 
(United States of America and Canada).  
Eligibility criteria: 
 Inclusion criteria: 
A subject will be considered for inclusion in the study if she meets all of the following 
criteria: 
1. Heterosexually active female at risk for pregnancy and requesting contraception. 
2. Negative serum pregnancy test at subject screening. 
3. Aged 16 to 50 years (inclusive) at the time of signing the informed consent (IC). 


 
 
  
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4. Willing to use the investigational product as the primary method of contraception for 
13 consecutive cycles. 
5. Good physical and mental health on the basis of medical, surgical and gynecological 
history, physical examination, gynecological examination, clinical laboratory, and 
vital signs. 
6. Body mass index (BMI) below or equal to (≤) 35.0 kg/m2. 
7. Able to fulfill the requirements of the protocol and have indicated a willingness to 
participate in the study by providing written IC. 
8. Willing and able to complete the diaries and questionnaires. 
 Exclusion Criteria 
A subject will be excluded from participation if she meets any of the following criteria: 
1. For subjects who are not using hormonal contraception at screening, a menstrual 
cycle length shorter than 21 days or longer than 35 days.  
2. Clinically relevant abnormal laboratory result at screening in the opinion of the 
investigator with an understanding of the central laboratory normal range. 
3. Known hypersensitivity to any of the investigational product ingredients. 
4. Currently pregnant or with the intention to become pregnant during the course of the 
study. 
5. Currently breastfeeding or before two spontaneous menstruations have occurred 
after cessation of breastfeeding prior to start of trial medication. 
6. Less than 6 weeks since last delivery/2nd trimester abortion and before spontaneous 
menstruation has occurred following a delivery or 2nd trimester abortion. 
7. Smoking nicotine-containing products if > 35 years old. 
8. Dyslipoproteinemia requiring active treatment with antilipidemic agent.  
9. Diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, 
other) or diabetes mellitus of more than 20 year duration. 
10. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure 
values of: 
a. systolic blood pressure ≥ 140 mmHg and/or,  
b. diastolic blood pressure ≥ 90 mmHg.  
11. Personal history of deep vein thrombosis or pulmonary embolism. 
12. Current prolonged immobilization or major surgery with prolonged immobilization 
planned in the next 12 months. 
13. Known inherited or acquired hypercoagulopathies (e.g. antiphospholipid syndrome) 
or thrombogenic mutations (e.g. factor V Leiden, prothrombin mutation, protein S, 
protein C and antithrombin deficiencies). 
14. Current treatment with anticoagulants. 
15. Presence or history of arterial thromboembolism (e.g. angina pectoris, ischemic heart 
disease, cerebral stroke or transient ischemic attack). 
16. Complicated valvular heart disease (pulmonary hypertension, atrial fibrillation, 
subacute bacterial endocarditis). 


 
 
  
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17. History of pregnancy-related cardiomyopathy or moderately or severely impaired 
cardiac function. 
18. Systemic lupus erythematosus. 
19. Presence or history of migraine with aura at any age or migraine without aura if >35 
years old. 
20. Within the past 6 months, has had undiagnosed (unexplained) abnormal vaginal 
bleeding, or any abnormal bleeding that is expected to recur during the trial (e.g., 
bleeding from cervical polyp, recurrent bleeding after sex). 
21. In case of Chlamydial or gonococcal infection at screening, when no treatment 
initiated at subject enrollment. 
22. Abnormal Pap test (written documentation of prior test or test at screening exam) 
based on the following criteria: 
 Pap test in the past 18 months with ASC-US unless: 
o less than 21 years of age; or 
o a repeat Pap test at least 6 months later was normal; or 
o reflex HPV testing was performed and was negative for high-risk 
oncogene human-papilloma-virus (HPV). 
 Pap test in the past 18 months with LSIL unless less than 21 years of age. 
 Pap test in the past 18 months with ASC-H, atypical glandular cells, HSIL or 
malignant cells. 
23. Presence of an undiagnosed breast mass. 
24. Current symptomatic gallbladder disease. 
25. History of COC-related cholestasis. 
26. Presence or history of severe hepatic disease as long as liver function values have 
not returned to normal. 
27. Presence or history of pancreatitis if associated with hypertriglyceridemia.  
28. Porphyria. 
29. Presence or history of hepatocellular adenoma or malignant liver tumor. 
30. Renal impairment (GFR < 60 mL/min/1.73m²). 
31. Hyperkaliemia or presence of conditions that predispose to hyperkaliemia such as 
renal impairment, hepatic impairment, adrenal insufficiency and women receiving 
daily, long-term treatment for chronic conditions or diseases with medications that 
may increase serum potassium concentration (e.g. ACE inhibitors, angiotensin-II 
receptor antagonists, potassium-sparing diuretics, potassium supplementation, 
heparin, aldosterone antagonist and non-steroidal anti-inflammatory drugs). 
32. History of organ transplantation within 5 years before screening or chronic disease 
potentially necessitating organ transplantation during the anticipated course of the 
study. 
33. Presence or history of hormone-related malignancy. 
34. History of non-hormone-related malignancy within 5 years before screening. 
Subjects with a non-melanoma skin cancer are allowed in the study. 
35. Current regular use or regular use within 1 month prior to subject enrollment of drugs 
potentially triggering interactions with COCs including but not limited to: 


 
 
  
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a. Cytochrome P450 3A4 (CYP 3A4) inducers: barbiturates, primidone, 
bosentan, 
felbamate, 
griseofulvin, 
oxcarbazepine, 
topiramate, 
carbamazepine, phenytoin, rifampicin, St John’s wort. 
b. CYP 3A4 inhibitors: azole antifungals, phenylbutazone, modafinil,  
cimetidine, verapamil, macrolides, diltiazem and grapefruit juice. 
c. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease 
inhibitors and non-nucleoside reverse transcriptase inhibitors. 
36. Use of an injectable hormonal method of contraception within 10 months (300 days) 
prior to screening of an injection with a 3-month duration, within 6 months (180 
days) prior to screening of an injection with a 2-month duration, within 3 months (90 
days) prior to screening of an injection with a 1-month duration. 
37. History of alcohol or drug abuse (including laxatives) within 12 months prior to 
screening. 
38. Any prior procedure, disease or condition that could result in altered absorption, 
excessive accumulation, impaired metabolism, or altered excretion of the 
investigational product. 
39. Uncontrolled thyroid disorders. 
40. Participation in another investigational drug clinical study within 1 month (30 days) 
or have received an investigational drug within the last 3 months (90 days) prior to 
study entry. Subjects who participated in an oral contraceptive clinical study, using 
FDA/EU approved active ingredients, may be enrolled 2 months (60 days) after 
completing the preceding study.  
41. Sponsor, the Contract Research Organization (CRO) or Investigator’s site personnel 
directly affiliated with this study. 
42. Is judged by the Investigator to be unsuitable for any reason. 
Investigational Product; Dose; and Mode of Administration: 
The investigational product is a 15 mg E4/3 mg DRSP tablet administered orally once daily 
in a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets). 
Duration of the study:   
Overall treatment duration is up to thirteen 28-day cycles, i.e., 12 months. 
Those subjects who discontinue due to a pregnancy wish will be followed-up for a maximum 
of one year after study discontinuation for return of spontaneous menstruation and until 
pregnancy or initiation of a contraceptive method (whichever occurs first). 
Statistical Methods: 
For the efficacy analyses, the pregnancy rates will be expressed as: 
- 
Pearl Index (number of pregnancies per 100 woman years due to method and user 
failure) with a two-sided 95% confidence interval (CI); 
- 
Method failure Pearl Index (number of pregnancies per 100 woman years due to 
method failure only) with a two-sided 95% CI; 
- 
Life-table analysis (cumulative pregnancy rate). 


 
 
  
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For Pearl index calculations, thirteen 28-day cycles constitute one woman-year. 
Primary Efficacy Analysis:  
Pearl Index for subjects aged 16 to 35 years, inclusive, at the time of screening. 
 
Secondary Efficacy Analyses: 
 Method failure Pearl Index and life-table analysis for subjects aged 16 to 35 years, 
inclusive, at the time of screening. 
 Pearl Index, method failure Pearl Index and life-table analysis for the overall study 
population (16 to 50 years). 
 
Additional Summaries: 
 Occurrence of scheduled and unscheduled vaginal bleeding/spotting in the overall 
study population. 
 Compliance analysis based on tablet intake in the overall study population. 
 Number, frequency, type and intensity of AEs and SAEs in the overall study 
population. 
 Descriptive summaries for other safety parameters including clinical labs, physical 
exams, gynecological exams, and vital signs. 
 Descriptive summaries of scores of well-being questionnaires. 
 Population PK model (using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects). PK parameters will include, but not be limited to: 
o Apparent clearance (CL/F). 
o Central volume of distribution (V/F). 
o Lag time of Absorption (tlag), if necessary. 
o Relative bioavailability for fed vs fasted state 
o Maximum concentration (Cmax). 
o Time to Cmax (Tmax). 
o Extent of exposure for the dosing interval (AUCtau). 
o Terminal half-life (t1/2). 
Continuous variables will be summarized using descriptive statistics (mean, median, 25th 
percentile, 75th percentile, standard deviation (SD), standard error of the mean (SEM), 
minimum, maximum, and number of subjects) and all categorical variables will be 
summarized using frequency distributions (number and percentage of subjects), as 
appropriate. 
Initial estimates of PK parameters (e.g., CL/F, V/F, tlag) will be determined using 
exploratory compartmental analyses. These estimates will be employed to build an 
appropriate population PK model. The primary parameters will include (but not be limited 
to) CL/F, V/F, tlag and relative bioavailability for fed vs fasted. The impact of individual 
characteristics (body weight, race, smoking, and fed/fasted condition) on the PK parameters 
will be explored and included in the population model if significant. Individual estimates of 


 
 
  
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the parameters and additional PK variables will be generated based on the population model. 
Covariate analyses will be performed separately for the PK of E4 and DRSP. 


 
 
  
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
SYNOPSIS .........................................................................................................................3 
3 
TABLE OF CONTENTS .................................................................................................10 
4 
LIST OF ABBREVIATIONS ..........................................................................................14 
5 
DEFINITION OF THE TERMS ......................................................................................16 
6 
STUDY ADMINISTRATIVE STRUCTURE .................................................................17 
7 
INTRODUCTION ...........................................................................................................19 
7.1 
Background ............................................................................................................19 
7.2 
Prior Clinical Experience .......................................................................................20 
8 
STUDY OBJECTIVES ....................................................................................................22 
8.1 
Primary Objective(s) ..............................................................................................22 
8.2 
Secondary Efficacy Objective(s) ...........................................................................22 
8.3 
Other Secondary Objective(s) ................................................................................22 
9 
INVESTIGATIONAL PLAN ..........................................................................................23 
9.1 
Overall Study Design and Plan ..............................................................................23 
9.2 
Rationale for Study Design ....................................................................................24 
9.3 
Selection of Study Population ................................................................................24 
9.3.1 
Inclusion Criteria .........................................................................................25 
9.3.2 
Exclusion Criteria ........................................................................................25 
9.3.3 
Subject Identification ...................................................................................27 
9.4 
Study Treatment .....................................................................................................28 
9.4.1 
Identity of Investigational Products .............................................................28 
9.4.1.1 
Labeling .............................................................................................28 
9.4.1.2 
Storage and Drug Accountability .......................................................29 
9.4.2 
Method of Assigning Subjects to Treatment ...............................................29 
9.4.3 
Treatment Compliance .................................................................................30 
9.4.4 
Selection of Doses and Timing of Administration in the Study ..................30 
9.4.4.1 
Instructions for starting the first pack of tablets ................................30 
9.4.4.2 
Dosing Instructions ............................................................................31 
9.4.4.3 
Instructions in case of missed tablet(s) or in conditions potentially 
reducing the contraceptive efficacy ...................................................31 
9.4.4.4 
In case of short-term intake of drugs that may decrease the 
efficacy of the COC ...........................................................................33 
9.4.4.5 
Use of the investigational product in case of bleeding/spotting 
episode ...............................................................................................33 


 
 
  
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9.4.4.6 
Use of the investigational product in the event of a missed 
menstrual period.................................................................................33 
9.4.5 
Blinding........................................................................................................33 
9.4.6 
Restrictions ..................................................................................................33 
9.4.6.1 
Prior and Concomitant Therapy .........................................................33 
9.4.6.2 
Condoms and other contraceptive methods .......................................35 
9.4.7 
Treatment beyond the clinical trial ..............................................................35 
9.5 
Study Activities ......................................................................................................35 
9.5.1 
Visit 1: Screening Visit ................................................................................35 
9.5.2 
Visit 2: Subject Enrollment ..........................................................................37 
9.5.3 
Treatment Period (from Cycle 1 Day 1 until Cycle 13 Day 28) ..................38 
9.5.3.1 
Visit 3 (Cycle 2, between Day 1 and Day 14) ...................................38 
9.5.3.2 
Visit 4 (Cycle 4, between Day 1 and 14) ...........................................39 
9.5.3.3 
Visit 5 (Cycle 7, between Day 1 and 14) ...........................................40 
9.5.3.4 
Visit 6 (Cycle 10, between Day 1 and 14) .........................................40 
9.5.3.5 
Visit 7 (Cycle 14, between Day 16 and 23), End of Treatment 
Visit ....................................................................................................41 
9.5.4 
Early Termination Visit ...............................................................................42 
9.5.5 
Unscheduled Visit ........................................................................................43 
9.6 
Study Variables and Procedure Descriptions .........................................................43 
9.6.1 
Subject Diary ...............................................................................................43 
9.6.2 
Efficacy Assessments...................................................................................44 
9.6.2.1 
Pregnancy Testing and Estimating Date of Conception ....................44 
9.6.2.2 
Pregnancy Reporting ..........................................................................45 
9.6.3 
Safety Variables ...........................................................................................46 
9.6.3.1 
Adverse Events ..................................................................................46 
9.6.3.2 
Extent of Exposure .............................................................................51 
9.6.3.3 
Clinical Laboratory Evaluations ........................................................51 
9.6.3.4 
Physical Examination.........................................................................52 
9.6.3.5 
Height, Weight and Body Mass Index ...............................................52 
9.6.3.6 
Gynecological Examination, Chlamydia test, Gonorrhea test and 
Cervical Cytology ..............................................................................52 
9.6.3.7 
Vital Signs ..........................................................................................53 
9.6.4 
Other Evaluations.........................................................................................53 
9.6.4.1 
Incidence of vaginal bleeding/spotting ..............................................54 
9.6.4.2 
Population Pharmacokinetic Substudy ..............................................54 
9.6.4.3 
Compliance ........................................................................................55 


 
 
  
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9.6.4.4 
Demographics ....................................................................................55 
9.6.4.5 
Prior and Concomitant Medication Use .............................................55 
9.6.4.6 
Medical/Surgical History ...................................................................56 
9.6.4.7 
Gynecological History .......................................................................56 
9.6.4.8 
Pregnancy Risk and Back-up Contraception Use ..............................57 
9.6.4.9 
Contraceptive Counseling ..................................................................57 
9.6.4.10 
Acceptability of Trial Medication ......................................................58 
9.6.4.11 
Subjects’ well-being...........................................................................58 
9.6.4.12 
Return of spontaneous menstruation and return to fertility ...............58 
10 ETHICS............................................................................................................................59 
10.1 
Ethics Committee ...................................................................................................59 
10.2 
Ethical Conduct of Study .......................................................................................59 
10.3 
Subject Information and Consent...........................................................................59 
10.4 
Subject Confidentiality ..........................................................................................60 
11 QUALITY CONTROL AND ASSURANCE .................................................................61 
12 PLANNED STATISTICAL METHODS ........................................................................62 
12.1 
Determination of Sample Size ...............................................................................62 
12.2 
Analysis Populations and Datasets ........................................................................62 
12.3 
General Statistical Procedures ...............................................................................63 
12.4 
Efficacy Analyses ..................................................................................................63 
12.4.1 
Efficacy Endpoints .......................................................................................64 
12.4.2 
Statistical Analysis .......................................................................................64 
12.4.2.1 
Confidence Intervals for the Pearl Indices .........................................64 
12.4.2.2 
Life-Table Rates.................................................................................64 
12.4.3 
Statistical Subgroup Analyses......................................................................65 
12.5 
Safety Analyses ......................................................................................................65 
12.5.1 
Adverse Events ............................................................................................65 
12.5.2 
Extent of Exposure .......................................................................................66 
12.5.3 
Clinical Laboratory Evaluations ..................................................................66 
12.5.4 
Physical examination ...................................................................................66 
12.5.5 
Gynecological examination .........................................................................67 
12.5.6 
Vital Signs ....................................................................................................67 
12.5.7 
Height, Weight and BMI..............................................................................67 
12.6 
Other Assessments or Analyses .............................................................................67 
12.6.1 
Bleeding and spotting ..................................................................................67 
12.6.2 
Disposition ...................................................................................................69 


 
 
  
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12.6.3 
Demographic and Other Pre-treatment Characteristics ...............................69 
12.6.4 
Prior and Concomitant Medications ............................................................69 
12.6.5 
Treatment Compliance .................................................................................70 
12.6.6 
Protocol Deviations ......................................................................................70 
12.6.7 
Quality of Life..............................................................................................70 
12.6.8 
Follow-Up Evaluations ................................................................................70 
12.6.9 
Population Pharmacokinetic Substudy ........................................................71 
13 STUDY MANAGEMENT ..............................................................................................72 
13.1 
Monitoring .............................................................................................................72 
13.2 
Protocol amendments .............................................................................................72 
13.3 
Protocol deviations.................................................................................................73 
13.4 
Withdrawal of Subjects ..........................................................................................73 
13.5 
Termination of the Study .......................................................................................74 
14 DOCUMENTATION REQUIREMENTS AND RECORDKEEPING ...........................75 
14.1 
Source Documentation, Data access and Monitoring ............................................75 
14.2 
Data Capture in electronic CRFs and Discrepancy Management ..........................75 
14.3 
RECORD KEEPING .............................................................................................75 
15 OTHER INFORMATION ...............................................................................................77 
15.1 
Financing and Insurance ........................................................................................77 
15.2 
Publication and Disclosure Policy .........................................................................77 
16 REFERENCE LIST .........................................................................................................78 
17 APPENDICES .................................................................................................................79 
 
List of tables 
Table 1: Bleeding and spotting definitions ..................................................................68 
Table 2: Schedule of Events .........................................................................................80 
 
 


 
 
  
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4 
LIST OF ABBREVIATIONS  
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APC 
Active protein C 
ASC-H 
Atypical squamous cells with possible high-grade squamous 
intraepithelial lesion 
ASC-US 
Atypical squamous cells of undetermined significance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CBG 
Corticosteroid binding globulin 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CIN 
Cervical intraepithelial neoplasia 
CIS 
Carcinoma in situ 
COC 
Combined oral contraceptive 
CRO 
Contract research organization 
CYP 3A4 
Cytochrome P450 3A4 
DRSP 
Drospirenone 
E2 
Estradiol 
E2V 
Estradiol valerate 
E4 
Estetrol 
eCRF 
Electronic case report form 
EE 
Ethinylestradiol 
EMA 
European medicines agency 
FDA 
Food and drug administration 
EMR 
Electronic medical records 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GMP 
Good manufacturing practice 


 
 
  
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HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
IC 
Informed consent 
ICH 
International conference on harmonization of technical 
requirements for registration of pharmaceuticals for human use 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LGSIL 
Low-grade squamous intraepithelial lesion 
LH 
Luteinizing hormone 
LNG 
Levonorgestrel 
MedDRA 
Medical dictionary for regulatory activities 
PP 
Per-protocol 
Q-LES-Q-SF 
Quality of life enjoyment and satisfaction questionnaire short 
form 
RP 
Reference period  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
standard deviation 
SEM 
standard error of mean 
SHBG 
Sex hormone binding globulin 
STI 
Sexually transmitted infection 
TEAE 
Treatment emergent adverse event 
t-PA 
Tissue-type plasminogen activator 
VTE 
Venous thromboembolism 
WHO 
World health organization 
 


 
 
  
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5 
DEFINITION OF THE TERMS 
Barrier Contraception 
Birth control methods which physically block or otherwise prevent 
sperm from entering the uterus and reaching the egg for fertilization, 
including spermicides, sponges, condoms, diaphragms, and cervical 
caps. 
Pre-treatment pregnancy 
Pre-treatment pregnancies are pregnancies with an estimated date of 
conception before the first intake of trial medication. 
On-treatment pregnancy 
On-treatment pregnancies are pregnancies with an estimated date of 
conception within the in-treatment period i.e. Day 1 to 7 days after 
the last intake of investigational product (whether active or inactive 
tablet). 
Post-treatment pregnancy 
Post-treatment pregnancies are pregnancies with an estimated date 
of conception after the in-treatment period i.e. more than 7 days after 
the intake of investigational product (whether active or inactive 
tablet). 
Pearl Index 
The Pearl index is defined as the number of pregnancies per 100 
woman-years of exposure: 
𝑃𝑒𝑎𝑟𝑙 𝐼𝑛𝑑𝑒𝑥
=
1300 ×  number of "on −treatment" pregnancies
number of women −28 −day equivalent cycles of treatment 
 
The Pearl Index calculation only takes into account at risk cycles 
defined as cycles during which: 
- 
no other contraceptive methods were used and, 
- 
the subject confirms that she has had intercourse. 
Method failure Pearl Index 
The method failure Pearl Index is calculated using the same method 
used for the Pearl Index, but includes only those pregnancies that 
were classified as method failure and not the pregnancies due to user 
failure, i.e. incorrect intake of the contraceptive method.  
Starters/Switchers 
- Starters: all subjects who have not used hormonal contraceptive(s) 
for 3 months before first investigational treatment intake. 
- Switchers: all subjects who have used a hormonal contraceptive 
during the 3 months before first investigational treatment intake. 
- True new users: all subjects who have never been using hormonal 
contraception. 
Vaginal bleeding 
Evidence of vaginal blood loss that requires the use of sanitary 
protection with a tampon, pad or pantyliner. 
Vaginal spotting 
Evidence of minimal vaginal blood loss that does not require new 
use of sanitary protection, including pantyliners. 
 
 


 
 
  
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6 
STUDY ADMINISTRATIVE STRUCTURE 
The study will be performed in approximately 80 centers in North America with approximately 
90% of subjects in United States of America and 10% of subjects in Canada.   
Estetra SPRL is the Sponsor of this study.   
The Contract Research Organization (CRO) PRA Health Sciences will perform the following 
activities on behalf of the Sponsor for this study: regulatory submissions, project management 
(including site contracts, third party vendor management, etc.), clinical operations, clinical 
monitoring, medical and safety monitoring, data management, analysis and reporting. 
Central facilities will be used for the analysis and storage of laboratory assessments. Details of 
the central facilities and handling of samples will be provided in separate manuals. 
On the approval date of this protocol, the administrative structure and the external 
organizations supporting the study were as follows: 
Sponsor 
Estetra SPRL 
Rue Saint Georges 5-7 
4000 Liège 
Belgium 
Telephone: +32 4 349 28 22 
Fax: +32 4 349 28 21 
 
CRO  
PRA Health Sciences 
4130 ParkLake Avenue, Suite 400 
Raleigh, NC  27612 
USA 
Telephone: +1 (919) 786-8200 
Fax: +1 (919)786-8201 
 
Central Laboratory 
(for both laboratory 
and Population 
pharmacokinetic 
(PK) Substudy 
sample analysis) 
Eurofins Central Laboratory Lancaster 
2430 New Holland Pike 
Lancaster, PA 17601 
USA 
 
PRA Health Sciences - Early Development Services 
Bioanalytical Laboratory 
11070 Strang Line Road 


 
 
  
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Lenexa, KS 66215 
USA 
 
 
 


 
 
  
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7 
INTRODUCTION 
7.1 Background 
Combined oral contraceptives (COCs) are medications taken orally combining a progestin and 
an estrogen. The function of the progestin is to inhibit ovulation by a central feedback 
mechanism resulting in decreased luteinizing hormone (LH) secretion by the pituitary gland.  
The estrogen component also contributes to contraceptive activity by inhibiting the secretion 
of follicle-stimulating hormone (FSH) but its major function is to provide stability to the 
endometrium and consequently to provide acceptable cycle control and bleeding pattern.  
COCs are widely used in the industrialized world.  They have been shown to be highly effective 
in terms of contraception.  
The potent synthetic estrogen, ethinylestradiol (EE), is the most frequently used estrogen in 
COCs. EE is easily absorbed when administered orally. Products containing EE generally have 
a good bleeding profile; however EE is also responsible for most of the side effects experienced 
by COC users. Among those, a rare but potentially very serious event is venous 
thromboembolism (VTE). The increased risk of thromboembolism among COC users is 
principally due to the strong impact of EE on hepatic synthesis functions, which leads to an 
increased production of several proteins involved in the coagulation and inflammatory 
pathways. As a consequence, an imbalance appears between pro- and anticoagulant circulating 
factors in favor to pro-coagulation. Beside the thromboembolism risk, EE is also associated 
with water retention (responsible of breast tension, edema, weight increase, nausea, headache 
and liability of humor) as well as with an increased risk of cholangiopathy.  
To improve the safety profile of COCs, research and development has focused on two main 
approaches. First, the dose of EE has been progressively lowered from > 75 µg to as low as 
10 µg. As EE doses decrease, the incidence of irregular and potentially unacceptable bleeding 
profiles increases. The second approach has been to replace EE with a naturally occurring 
estrogen: new COCs containing estradiol (E2) or estradiol valerate (E2V) have recently been 
developed, with the prospect of decreasing the metabolic impact from the estrogen component 
of COCs.   
Estetra SPRL is developing a new COC containing a synthetic form of natural estrogen, estetrol 
(E4), in association with drospirenone (DRSP), a well-characterized and widely used 
contraceptive progestin. E4 is only produced by the human fetal liver during pregnancy and 
reaches the maternal circulation through the placenta. E4 has been isolated in maternal urine 
as early as week 9 of gestation. At term, the hormone is found at relatively high concentrations 
(about 1 ng/mL) in maternal plasma and over ten times higher in fetal plasma.  
 
 


 
 
  
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7.2 Prior Clinical Experience 
Estetrol  
In two Phase 1 clinical studies (PR3050 and PR3054) performed in healthy postmenopausal 
women, E4 was associated with a good safety and tolerability profile when it was taken orally 
as a single dose up to 100 mg and as daily multiple doses up to 40 mg during 28 consecutive 
days. Oral intake of multiple rising doses of E4 demonstrated an anti-gonadotropic activity 
characterized by a dose-dependent decrease in both FSH and LH levels. This study also 
documented a significant increase in endometrial thickness in accordance with E4’s estrogenic 
actions.  
Estetrol/Drospirenone 
The safety and efficacy of E4 in combination with DRSP were studied in healthy 
premenopausal women enrolled in two Phase 2 clinical studies called ES-C01 and ES-C02. 
Data from ES-C01 showed that 5 or 10 mg E4 combined with 3 mg DRSP administered in a 
24/4-day regimen for three treatment cycles exert a complete inhibition of ovulation.1 Ovarian 
activity decreases with increasing dose of E4. In addition, very limited to no impact on hepatic 
metabolism was observed with the E4/DRSP combinations as demonstrated by measurement 
before and after three treatment cycles of triglycerides2 and surrogate markers of hemostasis 
such as D-dimer, Prothrombin fragment 1+2, inhibitors of coagulation (Active Protein C 
[APC] sensitivity, antithrombin III, APC resistance, protein S activity), liver factors 
(fibrinogen and prothrombin), endothelial factors (E-selectin and tissue-type plasminogen 
activator [tPA]) and carrier proteins (corticosteroid binding globulin [CBG], sex hormone 
binding globulin [SHBG] and ceruloplasmin).2 Decrease from baseline in the carrier proteins 
was noted after one cycle of treatment. These findings suggest limited impact of the E4/DRSP 
combination on the coagulation pathway.  
The combination of 3 mg DRSP with either 15 mg E4 or 20 mg E4 administered in a 24/4-day 
regimen was evaluated in the ES-C02 study, a six-cycle treatment study focusing on vaginal 
bleeding pattern and cycle control. A high rate of expected withdrawal bleeding (96.5%) and 
a low incidence of unscheduled bleeding/spotting episodes (16.9%) were observed with the 
15 mg E4/3 mg DRSP combination. In addition, the E4/DRSP combinations demonstrated a 
good safety and tolerability profile. A low frequency of adverse events (AEs) with the 15 mg 
E4/3 mg DRSP combination was recorded and all AEs were similar to those classically 
observed with COCs. Finally, no ovulations were observed during this study demonstrating 
the potential for high contraceptive reliability of the E4/DRSP combinations studied. 
From the different studies performed thus far with E4, it can be concluded that an E4-
containing COC is well tolerated. No safety concern was observed with any E4 combination. 
However, until further evaluation in larger populations, the classical COC contraindications 
will apply to the 15 mg E4/3 mg DRSP combination. 


 
 
  
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Based on the results obtained from the Phase 2 studies, the regimen of 15 mg E4 combined 
with 3 mg DRSP was selected as the optimal combination (minimum effective dose) for the 
Phase 3 program. 
 


 
 
  
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8 
STUDY OBJECTIVES 
8.1 
Primary Objective(s) 
The primary objective of this study is to evaluate the contraceptive efficacy of 15 mg E4/3 mg 
DRSP using the Pearl Index in subjects aged 16 to 35 years, inclusive, at the time of screening. 
8.2 
Secondary Efficacy Objective(s) 
The secondary objectives of this study are: 
1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method 
failure Pearl Index and life-table analysis in subjects aged 16 to 35 years, inclusive, at 
the time of screening. 
2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index, 
the method failure Pearl Index and life-table analysis in the overall study population. 
8.3 
Other Secondary Objective(s) 
1. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg DRSP. 
2. To evaluate general safety of 15 mg E4/3 mg DRSP.  
3. To evaluate the impact of 15 mg E4/3 mg DRSP on physical, psychological, and social 
functioning and well-being. 
4. To assess the effect of various individual characteristics/ covariates (body weight, race, 
smoking, and fed/fasted condition) on the PKs of 15 mg E4/3 mg DRSP (Population 
PK Substudy). 
 
 


 
 
  
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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study is a multicenter, open-label, single-arm study. 
The total duration of the study, including the screening, will range from 387 to 467 days for 
the participating subjects, which is approximately a year and one month. Those subjects who 
discontinue due to a pregnancy wish will be followed-up for a maximum of one year after 
study discontinuation for return of spontaneous menstruation and until pregnancy or initiation 
of a contraceptive method (whichever occurs first).  
Approximately 2000 healthy female subjects at risk for pregnancy, between 16 and 50 years 
old (inclusive, at the time of screening), and requesting contraception will be enrolled in the 
study and initiate the investigational product. In total, 1800 subjects will be 16 to 35 years old 
(inclusive). Recruitment may be stopped when 2000 subjects have initiated the investigational 
product if the required number of subjects for the primary analysis (1800 subjects in the age 
group up to 35 years) has been reached. Recruitment in the age group > 35 years will be stopped 
when 200 subjects have initiated the investigational product. 
Eligible subjects will be treated with 15 mg E4/3 mg DRSP for up to 13 consecutive cycles. 
The treatment must be taken once daily at approximately the same time of the day in a 24/4-
day regimen, i.e. 24 active tablets followed by 4 placebo tablets (4-day hormone free interval). 
The primary objective of the study is to evaluate the contraceptive efficacy of the new COC, 
using the Pearl Index calculation (which reflects the pregnancy rate associated with a 
contraceptive method) among the subjects aged 16 to 35 years inclusive.  
The contraceptive efficacy will also be evaluated using the method failure Pearl Index (which 
reflects the pregnancy rate due to method failure only) and life-table analysis in the subjects 
aged 16 to 35 years inclusive and in the overall study population. 
The general safety will be evaluated by the determination of routine laboratory parameters, 
vital signs, by performing physical, gynecological and breast examinations and by recording 
number, frequency, type and intensity of AEs and serious adverse events (SAEs).  
Participating subjects will be asked to record daily in a subject diary their bleeding/spotting 
episodes. This will allow evaluating the bleeding pattern and the cycle control associated with 
the investigational product. 
Treatment compliance will be assessed using data from the subject diary across the entire study 
and by cycle. The subject diary will also be used to determine whether or not a cycle is at risk 
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Physical, psychological and social functioning and well-being associated with the 
investigational product will be assessed with well-established questionnaires. A study schedule 
of events is provided in Appendix 1. Details and descriptions of study procedures are contained 
in the following sections. 
Population PK will be assessed using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects to address the relationship between E4 and DRSP PK 
parameters and various individual characteristics (e.g., body weight, race, smoking, and 
fed/fasted condition). Blood samples for PK analysis will be obtained at Visits 3 and 4 between 
Days 10 and 14 of Cycles 2 and 4 (see Section 9.6.4.2). 
 
9.2 
Rationale for Study Design 
The design of this study is in line with the final minutes of the Advisory Committee for 
Reproductive Health Drugs meeting (FDA)3 held on January 23 and 24, 2007, the 
recommendations made by Kapp et al.4 and the requirements of the European Medicines 
Agency (EMA) and the EMEA/CPMP/EWP/519/98 Rev 1 Guideline on Clinical Investigation 
of Steroid Contraceptives in Women5 which states that: 
- 
Studies including an active comparator are not generally requested for efficacy 
purposes; 
- 
The duration of efficacy studies should be six months to one year or more;  
- 
For any new contraceptive, at least 400 women should have completed one year of 
treatment. 
This study is a multicenter, open-label, single-arm study which will allow quantification of the 
efficacy of the investigational product by calculating the pregnancy rate. The size of the study 
is also adequate to allow an assessment of the general safety and bleeding profile associated 
with the investigational product. 
The study design was discussed with FDA during end of phase 2 meeting as well as EMA 
during scientific advice (EMA/CHMP/SAWP/629721/2012). 
9.3 
Selection of Study Population 
This study will include healthy female subjects at risk for pregnancy, between 16 and 50 years 
old (inclusive) at the time of screening, and expressing the need for and desire to use 
contraception for at least 13 consecutive cycles.  
The following eligibility criteria will be checked at Visit 1 and Visit 2 (see Sections 9.5.1 and 
9.5.2). 
 


 
 
  
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9.3.1 
Inclusion Criteria 
A subject will be considered for inclusion in the study if she meets all of the following criteria: 
1. Heterosexually active female at risk for pregnancy and requesting contraception. 
2. Negative serum pregnancy test at subject screening. 
3. Aged 16 to 50 years (inclusive) at the time of signing the informed consent (IC). 
4. Willing to use the investigational product as the primary method of contraception for 
13 consecutive cycles. 
5. Good physical and mental health on the basis of medical, surgical and gynecological 
history, physical examination, gynecological examination, clinical laboratory, and vital 
signs. 
6. Body mass index (BMI) below or equal to (≤) 35.0 kg/m2. 
7. Able to fulfill the requirements of the protocol and have indicated a willingness to 
participate in the study by providing written IC. 
8. Willing and able to complete the diaries and questionnaires. 
 
9.3.2 
Exclusion Criteria 
A subject will be excluded from participation if she meets any of the following criteria: 
1. For subjects who are not using hormonal contraception at screening, a menstrual cycle 
length shorter than 21 days or longer than 35 days.  
2. Clinically relevant abnormal laboratory result at screening in the opinion of the 
investigator with an understanding of the central laboratory normal range.  
3. Known hypersensitivity to any of the investigational product ingredients. 
4. Currently pregnant or with the intention to become pregnant during the course of the 
study. 
5. Currently breastfeeding or before two spontaneous menstruations have occurred after 
cessation of breastfeeding prior to start of trial medication. 
6. Less than 6 weeks since last delivery/2nd trimester of abortion and before spontaneous 
menstruation has occurred following a delivery or 2nd trimester of abortion. 
7. Smoking nicotine-containing products if ≥ 35 years old. 
8. Dyslipoproteinemia requiring active treatment with antilipidemic agent.  
9. Diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, 
other) or diabetes mellitus of more than 20-year duration. 
10. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure 
values of: 
a. systolic blood pressure ≥ 140 mmHg and/or,  
b. diastolic blood pressure ≥ 90 mmHg . 
11. Personal history of deep vein thrombosis or pulmonary embolism. 
12. Current prolonged immobilization or major surgery with prolonged immobilization 
planned in the next 12 months. 


 
 
  
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13. Known inherited or acquired hypercoagulopathies (e.g. antiphospholipid syndrome) or 
thrombogenic mutations (e.g. factor V Leiden, prothrombin mutation, protein S, 
protein C, and antithrombin deficiencies). 
14. Current treatment with anticoagulants. 
15. Presence or history of arterial thromboembolism (e.g. angina pectoris, ischemic heart 
disease, cerebral stroke or transient ischemic attack). 
16. Complicated valvular heart disease (pulmonary hypertension, atrial fibrillation, 
subacute bacterial endocarditis). 
17. History of pregnancy-related cardiomyopathy or moderately or severely impaired 
cardiac function. 
18. Systemic lupus erythematosus. 
19. Presence or history of migraine with aura at any age or migraine without aura if  35 
years old.  
20. Within the past 6 months, has had undiagnosed (unexplained) abnormal vaginal 
bleeding, or any abnormal bleeding that is expected to recur during the trial (e.g., 
bleeding from cervical polyp, recurrent bleeding after sex). 
21. In case of Chlamydial or gonococcal infection at screening, when no treatment initiated 
at subject enrollment. 
22. Abnormal Pap test (written documentation of prior test or test at screening exam) based 
on the following criteria: 
 Pap test in the past 18 months with ASC-US unless: 
o less than 21 years of age; or 
o a repeat Pap test at least 6 months later was normal; or 
o reflex HPV testing was performed and was negative for high-risk oncogene 
human-papilloma-virus (HPV). 
 Pap test in the past 18 months with LSIL unless less than 21 years of age. 
 Pap test in the past 18 months with ASC-H, atypical glandular cells, HSIL or 
malignant cells. 
23. Presence of an undiagnosed breast mass. 
24. Current symptomatic gallbladder disease. 
25. History of COC-related cholestasis. 
26. Presence or history of severe hepatic disease as long as liver function values have not 
returned to normal. 
27. Presence or history of pancreatitis if associated with hypertriglyceridemia.  
28. Porphyria. 
29. Presence or history of hepatocellular adenoma or malignant liver tumors. 
30. Renal impairment (GFR < 60 mL/min/1.73m²). 
31. Hyperkaliemia or presence of conditions that predispose to hyperkaliemia such as renal 
impairment, hepatic impairment, adrenal insufficiency and women receiving daily, 
long-term treatment for chronic conditions or diseases with medications that may 
increase serum potassium concentration (e.g. ACE inhibitors, angiotensin-II receptor 
antagonists, potassium-sparing diuretics, potassium supplementation, heparin, 
aldosterone antagonist and non-steroidal anti-inflammatory drugs). 


 
 
  
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32. History of organ transplantation within 5 years before screening or chronic disease 
potentially necessitating organ transplantation during the anticipated course of the 
study. 
33. Presence or history of hormone-related malignancy. 
34. History of non-hormone-related malignancy within 5 years before screening. Subjects 
with a non-melanoma skin cancer are allowed in the study. 
35. Current regular use or regular use within 1 month prior to subject enrollment of drugs 
potentially triggering interactions with COCs including but not limited to: 
o Cytochrome P450 3A4 (CYP 3A4) inducers: barbiturates, primidone, bosentan, 
felbamate, griseofulvin, oxcarbazepine, topiramate, carbamazepine, phenytoin, 
rifampicin, St John’s wort. 
o CYP 3A4 inhibitors: azole antifungals, phenylbutazone, modafinil,   cimetidine, 
verapamil, macrolides, diltiazem and grapefruit juice. 
o Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease 
inhibitors and non-nucleoside reverse transcriptase inhibitors. 
36. Use of an injectable hormonal method of contraception within 10 months (300 days) 
prior to screening of an injection with a 3-month duration, within 6 months (180 days) 
prior to screening of an injection with a 2-month duration, within 3 months (90 days) 
prior to screening of an injection with a 1-month duration. 
37. History of alcohol or drug abuse (including laxatives) within 12 months prior to 
screening. 
38. Any prior procedure, disease or condition that could result in altered absorption, 
excessive accumulation, impaired metabolism, or altered excretion of the 
investigational product. 
39. Uncontrolled thyroid disorders. 
40. Participation in another investigational drug clinical study within 1 month (30 days) or 
have received an investigational drug within the last 3 months (90 days) prior to study 
entry. Subjects who participated in an oral contraceptive clinical study, using FDA/EU 
approved active ingredients, may be enrolled 2 months (60 days) after completing the 
preceding study.  
41. Sponsor, CRO or Investigator’s site personnel directly affiliated with this study. 
42. Is judged by the Investigator to be unsuitable for any reason. 
 
9.3.3 
Subject Identification 
Subject study identification numbers will be assigned at the Screening Visit. Subject numbers 
will be consecutive at each study site beginning with 001. Site numbering will begin at the 
number 201. Subject identification will consist of the site number (3 digits) followed by the 
subject number (3 digits), e.g., the first subject at Site 201 would be 201001 and the fifth 
subject at Site 235 would be 235005. Subject numbers will be consecutive at each study site 
beginning with 001. Subject identification numbers will be used throughout the trial. 


 
 
  
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9.4 
Study Treatment 
9.4.1 
Identity of Investigational Products 
The investigational products are manufactured by Haupt Pharma, Munster, Germany, in 
accordance with applicable current Good Manufacturing Practice (GMP). 
The following investigational products will be administered: 
Dosage form description 24 pink tablets containing 15 mg E4/3 mg DRSP  
4 white placebo tablets  
Package description 
Blister pack (PVC/Aluminum) containing 28 tablets (24 pink 
and 4 white tablets) 
Dose per time unit  
1 tablet daily 
Dispensing 
Dispense the blister as follows per subject: 
- 4 blisters on Visit 2 and then 3 blisters on Visits 4 (Cycle 4), 5 
(Cycle 7) and 6 (Cycle 10). 
- 1 spare blister on Visit 2 and, if necessary, on Visit 4, 5 and/or 
6. 
 
9.4.1.1 
Labeling 
The investigational product will be labeled according to regulations and local requirements 
and will contain at minimum the following information: 
 Drug name or number/code 
 Protocol number 
 Blister content (24 pink tablets containing 15 mg E4/3 mg DRSP and 4 white 
placebo tablets) 
 Lot number 
 Expiry date 
 For oral administration 
 Storage conditions 
 Caution: New Drug – Limited by Federal (or United States) law to investigational 
use. 
 Treatment number 
 Manufacturer’s name and address 
 Keep out of reach of children 
 


 
 
  
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9.4.1.2 
Storage and Drug Accountability 
The Investigator will be responsible for the suitable storage of the investigational product in 
compliance with the storage instructions and must restrict access to the study personnel only. 
Under no circumstances will the Investigator allow the investigational products to be used 
other than as directed by this protocol.  The investigational product must be protected from 
unauthorized access (e.g. in a locked storage facility). Appropriate storage conditions at the 
site must be ensured either by controlled room temperature or by completion of a temperature 
log in accordance with local requirements and storage instructions on a regular basis, showing 
minimum and maximum temperatures reached over the time interval.  The Principal 
Investigator will have overall responsibility for the use of the investigational product at the 
site. The Principal Investigator or Designee will confirm receipt of the investigational product 
and will verify the contents of the shipment, using an interactive web response system (IWRS) 
upon receipt of the product. The Investigator or Designee shall maintain accurate 
investigational product inventory records, including the quantities and date of receipt of 
supplies from the Sponsor, and the quantities and dates of dispensing to each study subject. 
Shipping and handling of all investigational products will be conform to ICH-GCP guidelines, 
GMP and Local regulatory guidelines.    
At Visits 3, 4, 5, and 6, the Investigator should collect the investigational product (unused and 
empty) including spare blister if used (even if partially used) of the completed treatment cycles 
for drug accountability. Unused spare blister will be left for the subject. Used spare blisters 
will be replaced by a new spare blister. At Visit 7, the Investigator should collect all unused 
investigational product including spare blister (used or not), empty blisters for final drug 
accountability. 
At completion of the study, to satisfy regulatory requirements regarding drug accountability, 
all investigational products will be stored, inventoried, reconciled, and destroyed or returned 
to the Sponsor according to applicable regulations.  A written explanation must be provided 
for any discrepancies. The study monitor must review all records of drug accountability prior 
to the return or destruction of any supplies. 
This drug accountability log must be available for inspection during an audit (e.g., by Sponsor 
or a regulatory agency).  At the conclusion of the study, the Investigator must provide a copy 
of this record to the Sponsor. 
9.4.2 
Method of Assigning Subjects to Treatment 
This is a 1-treatment arm open-label study.  The subject will undergo screening where 
pretreatment clinical evaluations and specific procedures will be completed at the Screening 
Visit. Authorized site personnel will acknowledge that the subject met all of the specified 
inclusion criteria and none of the exclusion criteria before subject enrolment. 
At enrollment visit, after IWRS contact, investigational product packs labeled with study 
information will be assigned to the subject. 


 
 
  
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9.4.3 
Treatment Compliance 
Treatment compliance for the investigational product will be assessed based on the response 
values entered by the subject in the diary on a daily basis (see Section 9.6.1). A comparison 
will be made between the number of tablets expected to be used, based on the total number of 
treatment days, and the number of tablets taken according to the subject’s diary.  
In addition, the data will be used to identify when a pill has been missed.  
At each visit, the diary entries will be compared to the returned tablets to ensure consistency 
but the diary data will be used for compliance assessment. In case of discrepancy between the 
diary data and the returned tablets, the investigator will discuss with the subject and document 
this in the source data.  
9.4.4 
Selection of Doses and Timing of Administration in the Study 
The daily dose used in this study, i.e. 15 mg E4 and 3 mg DRSP, has been selected on the basis 
of the data generated during the Phase 2 program. It was associated with a high inhibition of 
ovarian function, no ovulation, a good safety profile, and the most favorable bleeding 
pattern/cycle control observed among the different E4 combinations that were evaluated (see 
Section 7.2). 
The investigational product is administered once daily following a 24/4-day regimen, i.e. one 
15 mg E4/3 mg DRSP active tablet per day for 24 consecutive days followed by one placebo 
tablet per day for 4 consecutive days.  
This 28-day cyclic regimen must be taken for up to 13 consecutive cycles. The treatment must 
be taken once daily at approximately the same time of the day. 
9.4.4.1 
Instructions for starting the first pack of tablets 
 Women who did not use any contraceptive method or who used a barrier 
contraceptive method will be instructed to begin the investigational product on the 
first day of the next menstrual bleeding. Starting on Days 2-5 is also allowed, but a 
condom must be used until the subject has completed 7 days of uninterrupted active 
tablet intake. If the menstrual cycle prior to start of first pack of tablets is shorter 
than 21 days or longer than 35 days, the subject should not start the investigational 
product and will be withdrawn from the study (section 13.4). The subject should 
contact the study staff as soon as possible to schedule an Early Termination Visit 
(section 9.5.4) and to discuss an alternative contraception to use (section 9.6.4.9).                          
 Women switching from another COC or progestin-only pill will start the 
investigational product at the time when the next pill pack of the previous pill would 
have been due. 
 Women switching from a hormonal vaginal ring or transdermal patch will start the 
investigational product when the next application would have been due. 


 
 
  
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 Women switching from an injectable hormonal method of contraception will start 
the investigational product on the first day of spontaneous menstrual bleeding 
following an interval after the last injection, which can vary depending of the form:  
 10 months after the injection of a product with a 3-month duration; 
 6 months after the injection of a product with a 2-month duration; 
 3 months after the injection of a product with a 1-month duration.  
Starting on Days 2-5 is also allowed, but a condom must be used until the subject 
has completed 7 days of uninterrupted active tablet intake.   
 Women switching from an intrauterine or dermally implantable contraceptive will 
start the investigational product on the day of removal. A condom must be used 
until the subject has completed 7 days of uninterrupted active tablet intake. 
The first day of the first pink tablet intake after enrollment is Day 1.  The subject places one 
of the 7 self-adhesive day label strips that corresponds to her Day 1 starting day onto the card 
of the blister to indicate the day she started. The study staff will show the subject how to fix 
the first label.  
She then starts taking one tablet daily, at approximately the same time of the day, beginning 
with the first pink tablet in the top row.  The subject completes her 28-tablet regimen when she 
has taken the last tablet in the blister pack.   
9.4.4.2 
Dosing Instructions 
Each time investigational product is dispensed to the subject, site personnel will instruct the 
subject as follows:  
 Take one pink tablet every day for 24 consecutive days (Day 1 through Day 24), 
followed by one white placebo tablet every day for 4 consecutive days (Day 25 
through Day 28). 
 When the pack of tablets is empty, start the next pack on the next day after the last 
white tablet of the previous pack has been taken. When starting a new pack of 
tablets, take the first pink tablet of the pack. There should be no interruption 
between two blister packs. 
 Take the investigational product at approximately the same time each day 
throughout the study.  The time of day should be determined by the subject.  
 Return all blister packs to site personnel at the following visit. 
 
9.4.4.3 
Instructions in case of missed tablet(s) or in conditions potentially 
reducing the contraceptive efficacy 
If the subject has vomiting or diarrhea within 4 hours of tablet intake, she should take 
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If the subject inadvertently misses one or more of the tablets, the following instructions 
must be followed6:   
 If one active pink tablet is late (< 24 hours since a tablet should have been 
taken) or if one active pink tablet has been missed (24 to < 48 hours since a 
tablet should have been taken):  
o Take the late or missed active pink tablet as soon as possible. 
o Continue taking the remaining active pink tablets at the usual time 
(even if it means taking two active pink tablets on the same day). 
o Use of condom is not required. 
 If two or more consecutive active pink tablets have been missed (≥ 48 hours 
since a tablet should have been taken): 
o If between Day 1 & Day 17: 
 Take the most recent missed active pink tablet as soon as 
possible (any other missed tablets should be discarded). 
 Continue taking the remaining active pink tablets at the usual 
time (even if it means taking two tablets on the same day). 
 Use condom or avoid sexual intercourse until 7 days of 
uninterrupted active pink tablet intake. 
 Consider emergency contraception as per current practice if 
the woman had unprotected intercourse during the missed 
pill interval. 
o If between Day 18 & Day 24:  
 Omit the hormone-free interval by finishing the active pink 
tablets in the current pack and starting a new pack the next 
day. 
 If unable to start a new pack immediately, use condoms or 
avoid sexual intercourse until 7 days of uninterrupted active 
pink tablet intake from the new pack. 
 If this occurs during the last cycle, the subject should contact 
the study staff to know what she has to do with the next 
contraception. 
If the subject inadvertently misses any of the white placebo tablets: 
 Skip the missed white placebo tablet(s) and the remaining tablets are taken 
at the regular time.  
 Use of condoms is not required during this time.   


 
 
  
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Anytime a subsequent cycle of the product/pack is started later than the day following 
administration of the last white tablet, the subject should use condoms until she has taken pink 
tablets daily for 7 consecutive days. 
 
9.4.4.4 
In case of short-term intake of drugs that may decrease the efficacy of 
the COC  
Subject is allowed to take drugs potentially decreasing the efficacy of the COC for a maximal 
period of 10 consecutive days (for example, CYP 3A4 inducers). Subjects must be instructed 
to use condoms when these drugs are used and during 7 days of uninterrupted pink tablet intake 
after finishing the medication. 
 
9.4.4.5 
Use of the investigational product in case of bleeding/spotting episode 
Scheduled bleeding is expected to begin within a few days of taking the last active tablet (i.e. 
pink tablet), but may begin sooner or later. If spotting occurs while on the usual regimen of 
one tablet daily, the subject should continue medication without interruption.  She should be 
instructed that this type of bleeding is often transient and without significance.  However, if 
the bleeding is persistent or prolonged, nonfunctional causes may be considered and the subject 
should be advised to call the Investigator who will decide the best management for the subject. 
The bleeding profile will be recorded by the subject on a subject diary.  
9.4.4.6 
Use of the investigational product in the event of a missed menstrual 
period 
A missed menstrual period may occur even if the subject adhered to the prescribed dosage 
regimen. However, as the contraceptive method used in this study is still under investigation, 
a rapid detection of any pregnancy is necessary. For this reason, if the subject presents a missed 
period, she will be instructed to use the home urine pregnancy test provided by the study staff 
to rule out pregnancy before continuing the contraceptive regimen (see Section 9.6.2).   
9.4.5 
Blinding 
This is an open-label study. 
9.4.6 
Restrictions 
9.4.6.1 
Prior and Concomitant Therapy 
Medications with an end date occurring before the first investigational product dose date in the 
treatment period will be identified as prior medications. Medications with a start date occurring 
on or after the first investigational product dose date in the treatment period or medications 


 
 
  
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with a start date prior to the first investigational product dose date and an end date on or after 
the first investigational product dose date will be identified as concomitant medications. 
Unauthorized Prior Therapies: 
 Use of an injectable hormonal method of contraception within 10 months (300 
days) prior to screening for an injection with a 3-month duration, within 6 months 
(180 days) prior to screening for an injection with a 2-month duration, within 3 
months (90 days) prior to screening for an injection with a 1-month duration. 
 Use of drugs potentially triggering interactions with COC within one month prior 
to subjects’ enrollment. This includes, but is not limited to: 
o CYP 3A4 inducers: barbiturates, primidone, bosentan, felbamate, griseofulvin, 
oxcarbazepine, topiramate, carbamazepine, phenytoin, rifampicin, St John’s 
wort. 
o CYP 3A4 inhibitors: azole antifungals, phenylbutazone, modafinil, cimetidine, 
verapamil, macrolides, diltiazem and grapefruit juice. 
o HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase 
inhibitors. 
Unauthorized Concomitant Therapies: 
 Use of any contraceptive method other than the investigational product.  
Note: use of condoms is only allowed during the course of the study to avoid 
transmission of sexually transmitted infections (STIs), or in case of missed tablets, 
or when unauthorized concomitant therapies are used. Condom use must be 
recorded in the subject diary.  
 Daily, long-term treatment for chronic conditions or diseases with medications that 
may increase serum potassium concentration (e.g. ACE inhibitors, angiotensin-II 
receptor antagonists, potassium-sparing diuretics, potassium supplementation, 
heparin, aldosterone antagonist and non-steroidal anti-inflammatory drugs). 
 Use of drugs potentially triggering interactions with COC. This includes, but is not 
limited to: 
o CYP 3A4 inducers: barbiturates, primidone, bosentan, felbamate, griseofulvin, 
oxcarbazepine, topiramate, carbamazepine, phenytoin, rifampicin, St John’s 
wort.  
o CYP 3A4 inhibitors: azole antifungals, phenylbutazone, modafinil,   cimetidine, 
verapamil, macrolides, diltiazem and grapefruit juice. 
o HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase 
inhibitors. 
These drugs or herbal products may decrease the effectiveness of hormonal 
contraceptives or increase breakthrough bleeding. Subjects must be instructed 
to use a back-up contraceptive method when these drugs are used, up to and 


 
 
  
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including the next 7 days after finishing the concomitant therapy and to record 
this back-up contraception in the subject diary (see Section 9.6.1). It is the 
responsibility of the Investigator to ensure that any change in concomitant 
medications during the study is recorded in the source documentation and 
entered in the electronic case report form (eCRF). 
Warning: oral contraceptives may interfere with the metabolism of other drugs. Accordingly, 
plasma and tissue concentrations may be affected (e.g. cyclosporine). Consult the prescribing 
information of concomitant drugs for possible interactions with oral contraceptives. 
9.4.6.2 
Condoms and other contraceptive methods 
Use of condoms is allowed during the course of the study only to avoid transmission of STIs 
or in case of missed tablet(s) or unauthorized concomitant therapies. Condom use must be 
recorded in the subject diary. Use of any other contraceptive methods must also be recorded in 
the subject diary (see Section 9.6.1). The cycles during which condom(s) or other contraceptive 
method(s) than the investigational product were used will be excluded from the Pearl Index 
calculation. 
9.4.7 
Treatment beyond the clinical trial 
Post-treatment contraceptive counseling should be given to each subject at Visit 6 and at the 
Early Termination Visit in case of premature study termination. Post-treatment contraceptive 
treatment should be started no later than on the day following the last tablet intake of the trial 
medication. 
9.5 
Study Activities 
The following sections provide details of the study activities which are summarized in the 
Schedule of Events (Appendix 1). The study will include 1 Screening Visit (Visit 1), 1 
enrollment Visit (Visit 2), 4 in-treatment Visits (Visits 3 to 6) and 1 exit Visit (Visit 7). 
At any time during the study, an Unscheduled Visit may occur in case of suspicion of 
pregnancy. 
9.5.1 
Visit 1: Screening Visit  
The subject must be fasting for at least 8 hours (overnight fast) before the Screening Visit. 
Prior to conducting any screening procedures, subjects will be given a full description of the 
nature of the study. The purpose, timing, procedures, and risks of the study will be explained 
to the subject, including requirements for enrollment and participation in the study, medication 
restrictions during the study, and requirements for washout of certain medications that the 
subject may already be taking. The eligible subject who is willing to participate in the study 
will then be required to provide written consent. The Investigator or a designated medically 


 
 
  
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qualified member of the study staff will interview potential participants to establish their 
eligibility for inclusion in the study.   
Potential subjects will be screened according to the inclusion and exclusion criteria within 45 
days prior to the subject enrollment visit (Visit 2). Subjects who were eligible for the study but 
did not enroll within 45 days of screening (Visit 1) can be re-screened. Re-screening requires 
all Visit 1 assessments to be repeated. The Investigator will maintain a log of all subjects 
screened for participation and record the reason(s) for excluding potential subjects. 
The following will be performed to determine eligibility: 
1. Obtain signed IC from subjects. Subjects will receive a copy of the IC (see Section 
10.3); 
2. Review and document inclusion and exclusion criteria (see Sections 9.3.1 and 9.3.2); 
3. Record demographic information (see Section 9.6.4.4); 
4. Obtain medical and surgical history (see Section 9.6.4.6); 
5. Obtain gynecological history including identification of the previous contraceptive 
method used, if any (see Section 9.6.4.7); 
6. Obtain prior medication use information (see Section 9.6.4.5); 
7. Perform a physical examination (see Section 9.6.3.4); 
8. Perform a gynecological examination including breast examination (see Section 
9.6.3.6); 
9. Obtain cervical cytology (see Section 9.6.3.6); 
10. Perform a Chlamydia test (see Section 9.6.3.6); 
11. Perform a gonorrhea test (see Section 9.6.3.6); 
12. Collect fasting (8-hour) blood samples for hematology, biochemistry and pregnancy 
test (see Sections 9.6.2.1 and 9.6.3.3); 
13. Measure vital signs (see Section 9.6.3.7); 
14. Measure height and weight, and calculate BMI (see Section 9.6.3.5); 
15. Schedule the next study visit. 


 
 
  
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9.5.2 
Visit 2: Subject Enrollment 
The Visit 2 will occur within 45 days after the Screening Visit (Visit 1), when the entire 
laboratory results of the subject have been received. 
On the basis of the laboratory results, the Investigator must assess the eligibility of the subject.  
In case of positive Chlamydia or gonorrhea test result (see Section 9.6.3.6), the subject will be 
treated before enrollment. Choice of treatment is left at the Investigator’s discretion. 
During Visit 2, the following procedures will be performed: 
1. Review, confirm and document inclusion and exclusion criteria (see Sections 9.3.1 and 
9.3.2); 
2. Obtain prior medication use information (see Section 9.6.4.5 and Section 9.4.6 for 
restrictions); 
3. If all screening assessments are acceptable and all inclusion criteria and no exclusion 
criteria have been met, the subject will be enrolled in the study;  
4. Perform a Chlamydia and gonorrhea test, if indicated (see Section 9.6.3.6); 
5. Measure vital signs (see Section 9.6.3.7); 
6. Dispense investigational products for Cycle 1-4 and one spare blister pack and give the 
subject the instructions for use (see Section 9.4.4.2); 
7. Dispense subject diary and give the subject the instructions for use (see Section 9.6.1); 
8. Dispense home urine pregnancy test kits with the instructions for use. Subject should 
perform a urinary pregnancy test just before the intake of the first pink tablet, preferably 
with first urine in the morning. The result has to be recorded in the diary. The subject 
should only start with the trial medication when the pregnancy test is negative (not 
pregnant). If the pregnancy test is positive, the subject should not take any trial 
medication and contact the Investigator. The Investigator should arrange for an 
Unscheduled Visit (see Section 9.5.5) to confirm the pregnancy, complete the 
Pregnancy Report Form if the pregnancy is confirmed (see Section 9.6.2.1) and the 
subject should be withdrawn; 
9. Query the subject as to the occurrence of any AE(s) and record any AE(s) observed or 
spontaneously volunteered by the subject (see Section 9.6.3.1); 
10. Dispense the questionnaires and give the subject the instructions for completion (see 
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11. Schedule or confirm the next study visit and the follow-up phone call; 
12. Instruct the subject to come to the next visit with her subject diary and the unused 
investigational product, including empty blisters, spare and boxes; 
13. Instruct any subject not on a hormonal contraceptive and who does not start the 
investigational product at the enrollment visit to contact the site immediately if her next 
menses occurs at earlier than 21 days or is delayed such that her cycle length exceeds 
35 days, and that she should not start the investigational product if either of these 
happens; 
14. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product 
before contacting the site; 
15. Complete a follow-up call within 7 days following the expected start date of the 
treatment to remind the subject to complete the diary entries. 
9.5.3 
Treatment Period (from Cycle 1 Day 1 until Cycle 13 Day 28) 
9.5.3.1 
Visit 3 (Cycle 2, between Day 1 and Day 14) 
The following procedures will be performed: 
1. Perform a Chlamydia and gonorrhea test, if indicated (see Section 9.6.3.6); 
2. Measure vital signs (see Section 9.6.3.7); 
3. Query the stop date of the previous contraceptive method; 
4. Investigational product return and drug accountability (see Section 9.4.1.2); 
5. Collect and review completed subject diary pages and return the diary to the subject 
(see Section 9.6.1); 
6. Ensure appropriate completion of the questionnaires; 
7. Collect blood samples from the subjects participating in the Population PK Substudy 
according to the sampling scheme outlined in Section 9.6.4.2. Note that Visit 3 for the 
subjects in the Population PK Substudy should be performed between Days 10 and 14; 
8. Query the subject as to the occurrence of any TEAE(s) and record any TEAE(s) 
observed or spontaneously volunteered by the subject (see Section 9.6.3.1); 
9. Obtain concomitant medication use (see Section 9.6.4.5 and Section 9.4.6 for 
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10. Schedule or confirm the next study visit; 
11. Instruct the subject to come to the next visit with her subject diary and the unused 
investigational product, including empty blisters, spare and boxes; 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product 
before contacting the site. 
9.5.3.2 
Visit 4 (Cycle 4, between Day 1 and 14) 
The following procedures will be performed: 
1. Perform a Chlamydia and gonorrhea test, if indicated (see Section 9.6.3.6); 
2. Measure vital signs (see Section 9.6.3.7); 
3. Measure weight and calculate BMI (see Section 9.6.3.5); 
4. Collect blood samples from the subjects participating in the Population PK Substudy 
according to the sampling scheme outlined in Section 9.6.4.2. Note that Visit 4 for the 
subjects in the Population PK Substudy should be performed between Days 10 and 14; 
5. Investigational product return and drug accountability (see Section 9.4.1.2); 
6. Dispense investigational products for the next 3 cycles and remind the subject the 
instructions for use (see Section 9.4.4.2); 
7. Collect and review completed subject diary pages and return the diary to the subject 
(see Section 9.6.1); 
8. Query the subject as to the occurrence of any TEAE(s) and record any TEAE(s) 
observed or spontaneously volunteered by the subject (see Section 9.6.3.1); 
9. Obtain concomitant medication use (see Section 9.6.4.5 and Section 9.4.6 for 
restrictions); 
10. Schedule or confirm the next study visit; 
11. Instruct the subject to come to the next visit in a fasted state, with her subject diary 
and the unused investigational products, including empty blisters, spare and boxes; 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product 
before contacting the site. 


 
 
  
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9.5.3.3 
Visit 5 (Cycle 7, between Day 1 and 14) 
The following procedures will be performed: 
1. Perform a Chlamydia and gonorrhea test, if indicated (see Section 9.6.3.6); 
2. Measure vital signs (see Section 9.6.3.7); 
3. Measure weight and calculate BMI (see Section 9.6.3.5); 
4. Investigational product return and drug accountability (see Section 9.4.1.2); 
5. Dispense investigational products for the next 3 cycles and remind the subject the 
instructions for use (see Section 9.4.4.2); 
6. Collect and review completed subject diary pages and return the diary to the subject 
(see Section 9.6.1); 
7. Query the subject as to the occurrence of any TEAE(s) and record any TEAE(s) 
observed or spontaneously volunteered by the subject (see Section 9.6.3.1); 
8. Obtain concomitant medication use (see Section 9.6.4.5 and Section 9.4.6 for 
restrictions); 
9. Collect fasting (8-hour) blood samples for biochemistry (see Sections 9.6.3.3); 
10. Schedule or confirm the next study visit; 
11. Instruct the subject to come to the next visit with her subject diary and the unused 
investigational products, including empty blisters, spare and boxes; 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product 
before contacting the site. 
9.5.3.4 
Visit 6 (Cycle 10, between Day 1 and 14) 
The following procedures will be performed: 
1. Perform a Chlamydia and gonorrhea test, if indicated (see Section 9.6.3.6); 
2. Measure vital signs (see Section 9.6.3.7); 
3. Investigational product return and drug accountability (see Section 9.4.1.2); 
4. Dispense investigational products for the next 3 cycles and remind the subject the 
instructions for use (see Section 9.4.4.2); 


 
 
  
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5. Collect and review completed subject diary pages and return the diary to the subject 
(see Section 9.6.1); 
6. Dispense the questionnaires and give the subject the instructions for completion 
(see Section 9.6.4.11); 
7. Query the subject as to the occurrence of any TEAE(s) and record any TEAE(s) 
observed or spontaneously volunteered by the subject (see Section 9.6.3.1); 
8. Obtain concomitant medication use (see Section 9.6.4.5 and Section 9.4.6 for 
restrictions); 
9. Give the subject counseling about the next contraceptive method to use at the end 
of the study (see Section 9.6.4.9); 
10. On the day the subject is expected to start the next contraceptive method (±1 day), 
perform a follow-up call to ensure subject’s compliance with this method (see 
Section 9.6.4.9). 
11. Schedule or confirm the next study visit; 
12. Instruct the subject to come to the next visit in a fasted state with her subject diary 
and the unused investigational products, including empty blisters, spare and boxes; 
13. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational 
product before contacting the site. 
9.5.3.5 
Visit 7 (Cycle 14, between Day 16 and 23), End of Treatment Visit 
The following procedures will be performed: 
1. Perform a physical examination (see Section 9.6.3.4); 
2. Measure weight and calculate BMI (see Section 9.6.3.5); 
3. Perform a gynecological examination including breast examination (see Section 
9.6.3.6);  
4. Collect fasting (8-hour) blood samples for hematology, biochemistry and pregnancy 
test (see Sections 9.6.2.1 and 9.6.3.3); 
5. Measure vital signs (see Section 9.6.3.7); 
6. Investigational product return and drug accountability (see Section 9.4.1.2); 


 
 
  
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7. Collect and review completed subject diary pages (see Section 9.6.1); 
8. Ensure appropriate completion of the questionnaires; 
9. Query the subject as to the occurrence of any TEAE(s) and record any TEAE(s) 
observed or spontaneously volunteered by the subject (see Section 9.6.3.1); 
10. Obtain concomitant medication use (see Section 9.6.4.5 and Section 9.4.6 for 
restrictions); 
11. Complete the End of Study Form. 
9.5.4 
Early Termination Visit  
A subject who desires early termination or is withdrawn from the study after the enrollment 
visit (Visit 2) (section 13.4) will require an Early Termination Visit. 
 Any subject who contacts the study site with a desire to discontinue study participation 
should be instructed at each visit to contact the study staff before discontinuing the 
study drug to be counseled about alternative contraception to use prior to the Early 
Termination Visit (see Section 9.6.4.9). Study sites may provide any prescription or 
non-prescription contraceptive to the subject as is medically appropriate per local 
standard of care other than an IUD or implant. If necessary, an unscheduled visit can 
occur to provide contraception (see Section 9.5.5). 
 A subject who presents to the study site for a scheduled visit and desires to discontinue 
study participation or is withdrawn from the study at that visit should be counseled 
about alternative contraception to use prior to the Early Termination Visit (see Section 
9.6.4.9). Study sites may provide any prescription or non-prescription contraceptive to 
the subject as is medically appropriate per local standard of care other than an IUD or 
implant. 
 A subject who presents to the study site for a scheduled visit who has not taken the 
study product for 16 days or more should have the scheduled visit procedures and the 
Early Termination Visit procedures completed at that time. The subject should be 
counseled about alternative contraception (see Section 9.6.4.9). Study sites may 
provide any prescription or non-prescription contraceptive to the subject as is medically 
appropriate per local standard of care. 
The Early Termination Visit should occur between 16 and 23 days after the last investigational 
product intake or immediately if the investigational product was never started. The procedures 
listed in Visit 7 (see Section 9.5.3.5) will be performed and the End of Study Form will be 
completed.  
Study site personnel will attempt to follow the progress of every subject admitted to the study 
through to study completion. If a subject fails to return for a scheduled visit, a reasonable effort 
should be made to contact the subject and ascertain the reason(s) for not returning. As a 
minimum, the site staff will contact the subject twice by phone and, if no response, will send 
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If a subject does not complete the study for any reason (including Investigator discretion), the 
reason and circumstances for the subject’s early termination must be fully documented.   
The Sponsor or Designee must be informed in a timely manner if any subject withdraws from 
the study, regardless of the cause. Withdrawn subjects may not be re-enrolled in the study and 
will not be replaced. 
9.5.5 
Unscheduled Visit 
At any time of the study, an Unscheduled Visit could occur in case of suspicion of pregnancy 
based on a positive pregnancy test performed at home by the subject, in case the Investigator 
judges it necessary to examine a subject who would present a potential significant adverse 
event in the Investigator’s opinion, or if alternative contraception is needed for a subject 
planning early termination. Additional assessments can be performed at the Investigator’s 
discretion. 
9.6 
Study Variables and Procedure Descriptions 
9.6.1 
Subject Diary 
Subject diaries will be given to the participating subjects at Visit 2. Subjects will be instructed 
on how to complete it by the Investigator or Designee.  
The following information is to be recorded in the subject diary: 
- 
Date of the intake of the first tablet at each cycle; 
- 
Tablet intake on a daily basis; 
- 
Absence or occurrence of vaginal bleeding/spotting event(s) on a daily basis: 
 0 = Absence of vaginal bleeding or spotting; 
 1 = Spotting: evidence of minimal vaginal blood loss that does not 
require new use of sanitary protection, including pantyliners; 
 2 = Bleeding: evidence of vaginal blood loss that requires the use of 
sanitary protection with a tampon, pad or pantyliner; 
- 
Use of contraceptive method other than the investigational product (e.g. condom) 
during the cycle;  
- 
Occurrence of heterosexual intercourse during the cycle; 
- 
Result of the urine pregnancy test(s) performed at home (at cycle 1 before the first pill 
intake and at subsequent cycles in case of absence of menstruation). 


 
 
  
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At Visits 3, 4, 5, 6 and 7, the completed pages of the subject diary will be collected and 
reviewed by the Investigator. At Visits 3, 4, 5, and 6 the subject diary will be returned to the 
subject for further completion. At Visit 7, the fully completed last pages of the subject diary 
will be returned by the subject. 
9.6.2 
Efficacy Assessments 
Contraceptive efficacy will be based on the Pearl Index, the method failure Pearl Index and the 
cumulative pregnancy rate.  
On-treatment pregnancies are defined as pregnancies with an estimated date of conception 
within the in-treatment period (Day 1 to 7 days after the intake of investigational product, 
whether active or inactive tablet). 
Pre-treatment pregnancies are pregnancies with an estimated date of conception before the first 
intake of trial medication. 
Post-treatment pregnancies are pregnancies with an estimated date of conception after the in-
treatment period (> 7 days after the intake of investigational product, whether active or inactive 
tablet). 
9.6.2.1 
Pregnancy Testing and Estimating Date of Conception 
The occurrence of pregnancies will be evaluated during the study by performing: 
- 
At Screening Visit (Visit 1) and Visit 7: a serum pregnancy test; 
- 
Just before intake of the first study medication and in case of missing menstrual period, 
the subject will perform a urine pregnancy test at home. For that purpose, home 
pregnancy kits will be provided to all subjects at Visit 2 and the subjects will be 
instructed on how to use it. In case of positive urine pregnancy test result, the subject 
will be instructed to contact the study staff immediately and the subject will be 
instructed not to take the investigational product. An appointment will be scheduled 
with the study staff for the pregnancy follow-up as soon as possible. The subject will 
be asked to record in the subject diary (see Section 9.6.1) the result of the urine 
pregnancy test performed at home; 
At any time: the subject is asked to contact immediately the study staff in the event of a 
suspected pregnancy. An appointment will be scheduled with the study staff for the pregnancy 
confirmation as soon as possible. The Investigator and or Designee will make every effort to 
see the subject as soon as possible to perform a serum pregnancy test.   
All subjects for whom a pregnancy is suspected due to a positive serum pregnancy test will be 
carefully evaluated and assessed to determine the estimated date of conception.  The preferred 
method is to perform an ultrasound to define the estimated age of the pregnancy; the estimated 
date of conception will then be calculated from this result.  In addition, information about all 


 
 
  
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pregnancy tests, about bleeding and study drug intake (which must be reconciled with subject 
diary data), information about concomitant medications (which must be reconciled with 
information in the eCRF) will be obtained.  The Sponsor and Site Monitor must be notified 
and available information captured.  All information must be documented using the Pregnancy 
Report Form.  
Information pertaining to the reporting of pregnancy should be captured on the Pregnancy 
Report Form. This form will be used for initial and follow-up reporting. The form should be 
completed and returned to the PRA Safety team. The subject will be followed until the outcome 
of pregnancy is known.   
9.6.2.2 
Pregnancy Reporting 
Pregnancy will not be considered an AE but, because of its importance, information about each 
pregnancy should be treated in an urgent manner.  The Sponsor or Designee must be notified 
within 24 hours of the suspected diagnosis and all follow-up information should be obtained 
promptly. 
If during the course of the study, a subject is found to be pregnant, the investigational product 
will be discontinued and study participation terminated.  
The site will submit a Pregnancy Report Form to the Safety Monitor. 
The following contact will be used for all communications with the Safety Monitor/Drug 
Safety of this study: 
PRA Safety & Risk Management 
Fax: +1 (888) 772-6919 
Email: CHOSafety@prahs.com 
All pregnancies identified during the course of the study in a subject who was using the 
investigational product will be monitored to completion, i.e., approximately 9 month follow-
up in the case of live birth or until outcome information is obtained. Information will also be 
collected on any maternal or fetal complications. Miscarriage and any congenital abnormalities 
or birth defects will be classified as SAEs. Pregnancy outcome information will be recorded 
on specific forms and the data will be analyzed within the drug safety assessment.  Every 
attempt should be made to obtain outcome data including hospital or medical records.  
If a subject becomes pregnant and states she never started the investigational product, the 
pregnancy does not have to be monitored if the subject returns all of the investigational product 
(proving she never started the investigational product). 
 


 
 
  
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9.6.3 
Safety Variables 
Safety evaluations will include the following: 
 General safety will be assessed in terms of occurrence of AEs/SAEs;  
 Extent of exposure 
 Clinical laboratory evaluations 
 Physical examination 
 Gynecological examination  
 Vital signs 
9.6.3.1 
Adverse Events 
AEs will be assessed from the time of signing the IC until exit from the study.  At every study 
visit from Visit 2, subjects will be asked an indirect standard question to elicit any medically 
related changes in their well-being.  They will also be asked if they have been hospitalized, 
had any accidents, used any new medications, or changed any current medication regimens 
(both prescription and over-the-counter medications). 
Definition of Terms 
Adverse Event (AE):  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. In addition to novel events, an AE may be an 
exacerbation of a pre-existing medical condition that was present before the subject was 
assigned to a treatment group.  Each AE is described using all three of the following 
classifications: expected or unexpected; related or unrelated; and serious or non-serious.  
Additionally, intensity of the event is also described. 
Treatment-emergent adverse event (TEAE): A TEAE is any AE not present prior to the 
initiation of the treatments or any event already present that worsens in either intensity or 
frequency following exposure to the treatment. Since the starting point for AEs collection is 
the signing of the IC, not the start of the study treatment, the AEs recorded prior to first 
investigational product administration are designated as AEs while those that occur or worsen 
after the initiation of the investigational product are designated as TEAEs.   
Exacerbation of Pre-Existing Medical Condition:  An increase in the frequency or severity 
of a medical condition that is present before first investigational product administration.  Any 
medical condition that is present before first investigational product administration and that 
does not deteriorate should not be reported as an AE. 


 
 
  
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Expected: The determination of whether an AE is expected is based on previous experience 
with the investigational product, as follows: 
Expected AEs are AEs that have already been identified during the investigational product’s 
use, or are a known complication of standard medical procedures that may be conducted as 
part of the clinical study. 
Expected AEs are defined as those described in the Investigator’s Brochure (IB).  If an event 
increases in intensity or severity from that described in the IB, it will be considered unexpected. 
Unexpected AEs are all other AEs which are not deemed anticipated.  Note that anticipated 
AEs which are more severe must also be considered unanticipated AEs. 
Severity: The severity of each AE should be recorded as mild, moderate, or severe according 
to the following definition: 
Mild – transient and well-tolerated by the study subject, 
Moderate – causes discomfort and a temporary interference with daily living, 
Severe – substantially interferes with daily living to the point of being incapacitating and/or 
life threatening. 
Adverse Event Causality: 
The Investigator will evaluate the relationship of each AE to study drug and/or study 
procedures according to the following definitions:  
 
Category Criteria 
Final Reporting of Relationship to 
Study Drug 
Highly 
probable 
-Event 
or 
laboratory 
test 
abnormality, with plausible time 
relationship to drug intake. 
-Cannot be explained by disease or 
other drugs. 
-Response to withdrawal plausible 
(pharmacologically, 
pathologically). 
Related 


 
 
  
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Category Criteria 
Final Reporting of Relationship to 
Study Drug 
-Event pharmacologically and/or 
phenomenologically related. 
-Rechallenge 
satisfactory, 
if 
necessary. 
Probable 
-Event 
or 
laboratory 
test 
abnormality, with reasonable time 
relationship to investigational drug 
intake. 
-Unlikely to be attributed to 
disease or other drugs. 
-Response to withdrawal clinically 
reasonable. 
-Rechallenge not required. 
Possible 
-Event 
or 
laboratory 
test 
abnormality, with reasonable time 
relationship to investigational drug 
intake. 
-Could also be explained by 
disease or other drugs. 
-Information on drug withdrawal 
may be lacking or unclear. 
Unlikely 
-Event 
or 
laboratory 
test 
abnormality, with a time to 
investigational product intake that 
makes a relationship improbable 
(but not impossible). 
-Disease or other drugs provide 
plausible explanations. 
Not Related 


 
 
  
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Category Criteria 
Final Reporting of Relationship to 
Study Drug 
Not 
Related 
Event 
due to 
underlying or 
concurrent illness, complications, 
concurrent treatments or effect of 
another concurrent drug/therapy 
and is not associated to the 
investigational drug. 
 
Serious:  An AE is considered “serious” if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes:  
• Death: the AE causes or contributes to the death.  Death is usually considered to be the 
outcome of an event; the event that leads to death is defined as the SAE. 
• A life-threatening adverse event: if, in the view of the Investigator or Sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization: the AE requires at least 
a 24-hour inpatient hospitalization or prolongs a hospitalization beyond the expected length 
of stay. Hospital admissions for surgery planned before study entry, for social reasons or 
for normal disease management procedures are not to be considered SAE according to this 
criterion.  Where the protocol or the standard management of the disease under study 
requires planned hospitalizations for disease or treatment management, this should not be 
considered a serious criterion leading to expedited reporting. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• Congenital anomaly/birth defect: an adverse outcome in a child or fetus of a patient 
exposed to the investigational product before conception or during pregnancy. 
• Important medical event: such an event may not result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based upon appropriate 
medical judgment; it may jeopardize the 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 dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
For the purpose of this study, all events that meet the regulatory definition of an SAE that occur 
at any time during the study will be reported to the Sponsor as SAEs. Any SAE requires 


 
 
  
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expedited reporting to Sponsor regardless of its relationship to the investigational product. 
Non-SAEs are all other AEs not deemed serious. 
Investigator Obligations 
Assessing and Following:  The Investigator is responsible for assessing all AEs that occur at 
any time during the study. The Investigator must make a determination of relatedness, 
seriousness, and intensity on the Adverse Events page of the eCRF for each AE.  All AEs must 
be followed to adequate resolution or stabilization.  If the AE has not resolved or stabilized by 
the time the subject completes the final study visit, the Investigator will follow the status of 
the subject's AE for at least 30 days beyond the subject's final study visit, unless directed 
otherwise by the Sponsor. 
Documenting:  All AEs during the study will be documented in the subject’s medical record.  
This information will then be transcribed on the AEs page of the eCRF by designated study 
personnel.  Required information includes a description of the event, date of onset, date of 
resolution, if death occurred, the action taken to manage the AE, as well as relatedness, 
seriousness, and intensity. 
AE information must be recorded regardless of its relatedness to the use of the investigational 
product.  AEs resulting from concurrent illnesses, reactions to concurrent medications, or 
progression of disease states must also be reported. 
Reporting:  1) The Investigator is responsible for reporting AEs to the Institutional Review 
Board (IRB) according to agreements and instructions from that committee that oversees this 
research, as well as according to applicable regulations. 2) Additionally, all AEs will be 
reported to the Sponsor or Designee on the eCRF, and all SAEs, whether expected or 
unexpected, related or unrelated, must be reported to PRA Drug Safety , by 24/7 e-mail or 
facsimile using the “Serious Adverse Event Report” form provided by the Sponsor or 
Designee, within 24 hours after the Investigator first learns of the event   In addition to the 
form, the following completed eCRF pages containing relevant information must also be 
faxed/mailed to the PRA Drug Safety: Medical History and Current Medications. The 
Investigator is responsible for reporting any new or relevant follow-up information on the 
SAEs within 24 hours after the investigator learns of the new information.  The Investigator 
should cooperate and furnish additional information, including copies of pertinent records if 
necessary, to assist the safety team in their evaluation of the event. 
Medical Emergencies and Emergency Protocol Deviations 
In medical emergencies, the Investigator will use medical judgment and remove the subject 
from immediate harm.  The Investigator will then immediately notify the Safety Monitor and 
the IRB regarding the type of emergency and the course of action taken. 
An investigator shall notify the Safety Monitor and the reviewing IRB of any deviation from 
the investigational plan to protect the life or physical well-being of a subject in an emergency.  


 
 
  
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Such notice shall be given as soon as possible, but in no event later than 5 working days after 
the emergency occurred.  Except in such an emergency, prior approval by the Safety Monitor 
is required for any changes in or deviations from the protocol.  All deviations must be 
documented on the eCRF. 
The following contact will be used for all communications with the Safety Monitor/Drug 
Safety of this study: 
PRA Safety & Risk Management 
Fax: +1 (888) 772-6919 
Email: CHOSafety@prahs.com 
Sponsor Reporting Obligations 
Sponsor or Designee will forward all reportable AEs to the appropriate regulatory authorities, 
ECs, and participating Investigators according to 21 Code of Federal Regulations (CFR) 312, 
and any other applicable regulations. 
9.6.3.2 
Extent of Exposure 
The extent of exposure to the investigational product will be determined from the first and last 
dosing dates during the treatment period and is derived as the last dose date – the first dose 
date + 1.  
9.6.3.3 
Clinical Laboratory Evaluations 
Methods for blood sample collection, processing, and shipment are described in instructional 
materials provided to investigational sites.   
Any remaining retainable biological samples will be stored at the central laboratory or designee 
at the latest until the marketing authorization. These samples may be used for future additional 
analysis in the context of the E4/DRSP development program.  
At Visit 1 and 7, blood hematology, biochemistry and lipids will be assessed (see Appendix 
2). At Visit 5, the following biochemistry parameters will be assessed: glycaemia, glycated 
hemoglobin, total cholesterol, HDL- and LDL-cholesterol, triglycerides, Lactate 
dehydrogenase (LDH) 1 and LDH 2, renal function (urea, creatinine, and glomerular filtration 
rate [GFR]) and ionogram (Na, K, Cl, Ca2+, P, HCO3-). Subject should be fasting for 8 hours 
before blood collection. 
All out-of-range laboratory values that are considered by the Investigator to be clinically 
significant will be recorded as AEs (see Section 9.6.3.1) 


 
 
  
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9.6.3.4 
Physical Examination 
A physical examination will be performed at Screening Visit and Visit 7. The physical 
examination will include an evaluation of the following: body as a whole, skin, head, eyes, 
ears, nose, and throat (HEENT), neck, cardiovascular, respiratory, musculoskeletal, 
neurologic, lymphatic/thyroid, abdomen. 
When reporting the results of the physical examination, the use of the “Abnormal” category 
will be reserved for findings that are considered clinically significant, in the opinion of the 
Investigator; the “Normal” category will include “Abnormal” results that are not clinically 
significant, as well as no findings.   
All abnormal findings will be recorded as AEs (see Section 9.6.3.1). 
9.6.3.5 
Height, Weight and Body Mass Index 
Height will be recorded at Screening Visit only. Weight will be recorded at Screening Visit, 
Visit 4, Visit 5 and Visit 7. At each center the same balance will be used for all measurements. 
Subjects will wear only indoor clothing without shoes. BMI will be calculated at the Screening 
Visit, Visit 4, Visit 5 and Visit 7 using the following formula:  
𝑊𝑒𝑖𝑔ℎ𝑡
𝐻𝑒𝑖𝑔ℎ𝑡² (kg/m²). 
9.6.3.6 
Gynecological Examination, Chlamydia test, Gonorrhea test and Cervical 
Cytology 
A gynecological examination will be performed at Screening Visit and Visit 7. The 
gynecological examination will include an evaluation of the following: breast examination 
(performed by palpation) and assessment of the adnexa, cervix, uterus, vagina, and external 
genitalia.   
When reporting the results of the gynecological examination, the use of the “Abnormal” 
category will be reserved for findings that are considered clinically significant, in the opinion 
of the Investigator; the “Normal” category will include “Abnormal” results that are not 
clinically significant, as well as no findings. 
All abnormal findings will be recorded as AEs (see Section 9.6.3.1). 
A Chlamydia testing will be performed using a vaginal swab: 
 At Screening (Visit 1) for all subjects. 
 At Visits 2, 3, 4, 5 and 6 for subjects who reported a change in sexual partner since the 
last study visit. 


 
 
  
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In case of positive Chlamydia test result, the subject will be treated, at the Investigator’s 
discretion as this infection can influence the vaginal bleeding pattern. In case of positive 
Chlamydia test result at screening, the subject will start treatment before she is enrolled.  
A gonorrhea testing will be performed using a vaginal swab: 
 At Screening (Visit 1) for all subjects.  
 At Visits 2, 3, 4, 5, and 6 for subjects who reported a change in sexual partner since the 
last study visit.  
In case of positive gonorrhea test result, the subject will be treated, at the Investigator’s 
discretion as this infection can influence the vaginal bleeding pattern. In case of positive 
gonorrhea test result at screening, the subject will start treatment before she is enrolled.  
 
For cervical cytology, Pap testing will be performed at Screening in all women 20 years 0 
months of age or older if no documented Pap test has been performed in the last 18 months.  
The enrollment visit cannot be performed until this Pap test result is available and the subject 
meets entry criteria. A copy of any Pap test or follow-up testing used for determination of study 
eligibility or during study follow-up must be obtained and included in the study record.  If not 
available at the time of the visit for which the documentation is required then the Pap test 
should be performed per protocol. The results of the Pap test will be reported using the 
Bethesda Pap Smear Classification7 as detailed in Appendix 3. If the Pap test at the Screening 
Visit presents abnormal result (i.e. dysplasia, cervical intraepithelial neoplasia, squamous 
intraepithelial lesion, carcinoma in situ, invasive carcinoma), the subject cannot be enrolled in 
the study.  Enrollment of a subject with an ASCUS interpretation is permitted if the subject is 
less than 21 years of age or HPV reflex test is negative for high-risk oncogene virus. If the 
ASCUS interpretation was done on the Pap test performed in the past 18 months, enrollment 
of the subject is allowed if a repeat Pap test 6 months later was normal.   
All abnormal findings in cervical cytology after subject enrolment that are considered by the 
Investigator to be clinically significant will be recorded as AEs (see Section 9.6.3.1). 
9.6.3.7 
Vital Signs 
Vital signs will be measured at Screening Visit, Visits 2, 3, 4, 5, 6, and 7. 
Vital signs will include sitting systolic and diastolic blood pressures and heart rate. Blood 
pressure measurements will be made using a sphygmomanometer with an appropriate cuff size 
for the individual subject.  Measurements will be taken while the subject is seated after at least 
5 minutes at rest. 
All abnormal findings in vital signs that are considered by the Investigator to be clinically 
significant will be recorded as AEs (see Section 9.6.3.1). 
9.6.4 
Other Evaluations 
Other assessments include the following: 


 
 
  
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- 
Vaginal bleeding pattern will be assessed based on the incidence of vaginal 
bleeding/spotting episodes; 
- 
Compliance will be assessed based on tablet intake;  
- 
Demographics; 
- 
Prior/Concomitant medication use; 
- 
Medical/surgical history; 
- 
Gynecological history; 
- 
Pregnancy risk and back-up contraception use; 
- 
Acceptability of trial medication; 
- 
Subjects’ well-being; 
- 
Contraceptive counseling; 
- 
Return of spontaneous menstruation and return to fertility. 
9.6.4.1 
Incidence of vaginal bleeding/spotting  
Subjects will be asked to record in the subject diary (see Section 9.6.1) the absence or the 
occurrence of vaginal bleeding or spotting on a daily basis using the following definitions: 
0 = Absence of vaginal bleeding or spotting; 
1 = Spotting: evidence of minimal vaginal blood loss that does not require new use of sanitary 
protection, including pantyliners; 
2 = Bleeding: evidence of vaginal blood loss that requires the use of sanitary protection with a 
tampon, pad or pantyliner. 
9.6.4.2 
Population Pharmacokinetic Substudy 
Population PK will be assessed using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects to address the relationship between PK parameters and various 
individual characteristics (e.g., body weight, race, smoking, and fed/fasted condition). Blood 
samples for PK analysis will be obtained at Visits 3 and 4 between Days 10 and 14 of Cycles 
2 and 4.  
All subjects enrolled in the Population PK Substudy will be required to check-in to the site for 
Visits 3 and 4 between Days 10 and 14 of Cycles 2 and 4, respectively. 


 
 
  
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Two PK samples will be taken from the subjects in the Population PK Substudy at Visits 3 and 
4. All subjects included in the Substudy will provide a sample for PK analysis at the time they 
check into the site (PK sampling 1). An additional blood sample (PK sampling 2) will be 
collected approximately two hours after the first sample.  
 
Depending on the time scheduled for the study site visit (Visit 3 & 4), subjects will be 
instructed on when they need to take their medication – either as usually done at home or on 
site. 
- 
If the appointement is scheduled in the morning and the subject usually takes her study 
medication in the morning, she should take it at the study site. One blood sample will 
be taken before dosing and the second blood sample will be taken within 2-hour 
postdose.  
- 
If the appointement is scheduled in the morning and the subject usually takes her study 
medication in the evening, she should take it in the evening before the visit at their 
regular time. The subject should record the time of the dosing in the Diary.  
- 
A subject who usually takes her study medication during the day should take it at usual 
time and come to the site when possible to have the 2 blood samples taken. The subject 
should record the time of dosing in the Diary. 
The following timings will be recorded by the site personnel in the eCRF: 
- 
The exact times of the last study medication dosing and the PK samplings 1 and 2.  
- 
The time of the last meal intake before the last study medication dosing before study 
visit. 
Plasma concentration data will be used to build an appropriate population PK model. 
Only a selection of the sites will participate in the Population PK Substudy. 
9.6.4.3 
Compliance 
Compliance (see also Section 9.4.3) to the investigational product will be evaluated using data 
recorded in the subject diary. Subjects will be asked to record tablet intake in the subject diary 
(see Section 9.6.1) on a daily basis. 
9.6.4.4 
Demographics 
Demographic data include age, education, ethnicity and race. 
9.6.4.5 
Prior and Concomitant Medication Use 
Medications with an end date occurring before the first investigational product dose date in the 
treatment period will be identified as prior medications. Medications with a start date occurring 
on or after the first investigational product dose date in the treatment period or medications 


 
 
  
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with a start date prior to the first investigational product dose date and an end date on or after 
the first treatment start date will be identified as concomitant medications. 
MEDICATION HISTORY – PRIOR MEDICATION USE 
Any medications taken in the last month prior to the Screening Visit will be recorded at 
Screening Visit and Visit 2 with the start and stop dates (see Section 9.4.6 for restrictions). 
All hormonal contraceptives used via the following routes and within the timeframe specified 
prior to the Screening Visit will be recorded and the start and stop dates will also be recorded 
as specified below: 
 Progestational implants; progestin, estrogen, or progestational injectable drug 
therapy within 12 months; 
 Intrauterine hormonal contraceptives within 6 months; 
 Oral, intravaginal or transdermal combined or progestin-only contraceptives within 
3 months. 
 
CONCOMITANT MEDICATION USE 
Subjects will be queried at Visits 3, 4, 5, 6, and 7 concerning the use of medications (see 
Section 9.4.6 for restrictions). Concurrent medications used by the subjects will be documented 
including the name of the drug, the dose, the frequency, and route of administration, the date 
of initiation and discontinuation, and the reason for administration. 
The reason for use or change of dose of a concomitant therapy may need to be reported as an 
AE (see Section 9.6.3.1). 
9.6.4.6 
Medical/Surgical History 
The medical and surgical history of the subject will be recorded at the Screening Visit. 
This includes a review of: 
- 
All body systems, 
- 
Cardiovascular 
risk 
factors: 
diabetes 
mellitus, 
dyslipoproteinemia, 
arterial 
hypertension, alcohol and illicit drug consumption, and tobacco use, 
- 
Previous surgical intervention(s), including indication, date and outcome.  
 
9.6.4.7 
Gynecological History 
The gynecological history of the subject will be recorded at the Screening Visit. 
This includes: 


 
 
  
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- 
Gravidity and parity status; 
- 
Menstrual cycle length for starters; 
- 
Dysmenorrhea; 
- 
Previous contraceptive method used. This includes, but is not limited to COC, 
progestin-only oral contraceptive, barrier methods, intrauterine devices, etc; 
- 
History of pregnancy during accurate hormonal contraceptive use. 
 
9.6.4.8 
Pregnancy Risk and Back-up Contraception Use 
Subject will be asked to record in the subject diary (see Section 9.6.1) for each cycle the 
occurrence of intercourse and the use of back-up contraception (e.g. use of condoms) if any.  
9.6.4.9 
Contraceptive Counseling 
At Visit 6, the subject will be counseled about her future contraception. The choice of the 
contraceptive method is left to the Investigator’s discretion.  
A subject who desires early termination or is withdrawn from the study (see Section 13.4) after 
the enrollment visit (Visit 2) will be counseled about future contraception. 
 Any subject who contacts the study site with a desire to discontinue study participation 
should be instructed at each visit to contact the study staff before discontinuing the 
study drug to be counseled about alternative contraception to use prior to the Early 
Termination Visit. Study sites may provide any prescription or non-prescription 
contraceptive to the subject as is medically appropriate per local standard of care other 
than an IUD or implant. If necessary, an unscheduled visit can occur to provide 
contraception (see section 9.5.5). 
 A subject who presents to the study site for a scheduled visit and desires to discontinue 
study participation or is withdrawn from the study at that visit should be counseled 
about alternative contraception to use prior to the Early Termination Visit. Study sites 
may provide any prescription or non-prescription contraceptive to the subject as is 
medically appropriate per local standard of care other than an IUD or implant. 
 A subject who presents to the study site for a scheduled visit who has not taken the 
study product for 16 days or more should have the scheduled visit procedures and the 
Early Termination Visit procedures completed at that time. The subject should be 
counseled about alternative contraception. Study sites may provide any prescription or 
non-prescription contraceptive to the subject as is medically appropriate per local 
standard of care. 


 
 
  
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On the day the subject is expected to start this contraception (± 1 day), the 
Investigator/Designee will contact the subject by phone to ensure her compliance with the 
counseled contraceptive method.  
9.6.4.10 
Acceptability of Trial Medication 
The acceptability of the trial medication will be assessed by analysis of discontinuation rates 
and reasons for discontinuations. Subject’s premature discontinuation must be documented on 
the Treatment Discontinuation Form, including the most important reason for discontinuation. 
The most important reason for discontinuation will be categorized as AE, lost to follow-up, 
subject request, protocol deviation, pregnancy, pregnancy wish or other. Subjects that complete 
the study must be documented on the End of Study Form. 
9.6.4.11 
Subjects’ well-being 
Subjects’ well-being will be evaluated using two well-established questionnaires: the Quality 
of Life Enjoyment and Satisfaction Questionnaire – Short Form and the Menstrual Distress 
Questionnaire.  
The baseline questionnaires will be given to the subject at Visit 2. The subject will be instructed 
to fill them in at home on or before the first day of study medication intake (Day 1). At the 
next visit, the study site personnel will ensure for the questionnaire completion. 
The end-of-treatment questionnaires will be given to the subject at Visit 6. The subject will be 
instructed to fill them in at home between Day 7 and Day 14 of the 13th treatment cycle. At the 
next visit, the study site personnel will ensure for the questionnaire completion. 
In case of premature study discontinuation, the subjects will be asked to fill in the 
questionnaires during the Early Termination Visit. 
  
9.6.4.12 
Return of spontaneous menstruation and return to fertility 
Each woman who discontinues the study early due to a pregnancy wish will be followed after 
study treatment discontinuation to evaluate return of spontaneous menstruation and return of 
fertility.  
They will be contacted every 6-8 weeks for a maximum of one year after study discontinuation. 
The date of the first spontaneous menstruation after study discontinuation will be recorded in 
the eCRF and follow-up will be continued. Once a pregnancy is reported or once a new 
contraceptive method has been started, the expected date of pregnancy term or of contraceptive 
treatment initiation will be recorded in the eCRF and no further follow-up contact will be done. 
In case of pregnancy, the estimated date of conception will be derived from the expected date 
of pregnancy term.


 
 
  
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10 ETHICS 
10.1 Ethics Committee 
The protocol and supporting documents for this study will be reviewed and approved by an 
appropriately constituted IRB prior to study initiation. 
All reviews and approvals will be in accordance with Good Clinical Practice (GCP) as 
contained in the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guidelines (E6) and United States (US) 
CFR governing Institutional Review Boards (IRBs) (Title 21, Part 56). 
A letter from the IRB documenting approval of the Investigator (who must be identified by 
name), the protocol (must be identified by title) and the subject consent form must be received 
by Estetra SPRL (referred hereafter as Sponsor) or its Designee prior to study initiation.  A 
progress report will be submitted by the Investigator to the IRB at intervals specified by the 
IRB, but not less than annually.  A copy of this progress report will be sent to Sponsor.  After 
completion of the study, the Investigator will submit a signed clinical safety summary of the 
study to the IRB. 
10.2 Ethical Conduct of Study 
The study will be conducted in accordance with GCP as contained in ICH Guidelines and US 
CFR governing the protection of human subjects (Title 21, Part 50) and the obligations of 
clinical Investigators (Title 21, Parts 312.60 through 312.69).  The study will also be conducted 
in accordance with the World Medical Association Declaration of Helsinki and all 
amendments. 
Sponsor or Designee is responsible for the ongoing safety evaluation of the investigational 
product and will expedite the notification of all participating Investigators and regulatory 
authorities of findings that are both serious and unexpected and/or that could adversely affect 
the safety of subjects, the conduct of the study or alter the IRB’s approval to continue the study. 
10.3 Subject Information and Consent 
The Investigator will ensure that written IC is obtained from each subject in accordance with 
applicable regulations. 
Subjects will be interviewed at the Screening Visit by qualified staff at the site and will be 
provided with a full description of the nature and purpose of the study. The subject will be 
given adequate time to consider the requirements and risks associated with participation in the 
study.  Each subject will provide written and signed IC prior to participating in any study 
procedures.  The original signed consent forms will be retained on file at the clinical site and 
a copy will be given to the subject. Source documentation will also document that IC was 
obtained prior to the subject’s participation in the study.  


 
 
  
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10.4 Subject Confidentiality 
The Sponsor ensures that the following have permission to review all study-related documents: 
monitor, auditor, IRB and regulatory authorities. The subject’s identity and study-related 
records will remain confidential throughout the duration of the study data collection and 
reporting process. 
A unique subject identification code will be assigned to each potential study subject.  The 
identification code protects the subject’s identity and is used in lieu of the subject’s name when 
reporting subject data.  The data will always maintain the confidentiality of the subject. 
The Investigator or Designee will review the subject data, which will be referenced using the 
subject identifier. At the conclusion of the study, the data obtained may be presented to regional 
regulatory authorities but the subject’s identity will not be revealed.  In addition, if any clinical 
data obtained from the study are published in scientific journals or presented at scientific 
meetings, the subject’s identity will not be revealed. 
 
 


 
 
  
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11 QUALITY CONTROL AND ASSURANCE 
The Sponsor and Designee will implement and maintain quality control procedures to ensure 
that this study is conducted and data are generated, documented, and reported in compliance 
with the protocol, GCP and applicable regulatory requirements. 
The Sponsor or Designee will routinely conduct monitoring and/or auditing visits to the study 
centers to verify the adherence to the study protocol, the protection of the rights and well-being 
of the subjects; and the accuracy and completeness of reported study data recorded on the 
source documentation. 
 


 
 
  
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12 PLANNED STATISTICAL METHODS 
Detailed plans for the statistical methods will be provided in a Statistical Analysis Plan which 
will be finalized prior to database lock. 
12.1 Determination of Sample Size 
Sample size is based on needing a sufficient number of cycles such that the difference between 
the Pearl Index and the upper limit of the two-sided 95% confidence interval (CI) for the Pearl 
Index does not exceed 1.  Assuming that the true Pearl Index is 1.0 and that a Poisson model 
is used to derive the CIs, then at least 12,337 at risk cycles are required for a power of 90% in 
the 16 to 35 year old population.8. If a not at risk cycle rate of 20% and a dropout rate of 
approximately 45% (assuming that we have an average of 4 cycles for subjects that 
discontinue) are assumed, approximately 1800 16 to 35 year old subjects need to be enrolled 
and initiate the investigational product.  Additionally, it is planned for a maximum of 200 
subjects > 35 years to be enrolled and initiate the investigational product. Therefore, in total, 
approximately 2000 subjects will be enrolled in the study and initiate the investigational 
product. Additionally, a subset of approximately 500 subjects will be enrolled in the PK 
Substudy. 
12.2 Analysis Populations and Datasets 
Statistical analysis and data tabulation will be performed using the following analysis 
populations unless specified otherwise: 
 Screened population includes all subjects who signed an IC form. 
 Enrolled population includes all enrolled subjects. 
 Safety population includes all enrolled subjects who receive at least one dose of test 
article. 
 Intention-to-Treat (ITT) population includes all enrolled subjects who receive at least 
one dose of test article.  The ITT population is the same as the Safety population for 
this study. 
 Per-protocol (PP) population includes all subjects in the ITT population who complete 
the study and do not have any important protocol deviations that impact the statistical 
analysis. The PP population may differ for the different endpoints. 
 PK population includes all subjects enrolled in the PK Substudy who provide 
concentration data for at least one sample. 
 


 
 
  
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12.3 General Statistical Procedures  
All the analyses will be conducted with SAS using procedures appropriate for the particular 
analysis. 
The descriptive statistics for all the continuous variables presented will be mean, median, 25th 
percentile, 75th percentile, standard deviation (SD), standard error of mean (SEM), minimum, 
maximum, and number of subjects.   
Categorical variables will be summarized using counts and percentages. 
Baseline will be defined as the most recent assessment prior to first dose of study medication. 
12.4 Efficacy Analyses 
The efficacy analysis will be based on the Pearl Index. The Pearl Index, defined as the 
number of pregnancies per 100 women-years of treatment, will be calculated as 
𝑃𝑒𝑎𝑟𝑙 𝐼𝑛𝑑𝑒𝑥=
1300 ×  number of on −treatment pregnancies
number of women −28 day equivalent cycles of treatment 
Only at risk cycles, i.e. cycles in which no other methods of birth control (including condoms) 
are used and during which the subjects confirmed that sexual intercourse has occurred, will be 
included in the denominator of the Pearl Index calculation. The subject diary data will be used 
to determine whether additional birth control methods were used and whether the subject has 
had intercourse. 
Note that if conception occurs in a cycle, then that cycle will be included in the denominator 
even if other methods of birth control were used during that cycle or the subject did not confirm 
that they had had sexual intercourse. Cycles after the cycle of conception will be excluded from 
the denominator. All on-treatment pregnancies will be included in the numerator for the Pearl 
Index.   
On-treatment pregnancy is defined as pregnancy with an estimated date of conception within 
the on-treatment period, i.e. Day 1 to 7 days after the intake of investigational product (whether 
active or inactive tablet). In cases where the date of conception cannot be established 
unequivocally (e.g. subjects is lost to follow-up), this pregnancy will be considered an on-
treatment pregnancy. For calculation purposes a cycle will be defined as 28 days. 
The method failure Pearl Index is calculated using the same method as the Pearl Index, but 
includes only those pregnancies that were classified as method failure and not pregnancies due 
to user failure, i.e. incorrect intake of the contraceptive product. Compliance data will be used 
to determine if the pregnancy was due to user failure. 
Each on-treatment pregnancy will be reviewed and classified as either a method failure or a 
user failure pregnancy prior to database lock. Pregnancies will only be designated as user 


 
 
  
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failures if there is documentation that the subject did not use the test article correctly during 
the treatment cycle the conception occurred, including the instructions to be followed in case 
of missed pill(s). 
12.4.1 
Efficacy Endpoints 
The efficacy endpoints are: 
 Pearl Index for subjects aged of 16 to 35 years, inclusive, at screening; 
 Pearl Index for all ages; 
 Method failure Pearl Index for subjects aged 16 to 35 years old, inclusive, at screening; 
 Method failure Pearl Index for all ages. 
 
The primary efficacy endpoint will be the Pearl Index in the ITT population aged 16 to 35 
years, inclusive, at Screening with at risk cycles (cycles in which no other methods of birth 
control (including condoms) are used and during which the subjects confirmed that sexual 
intercourse has occurred). Subjects in this age group will not be censored on their 36th birthday 
for the pregnancy assessment. 
 
12.4.2 
Statistical Analysis 
12.4.2.1 
Confidence Intervals for the Pearl Indices 
The 95% CI for the Pearl Indices will be presented for the 16 to 35 year age group and overall 
and for method failure for the ITT population including only at risk cycles in the denominator. 
For historical comparison the Pearl Index will also be calculated using the same method as 
described above including all at risk cycles and cycles where the subject did not have 
intercourse and did not use back-up contraception in the denominator. 
The 95% CI for Pearl Indices will be calculated based on using a Poisson distribution.   
12.4.2.2 
Life-Table Rates  
In addition, the cumulative pregnancy rate, as determined by life-table methods, together with 
the corresponding 95% CIs will be presented for all pregnancies and for all method failure 
pregnancies in the ITT population. This will be repeated for all ages and for subject’s age 16 to 
35 years inclusive at Screening. 
Life-table analyses will provide one-year life-table pregnancy rates for each efficacy endpoint 
(i.e. for all pregnancies as used in the Pearl Index and for all method failure pregnancies as used in 
the method failure Pearl Index).  The life-table analysis will evaluate the cumulative probability 
of pregnancy by cycle using PROC LIFETEST in SAS where the time variable is the cycle 


 
 
  
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where the estimated conception occurred for subjects who had an on-treatment event of 
pregnancy. Subjects who did not have an on-treatment event of pregnancy will be censored on 
the cycle at which they discontinued from the study. Cumulative probabilities of pregnancy 
and 95% CIs will be calculated based on Kaplan-Meier estimates through Cycle 13. 
Additionally, the estimated survivor function against time (cycle) will be provided. 
12.4.3 
Statistical Subgroup Analyses  
If the sample size is adequate, subgroup analyses will be performed for the following 
categories: 
 BMI categories (< 30, ≥ 30); 
 Race category (White, Black, Asian, Other); 
 Starters/Switchers; 
 Smokers/Non-smokers; 
 Age (16-25; 25-35 and > 35 years old). 
12.5 Safety Analyses 
Safety variables will be summarized for the Safety population using descriptive statistics and 
frequency distributions as defined in the following sections.  
12.5.1 
Adverse Events 
TEAEs will be classified into a standardized terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA) system organ classifications and preferred terms.  The latest 
available version of MedDRA will be used as coding dictionary.  Prior to database lock, the 
coding will be updated using the current version of MedDRA.  The incidence of TEAEs will 
be summarized for the Safety population.  Although a preferred term or system organ class 
may be reported more than once for a subject, each subject will only be counted once in the 
incidence count for that preferred term or system organ class.  Summaries of the following 
types will be provided: 
• Overall summary of TEAEs. 
• Summary of TEAEs by MedDRA system organ class, MedDRA preferred term, 
investigational product relationship, and intensity. 
• Summary of TEAEs by MedDRA preferred term and investigational product relationship 
in descending order of frequency. 
• Summary of treatment-emergent SAEs by MedDRA system organ class, MedDRA 
preferred term, and investigational product relationship. 


 
 
  
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• Summary of TEAEs by MedDRA system organ class, MedDRA preferred term, and 
investigational product relationship for the primary events leading to premature 
discontinuation from the study. 
 
These summaries will present the number and percentage of subjects reporting an AE for each 
classification level as well as the number of events reported.  The denominator for calculating 
the percentages for summaries will be based on the number of subjects in the overall Safety 
population. 
All AEs, SAEs and deaths, SAEs considered to be related to treatment, and AEs leading to 
premature discontinuation from the study will also be provided in data listings including non-
treatment emergent events. 
12.5.2 
Extent of Exposure 
The duration of exposure in days will be summarized using descriptive statistics for the 
Safety/ITT population.  Duration of exposure will be calculated as the difference between last 
tablet intake date and the first tablet intake date plus 1.  
Additionally, these summaries will present the number and percentage of subjects exposed for 
at least 26 weeks and at least 52 weeks. The denominators for calculating the percentages will 
be based on the number of subjects in the Safety population. 
12.5.3 
Clinical Laboratory Evaluations 
For continuous clinical laboratory analytes, the absolute value and change from baseline will 
be summarized by analyte and visit using descriptive statistics for the Safety population.  
Categorical laboratory analytes, classified as normal or abnormal, will be summarized by 
analyte and visit using the number and percentage of subjects in each category for the Safety 
population.  The denominators for calculating the percentages will be based on the number of 
subjects with non-missing assessments at a particular visit for the Safety population. 
Shifts to values outside of the normal range will be presented by analyte and visit and will be 
summarized by the number and percentage of subjects with evaluable shifts. An evaluable shift 
is one where both the Screening Visit value and the on-treatment or early termination value 
are recorded for subjects in the Safety population. The denominators for calculating the 
percentages will be the number of subjects with an evaluable shift. 
All clinical laboratory values, abnormal clinical laboratory values, and clinical significant 
laboratory values will also be provided in data listings. 
12.5.4 
Physical examination 
Physical examination assessments will be summarized for the Safety population by visit.  For 
each body system and assessment category, the number and percentage of subjects will be 


 
 
  
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presented.  The denominators for calculating the percentages will be based on the number of 
subjects evaluated for a particular body system. 
12.5.5 
Gynecological examination 
Gynecologic examination assessments will be summarized for the Safety population by visit.  
For each assessment category, the number and percentage of subjects will be presented.   
12.5.6 
Vital Signs 
Vital sign measurements for the Safety population will be summarized using descriptive 
statistics by visit.  The change from baseline will also be summarized in the same manner. 
12.5.7 
Height, Weight and BMI 
Weight measurements and BMI calculation for the Safety population will be summarized using 
descriptive statistics by visit.  The change from baseline will also be summarized in the same 
manner. 
Height at baseline (Visit 1) will be summarized using descriptive statistics. 
12.6 Other Assessments or Analyses 
12.6.1 
Bleeding and spotting 
Bleeding/spotting data will be summarized according to the methods suggested by Mishell et 
al. 9.   


 
 
  
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Table 1: Bleeding and spotting definitions 
Term 
Definition 
Bleeding  
Evidence of vaginal blood loss that requires the use of sanitary 
protection with a tampon, pad or pantyliner. 
Spotting 
Evidence of minimal vaginal blood loss that does not require new use of 
sanitary protection, including pantyliners. 
Episode of 
Bleeding/Spotting 
Bleeding/spotting days bounded on either end by 2 days of no bleeding 
or spotting. 
Scheduled 
Bleeding/Spotting 
Any bleeding/spotting that occurs during the hormone-free interval (i.e. 
Days 25 – 28) and continues through Days 1-3 of the subsequent active 
cycle, 
and 
Any bleeding/spotting that occurs while taking active hormones during 
Days 1-7 of the first cycle. 
Unscheduled 
Bleeding 
Any bleeding that occurs while taking active hormones that does not 
meet the criteria for scheduled bleeding. 
Unscheduled 
Spotting 
Any spotting that occurs while taking active hormones that does not 
meet the criteria for scheduled spotting. 
 
Bleeding patterns will be analyzed in the ITT and PP populations using data from the subject 
diary. Criteria for exclusion of cycles from the PP analysis of bleeding patterns will be defined 
in the statistical analysis plan (SAP) based on specific protocol deviations thought to have a 
potential to impact the subjects bleeding patterns that occurred during that cycle. Vaginal 
bleeding will be classified as spotting or bleeding and scheduled and unscheduled based on the 
definitions in Table 1.  
There will be two types of reference periods (RP) evaluated for this study: 
 Reference period based on 28-days (or cycle) – 13 cycles 
 Reference period based on 91 days  
The analysis will include all subjects in the respective analysis population with at least 1 
evaluable reference period.  One or two consecutive days with missing bleeding information 
will be interpolated with the bleeding information from the previous day.  For three or more 
consecutive days with missing bleeding information, missing data will be interpolated using 
the worst bleeding observation of the bordering days. 
Summaries of bleeding/spotting data include but are not limited to the following: 
 Number and percentage of subjects with unscheduled bleeding and/or spotting 
episodes for each reference period. 


 
 
  
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 Percentage of subjects with bleeding and/or spotting including both scheduled and 
unscheduled for each day presented in a graphical display. 
 Number and percentage of subjects with absence of any bleeding or spotting for each 
reference period. 
 Descriptive statistics (e.g., mean, SD, median, minimum, and maximum) for the 
number of days of bleeding and/or spotting, bleeding only, and spotting only within a 
reference period for: 
o Total Days (Unscheduled + Scheduled) 
o Unscheduled Days 
o Scheduled Days 
Additionally, bleeding data may be summarized for some subgroups specified in Section 
12.4.3.  
12.6.2 
Disposition 
The disposition of subjects will be summarized including the number of subjects screened, 
enrolled, treated, discontinued (including reason for discontinuation) and completed. In 
addition, the number of subjects included in each of the analysis populations will be 
summarized. The cumulative discontinuation rate, as determined by life-table methods, 
together with the corresponding 95% CIs will be presented.   
12.6.3 
Demographic and Other Pre-treatment Characteristics 
Subject demographic as well as medical history will be summarized for each analysis 
population using descriptive statistics for continuous variables and frequency distributions 
(number and percentage of subjects) for categorical variables.  Summaries will be provided 
overall and by race and BMI categories in the Safety/ITT and PP populations. 
 
12.6.4 
Prior and Concomitant Medications 
Medication usage will be coded using the World Health Organization (WHO) Drug Dictionary. 
Medications will be presented by WHO Drug Anatomical/Therapeutic/Chemical category and 
WHO Drug preferred name. Summaries will be presented for prior (prior to treatment period) 
medication use and concomitant (during treatment period) medication use. 
Medications with an end date occurring before the first investigational product dose date in the 
treatment period will be identified as prior medications.  Medications with a start date 
occurring on or after the first investigational product dose date in the treatment period or 
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on or after the first investigational product dose date will be identified as concomitant 
medications. All summaries will present the number and percentage of subjects for each 
medication. The denominators for calculating the percentages will be based on the number of 
subjects in the Safety population. 
12.6.5 
Treatment Compliance 
Treatment compliance by cycle will be presented using the subject diaries based on number of 
tablets taken divided by the number of tablets that should have been taken. The number and 
percentage of subjects missing no tablets, 1 tablet, 2 tablets and more than 2 tablets will be 
summarized for each cycle. Summaries will be presented using descriptive statistics in the 
Safety population. 
12.6.6 
 Protocol Deviations 
The number and percentage of subjects who had an important protocol deviation will be 
summarized for the enrolled population. 
12.6.7 
Quality of Life 
The total score of the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form 
(Q-LES-Q-SF) (Appendix 4) will be derived by summing the first 14 items to obtain the raw 
total score, which is then transformed into a percentage maximum using the following formula: 
(raw score – 14)/56. The absolute values and change from baseline of the percentage 
maximum, how satisfied the subject has been with the medication and how would the subject 
rate the overall life satisfaction and contentment during the past week will be summarized 
descriptively by visit. 
The Menstrual Distress Questionnaire will be scored according to the manual (Appendix 5) 10. 
The absolute values and change from baseline for the scores for pain, water retention, 
autonomic reactions, negative affect, impaired concentration, behavior change, arousal and 
control will be summarized descriptively by visit. Summaries will be provided overall and by 
switchers and starters separately. 
12.6.8 
Follow-Up Evaluations 
The number and percentage of subjects who had pregnancy confirmation, returned to menses 
and received a new contraceptive method after the treatment termination will be summarized. 
The denominator used for the percentages will be the number of subjects in the Safety 
population who discontinued study medication due to a pregnancy wish. 
The time from last dose of study medication to return of menses will be summarized using 
descriptive statistics in the Safety population.  


 
 
  
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The following will be summarized using descriptive statistics for subjects in the Safety 
population who discontinued study medication due to a pregnancy wish who selected the 
corresponding fertility information: 
 Time from last dose of study medication to estimated date of conception; 
 Time from last dose of study medication to new contraceptive method. 
 
12.6.9 
Population Pharmacokinetic Substudy 
Plasma concentration data for E4 and DRSP will be summarized using descriptive statistics by 
cycle and sampling time range (ranges will be defined in the Statistical Analysis Plan) for the 
PK population. Descriptive summaries will be provided overall and by race, BMI categories 
(< 30, ≥ 30), smoking status (smokers, non-smokers), and fed/fasted condition. Additionally, 
concentration data will be displayed graphically with regression lines overall, and by race, BMI 
categories, and smoking status for each cycle. 
Individual plasma concentration-time data will be pooled for the PK analyses. Initially, the 
data will be subjected to exploratory compartmental analysis to determine the primary 
parameters such as: 
 Apparent clearance (CL/F). 
 Central volume of distribution (V/F). 
 Lag time of Absorption (tlag), if necessary. 
 Relative bioavailability for fed vs fasted state. 
The initial estimates obtained from the exploratory analyses will be employed using Bayesian 
analysis to build an appropriate population PK model. The analyzed parameters will include, 
but not be limited to: 
 Maximum concentration (Cmax). 
 Time to maximum concentration (Tmax). 
 Extent of exposure for dosing interval (AUCtau). 
 Terminal half-life (t1/2). 
The estimated population mean values will be utilized in conjunction with the individual 
subject concentrations to determine inter-individual variability. If inter-individual variability 
is unable to be assessed on any individual parameter, the population mean values alone may 
be used. The impact of individual characteristics on the parameters will be explored and 
included in the population model if significant. Individual estimates of the above parameters 
and additional PK variables will be generated based on the population model. The basic model 
will be evaluated for random scatteredness by residual variability analysis. The model will 
further be validated using various diagnostic techniques, as necessary. Covariate analyses will 
be performed separately for the PK of E4 and DRSP. 


 
 
  
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13 STUDY MANAGEMENT 
13.1 Monitoring 
The Investigator will be responsible for preparing and maintaining adequate and accurate 
source documents (medical records, raw data collection forms, etc.) designed to record all 
observations and other pertinent data for each subject treated with the study drug.  The 
Investigator will allow representatives of the Sponsor, contract Designees, authorized 
regulatory authority inspectors, and the ECs to have direct access to all documents pertaining 
to the study.  The Investigator is to immediately notify the Sponsor (or its representative) of 
any regulatory authority inspections.  The Investigator will be informed about the outcome of 
any Sponsor audit. 
This study will be monitored regularly, by or under supervision of a monitor from the Sponsor’ 
representative.  The frequency of monitoring visits will be agreed upon by the Sponsor’s 
representative and the study staff.  
Monitoring visits will take place on a regular basis according to the enrollment rate and number 
of subjects enrolled at each investigational site.  During these visits, the monitor will check the 
completion of the eCRF entries, compliance with the study protocol and with GCP - ICH, and 
their agreement with the source data.  The monitor will also verify the correct use of the study 
drug.  At a final visit, the monitor will check all remaining material including the remaining 
quantities of the study drug and will organize their return to the Sponsor or Designee.  At each 
visit, the Investigator and staff will be expected to cooperate with the Sponsor’s 
representative(s) for the purposes of review and verification of protocol compliance, AE 
reporting, eCRFs, source documents, clinical supplies and inventory records, and any 
additional records as may have been previously arranged between the Investigator and the 
Sponsor’s representative(s). 
The Investigator and/or other designated study personnel are expected to contact the Sponsor’s 
representative with any study concerns and/or questions. Contact details are provided in the 
Site Operations Manual for the site. 
13.2 Protocol amendments 
The Sponsor may propose to amend this protocol at any time. 
No change to the protocol will be implemented until the Sponsor, the competent authorities 
and the IRB have reviewed and approved the amendment. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety.  All such procedures must have written documentation and be 
promptly reported to the Sponsor. 
 


 
 
  
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13.3 Protocol deviations 
A protocol deviation is any change, divergence or departure from the IRB approved protocol 
(intentional or unintentional). All deviations are to be documented at the site and reported to 
the IRB according to the IRB’s guidelines. 
In the event of an emergency, the Investigator shall implement any medical procedures deemed 
appropriate for subject safety. All such procedures must have written documentation and be 
promptly reported to the Sponsor.   
13.4 Withdrawal of Subjects 
Withdrawn subjects are those who do not complete all evaluations and procedures outlined in 
the protocol. Subjects who discontinue taking study drug for any reason must also be 
withdrawn from the study. Subjects may be withdrawn from the study because of one of the 
following: 
 Adverse Event: An AE that, in the opinion of the Investigator or Sponsor, suggests 
that continued participation in the study is not in the subject’s best interest for safety 
reasons.  The occurrence of a VTE or an arterial thromboembolic event will 
automatically lead to the immediate cessation of the study drug and is an absolute 
reason for discontinuing the subject participation in the trial. Only 1 AE can be 
noted to be the reason for withdrawal.  All AEs that are present when the subject 
withdraws from the study will be followed as described in Section 9.6.3.1. 
 Lost to Follow-up: Confirmed at minimum by two phone calls and a traceable letter 
without answer. 
 Subject Request: Subject requests for any reason to be withdrawn or withdraws her 
consent. 
 Protocol Deviation: A subject may be withdrawn from the study at the discretion 
of the Investigator or Sponsor due to poor compliance with protocol requirements 
that may compromise the study results or subject safety. 
 Pregnancy: If a subject becomes pregnant during the study, the subject will be 
withdrawn from the study and followed through conclusion of the pregnancy. 
 Pregnancy wish. 
 Other: Other reasons include but are not limited to: Investigator decision that it is 
in the subject’s best interest to be withdrawn, administrative reasons, relocation of 
subject, etc.   
If a subject is withdrawn from the study after enrolment visit (Visit 2), all Visit 7 assessments 
should be completed (see Section 9.5.3.5) and the subject should be counseled about alternative 
contraception to use (see Section 9.6.4.9).  Subjects withdrawn from the study will not be 
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13.5 Termination of the Study 
If the study is terminated prematurely or suspended, the appropriate IRB and regulatory 
authority(ies) will be promptly informed of the termination or suspension and will be provided 
the reason(s) for the termination or suspension.  All obligations and responsibilities of the 
Sponsor and the Investigator under GCP, the US CFR and the Declaration of Helsinki will 
remain in force if the study is terminated prematurely. 
 
 
 


 
 
  
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14 DOCUMENTATION REQUIREMENTS AND RECORDKEEPING 
14.1 Source Documentation, Data access and Monitoring 
The eCRFs represent a record of the subject’s experience in the study, therefore, the eCRF data 
must be supported by original (or source) medical records, as appropriate. EMR (Electronic 
Medical Records)  recorded directly into the eCRF is also considered source data when there 
are no other written or electronic records preceding the eCRF entry. 
Prior to enrolling a subject in the study, the Investigator must document his/her review of 
subject eligibility criteria in the source records for the subject, including the Investigator’s 
signature and date on any medical and laboratory reports indicating a review of the source data 
occurred.  The Investigator will continue to follow this practice for any subsequent medical 
and laboratory reports generated as a result of the clinical study. 
The Investigator agrees that the Sponsor or its designated agents, the IRB, the EMA, FDA or 
foreign regulatory agencies will have reasonable access to study source documentation for 
purposes of audit or inspection and monitoring visit review both during and after completion 
of the study. Monitoring visits provide the Sponsor and Designee with the opportunity to 
evaluate the progress of the study; to verify the accuracy and completeness of eCRFs; to ensure 
that all protocol requirements, applicable regulations and Investigator's obligations are being 
fulfilled; and to resolve any inconsistencies in the study records.   
14.2 Data Capture in electronic CRFs and Discrepancy Management 
Site personnel will be responsible for the completion and correction of eCRFs according to the 
protocol and other instructions provided by the Sponsor or their Designee. The Investigator is 
responsible for ensuring the completeness and accuracy of the data as evidenced by the 
Investigator’s signature and date once the subject has completed the study and all required 
study data has been entered into the eCRF. Information recorded by the subject into a Diary 
Card will be entered into the eCRFs by the site personnel.   
Since site personnel will enter data directly into a validated eCRF, programmatic data 
validation procedures will be employed to identify data discrepancies to site personnel at the 
time of entry and/or upon saving the data.  Designated site personnel will resolve any 
discrepancies via the eCRF.  Any additional findings upon clinical review by the Sponsor or 
their Designee will be entered into the system for review and resolution by site personnel.  A 
full audit trail of data changes following entry will be captured during the study in the 
electronic data management system.  The Investigator will be provided with a copy of all eCRF 
data for retention. 
14.3 RECORD KEEPING 
In compliance with ICH guidelines, the Investigator shall maintain adequate records for the 
study including copies of eCRFs for individual subjects, medical records, laboratory reports, 


 
 
  
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consent forms, test article disposition records, safety reports, information regarding 
participants who discontinued and other pertinent data. The Investigator shall maintain these 
records for a period of at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the test article. These records should be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. The Sponsor will 
inform the Investigator/institution as to when these records no longer need to be retained. 
 


 
 
  
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15 OTHER INFORMATION 
15.1 Financing and Insurance 
Financing and insurance is addressed in a separate agreement. 
15.2 Publication and Disclosure Policy 
The data that will be obtained in this study will be the property of the Sponsor, who will make 
reasonable efforts to assure that the results are published in a peer-reviewed journal. As some 
of the information concerning the investigational product and development activities at the 
Sponsor may be of strictly confidential nature, any manuscript or other presentation of data 
must first be reviewed by the Sponsor before its submission. 
 


 
 
  
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16 REFERENCE LIST 
 
1 
Duijkers, I. J. et al. Inhibition of ovulation by administration of estetrol in 
combination with drospirenone or levonorgestrel: Results of a phase II dose-finding 
pilot study. The European journal of contraception & reproductive health care : the 
official journal of the European Society of Contraception 20, 476-489, 
doi:10.3109/13625187.2015.1074675 (2015). 
2 
Mawet, M. et al. Unique effects on hepatic function, lipid metabolism, bone and 
growth endocrine parameters of estetrol in combined oral contraceptives. The 
European journal of contraception & reproductive health care : the official journal of 
the European Society of Contraception, 1-13, doi:10.3109/13625187.2015.1068934 
(2015). 
3 
Lockwood, C. & Watkins, T. A. FDA. Advisory Committee for Reproductive Health 
Drugs meeting. Final Summary Minutes. (2007). 
4 
Kapp, N., Curtis, K. M. & Borgatta, L. Study design to evaluate the safety and 
effectiveness of hormonal contraception for women. Clin.Obstet.Gynecol. 50, 850-
867, doi:10.1097/GRF.0b013e318159bf8a [doi];00003081-200712000-00003 [pii] 
(2007). 
5 
EMEA. The EMEA CHMP guideline on clinical investigation of steroid 
contraceptives in women. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
09/WC500003349.pdf (2005). 
6 
Division of Reproductive Health, N. C. f. C. D. P., Health Promotion, C. f. D. C. & 
Prevention. U.S. Selected Practice Recommendations for Contraceptive Use, 2013: 
adapted from the World Health Organization selected practice recommendations for 
contraceptive use, 2nd edition. MMWR Recomm Rep 62, 1-60 (2013). 
7 
Nayar, R. & Wilbur, D. C. The Pap Test and Bethesda 2014. "The reports of my 
demise have been greatly exaggerated." (after a quotation from Mark Twain). Acta 
Cytol 59, 121-132, doi:10.1159/000381842 (2015). 
8 
Gerlinger, C., Endrikat, J., van der Meulen, E. A., Dieben, T. O. & Dusterberg, B. 
Recommendation for confidence interval and sample size calculation for the Pearl 
Index. Eur.J.Contracept.Reprod.Health Care 8, 87-92 (2003). 
9 
Mishell, D. R., Jr. et al. Recommendations for standardization of data collection and 
analysis of bleeding in combined hormone contraceptive trials. Contraception 75, 11-
15, doi:S0010-7824(06)00325-8 [pii];10.1016/j.contraception.2006.08.012 [doi] 
(2007). 
10 
Moos, R. H. The development of a menstrual distress questionnaire. Psychosom Med 
30, 853-867 (1968). 
 
 


 
 
  
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17 APPENDICES 
Appendix 1 
Study Schedule of Events  
Appendix 2 
Clinical Laboratory Evaluations 
Appendix 3 
Bethesda Pap Smear Classification 
Appendix 4 
Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-
LES-Q-SF) 
Appendix 5 
Menstrual Distress Questionnaire (Form C-Cycle) 
Appendix 6 
Sponsor Signatures 
Appendix 7 
Contract Research Organization Signatures 
Appendix 8 
Investigator Signature 
Appendix 9 
Protocol Amendment – Summary of changes 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1. 
Study Schedule of Events 
Table 2: Schedule of Events 
Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14  
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and 
surgical History 
X 
 
 
 
 
 
 
 
Gynecological 
History 
X 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
X 
X 
Weight, Height and 
BMI2 
X 
 
 
X 
X 
 
X 
X 
Gynecological 
Examination 
(including breast) 
X 
 
 
 
 
 
X 
X 
Cervical Cytology 
(Pap)3 
X 
 
 
 
 
 
 
 
Chlamydia Testing 
X4 
X5 
X5 
X5 
X5 
X5 
 
 
Gonorrhea Testing 
X4 
X5 
X5 
X5 
X5 
X5 
 
 
Blood sample for 
Population PK 
Substudy6 
 
 
X 
X 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
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Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14  
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Serum Pregnancy 
Test7 
X 
 
 
 
 
 
X 
X 
Dispense Home 
Urine Pregnancy 
Test Kits 
 
X8 
 
 
 
 
 
 
Fasted clinical 
Laboratory tests 
(hematology and 
biochemistry) 
X9 
 
 
 
X10 
 
X9 
X9 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
 
 
Investigational 
Product Dispensing 
 
X 
 
X 
X 
X 
 
 
Investigational 
Product Return and 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
X 
Subject Diary 
Dispensing 
 
X 
 
 
 
 
 
 
Subject Diary 
Review and Return 
 
 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
 
 
 
 
 
 
TEAE Assessment 
 
 
X 
X 
X 
X 
X 
X 
Prior Medication 
X 
X 
 
 
 
 
 
 
Concomitant 
Medication 
 
 
X 
X 
X 
X 
X 
X 


 
 
 
 
 
 
 
 
 
 
 
 
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Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14  
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Stop Date of the 
Previous 
Contraceptive 
Method (if any) 
 
 
X 
 
 
 
 
 
Questionnaires 
dispensing 
 
X 
 
 
 
X 
 
 
Questionnaires 
completion check 
 
 
X 
 
 
 
X 
X 
Contraceptive 
Counseling 
 
 
 
 
 
X 
X 
X13 
Follow-up Call 
 
X14 
 
 
 
X15 
 
 
End of Study Form 
 
 
 
 
 
 
X 
X 
Return of 
spontaneous 
menstruation and 
return to fertility16 
 
 
 
 
 
 
 
 
1 Subject enrollment will occur within 45 days after the Screening Visit. 
2 Height will be recorded at Screening Visit only. 
3A written documentation of prior Pap test performed within 18 month before screening is allowed. No Pap test will be performed in subjects less than 20 years of age. 
4 Chlamydia and gonorrhea testing at screening should be performed for all subjects. 
5 Chlamydia and gonorrhea testing during Visits will be performed for subjects who reported a change in sexual partner since last test.  
6 Applies only to the approximately 500 subjects who participate in the Population PK Substudy. 
7 Pregnancy test (serum) also indicated in case of suspicion of pregnancy. 
8 Subject should perform urinary pregnancy test at home just before the first pill intake. Result should be recorded in the diary. 
9 Complete hematology and biochemistry (including glycaemia, glycated hemoglobin, total cholesterol, HDL- and LDL-cholesterol, and triglycerides) (see Appendix 2). 


 
 
 
 
 
 
 
 
 
 
 
 
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10 At Visit 5, the following biochemistry parameters will be assessed: glycaemia, glycated hemoglobin, LDH 1 and LDH 2, total cholesterol, HDL- and LDL-cholesterol, 
triglycerides, renal function (urea and creatinine), GFR, and ionogram (Na, K, Cl, Ca2+, P, HCO3-). 
11 Visit 3 and 4 for the subjects in the Population PK Substudy should be performed between Days 10 and 14 of Cycles 2 and 4. 
12 The Early Termination Visit should occur between 16 and 23 days after the last investigational product intake or immediately if the study product was never started. 
13 In case of early termination or withdrawal of subject who did not undergo a Visit 6: contraceptive counseling should be provided as soon as the site is aware of the subject’s 
desire for termination. 
14 Within 7 days following the expected start of treatment to remind the subject to complete the diary entries. 
15 On the day the subject is expected to start the next contraceptive method (± 1 day) to ensure subject’s compliance. 
16Women who discontinue the study due to a pregnancy wish will be followed up for a maximum of one year after study discontinuation for return of spontaneous menstruation 
and until pregnancy or initiation of a contraceptive method (whichever occurs first). 
AE=adverse event; BMI=body mass index; GFR=glomerular filtration rate; HDL=high-density lipoprotein; LDL=low-density lipoprotein; TEAE=treatment-emergent adverse 
event; LDH=lactate dehydrogenase 
 


 
 
 
 
 
 
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Appendix 2. 
Clinical Laboratory Evaluations 
Hematology 
Hemoglobin 
Mean cell volume 
Hematocrit 
White blood cell & Differential 
Red blood cell count 
Platelet count 
Serum Chemistries 
Albumin 
Total protein 
Alanine aminotransferase (ALAT) 
Serum creatinine 
Aspartate aminotransferase (ASAT) 
GFR 
Blood urea nitrogen  
Sodium 
Gamma glutamyl transferase (GGT) 
Potassium 
Glucose 
Calcium 
Glycated hemoglobin 
Chloride 
Lactate dehydrogenase (LDH) 1 and LDH 2  Bicarbonate 
Total bilirubin 
Phosphorus 
Lipid Profile 
Total cholesterol 
Triglycerides 
High density lipoprotein cholesterol 
Low density lipoprotein cholesterol 
 


 
 
 
 
 
 
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Appendix 3. 
Bethesda Pap Smear Classification7 
SPECIMEN TYPE: 
Indicate conventional smear (Pap smear) vs. liquid-based preparation vs. other 
STATEMENT ON SPECIMEN ADEQUACY 
 Satisfactory for evaluation (describe presence or absence of endocervical/transformation 
zone component and any other quality indicators, e.g., partially obscuring blood, 
inflammation, etc.) 
 Unsatisfactory for evaluation (specify reason) 
o Specimen rejected/not processed (specify reason) 
o Specimen processed and examined, but unsatisfactory for evaluation of epithelial 
abnormality because of (specify reason) 
GENERAL CATEGORIZATION (optional) 
 Negative for Intraepithelial Lesion or Malignancy 
 Other: See Interpretation/Result (e.g., endometrial cells in a woman ≥45 years of age) 
 Epithelial Cell Abnormality: See Interpretation/Result (specify ‘squamous’ or ‘glandular’ 
as appropriate) 
INTERPRETATION/RESULT 
NEGATIVE FOR INTRAEPITHELIAL LESION OR MALIGNANCY 
(When there is no cellular evidence of neoplasia, state this in the General Categorization above and/or 
in the Interpretation/Result section of the report—whether or not there are organisms or other non-
neoplastic findings) 
Non-neoplastic Findings (optional to report) 
 
Non-neoplastic cellular variations 
o Squamous metaplasia 
o Keratotic changes 
o Tubal metaplasia 
o Atrophy 


 
 
 
 
 
 
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o Pregnancy-associated changes 
 
Reactive cellular changes associated with: 
 Inflammation (includes typical repair) 
o Lymphocytic (follicular) cervicitis 
 Radiation 
 Intrauterine contraceptive device (IUD) 
 
Glandular cells status post hysterectomy 
Organisms 
 Trichomonas vaginalis 
 Fungal organisms morphologically consistent with Candida spp. 
 Shift in flora suggestive of bacterial vaginosis 
 Bacteria morphologically consistent with Actinomyces spp. 
 Cellular changes consistent with herpes simplex virus 
 Cellular changes consistent with cytomegalovirus 
OTHER  
 Endometrial cells (in a woman ≥45 years of age) 
(Specify if “negative for squamous intraepithelial lesion”) 
EPITHELIAL CELL ABNORMALITIES: 
 SQUAMOUS CELL 
 Atypical squamous cells 
o of undetermined significance (ASC-US)   
o cannot exclude HSIL (ASC-H) 
 Low-grade squamous intraepithelial lesion (LSIL) (encompassing:  HPV/ mild 
dysplasia/CIN 1) 


 
 
 
 
 
 
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 High-grade squamous intraepithelial lesion (HSIL) (encompassing:  moderate and 
severe dysplasia, CIS; CIN 2 and CIN 3) 
 with features suspicious for invasion (if invasion is suspected) 
 Squamous cell carcinoma 
 GLANDULAR CELL 
 Atypical 
o endocervical cells (NOS or specify in comments) 
o endometrial cells (NOS or specify in comments) 
o glandular cells (NOS or specify in comments) 
 Atypical 
o endocervical cells, favor neoplastic 
o glandular cells, favor neoplastic 
 Endocervical adenocarcinoma in situ 
 Adenocarcinoma 
o endocervical 
o endometrial 
o extrauterine 
o not otherwise specified (NOS) 
OTHER MALIGNANT NEOPLASMS: (specify) 
ADJUNCTIVE TESTING 
Provide a brief description of the test method(s) and report the result so that it is easily 
understood by the clinician. 
COMPUTER-ASSISTED INTERPRETATION OF CERVICAL CYTOLOGY 
If case examined by an automated device, specify device and result. 


 
 
 
 
 
 
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Appendix 4. 
Quality of Life Enjoyment and Satisfaction 
Questionnaire – Short Form (Q-LES-Q-SF) 
 


 
 
 
 
 
 
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Appendix 5. 
Menstrual Distress Questionnaire (Form C – Cycle)1 
 
Directions:  
The list below shows common symptoms and feelings associated with menstruation. For each 
item, choose the descriptive category below that best describes your experience during each of 
the three time periods indicated. That is, for each item, decide whether you have “no experience 
of symptom”, or whether your experience is “present, mild”, “present, moderate”, “present, 
strong” or “present, severe. Then write the number of the category in the space provided. If 
none of the categories exactly describes your experience, choose the one that most closely 
matches what you feel.  
Be sure to rate every item. When you are finished return the completed form to the person who 
gave it to you.  
 
Descriptive Categories  
0  
No experience of symptom  
1  
Present, mild  
2  
Present, moderate  
3  
Present, strong  
4  
Present, severe  
 
 
 
Most recent 
flow 
Four days 
before 
Remainder of 
cycle 
1. Muscle stiffness 
 
 
 
2. Headache 
 
 
 
3. Cramps 
 
 
 
4. Backache 
 
 
 
5. Fatigue 
 
 
 
6. General aches and pains 
 
 
 
7. Weight gain 
 
 
 
8. Skin blemish or disorder 
 
 
 
9. Painful or tender breasts 
 
 
 
10. Swelling (breasts, abdomen, ..) 
 
 
 
11. Dizziness, faintness 
 
 
 
12. Cold sweats 
 
 
 
13. Nausea, vomiting 
 
 
 
                                                 
1 Copyright © 1968, 1991, 2000, 2010 Rudolf H. Moos. All rights reserved.   


 
 
 
 
 
 
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Most recent 
flow 
Four days 
before 
Remainder of 
cycle 
14. Hot flashes 
 
 
 
15. Loneliness 
 
 
 
16. Anxiety 
 
 
 
17. Mood swings 
 
 
 
18. Crying 
 
 
 
19. Irritability 
 
 
 
20. Tension 
 
 
 
21. Feeling sad or blue 
 
 
 
22. Restlessness 
 
 
 
23. Insomnia 
 
 
 
24. Forgetfulness 
 
 
 
25. Confusion 
 
 
 
26. Poor judgment 
 
 
 
27. Difficulty concentrating 
 
 
 
28. Distractible 
 
 
 
29. Minor Accidents 
 
 
 
30. Poor motor coordination 
 
 
 
31. Poor school/work performance 
 
 
 
32. Take naps, stay in bed 
 
 
 
33. Stay at home 
 
 
 
34. Avoid social activities 
 
 
 
35. Decreased efficiency 
 
 
 
36. Affectionate 
 
 
 
37. Orderliness 
 
 
 
38. Excitement 
 
 
 
39. Feelings of well-being 
 
 
 
40. Bursts of energy, activity 
 
 
 
41. Feelings of suffocation 
 
 
 
42. Chest pains 
 
 
 
43. Ringing in the ears 
 
 
 
44. Heart pounding 
 
 
 
45. Numbness, tingling 
 
 
 
46. Blind Spots, fuzzy vision 
 
 
 
 


 
 
 
 
 
 
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Appendix 6. 
Sponsor Signatures 
Study Title: 
A Multicenter, Open-label, Single-Arm Study to Evaluate the 
Contraceptive Efficacy and Safety of a Combined Oral 
Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone 
Study Number: 
MIT-Es0001-C302 
Original protocol 
date: 
07 June 2016 – Version 1.1 
Amendment 1.0 
date: 
14 December 2016 
Amendment 1.1 
10 July 2017 
date 
 
 
 
This clinical study protocol was subject to critical review and has been approved by the 
Sponsor. The following personnel contributed to writing and/or approving this protocol: 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date:   
_________ 
Marie Mawet 
Medical Advisor 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Mitchell Creinin 
Senior Medical Advisor  
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Sophie Ledant 
Clinical Project Leader 


 
 
 
 
 
 
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Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Barbara Bovy 
Qualified Person for Pharmacovigilance 
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Francoise Bruyère 
Clinical Manager 
 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Valérie Gordenne 
Chief Scientific Officer 
 
 


 
 
 
 
 
 
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Appendix 7. 
Contract Research Organization Signatures 
Study Title: 
A Multicenter, Open-label, Single-Arm Study to Evaluate the 
Contraceptive Efficacy and Safety of a Combined Oral 
Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone 
Study Number: 
MIT-Es0001-C302 
Original protocol 
date: 
07 June 2016 – Version 1.1 
Amendment 1.0 
date: 
14 December 2016 
Amendment 1.1 
10 July 2017 
date 
 
 
 
 
 
This clinical study protocol was subject to critical review and has been approved by PRA 
Health Sciences.  
 
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Jess Read 
Principal Biostatistician 
PRA Health Sciences 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Vijaya Vundurti 
Drug Safety Associate 
PRA Health Sciences 
 
 
 
 


 
 
 
 
 
 
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Signature:  
 
 
 
 
 
 
 
Date:   
_________ 
Douglas Stewart 
Lead Data Manager 
PRA Health Sciences 


 
 
 
 
 
 
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Appendix 8. 
Investigator Signature 
Study Title: 
A Multicenter, Open-label, Single-Arm Study to Evaluate the 
Contraceptive Efficacy and Safety of a Combined Oral 
Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone 
Study Number: 
MIT-Es0001-C302 
Original protocol 
date: 
07 June 2016 – Version 1.1 
Amendment 1.0 
date: 
14 December 2016 
Amendment 1.1 
date 
10 July 2017 
 
This clinical study protocol was reviewed and has been approved by the Investigator. 
 
Name:__________________________________________ 
 
Function: _______________________________________ 
 
Institution:_______________________________________ 
 
 
Signature:  
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 


 
 
 
 
 
 
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Appendix 9. 
Protocol Amendment - Summary of changes 
Modified sections in Protocol: MIT-Es0001-C302 Amendment Version 1.0 
This section summarizes changes that have been performed between original protocol (Final 
Version 1.1 (07 June 2016) and Amendment Version 1.0 (14 December 2016). 
 
Note: wherever applicable, deleted text has been crossed out and added text has been 
printed in bold and italic characters. 
 
2 
SYNOPSIS 
Other Secondary Objectives: 
[…] 
4. To assess the effect of various individual characteristics/ covariates (body weight, race, 
and smoking, and fed/fasted condition) on the pharmacokinetics (PKs) of 15 mg E4/3 mg 
DRSP (Population PK Substudy). 
[…] 
 Eligibility criteria: 
Exclusion Criteria 
A subject will be excluded from participation if she meets any of the following criteria: 
[…] 
7. Smoking nicotine-containing products if ≥ 35 years old, at screening. 
16. Complicated valvular heart disease (pulmonary hypertension, arterial atrial fibrillation, 
subacute bacterial endocarditis). 
25. History of COC-related cholestasis. 
[…] 
Statistical Methods: 
[…] 
 
Additional Summaries: 
[…] 


 
 
 
 
 
 
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 Population PK model (using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects). PK parameters will include, but not be limited to: 
o […] 
o Relative bioavailability for fed vs fasted state 
o […] 
Initial estimates of PK parameters (e.g., CL/F, V/F, tlag) will be determined using 
exploratory compartmental analyses. These estimates will be employed to build an 
appropriate population PK model. The primary parameters will include (but not be limited 
to) Cmax, Tmax, AUCtau, and t1/2 CL/F, V/F, tlag and relative bioavailability for fed vs fasted. 
The impact of individual characteristics (body weight, race, and smoking, and fed/fasted 
condition) on the PK parameters will be explored and included in the population model if 
significant.  
[…] 
 
 
7 
INTRODUCTION 
7.1 Background 
[…] 
The potent synthetic estrogen, ethinylestradiol (EE), is the most frequently used estrogen in 
COCs. EE is easily observed absorbed when administered orally. 
[…] 
8  
STUDY OBJECTIVES 
 
8.3 Other Secondary Objective(s) 
 4. To assess the effect of various individual characteristics/ covariates (body weight, race,  
and smoking, and fed/fasted condition) on the PKs of 15 mg E4/3 mg DRSP (Population PK 
Substudy). 
 
9 
INVESTIGATIONAL PLAN 
9.1 Overall Study Design and Plan 
[…] 
The total duration of the study, including the screening, will range from 382 387 to 447 467 
days for the participating subjects, which is approximately a year and one month. 


 
 
 
 
 
 
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[…] 
Population PK will be assessed using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects to address the relationship between E4 and DRSP PK 
parameters and various individual characteristics (e.g., body weight, race, and smoking, and 
fed/fasted condition). Blood samples for PK analysis will be obtained at Visits 3 and 4 between 
Days 10 and 14 of Cycles 2 and 4 (section 9.6.4.2). 
9.3 Selection of Study Population 
[…] 
9.3.2 Exclusion Criteria 
A subject will be excluded from participation if she meets any of the following criteria: 
2. […] 
7. Smoking nicotine-containing products if ≥ 35 years old, at screening. 
16. Complicated valvular heart disease (pulmonary hypertension, arterial atrial fibrillation, 
subacute bacterial endocarditis). 
19. Presence or history of migraine with aura at any age or migraine without aura if >  35 
years old. 
25. History of COC-related cholestasis. 
26-42. […] 
9.4 Study Treatment 
9.4.4 Selection of Doses and Timing of Administration in the Study 
9.4.4.1 Instructions for starting the first pack of tablets 
 Women who did not use any contraceptive method or who used a barrier 
contraceptive method will be instructed to begin the investigational product on 
the first day of the next menstrual bleeding. Starting on Days 2-5 is also 
allowed, but a condom must be used until the subject has completed 7 days of 
uninterrupted active tablet intake. If the menstrual cycle prior to start of first 
pack of tablets is longer than 35 days or shorter than 21 days, the subject 
should not start the investigational product and will be withdrawn from the 
study (section 13.4). The subject should contact the study staff as soon as 
possible to schedule an Early Termination Visit (section 9.5.4) and to discuss 
an alternative contraception to use (section 9.6.4.9).                                                                 


 
 
 
 
 
 
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 […] 
 Women switching from an injectable hormonal method of contraception will 
start the investigational product on the first day of the spontaneous menstrual 
bleeding following an interval after the last injection, which can vary 
depending of the form:  
- 10 months after the injection of a product with a 3-month duration, ; 
- 6 months after the injection of a product with a 2-month duration and;  
- 3 months after the injection of a product with a 1-month duration.  
Starting on Days 2-5 is also allowed, but a condom must be used until the 
subject has completed 7 days of uninterrupted active tablet intake.   
 Women switching from an intrauterine or dermally implantable contraceptive 
will start the investigational product on the day of removal. A condom must be 
used until the subject has completed 7 days of uninterrupted active tablet 
intake. 
[…] 
9.4.4.2 Dosing Instructions 
[…] 
 […] 
 Return all blister packs to site personnel at the following visit. 
 
9.4.4.3 Instructions in case of missed tablet(s) or in conditions potentially reducing the 
contraceptive efficacy 
If the subject has vomiting or diarrhea within 4 hours of tablet intake, she should take 
another tablet from the extra pack as a replacement. 
If the subject inadvertently misses one or more of the tablets or 
 In case of vomiting within 4 hours after the tablet intake or, 
 In case of diarrhea within 4 hours after the tablet intake, 
the following instructions must be followed:6   
 […] 
 If two or more consecutive active pink tablets have been missed (≥ 48 hours 
since a tablet should have been taken): 
o If between Day 1 & Day 17: 


 
 
 
 
 
 
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 […] 
 Consider emergency contraception as per current practice 
if the woman had unprotected intercourse during the 
missed pill interval. 
o […] 
 
 A new pack of tablets should be started immediately after the day the last white 
tablet was taken. There should be no interruption between two blister packs.  
Anytime a subsequent cycle of the product/pack is started later than the day 
following administration of the last white tablet, the subject should use condoms 
until she has taken pink tablets daily for 7 consecutive days. 
 Return all blister packs to site personnel at the following visit. 
 
 
9.5 Study Activities 
[…] 
9.5.1 Visit 1: Screening Visit  
[…] 
Potential subjects will be screened according to the inclusion and exclusion criteria within 30 
45 days prior to the subject enrollment visit (Visit 2). Subjects who were eligible for the study 
but did not enroll within 45 days of screening (Visit 1) can be re-screened. Re-screening 
requires all Visit 1 assessments to be repeated. The Investigator will maintain a log of all 
subjects screened for participation and record the reason(s) for excluding potential subjects. 
[…] 
9.5.2 Visit 2: Subject Enrollment 
The Visit 2 will occur within 30 45 days after the Screening Visit (Visit 1), when the entire 
laboratory results of the subject have been received. 
[…] 
During Visit 2, the following procedures will be performed: 
1-10. […] 
11. Schedule or confirm the next study visit and the follow-up phone call; 
12. […] 


 
 
 
 
 
 
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13. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product before 
contacting the site; 
14. […] 
9.5.3 Treatment Period (from Cycle 1 Day 1 until Cycle 13 Day 28) 
9.5.3.1 Visit 3 (Cycle 2, between Day 1 and Day 14) 
[…] 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product before 
contacting the site. 
9.5.3.2 Visit 4 (Cycle 4, between Day 1 and 14) 
[…] 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product before 
contacting the site. 
9.5.3.3 Visit 5 (Cycle 7, between Day 1 and 14) 
[…] 
12. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product before 
contacting the site. 
9.5.3.4 Visit 6 (Cycle 10, between Day 1 and 14) 
[…] 
13. Instruct the subject to contact the site immediately if she decides to discontinue the 
investigational product and, if possible, to not discontinue the investigational product before 
contacting the site. 
9.5.3.5 Visit 7 (Cycle 14, between Day 16 and 23), End of Treatment Visit 
1-10. […] 
11. Complete the End of Study Termination Form. 
 
9.5.4 Early Termination Visit  
In case of early termination or withdrawal of subject (see Section 13.5), the procedures listed 
in Visit 7 (see Section 9.5.3.5) will be performed and Treatment Discontinuation Form will be 


 
 
 
 
 
 
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completed. In addition, the subject will be counseled about the next contraceptive method to 
use (see Section 9.6.4.9). 
A subject who desires early termination or is withdrawn from the study after the enrollment 
visit (Visit 2) (see Section 13.4) will require an Early Termination Visit. 
 Any subject who contacts the study site with a desire to discontinue study 
participation should be instructed at each visit to contact the study staff before 
discontinuing the study drug to be counseled about alternative contraception to use 
prior to the Early Termination Visit (see Section 9.6.4.9).  Study sites may provide 
any prescription or non-prescription contraceptive to the subject as is medically 
appropriate per local standard of care other than an IUD or implant. If necessary, 
an unscheduled visit can occur to provide contraception (see Section 9.5.5). 
 A subject who presents to the study site for a scheduled visit and desires to 
discontinue study participation or is withdrawn from the study at that visit should be 
counseled about alternative contraception to use prior to the Early Termination Visit 
(see Section 9.6.4.9). Study sites may provide any prescription or non-prescription 
contraceptive to the subject as is medically appropriate per local standard of care 
other than an IUD or implant. 
 A subject who presents to the study site for a scheduled visit who has not taken the 
study product for 16 days or more should have the scheduled visit procedures and 
the Early Termination Visit procedures completed at that time. The subject should 
be counseled about alternative contraception (see Section 9.6.4.9). Study sites may 
provide any prescription or non-prescription contraceptive to the subject as is 
medically appropriate per local standard of care. 
An Early Termination Visit should occur between 16 and 23 days after the last 
investigational product intake or immediately if the investigational product was never 
started. The procedures listed in Visit 7 (see Section 9.5.3.5) will be performed and the End 
of Study Form will be completed.  
[…] 
9.5.5 Unscheduled Visit 
At any time of the study, an Unscheduled Visit could occur in case of suspicion of pregnancy 
based on a positive pregnancy test performed at home by the subject or, in case the Investigator 
judges it necessary to examine a subject who would present a potential significant adverse 
event in the Investigator’s opinion, or if alternative contraception is needed for a subject 
planning early termination. Additional assessments can be performed at the Investigator’s 
discretion. 
9.6 Study Variables and Procedure Descriptions 
9.6.2 Efficacy assessments 
 9.6.2.2 Pregnancy Reporting 
[…] 


 
 
 
 
 
 
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All on-treatment pregnancies identified during the course of the study in a subject who was 
using the investigational product will be monitored to completion, i.e., approximately 9 month 
follow-up in the case of live birth or until outcome information is obtained. […].                              
If a subject becomes pregnant and states she never started the investigational product, the 
pregnancy does not have to be monitored if the subject returns all of the investigational 
product (proving she never started the investigational product). 
 
9.6.3 Safety variables 
 
9.6.3.6 Gynecological Examination, Chlamydia test, Gonorrhea test and Cervical Cytology 
[…] 
Enrollment of a subject with an ASC-US ASCUS interpretation is permitted if the subject is 
less than 21 years of age or HPV reflex test is negative for high-risk oncogene virus. 
[…] 
 
9.6.4.2 Population Pharmacokinetic Substudy 
Population PK will be assessed using plasma E4 and DRSP concentration data from a subset 
of approximately 500 subjects to address the relationship between PK parameters and various 
individual characteristics (e.g., body weight, race, and smoking, and fed/fasted condition). 
Blood samples for PK analysis will be obtained at Visits 3 and 4 between Days 10 and 14 of 
Cycles 2 and 4.  
[…] 
Two PK samples will be taken from the subjects in the Population PK Substudy at Visits 3 and 
4. All subjects included in the Substudy will provide a sample for PK analysis at the time they 
check into the site (PK sampling 1). An additional blood sample (PK sampling 2) will be 
collected approximately two hours after the first sample.  
Depending on the time scheduled for the study site visit (Visit 3 & 4), subjects will be 
instructed on when they need to take their medication – either as usually done at home or 
on site. 
- 
If the appointement is scheduled in the morning and the subject usually takes her 
study medication in the morning, she should take it at the study site. One blood 
sample will be taken before dosing and the second blood sample will be taken within 
2-hour postdose.  
- 
If the appointement is scheduled in the morning and the subject usually takes her 
study medication in the evening, she should take it in the evening before the visit at 
their regular time. The subject should record the time of the dosing in the Diary.  


 
 
 
 
 
 
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- 
A Subject who usually takes her study medication during the day should take it at 
usual time and come to the site when possible to have the 2 blood samples taken. The 
subject should record the time of dosing in the Diary. 
The exact times of following timings the last study medication dosing and the PK sampling 
will be recorded by the site personnel in the eCRF: 
- 
The exact times of the last study medication dosing and the PK samplings 1 and 2.  
- 
The time of the last meal intake before the last study medication dosing before study 
visit. 
 
[…] 
9.6.4.9 Contraceptive counseling 
At Visit 6 and at the Early Termination Visit in case of premature study termination, the 
subject will be counseled about her future contraception. The choice of the contraceptive 
method is left at to the Investigator’s discretion.  
A subject who desires early termination or is withdrawn from the study (see Section 13.4) 
after the enrollment visit (Visit 2) will be counseled about future contraception. 
 Any subject who contacts the study site with a desire to discontinue study 
participation should be instructed at each visit to contact the study staff before 
discontinuing the study drug to be counseled about alternative contraception to use 
prior to the Early Termination Visit.  Study sites may provide any prescription or 
non-prescription contraceptive to the subject as is medically appropriate per local 
standard of care other than an IUD or implant. If necessary, an unscheduled visit 
can occur to provide contraception (see Section 9.5.5). 
 A subject who presents to the study site for a scheduled visit and desires to 
discontinue study participation or is withdrawn from the study at that visit should be 
counseled about alternative contraception to use prior to the Early Termination Visit. 
Study sites may provide any prescription or non-prescription contraceptive to the 
subject as is medically appropriate per local standard of care other than an IUD or 
implant. 
 
A subject who presents to the study site for a scheduled visit who has not taken the 
study product for 16 days or more should have the scheduled visit procedures and 
the Early Termination Visit procedures completed at that time. The subject should 
be counseled about alternative contraception. Study sites may provide any 
prescription or non-prescription contraceptive to the subject as is medically 
appropriate per local standard of care. 
[…] 
9.6.4.11 Subjects’ well-being 


 
 
 
 
 
 
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[…] 
The baseline questionnaires will be given to the subject at Visit 2. The subject will be instructed 
to fill them in at home on or before the first day of study medication intake (Day 1). At the 
next visit, the study site personnel will ensure for the questionnaire completion. 
9.6.4.12 Return of spontaneous menstruation and return to fertility 
Each woman who discontinues the study early due to a pregnancy wish will be followed after 
study treatment discontinuation to evaluate return of spontaneous menstruation and return of 
fertility.  
They will be contacted by phone every 6-8 weeks for a maximum of one year after study 
discontinuation. 
[…] 
12 
PLANNED STATISTICAL METHODS 
12.6 Other Assessments or Analyses 
12.6.7 Quality of Life 
[…] 
The absolute values and change from baseline for the scores for pain, water retention, 
autonomic reactions, negative affect, impaired concentration, behaviour change, arousal and 
control will be summarized descriptively by visit. 
[…] 
12.6.9 Population Pharmacokinetic Substudy 
Plasma concentration data for E4 and DRSP will be summarized using descriptive statistics by 
cycle and sampling time range (ranges will be defined in the Statistical Analysis Plan) for the 
PK population. Descriptive summaries will be provided overall and by race, BMI categories 
(< 30, ≥ 30), and smoking status (smokers, non-smokers), and fed/fasted condition. 
Additionally, concentration data will be displayed graphically with regression lines overall, 
and by race, BMI categories, and smoking status for each cycle. 
Individual plasma concentration-time data will be pooled for the PK analyses. Initially, the 
data will be subjected to exploratory compartmental analysis to determine the basic primary 
parameters such as: 
 
[…] 
 Relative bioavailability for fed vs fasted state. 


 
 
 
 
 
 
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The initial estimates obtained from the exploratory analyses will be employed using non linear 
mixed effect modeling Bayesian analysis to build an appropriate population PK model. The 
analyzed parameters will include, but not be limited to: 
[…] 
13 
STUDY MANAGEMENT 
13.4 Withdrawal of Subjects 
[…] 
If a subject is withdrawn from the study following the start of study drug after enrolment visit 
(Visit 2), all Visit 7 assessments should be completed (see Section 9.5.3.5) and the subject 
should be counseled about alternative contraception to use (see Section 9.6.4.9). Subjects 
withdrawn from the study will not be replaced. 
 
17 
Appendices 


 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1 Study Schedule of Events 
Table 2: Schedule of Events 
Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14 / Early 
termination 
Visit 
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and 
surgical History 
X 
 
 
 
 
 
 
 
Gynecological 
History 
X 
 
 
 
 
 
 
 
Physical 
Examination 
X 
 
 
 
 
 
X 
X 
Weight, Height 
and BMI2 
X 
 
 
X 
X 
 
X 
X 
Gynecological 
Examination 
(including breast) 
X 
 
 
 
 
 
X 
X 
Cervical Cytology 
(Pap)3 
X 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
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Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14 / Early 
termination 
Visit 
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Chlamydia 
Testing 
X4 
X5 
X5 
X5 
X5 
X5 
 
 
Gonorrhea 
Testing 
X4 
X5 
X5 
X5 
X5 
X5 
 
 
Blood sample for 
Population PK 
Substudy6 
 
 
X 
X 
 
 
 
 
Serum Pregnancy 
Test7 
X 
 
 
 
 
 
X 
X 
Dispense Home 
Urine Pregnancy 
Test Kits 
 
X8 
 
 
 
 
 
 
Fasted clinical 
Laboratory tests 
(hematology and 
biochemistry) 
X9 
 
 
 
X10 
 
X9 
X9 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
 
 
Investigational 
Product 
Dispensing 
 
X 
 
X 
X 
X 
 
 
Investigational 
Product Return 
and Drug 
Accountability 
 
 
X 
X 
X 
X 
X 
X 


 
 
 
 
 
 
 
 
 
 
 
 
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Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14 / Early 
termination 
Visit 
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Subject Diary 
Dispensing 
 
X 
 
 
 
 
 
 
Subject Diary 
Review and 
Return 
 
 
X 
X 
X 
X 
X/ 
X 
AE Assessment 
 
X 
 
 
 
 
 
 
TEAE Assessment 
 
 
X 
X 
X 
X 
X 
X 
Prior Medication 
X 
X 
 
 
 
 
 
 
Concomitant 
Medication 
 
 
X 
X 
X 
X 
X 
X 
Stop Date of the 
Previous 
Contraceptive 
Method (if any) 
 
 
X 
 
 
 
 
 
Questionnaires 
dispensing 
 
X 
 
 
 
X 
 
 
Questionnaires 
completion check 
 
 
X 
 
 
 
X 
 
 X 
Contraceptive 
Counseling 
 
 
 
 
 
X 
X 
X13 
Follow-up Call 
 
X1314 
 
 
 
X1415 
 
 
End of Study 
Form 
 
 
 
 
 
 
X 
X 


 
 
 
 
 
 
 
 
 
 
 
 
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Visit 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Early 
Termination 
Visit12 
Treatment Cycle 
Screening 
Visit 
Subject 
Enrollment1 
During Cycle 
2 
During Cycle 
4 
During Cycle 
7 
During Cycle 
10 
During Cycle 
14 / Early 
termination 
Visit 
 
Treatment Cycle 
Day 
 
 
Cycle Day 
1 – 1411 
Cycle Day 
1 - 1411 
Cycle Day 
1 - 14 
Cycle Day 
1 – 14 
Cycle Day 
16-23 
 
Return of 
spontaneous 
menstruation and 
return to 
fertility1516 
 
 
 
 
 
 
 
 
1 Subject enrollment will occur within 30 45 days after the Screening Visit. 
[…] 
12 The Early Termination Visit should occur between 16 and 23 days after the last investigational product intake or immediately if the study product was never started. 
1213 In case of early termination or withdrawal of subject who did not undergo a Visit 6: contraceptive counseling should be provided as soon as the site is aware of the subject’s 
desire for termination. 
1314 Approximately Within 7 days following the expected start of treatment to remind the subject to complete the diary entries. 
1415 […] 
1516 […] 
 
 


 
 
 
 
 
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Appendix 6 Sponsor Signatures 
 
[…] 
 
Signature: 
 
 
Date:  
 
Karina Putineanu 
Head of Clinical Development 
 
 
Signature: 
 
 
Date:  
 
Linda Lebon 
Regulatory Affairs & Drug Development Expert 
 
[…] 
 
Modified sections in Protocol: MIT-Es0001-C302 Amendment Version 1.1 
This section summarizes changes that have been performed between Amendment Version 1.0 
(14 December 2016) and Amendment Version 1.1 (10 July 2017) 
 
Note: wherever applicable, deleted text has been crossed out (double strikethrough) and 
added text has been printed in bold, underlined and italic characters. 
2 SYNOPSIS 
Study Population:  
Approximately 2000 healthy female subjects at risk for pregnancy, between 16 and 50 years 
old, inclusive (at the time of screening), and requesting contraception will be enrolled in the 
study and initiate the investigational product. In total 1800 subjects will be 16 to 35 years 
old, inclusive (at the time of screening). Recruitment may be stopped when 2000 subjects 
have been enrolled initiated the investigational product if the required number of subjects 
for the primary analysis (1800 subjects in the age group up to and including 35 years) has 
been reached. Recruitment in the age group > 35 years will be stopped when 200 subjects 
have been enrolled initiated the investigational product. Approximately 500 of these 
subjects will be included in the Population PK Substudy. 
Study Locations:  
This clinical study will be conducted in up to approximately 70 80 centers in North America 
(United States of America and Canada).  
[…] 
Duration of the study:   


 
 
 
 
 
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Overall treatment duration is up to thirteen 28-day cycles, i.e., 12 months. 
[…] 
Statistical Methods: 
[…] 
For Pearl index calculations, thirteen 28-day cycles constitute one woman-year. 
[…] 
 
6 STUDY ADMINISTRATIVE STRUCTURE 
The study will be performed in approximately 70 80 centers in North America with 
approximately 90% of subjects in United States of America and 10% of subjects in Canada.   
9 INVESTIGATIONAL PLAN 
9.1 Overall Study Design and Plan 
[…] 
Approximately 2000 healthy female subjects at risk for pregnancy, between 16 and 50 years 
old (inclusive, at the time of screening), and requesting contraception will be enrolled in the 
study and initiate the investigational product. In total, 1800 subjects will be 16 to 35 years 
old (inclusive). Recruitment may be stopped when 2000 subjects have been enrolled initiated 
the investigational product if the required number of subjects for the primary analysis (1800 
subjects in the age group up to 35 years) has been reached. Recruitment in the age group > 35 
years will be stopped when 200 subjects have been enrolled initiated the investigational 
product. 
Eligible subjects will be treated with 15 mg E4/3 mg DRSP for up to 13 consecutive cycles. 
[…] 
9.4 Study Treatment 
9.4.4 Selection of Doses and Timing of Administration in the Study 
[…] 
This 28-day cyclic regimen must be taken for up to 13 consecutive cycles. The treatment must 
be taken once daily at approximately the same time of the day. 
[…] 
9.5 Study Activities 
9.5.2 Visit 2: Subject Enrollment 
[…] 


 
 
 
 
 
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13. Instruct any subject not on a hormonal contraceptive and who does not start the 
investigational product at the enrollment visit to contact the site immediately if her next 
menses occurs at earlier than 21 days or is delayed such that her cycle length exceeds 35 
days, and that she should not start the investigational product if either of these happens; 
 […] 
12 PLANNED STATISTICAL METHODS 
12.1 Determination of Sample Size 
[…].  If a not at risk cycle rate of 20% and a dropout rate of approximately 45% (assuming that 
we have an average of 4 cycles for subjects that discontinue) are assumed, approximately 1800 
16 to 35 year old subjects need to be enrolled and initiate the investigational 
product.  Additionally, it is planned to enroll for a maximum of 200 subjects > 35 years to be 
enrolled and initiate the investigational product. Therefore, in total, approximately 2000 
subjects will be enrolled in the study and initiate the investigational product. Additionally, a 
subset of approximately 500 subjects will be enrolled in the PK Substudy. 
12.4 Efficacy Analyses 
[…] 
12.4.2 Statistical Analysis 
12.4.2.2 Life-Table Rates 
[…] 
Cumulative probabilities of pregnancy and 95% CIs will be calculated based on Kaplan-Meier 
estimates for through Cycle 13. Additionally, the estimated survivor function against time 
(cycle) will be provided. 
 
Appendix 6. Sponsor Signatures 
 
 
Signature: 
 
 
 
 
 
Date:  
 
Karina Putineanu 
Head of Clinical Development 
Françoise Bruyère 
Clinical Manager 
 
Appendix 7. Contract Research Organization Signatures 
 
 
Signature: 
 
 
 
 
 
Date:  
 
Lyn Taylor 


 
 
 
 
 
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Jess Read 
Principal Biostatistician 
PRA Health Sciences 
 
Signature: 
 
 
 
 
 
Date:  
 
Ramdas Kanase 
Vijaya Vundurti 
Drug Safety Associate 
PRA Health Sciences 
 
Signature: 
 
 
 
 
 
Date:  
 
LaTonya Bufford 
Douglas Stewart  
Lead Data Manager 
PRA Health Sciences 

SAP_000.pdf: 
Statistical Analysis Plan 
Final 
Effective Date: 11-Dec-2018/Version 3.0 
Sponsor: Estetra 
Protocol no: MIT-Es0001-C302 
PRS 005 T 17 E 
Page 1 of 45 
Strictly Confidential. © 2004-2014, PRA Health Sciences. All rights reserved. 
 
Statistical Analysis Plan 
 
Sponsor: 
Estetra 
Protocol No: 
MIT-Es0001-C302 
Version No./Date 
Final 1.1/10-July-2017 
Title 
A Multicenter, Open-label, Single-Arm Study to Evaluate the 
Contraceptive Efficacy and Safety of a Combined Oral 
Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone 
ClinicalTrials.gov 
registration No. 
NCT02817841 
CRF Version 
No./Date 
3.0/18-July-2017 
PRA Project Id: 
MHUEC302-ESC302 
SAP Version 
No./Date: 
3.0/11 December 2018 
Approvals 
Sponsor 
Sponsor Name: 
Estetra SPRL 
Representative/ Title: 
Sophie Ledant, Clinical Project Leader 
Signature /Date: 
 
 
Sponsor Name: 
Estetra SPRL 
Representative/ Title: 
Marie Mawet, Medical Advisor 
Signature /Date: 
 
 
PRA 
Project Manager/Title: 
Laëtitia Poher, Project Director 
Signature /Date: 
 
 
Biostatistician / Title: 
Jess Sadler, Senior Principal Biostatistician 
Signature /Date: 
 
 
 
 


Statistical Analysis Plan 
Final 
Effective Date: 11-Dec-2018/Version 3.0 
Sponsor: Estetra 
Protocol no: MIT-Es0001-C302 
PRS 005 T 17 E 
Page 2 of 45 
Strictly Confidential. © 2004-2014, PRA Health Sciences. All rights reserved. 
Table of Contents 
Approvals .................................................................................................................................................................................... 1 
Table of Contents ..................................................................................................................................................................... 2 
1.0 Introduction ....................................................................................................................................................................... 5 
2.0 Study Objectives ............................................................................................................................................................... 5 
2.1 Primary Objective ....................................................................................................................................................... 5 
2.2 Secondary Efficacy Objectives................................................................................................................................ 5 
2.3 Other Secondary Objectives .................................................................................................................................... 5 
3.0 Study Design ....................................................................................................................................................................... 5 
3.1 Sample Size Considerations .................................................................................................................................... 6 
4.0 Study Variables and Covariates .................................................................................................................................. 6 
4.1 Primary Variable.......................................................................................................................................................... 6 
4.2 Secondary Variables ................................................................................................................................................... 7 
4.2.1 Efficacy .................................................................................................................................................................... 7 
4.2.2 Other Secondary Variables ............................................................................................................................. 7 
4.3 Predetermined Subgroups ...................................................................................................................................... 7 
5.0 Definitions ........................................................................................................................................................................... 8 
5.1 Cycle .................................................................................................................................................................................. 8 
5.1.1 At-risk Cycle for Pearl Index .......................................................................................................................... 8 
5.1.2 Evaluable Cycle and Reference Period for Bleeding Data .................................................................. 9 
5.2 Baseline and Change from Baseline ................................................................................................................... 11 
5.3 On-Treatment Period ............................................................................................................................................... 11 
5.4 Body Mass Index ........................................................................................................................................................ 11 
5.5 Switchers, Starters and True New Users ......................................................................................................... 11 
5.6 Prior, Post-Study Treatment and Concomitant Medication Use ............................................................ 12 
5.7 Study Treatment Compliance ............................................................................................................................... 12 
5.7.1 Compliance analysis by cycle ....................................................................................................................... 12 
5.7.2 Overall compliance ........................................................................................................................................... 13 
5.8 Extent of Exposure .................................................................................................................................................... 13 
5.9 Pregnancy Related Definitions ............................................................................................................................ 14 
5.9.1 Pre-Treatment Pregnancies.......................................................................................................................... 14 
5.9.2 On-Treatment Pregnancies ........................................................................................................................... 14 
5.9.3 Post-Treatment Pregnancies ........................................................................................................................ 14 
5.9.4 Method and User Failure Pregnancies ..................................................................................................... 14 
5.10 Bleeding Patterns ................................................................................................................................................... 15 
5.10.1 Definitions of Bleeding and Spotting...................................................................................................... 15 
5.10.2 Cycle analysis ................................................................................................................................................... 15 
5.10.3 Reference Periods (RPs) .............................................................................................................................. 17 
5.10.4 Bleeding Endpoints for the Cycle Analysis .......................................................................................... 17 
5.10.5 Bleeding Endpoints for Analyses by RP ................................................................................................ 19 
5.11 Treatment-Emergent Adverse Event (TEAE) ............................................................................................. 19 
5.12 Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) ............... 19 
5.13 Menstrual Distress Questionnaire ................................................................................................................... 20 
5.14 Return to Fertility ................................................................................................................................................... 20 
5.15 Methods for Handling Missing Data ................................................................................................................ 20 
5.15.1 Missing Data Related to the Pearl Index and Pill Intake ................................................................ 20 
5.15.2 Missing Bleeding Data .................................................................................................................................. 21 


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5.15.3 Missing or Partial Dates for Medications ............................................................................................. 21 
5.15.4 Missing or Partial Dates for AEs ............................................................................................................... 22 
5.15.5 Missing or Partial Treatment Start and Stop Dates ......................................................................... 22 
6.0 Analysis Sets ..................................................................................................................................................................... 23 
6.1 Screened Population ................................................................................................................................................ 23 
6.2 Enrolled Population ................................................................................................................................................. 23 
6.3 Safety Population ...................................................................................................................................................... 23 
6.4 Intention-to-Treat (ITT) Population ................................................................................................................. 23 
6.5 Per-Protocol (PP) Population ............................................................................................................................... 23 
6.6 Pharmacokinetics (PK) Population .................................................................................................................... 23 
7.0 Interim Analyses ............................................................................................................................................................. 24 
8.0 Data Review ...................................................................................................................................................................... 24 
8.1 Data Handling and Transfer .................................................................................................................................. 24 
8.2 Data Screening ............................................................................................................................................................ 24 
8.3 Data Review Meetings ............................................................................................................................................. 24 
9.0 Statistical Methods ........................................................................................................................................................ 24 
9.1 Subject Disposition ................................................................................................................................................... 25 
9.2 Protocol Deviations and Violations .................................................................................................................... 25 
9.3 Treatments ................................................................................................................................................................... 26 
9.3.1 Extent of Study Drug Exposure ................................................................................................................... 26 
9.3.2 Treatment Compliance ................................................................................................................................... 26 
9.3.3 Prior, Post-Study Treatment and Concomitant Medications .......................................................... 26 
9.4 Demographic and Baseline Characteristics .................................................................................................... 26 
9.5 Efficacy Analyses ....................................................................................................................................................... 27 
9.5.1 Primary Variable ............................................................................................................................................... 27 
9.5.2 Secondary Variables ........................................................................................................................................ 28 
9.5.3 Bleeding and Spotting ..................................................................................................................................... 30 
9.6 Safety Analyses ........................................................................................................................................................... 32 
9.6.1 Adverse Events .................................................................................................................................................. 32 
9.6.2 Deaths and Serious Adverse Events .......................................................................................................... 32 
9.6.3 Laboratory Data................................................................................................................................................. 33 
9.6.4 Vital Signs ............................................................................................................................................................. 34 
9.6.5 Physical and Gynecological Examinations .............................................................................................. 34 
9.7 Other Secondary Endpoints (Excluding PK) .................................................................................................. 34 
9.7.1 Quality of Life ..................................................................................................................................................... 34 
9.7.2 Follow-Up Evaluations.................................................................................................................................... 34 
9.8 Population Pharmacokinetics Analysis ............................................................................................................ 35 
9.8.1 Data Included in Analysis .............................................................................................................................. 35 
9.8.2 Objectives ............................................................................................................................................................. 35 
9.8.3 Assumptions ....................................................................................................................................................... 35 
9.8.4 Prespecified Hypotheses ................................................................................................................................ 35 
9.8.5 Study MIT-Es0001-C302 ................................................................................................................................ 36 
9.8.6 Study Es0001-C101.......................................................................................................................................... 36 
9.8.7 Study MIT-Es0001-C103 ................................................................................................................................ 37 
9.8.8 Data management ............................................................................................................................................. 37 
9.8.9 Data Deletion ...................................................................................................................................................... 38 
9.8.10 PopPK Model Development ....................................................................................................................... 38 
9.8.11 PopPK Model Evaluation ............................................................................................................................. 39 


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9.8.12 Reporting ........................................................................................................................................................... 39 
9.8.13 Source Files ....................................................................................................................................................... 40 
10.0 Validation ........................................................................................................................................................................ 41 
11.0 References ...................................................................................................................................................................... 41 
12.0 Amendment to the Statistical Analysis Plan ..................................................................................................... 41 
12.1 Amendment 1 from SAP dated 12 December 2016.................................................................................. 41 
12.2 Amendment 2 from SAP dated 13 November 2018 ................................................................................. 43 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 44 
 
 
 
 
 
 
 


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1.0 Introduction 
This statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Estetra Protocol MIT-Es0001-C302.  
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol amendment 1.1 dated 10 July 2017 and CRF version 
3.0 dated 18 July 2017. Any further changes to the protocol or CRF may necessitate updates to the SAP. 
2.0 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the contraceptive efficacy of 15 mg Estetrol (E4)/3 mg 
Drospirenone (DRSP) using the Pearl Index in subjects aged 16 to 35 years, inclusive, at the time of 
screening. 
2.2 Secondary Efficacy Objectives 
The secondary objectives of this study are: 
1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method failure Pearl 
Index and life-table analysis in subjects aged 16 to 35 years, inclusive, at the time of screening 
2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index, the method 
failure Pearl Index and life-table analysis in the overall study population 
2.3 Other Secondary Objectives 
1. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg DRSP 
2. To evaluate general safety of 15 mg E4/3 mg DRSP 
3. To evaluate the impact of 15 mg E4/3 mg DRSP on physical, psychological, and social functioning 
and well-being 
4. To assess the effect of various individual characteristics/covariates (e.g., body weight, race, and 
smoking) on the pharmacokinetics (PK) of 15 mg E4/3 mg DRSP (Population PK Substudy) 
3.0 Study Design 
This study is a multicenter, open-label, single-arm study. 
The total duration of the study, including the screening, will range from 382 to 447 days for most of the 
subjects, which is approximately 13-15 months. Those subjects who discontinue and desire pregnancy will 
be followed for a maximum of one year after study discontinuation for return of spontaneous menstruation 
and until pregnancy or initiation of a contraceptive method (whichever occurs first). 
Approximately 2000 healthy female subjects at-risk for pregnancy, between 16 and 50 years old (inclusive, 
at the time of screening), and requesting contraception will be enrolled in the study. In total 1800 subjects 
will be 16 to 35 years old (inclusive). Recruitment may be stopped when 2000 subjects have been enrolled 
if the required number of subjects for the primary analysis (1800 subjects in the age group up to 35 years) 
has been reached. Recruitment of women aged 36-50 years will be stopped when 200 subjects in this age 
range have been enrolled.  
Eligible subjects will be treated with 15 mg E4/3 mg DRSP for up to maximum of 13 consecutive cycles. 
The treatment must be taken once daily at approximately the same time of the day in a 24/4-day regimen, 
i.e. 24 active tablets followed by 4 placebo tablets (4-day hormone free interval). 


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The primary study objective is to evaluate the contraceptive efficacy of the new Combined Oral 
Contraceptive (COC), using the Pearl Index calculation (which reflects the pregnancy rate associated with 
a contraceptive method) among the subjects aged 16 to 35 years inclusive. 
The contraceptive efficacy will also be evaluated using the method failure Pearl Index (which reflects the 
pregnancy rate due to method failure only) and life-table analysis in the subjects aged 16 to 35 years 
inclusive and in the overall study population. 
The general safety will be evaluated by the determination of routine laboratory parameters, vital signs, by 
performing physical, gynecological and breast examinations and by recording number, frequency, type and 
intensity of adverse events (AEs) and serious adverse events (SAEs). 
Participating subjects will be asked to record daily in a subject diary their bleeding/spotting episodes. This 
will allow evaluating the bleeding pattern and the cycle control associated with the investigational product. 
Treatment compliance will be assessed using data from the subject diary across the entire study and by 
cycle and, in the case of a pregnancy, detailed information from a pregnancy narrative completed by the 
site Principal Investigator. The subject diary will also be used to determine whether or not a cycle is an at-
risk cycle for the Pearl Index calculation. In the primary analysis of the Pearl Index, at-risk cycles will be 
defined as cycles in which the following criteria are met: 
1. No other methods of birth control (including condoms and emergency contraception) are used by 
the subject as confirmed in the subject diary  
2. The subject confirmed that sexual intercourse occurred during the cycle in the subject diary 
Note that if conception occurs in a cycle, then that cycle will be included as an at-risk cycle in the 
denominator even if any other contraceptive method was used during that cycle or the subject did not 
confirm that sexual intercourse occurred. Cycles after the cycle of conception will not be included as at-risk 
cycles and will be excluded from the denominator. 
Physical, psychological and social functioning and well-being associated with the investigational product 
will be assessed with well-established questionnaires. A study schedule of events is provided in Appendix 
1 of the Protocol. Population PK will be assessed using plasma E4 and DRSP concentration data from a 
subset of approximately 500 subjects to evaluate the relationship between E4 and DRSP PK parameters 
and various characteristics (e.g., body weight, race, and smoking). Blood samples for PK analysis will be 
obtained at Visits 3 and 4 between Days 10 and 14 of Cycles 2 and 4.  
3.1 Sample Size Considerations 
Sample size is based on the need to have a sufficient number of cycles such that the difference between 
the Pearl Index and the upper limit of the two-sided 95% confidence interval (CI) for the Pearl Index does 
not exceed 1. Assuming that the true Pearl Index is 1.0 and that a Poisson model is used to derive the CIs, 
then at least 12,337 at-risk cycles are required for a power of 90% in the 16 to 35 year old population 
(Gerlinger et al., 2003).  
Assuming 80% of the study cycles are at-risk cycle and a dropout rate of approximately 45% (assuming 
that we have an average of 4 cycles for subjects that discontinue) are assumed, approximately 1800 16-
to-35 year old subjects need to be enrolled. Additionally, it is planned to enroll a maximum of 200 subjects 
36-50 years. Therefore, in total, approximately 2000 subjects will be enrolled in the study. Additionally, a 
subset of approximately 500 subjects will be enrolled in the PK Substudy.  
4.0 Study Variables and Covariates 
4.1 Primary Variable 
The primary efficacy variable will be the number of on-treatment pregnancies assessed by the Pearl Index 
in the ITT population aged 16 to 35 years, inclusive, at the time of screening with at-risk cycles (cycles in 


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which no other methods of birth control (including condoms and emergency contraception) are used and 
during which the subjects confirmed that sexual intercourse has occurred). 
4.2 Secondary Variables 
4.2.1 Efficacy 
The secondary efficacy variables are: 
1. The number of on-treatment pregnancies as assessed by the method failure Pearl Index and the 
cumulative pregnancy rate in subjects aged 16 to 35 years, inclusive, at the time of screening 
2. The number of on-treatment pregnancies as assessed by the Pearl Index, the method failure Pearl 
Index and the cumulative pregnancy rate in the overall study population 
4.2.2 Other Secondary Variables 
The other secondary variables are: 
1. Cycle control and bleeding patterns based on vaginal bleeding information recorded daily by the 
subjects in the diaries 
2. Safety data in the overall study population obtained from routine laboratory parameters, vital signs, 
and physical, gynecological and breast examinations, evaluated as the number, frequency, type 
and intensity of AEs and SAEs  
3. Change from baseline to end of treatment in the different items of well-established questionnaires 
to evaluate physical, psychological, and social functioning and well-being 
4. Plasma E4 and DRSP concentration data from a subset of approximately 500 subjects for the 
development of a population PK model (Population PK Substudy). PK parameters will include, but 
not be limited to: 
a. Apparent clearance (CL/F). 
b. Central volume of distribution (V/F). 
c. Lag time of Absorption (Tlag), if necessary. 
d. Maximum concentration (Cmax). 
e. Time to Cmax (Tmax). 
f. 
Extent of exposure for the dosing interval (AUCtau). 
g. Terminal half-life (t½). 
4.3 Predetermined Subgroups 
The key subgroup in this study is subjects aged 16 to 35 years, inclusive, at the time of screening. This 
subgroup is used for the primary efficacy population. All data regarding disposition, baseline characteristics, 
compliance, exposure and contraceptive efficacy will be presented for subjects aged 16 to 35 years and for 
all subjects within the specified analysis population.  
In addition, subgroup analyses will be performed for the Pearl Index and bleeding data (specifically 
unscheduled bleeding and spotting and the absence of scheduled bleeding) for the following categories: 
 
Body Mass Index (BMI) categories (< 30, ≥ 30 kg/m2) at Baseline 
 
Race category (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, Other Race) 
 
Starters (including true new users)/Switchers (see Section 5.5) 


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 
Smokers/Non-smokers at Baseline 
 
Age (≥ 16 to ≤ 25; > 25 to ≤ 35 and > 35 years old) at Screening 
The non-smokers group includes subjects who are former smokers and never smokers. The smokers group 
includes subjects who are current smokers. The other race group includes subjects who selected more 
than one race or whose race was recorded as other race on the CRF.  
Quality of life data will be presented for all subjects and for starters and switchers separately. 
5.0 Definitions 
5.1 Cycle 
The expected duration of a cycle is 28 days. A 28-day cycle consists of 24 days of active tablet intake 
followed by 4 days of inactive tablet intake and subjects who complete the study are expected to have 
completed thirteen 28-day cycles. 
All cycles will be determined using the start dates recorded in the diaries. The first day of a cycle is the start 
date recorded on the diary for that cycle and the last day of a cycle coincides with the day before the start 
date recorded on the diary for the next cycle. However, because the last cycle of use has no start date for 
a following cycle, the last day of the cycle will be assumed to be the date of last dose of study medication, 
whether this is an active or inactive tablet. The date of last dose of study medication in the last cycle will be 
derived from the data collected in the diary. 
If the conception is confirmed to be during a specific cycle in the narrative and this cycle is not in the diary 
data, then the cycle will be included as cycle in the exposure for the derivation of the Pearl Index. If the 
cycle in which conception occurred is not known, cycle(s) up to the one in which the positive pregnancy 
test occurred will be included in the exposure for the derivation of the Pearl Index. 
For the analysis of bleeding data, the cycle will be shifted by 3 days with the 3 days of the next cycle 
included in the previous cycle. For example, in the bleeding analysis Cycle 2 will be from Day 4 of Cycle 2 
to Day 3 of Cycle 3 inclusive.  
The start and stop times of a cycle will be determined before determining whether the cycle is evaluable for 
the Pearl Index or evaluable for the bleeding data. Data review meetings may be held to determine if cycles 
are at-risk cycles for the Pearl Index and if they are evaluable for the bleeding analysis prior to database 
lock (see Section 8.3) if the classification is not clear from the data collected and the rules in the SAP.  
5.1.1 At-risk Cycle for Pearl Index  
In the primary calculation of the Pearl Index (see Section 9.5.1 for details) and the Method failure Pearl 
Index, only at-risk cycles will be included in the derivation of the number of women-28 day equivalent cycles 
of treatment, which is used as the denominator. At-risk cycles will be defined as cycles in which the following 
criteria are both met: 
1. No other methods of birth control (including condoms and emergency contraception) are used by 
the subject as confirmed in the subject diary 
2. The subject confirmed that sexual intercourse occurred during the cycle in the subject diary 
This definition of at-risk cycles will be used as the denominator for the Pearl Index for on-treatment 
pregnancies and also for on-treatment method failure pregnancies. 
Two alternative calculations of the exposure (i.e., the denominator) will be performed to allow for 
comparisons with historical data: 
 
All exposure, which includes cycles with and without other methods of birth control and cycles with 
and without sexual intercourse. In this derivation of the Pearl Index all cycles are classed as at-


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risk cycles with the exception of any cycles after the cycle of conception in the case of pregnancy. 
This denominator will be used for the Pearl Index for on-treatment pregnancies only, 
 
Modified at-risk exposure, where only cycles with other methods of birth control are excluded, while 
occurrence of sexual intercourse is not taken into account. In this derivation of the Pearl Index, at-
risk cycles are defined as cycles in which no other methods of birth control (including condoms and 
emergency contraception) are used by the subject as confirmed in the subject diary. 
Two additional alternative definitions of at-risk cycles will be used for the derivation of the Pearl Index for 
method failure pregnancies. In the first of these definitions, cycles qualify if they meet all of the criteria 1 to 
8 listed below:  
1. No other methods of birth control (including condoms and emergency contraception) are used by 
the subject as confirmed in the subject diary 
2. The subject confirmed that sexual intercourse occurred during the cycle in the subject diary 
3. A subject does not have a user failure pregnancy with an estimated conception date in that cycle 
or prior to that cycle and does not have a method failure pregnancy with an estimated conception 
date prior to that cycle  
4. The subject does not receive unauthorized concomitant medication (see section 9.4.6.1 of the 
protocol) for at least one day during the cycle  
5. The subject does not miss 4 or more days of active pills during the cycle  
6. The subject does not miss 2 or more consecutive days of active pills during the cycle 
7. The length of the previous cycle is not longer than 28 days 
8. The subject had no adverse events of vomiting and/or diarrhea during the cycle 
In the second of these definitions, cycles qualify if they meet all of the criteria 1 and 3 to 8 listed above (i.e. 
occurrence of sexual intercourse is not taken into account),  
The following rules will be applied to all types of exposure:  
 
If conception occurs in a cycle, then that cycle will be included in the denominator, regardless of 
whether or not other methods of birth control were used during that cycle, or whether or not sexual 
intercourse was confirmed.  
 If the conception is confirmed to be during a specific cycle in the narrative and this cycle is 
not in the diary data, then the cycle will be included in the denominator, regardless of whether 
or not other methods of birth control were used during that cycle, or whether or not sexual 
intercourse was confirmed  
 The only exception is for user failure pregnancies, which will be excluded from the exposure 
definitions based on the compliance rules 3 to 8 above, since they do not meet criterion 3 
 
Cycles after the cycle of conception will be excluded from the denominator 
 
Missing data from the diary will be handled according to section 5.15.1. 
5.1.2 Evaluable Cycle and Reference Period for Bleeding Data  
Bleeding data will be analyzed by cycle and by 91-day reference period (RP). For the analysis of bleeding 
data by cycle, the cycle will be shifted by 3 days with the 3 days of the next cycle included in the previous 
cycle. For example, in the bleeding analysis Cycle 2 will be from Day 4 of Cycle 2 to Day 3 of Cycle 3 
inclusive. For the 3 days after Cycle 13, the last non-missing response for bleeding in Cycle 13 will be 
imputed. 


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In determining whether a cycle is evaluable for the bleeding analysis of a specific population, the cycle 
based on the diary data will be used rather than the shifted cycle used to present the data.  
For the ITT analysis, a cycle will be considered non-evaluable if: 
 
The length of the cycle is longer than 28 days.  
A cycle will be considered non-evaluable in the per-protocol (PP) analysis for bleeding data if any of the 
following criteria are met: 
1. A subject becomes pregnant in that cycle or prior to that cycle 
2. The length of the cycle is shorter than 22 days or longer than 28 days  
3. A subject did not have a hormone-free period towards the end of the cycle (i.e. there are not at 
least 4 days where an active tablet was not taken between the last day an active tablet was taken 
in this cycle and the first day an active tablet was taken in the next cycle) 
4. The subject received unauthorized concomitant medication (see section 9.4.6.1 of the protocol) 
thought to have the potential to impact the bleeding analysis for at least one day during the cycle  
5. Use of unauthorized pre-treatment and concomitant medication thought to have the potential to 
impact the bleeding analysis, if cycle starts within 28 days after discontinuation of unauthorized 
medication 
6. The subject had a positive test for chlamydia or gonorrhea during that cycle 
7. The subject missed 4 or more days of active pills during the cycle 
8. The subject missed 2 or more consecutive days of active pills during the cycle 
9. The subject had a procedure to the vagina, cervix or endometrium during the cycle  
A cycle with missing diary bleeding data will still be considered evaluable if the criteria above are not met 
and bleeding data can be imputed for days with missing data (see Section 5.15.2 for details). 
Three other analyses of bleeding data will be performed as follows: 
1. Using cycles in which all active pills were taken as per the instructions in the protocol. In this 
analysis, evaluable cycles will be defined as per the PP analysis but cycles where there was at 
least 1 day between Day 1 and Day 24 where an active pill was not taken will be excluded. 
2. Using cycles in which exactly 1 active pill was missed. In this analysis, evaluable cycles will be 
defined as per the ITT analysis but only cycles where there was exactly 1 missed active pill between 
Day 1 and Day 24 are included. 
3. Using cycles in which at least 2 active pills were missed. In this analysis, evaluable cycles will be 
defined as per the ITT analysis but only cycles where there were at least 2 missed active pills 
between Day 1 and Day 24 are included. 
In addition, an analysis by RP will be performed where there are 4 91-day RPs defined as follows: 
 
RP1 = Day 1 to Day 91 
 
RP2 = Day 92 to Day 182 
 
RP3 = Day 183 to Day 273 
 
RP4 = Day 274 to Day 364 
where Day 1 is the first day of Cycle 1 reported in the subject diary and then the remaining days are fixed 
using Day 1 as a reference. For example, Day 91 is 90 days after the date of the first day of Cycle 1. 
A RP will be considered to be non-evaluable in the ITT analysis when the RP is less than 91 days in duration 
(i.e. where the subject withdraws from the study during the RP). If there are any gaps between cycles in 


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terms of date within the RP (i.e. at the end of the 4-day inactive pill period of a given cycle, the subject does 
not directly restart with the first active pill of the next pill pack), then the RP will be excluded from the ITT 
Population. For example, if Cycle 1 Day 28 is 1 February 2018 and Cycle 2 Day 1 is 3 February, then RP1 
will be excluded from the ITT.  
A RP with missing bleeding diary data will still be considered evaluable if the criteria above are not met and 
bleeding data can be imputed for days with missing data (see Section 5.15.2 for details).  
5.2 Baseline and Change from Baseline 
The Baseline value for each assessment is defined as the last measurement taken prior to first 
administration of study medication, unless otherwise stated. When the date of the assessment is on the 
date of first administration, it will be assumed that the assessment was performed prior to first dose. The 
Baseline value for the Menstrual Distress Questionnaire will be the value collected at Visit 3 because the 
date of completion is not collected in eCRF for this questionnaire. 
For any parameter at a specific visit, change from Baseline is calculated as the value of that parameter at 
that visit minus the Baseline value of that parameter, as defined above. 
5.3 On-Treatment Period 
For contraceptive efficacy, the On-Treatment Period is defined as the period of time between the date of 
first dose of study medication and 7 days after the last dose of study medication (regardless of whether this 
is an active or inactive table), inclusive. If the subject has a pregnancy after the first dose of study medication 
and prior to the last dose of study medication, the On-Treatment Period is defined as the period of time 
between the date of first dose of study medication and the date of the estimated date of conception, 
inclusive. If the subject has a pregnancy when they are still on study medication but the estimated date of 
conception is missing because the date was not confirmed in an ultrasound, then the cycle and day of the 
estimated conception that is assigned from the narrative will be used to determine the end date. 
For TEAEs, the On-Treatment Period is defined as on or after the date of first dose of study medication.  
For medications, the On-Treatment Period is defined as the period of time between the date of first dose of 
study medication and the date of last dose of study medication (regardless of whether this is an active or 
inactive table), inclusive.  
If the subject had a period of time when study medication was not being taken between the date of first 
dose of study medication and the last dose of study medication, this time will still be considered to be during 
the On-Treatment Period. 
5.4 Body Mass Index 
BMI in kg/m2 will be calculated using the following formula: 
BMI= weight
height2 
Weight and height collected on the CRF will not be rounded prior to deriving BMI. 
5.5 Switchers, Starters and True New Users 
Starters are defined as subjects who have not used hormonal contraceptives within the 3 months prior to 
the date of first dose of study medication. 
Switchers are defined as subjects who have used hormonal contraceptives within the 3 months prior to the 
date of first dose of study medication. 
True new users are defined as subjects who have never received a hormonal contraceptive. This group of 
subjects is a subset of the group of subjects classed as starters. 


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5.6 Prior, Post-Study Treatment and Concomitant Medication Use 
Medications will be categorised as contraceptives and other medications that are not contraceptives.  
For contraceptives, the medications will be classed as prior if:  
 
The question “Taken prior to study?” on the eCRF is answered with Y or 
 
The medication start date is before the date of first dose of study medication  
The following contraceptive medications will be identified as concomitant contraceptives: 
 
Medications with a start date during the On-Treatment Period for medications (see Section 5.3 for 
details) 
 
Medications with a start date prior to the date of first dose of study medication and an end date 
after the date of first dose of study medication 
Any contraceptives with a missing end date will be considered to be ongoing at the end of study treatment 
and thus would be assumed to be after the first dose of study medication and therefore assigned as a 
concomitant contraceptive.  
Contraceptive medications can be classed as both prior and concomitant. 
Contraceptives with a start date occurring after the end of the On-Treatment Period for medications will be 
identified as post-study treatment contraceptives. Contraceptives with a start date prior to the date of first 
dose of study medication and an end date on the same date as the date of first dose of study medication 
will be assumed to be prior only and not concomitant.  
For other medications that are not contraceptives, medications with an end date occurring before the date 
of first dose of study medication will be identified as prior medications.  
Medications with a start date occurring after the end of the On-Treatment Period for medications will be 
identified as post-study treatment medications. 
The following medications will be identified as concomitant medications: 
 
Medications with a start date during the On-Treatment Period for medications (see Section 5.3 for 
details)  
 
Medications with a start date prior to the date of first dose of study medication and an end date on 
or after the date of first dose of study medication  
Any medications with a missing end date will be considered to be ongoing at the end of study treatment 
and thus would be assumed to be after the first dose of study medication and therefore assigned as a 
concomitant medication.  
Medications that are not contraceptives cannot be classed as both prior and concomitant.  
5.7 Study Treatment Compliance 
Treatment compliance for the investigational product will be assessed based on the data collected in the 
subject diary.  
5.7.1 Compliance analysis by cycle  
In the compliance analysis by cycle, a cycle will only be included if there is a reported start date for that 
cycle. Prior to calculating any compliance data by cycle, cycles are first determined using the start date of 
the cycle and the start date of the next cycle, per the rules in Section 5.1. In the compliance analysis by 
cycle, only days within the cycle after those rules have been applied are included in the derivation of the 
endpoints in this Section by cycle. 


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The treatment compliance will be calculated as a percentage and derived for each cycle that the subject 
started. For each cycle, the total number of pills (active or inactive) taken will be determined from the subject 
diary. If an entry of the number of active (pink) or inactive (white) pills is left blank in the diary, then it will 
be assumed that no pills were taken on that day. 
The compliance for a given cycle will be derived as  
100 𝑥 
𝑡ℎ𝑒 𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑐𝑦𝑐𝑙𝑒
𝑡ℎ𝑒 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑡𝑜 𝑏𝑒 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑐𝑦𝑐𝑙𝑒 
 
The number of pills expected to be taken during the cycle is derived as the end date of the cycle – start 
date of the cycle + 1 where the start and end dates of the cycles are determined using the rules in Section 
5.1. In the case of early termination from the study, in the last cycle for that subject, the number of pills 
expected to be taken during the cycle is calculated as the date of last dose of study medication – the start 
date of the cycle of interest + 1.  
In addition, the subject diary data will be used to identify when a pill has been missed. The number of 
missed pills will be derived for each cycle. In this situation, a pill is assumed to be missed if there is a day 
in the diary without an entry for the number of tablets or with 0 active and 0 inactive pills reported as taken. 
Any gaps between Day 28 of a cycle and Day 1 of the next cycle will be included as missed pills. For 
example, if the reported start date for Cycle 1 is 1 February and the reported start date for Cycle 2 is 3 
March, then the derived end date of Cycle 1 will be 2 March and 1-2 March will be included as 2 missed 
pills. If there are overlapping cycles in terms of dates, then the days will be included under the latest cycle 
and missed pills will be reported accordingly. For example, if the subject takes pills up to Day 24 in Cycle 
1, then starts Cycle 2 on the same date as Day 25 of Cycle 1, so Days 25 to Day 28 of Cycle 1 will not be 
included in Cycle1 and these will not be counted as missed pills for Cycle 1.  
5.7.2 Overall compliance 
In the derivation of overall compliance, all data collected on days between the date of first dose and date 
of last dose will be included in the derivation. The overall compliance will be determined by summing the 
total number of pills (active or inactive) taken across all cycles. The overall compliance will be calculated 
as 
100 𝑥 
𝑡ℎ𝑒 𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛 𝑎𝑐𝑟𝑜𝑠𝑠 𝑎𝑙𝑙 𝑐𝑦𝑐𝑙𝑒𝑠
𝑡ℎ𝑒 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒−𝑡ℎ𝑒 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 1 + 1 𝑖𝑛 𝑑𝑎𝑦𝑠  
In the above formula, the total number of pills taken during the cycles will be the sum of pills recorded 
across all days between the date of first dose of study medication and the date of last dose of study 
medication, inclusive. For example, if there is no start date reported for Cycle 1 and there are pills reported 
as taken in the diary for Cycle 1, then these pills reported in Cycle 1 will not be included in the total number 
of pills taken as the date of first dose of study medication will be the start date reported for Cycle 2. 
The total number of pills taken across all subjects will be derived by summing the number of pills taken 
across the study for all subjects in the Safety Population. 
For drug accountability, the number of active pills dispensed will be calculated by multiplying the number 
of blisters dispensed by 24. The number of inactive pills dispensed will be calculated by multiplying the 
number of blisters dispensed by 4. The number of active and inactive pills returned will be recorded on the 
CRF. 
5.8 Extent of Exposure 
The duration of total exposure to the investigational product in days will be determined from the first and 
last dosing dates during the treatment period and is derived as the last dose date – the first dose date + 1. 
The last dose date will be the date the last tablet was taken regardless of whether this is an active or inactive 
tablet. The total extent of exposure across all subjects in years will be derived by summing the total 
exposure in days across all subjects in the Safety Population and dividing it by 365.25 to convert the units 


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from days to years. This will be used in the derivation of event rates for adverse events as this represents 
the duration of the on-treatment period for treatment emergent adverse events. 
The duration of actual exposure to the investigational product in days will be determined by subtracting the 
total number of days where no pills were taken from the duration of total exposure. The total number of 
days where no pills were taken is equivalent to the total number of missed pills from Section 5.7 summed 
across all cycles for that subject. Days where no pills were taken include days between Day 28 of a cycle 
and Day 1 of the next cycle where there are gaps between cycles and days within a cycle where there are 
no active or inactive pills taken. The total extent of actual exposure across all subjects in years will be 
derived by summing the exposure in days across all subjects in the Safety Population and dividing it by 
365.25 to convert the units from days to years. 
The duration of actual exposure will be used to determine whether or not a subject has had at least 26 
weeks exposure and whether or not a subject has had at least 52 weeks exposure. 
The number of cycles of treatment will be derived for each subject by determining the number of cycles as 
per the definition provided in Section 5.1.  
5.9 Pregnancy Related Definitions 
The date of conception will be estimated for each reported pregnancy by the Principal investigator. This 
estimated date of conception will be used to determine whether the pregnancy was pre-, on- or post-
treatment. In addition, the estimated date of conception will be reviewed alongside the compliance data 
recorded on the subject diary and the pregnancy narrative completed by the PI to determine whether the 
pregnancy occurred in a compliant (Product Failure) or non-compliant (User-Failure) subject with 
compliance suggesting method failure and non-compliance suggesting user failure. The definitions of pre-
, on- and post-treatment pregnancies and for method and user failure pregnancies are provided below. 
5.9.1 Pre-Treatment Pregnancies 
Pre-treatment pregnancies are pregnancies with an estimated date of conception before the date of the 
first dose of study medication. 
5.9.2 On-Treatment Pregnancies 
On-treatment pregnancies are pregnancies with an estimated date of conception during the On-Treatment 
Period for contraceptive efficacy (see Section 5.3 for the definition of the On-Treatment Period). In cases 
where the date of conception cannot be established unequivocally (e.g. subjects is lost to follow up), this 
pregnancy will be considered as on-treatment pregnancy.  
For on-treatment pregnancies, the cycle and day within the cycle of conception will be assigned based on 
the diary data collected and the estimated conception date. If the on-treatment pregnancy has an estimated 
date of conception in the 7-days after the last dose of study medication, then the cycle of conception will 
be the cycle in which the last dose of study medication was taken and the day of conception will be not 
applicable. 
5.9.3 Post-Treatment Pregnancies 
Post-treatment pregnancies are pregnancies with an estimated date of conception after the end of the On-
Treatment Period for contraceptive efficacy. 
5.9.4 Method and User Failure Pregnancies  
User failure pregnancies are pregnancies where the subject did not take the study medication correctly as 
per Section 9.4.4 of the Protocol during the cycle in which the estimated date of conception occurred or 
used drugs that have the potential to trigger interactions with COC (Section 9.4.6 of the Protocol). 
Pregnancies not identified as due to user failure will be considered to be method failure pregnancies. The 
pregnancy narratives from the Principal Investigator are used to determine whether a pregnancy is a user 
or method failure pregnancy. 


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Each on-treatment pregnancy will be reviewed in conjunction with the data collected and classified as either 
a method failure or a user failure pregnancy prior to database lock.  
5.10 Bleeding Patterns 
The subject diary data will be used to characterize bleeding patterns. Bleeding data will be analyzed by 
cycle and by RP. 
5.10.1 Definitions of Bleeding and Spotting 
Definitions for bleeding and spotting used for the cycle and RP analysis are provided in Table 1 below. In 
the diary, “0” was to be ticked for no bleeding or spotting, “1” for spotting and “2” for bleeding. 
Table 1: Bleeding and spotting definitions 
Term 
Definition 
Bleeding 
Evidence of vaginal blood loss that requires the use of sanitary protection with a 
tampon, pad or pantyliner. 
Spotting 
Evidence of minimal vaginal blood loss that does not require new use of sanitary 
protection, including pantyliners. 
Bleeding day 
Day where bleeding (2) was reported for that day in the subject diary 
Spotting day 
Day where spotting (1) was reported for that day in the subject diary 
Bleeding/spotting-
free day 
Day where no bleeding or spotting (0) was reported in the subject diary 
 
Bleeding/Spotting 
episode 
One or more consecutive bleeding and/or spotting days where there are both 
bleeding and spotting days bounded on either end by 2 bleeding/spotting-free 
days 
Bleeding only 
episode 
One or more consecutive bleeding days where there are no spotting days bounded 
on either end by 2 bleeding/spotting-free days 
Spotting only 
episode 
One or more consecutive spotting days where there are no bleeding days bounded 
on either end by 2 bleeding/spotting-free days 
Bleeding/spotting-
free episode 
Two or more consecutive bleeding/spotting-free days bounded on either end by a 
bleeding or spotting day 
 
5.10.2 Cycle analysis 
5.10.2.1 Definition of cycles 
In the cycle analysis of a 24/4 regimen of a COC, an up to 7-day vaginal bleeding is scheduled to occur in 
conjunction with the first inactive tablet (Day 25) and end on Day 3 of the next cycle (expected bleeding 
period). In principle, no vaginal bleeding is expected to occur at other times during the cycle. This means 
that the remainder of the cycle constituted the expected non-bleeding period of 21 days. Therefore, any 
bleeding/spotting that occurs during the expected non-bleeding period (starting on Day 4 of the actual cycle 
up to and including Day 24) are considered as unscheduled. 
The following definitions (Table 2) will be used for the cycle analysis: 


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Table 2: Bleeding/spotting definitions used for the cycle analysis 
Scheduled 
Bleeding/Spotting 
(Withdrawal 
Bleeding/Spotting) 
Any bleeding/spotting that occurs during the hormone-free interval (i.e. Days 25 
– 28) and continues through Days 1-3 of the subsequent active cycle. 
Note: any bleeding/spotting that occurs while taking active hormones during 
Days 1-7 of the first cycle will be imputed as no bleeding. 
Unscheduled 
Bleeding/Spotting 
Any bleeding/spotting that occurs while taking active hormones that does not 
meet the criteria for scheduled bleeding/spotting. 
Unscheduled 
Bleeding 
Any bleeding that occurs while taking active hormones that does not meet the 
criteria for scheduled bleeding. 
Unscheduled 
Spotting 
Any spotting that occurs while taking active hormones that does not meet the 
criteria scheduled spotting. 
Early Withdrawal 
Bleeding/Spotting 
Any bleeding/spotting episode that starts before the scheduled bleeding/spotting 
period and continues into the scheduled bleeding/spotting period. 
Continued 
withdrawal 
bleeding/spotting 
Any bleeding/spotting episode that starts in the scheduled bleeding/spotting 
period and continues after the scheduled bleeding/spotting period. 
 
  
Based on these definitions, the cycle analysis of bleeding/spotting episodes will perform in two ways: 
 
a classical approach 
 
a modified cycle analysis  
5.10.2.2 Classical cycle analysis 
In the classical analysis, early and continued withdrawal bleeding are regarded as scheduled. 
The following rules will be used for the classical approach to classify each bleeding only episode, spotting 
only episode or bleeding/spotting episode as scheduled or unscheduled: 
The episode is defined as unscheduled, if any of the following criteria are met:  
 
The episode has a start date after Day 7 of Cycle 1 and an end date that is on or before Day 24 of 
Cycle 1 
 
For Cycles 2 to 13, the episode has a start date after Day 3 of the cycle and an end date that is on 
or before Day 24 of the cycle 
The episode is defined as scheduled (withdrawal bleeding and/or spotting), if any of the following criteria 
are met: 
 
The episode has a start date after Day 24 of the cycle and an end date that is on or before Day 3 
of the next cycle 
 
The episode has a start date after Day 24 of the cycle and an end date that is after Day 3 of the 
next cycle (continued withdrawal bleeding/spotting).  
o 
Note it is not possible to have continued withdrawal bleeding for Cycle 13 because data 
are not collected for Cycle 14 
 
The episode has a start date before Day 24 of the cycle and an end date on or after Day 25 (early 
withdrawal bleeding/spotting). 


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All bleeding days and spotting days will then be classified as scheduled or unscheduled based on whether 
the bleeding or spotting days are included in a scheduled or unscheduled episode using the rules in this 
Section above. A bleeding day or spotting day that occurs in a scheduled episode will be classified as 
scheduled and a bleeding day or spotting day that occurs in an unscheduled episode will be classified as 
unscheduled.  
5.10.2.3 Modified Cycle Analysis  
In the modified cycle analysis, the definitions of expected non-bleeding and expected bleeding periods are 
strictly followed, i.e., all bleeding episodes that overlap with expected non-bleeding intervals are considered 
unscheduled. Thus in this analysis, the definitions of scheduled and unscheduled bleeding/spotting 
episodes presented in the Table 2 are also applicable, but early and continued withdrawal bleedings are 
regarded as unscheduled. 
Therefore, in the derivation of endpoints where early and continued withdrawal bleeding are classed as 
unscheduled bleeding the following rules are used to classify each bleeding only episode, spotting only 
episode or bleeding/spotting episode as scheduled or unscheduled:  
The episode is defined as unscheduled, if any of the following criteria are met:  
 
The episode has a start date after Day 7 of Cycle 1 and an end date that is on or before Day 24 of 
Cycle 1 
 
For Cycles 2 to 13, the episode has a start date after Day 3 of the cycle and an end date that is on 
or before Day 24 of the cycle 
 
The episode has a start date after Day 24 of the cycle and an end date that is after Day 3 of the 
next cycle (continued withdrawal bleeding/spotting)  
o 
Note it is not possible to have continued withdrawal bleeding for Cycle 13 because data 
are not collected for Cycle 14 
 
The episode has a start date before Day 24 of the cycle and an end date that is on or after Day 25 
(early withdrawal bleeding/spotting) 
The episode is defined as scheduled (withdrawal bleeding and/or spotting), if the following criterion is met: 
 
The episode has a start date after Day 24 of the cycle and an end date that is on or before Day 3 
of the next cycle 
All bleeding days and spotting days will then be classified as scheduled or unscheduled based on whether 
the bleeding or spotting days are included in a scheduled or unscheduled episode in the same way as 
outlined for the classical analysis but using the rules in this Section above where early and continued 
withdrawal bleeding are classed as unscheduled episodes.  
5.10.3 Reference Periods (RPs) 
No additional definitions other than those displayed in Table 1 were used for the reference period analysis.  
5.10.4 Bleeding Endpoints for the Cycle Analysis 
For the cycle analysis, the evaluable cycles will be determined as described in Section 5.1 for each subject, 
missing data rules are provided in Section 5.15.2 and definitions of terminology are provided in Section 
5.10.1 and 5.10.2.  
Depending on the approach used for the cycle analysis (the classical approach versus the modified cycle 
analysis), for each evaluable cycle for each subject, the following will be determined: 
 
Whether there was at least one unscheduled bleeding only, spotting only or bleeding/spotting 
episode within that cycle (see Section 5.10.2 for definition). It will be assumed that there is at least 


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one unscheduled episode during the cycle if there is an unscheduled episode that starts in the cycle 
of interest 
 
Whether there was at least one unscheduled bleeding only episode within that cycle (see Section 
5.10.2 for definition) and no unscheduled bleeding/spotting episodes and no unscheduled spotting 
only episodes. It will be assumed that there is at least one unscheduled bleeding only episode 
during the cycle if there is an unscheduled bleeding only episode that starts in the cycle of interest 
 
Whether there was at least one unscheduled spotting only episode within that cycle (see Section 
5.10.2 for definition) and no unscheduled bleeding/spotting episodes and no unscheduled bleeding 
only episodes. It will be assumed that there is at least one unscheduled spotting only episode during 
the cycle if there is an unscheduled spotting only episode that starts in the cycle of interest 
 
Whether there is an absence of any bleeding or spotting (i.e. all days in the cycle are 
bleeding/spotting-free days)  
 
Whether there is an absence of scheduled bleeding only, spotting only and bleeding/spotting 
episodes (i.e. there is no scheduled episode with a start date during that cycle of interest)  
 
Whether there is early withdrawal bleeding or spotting in that cycle (i.e. there is either an early 
withdrawal bleeding only, spotting only or bleeding/spotting episode that starts during the cycle of 
interest) 
 
Whether there is continued withdrawal bleeding or spotting in that cycle (i.e. there is either a 
continued withdrawal bleeding only, spotting only or bleeding/spotting episode that starts during 
the cycle of interest)  
 
The total (scheduled + unscheduled) number of days with bleeding and/or spotting (i.e. the number 
of bleeding days + the number of spotting days within the bleeding only, spotting only and 
bleeding/spotting episodes that start during the cycle of interest) 
 
The total (scheduled + unscheduled) number of days with bleeding only (i.e. the number of bleeding 
days within the bleeding only and bleeding/spotting episodes that start during the cycle of interest) 
 
The total (scheduled + unscheduled) number of days with spotting only (i.e. the number of spotting 
days within the spotting only and bleeding/spotting episodes that start during the cycle of interest) 
 
The number of unscheduled days with bleeding and/or spotting (i.e. the number of bleeding days 
+ the number of spotting days within the unscheduled bleeding only, spotting only and 
bleeding/spotting episodes that start during the cycle of interest)  
 
The number of unscheduled days with bleeding only (i.e. the number of bleeding days within the 
unscheduled bleeding only and bleeding/spotting episodes that start during the cycle of interest) 
 
The number of unscheduled days with spotting only (i.e. the number of spotting days within the 
unscheduled spotting only and bleeding/spotting episodes that start during the cycle of interest)  
 
The number of scheduled days with bleeding and/or spotting (i.e. the number of bleeding days + 
the number of spotting days within the scheduled bleeding only, spotting only and bleeding/spotting 
episodes that start during the cycle of interest)  
 
The number of scheduled days with bleeding only (i.e. the number of bleeding days within the 
scheduled bleeding only and bleeding/spotting episodes that start during the cycle of interest) 
 
The number of scheduled days with spotting only (i.e. the number of spotting days within the 
scheduled spotting only and bleeding/spotting episodes that start during the cycle of interest) 
 
The start day for any scheduled bleeding episodes that have a start date within the cycle (if there 
are more than one scheduled bleeding episodes in the cycle, then only the start day of the earliest 
episode will be used)  


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5.10.5 Bleeding Endpoints for Analyses by RP 
For the analyses by RP, the evaluable RPs will be determined as described in Section 5.1.2 for each 
subject, missing data rules are provided in Section 5.15.2 and definitions of terminology are provided in 
Section 5.10.1.  
The following variables will be derived for each evaluable RP and subject: 
 
The total number of days with bleeding and/or spotting (i.e. the number of bleeding days + the 
number of spotting days within the bleeding only, spotting only and bleeding/spotting episodes 
that start during the RP of interest)  
 
The total number of days with bleeding only (i.e. the number of bleeding days within the 
bleeding only and bleeding/spotting episodes that start during the RP of interest) 
 
The total number of days with spotting only (i.e. the number of spotting days within the spotting 
only and bleeding/spotting episodes that start during the RP of interest) 
 
The number of bleeding and/or spotting episodes 
 
The mean duration of the bleeding and/or spotting episodes 
 
The number of bleeding and/or spotting free episodes  
 
The mean duration of the bleeding and/or spotting free episodes  
For the number of bleeding and/or spotting episodes in the RP, the number of episodes is defined as the 
number of bleeding only episodes + the number of spotting only episodes + the number of spotting/bleeding 
episodes with a start date during that RP. The duration of an episode is derived as the end date of the 
episode – start date of the episode + 1. The mean duration of episodes in the RP is derived from the 
duration of all episodes with a start date during that RP. The full duration of each of the episodes is used in 
the derivation of the mean duration, even if the episode continues beyond the end of the RP. 
5.11 Treatment-Emergent Adverse Event (TEAE) 
A TEAE is defined as an AE with a start date or worsening during the On-Treatment Period for TEAEs (see 
Section 5.3 for definition of the On-Treatment Period). 
If the start date for an AE is missing and the end date is either missing or on or after the date of first dose 
of study medication, then the AE will be assumed to be treatment-emergent. However, if the start date for 
an AE is missing and the end date is recorded and is before the first dose of study medication, then the AE 
will be assumed to be non-treatment emergent. 
5.12 Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-
LES-Q-SF) 
The total score of the Q-LES-Q-SF (see Appendix 4 of the Protocol) will be derived by summing the first 14 
items to obtain the raw total score. The raw total score is then transformed into a percentage maximum 
using the following formula: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑀𝑎𝑥𝑖𝑚𝑢𝑚= (𝑟𝑎𝑤 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 –  14)
56
 
In the case of questions with missing results, if 10 or more questions are answered, then the percentage 
maximum is derived as follows: 
  
𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑀𝑎𝑥𝑖𝑚𝑢𝑚= (𝑟𝑎𝑤 𝑡𝑜𝑡𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 𝑓𝑜𝑟 𝑡ℎ𝑒 𝑞𝑢𝑒𝑠𝑡𝑖𝑜𝑛𝑠 𝑎𝑛𝑠𝑤𝑒𝑟 –  𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑞𝑢𝑒𝑠𝑡𝑖𝑜𝑛𝑠 𝑎𝑛𝑠𝑤𝑒𝑟)
(𝑡ℎ𝑒 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑞𝑢𝑒𝑠𝑡𝑖𝑜𝑛𝑠 𝑎𝑛𝑠𝑤𝑒𝑟𝑒𝑑 ×  4)
 
If fewer than 10 questions are answered, then the percentage maximum will be considered to be missing. 


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The change from Baseline at the end of treatment will be calculated for each subject. 
5.13 Menstrual Distress Questionnaire  
The Menstrual Distress Questionnaire (see Appendix 5 of the Protocol) will be scored according to the 
manual (Moos, 1968). The following scales will be derived by summing the items that fall within that 
specified category: pain, water retention, autonomic reactions, negative affect, impaired concentration, 
behavior change, arousal and control. Each of these are derived at each visit for the menstrual (most recent 
flow in CRF), premenstrual (4 days before in the CRF) and intermenstrual (remainder of the cycle in the 
CRF) phases by summing the items that fall under the specified scale. The scoring key is presented in 
Table 3 below. If the subject does not answer one item on any of the scale, then the scale is calculated by 
deriving the mean score for the answered items and adding that number to the sum of the answered items 
within that scale. If 2 or more items within a scale are not answered, then the scale is missing. The change 
from Baseline at the end of treatment will be calculated for each subject. 
Table 3: Menstrual Distress Questionnaire Scoring Key 
Scale 
Items 
Pain 
1, 2, 3, 4, 5, 6 
Water Retention 
7, 8, 9, 10 
Autonomic Reactions 
11, 12, 13, 14 
Negative Affect 
15, 16, 17, 18, 19, 20, 21, 22 
Impaired Concentration 
23, 24, 25, 26, 27, 28, 29, 30 
Behaviour Change 
31, 32, 33, 34, 35 
Arousal 
36, 37, 38, 39, 40 
Control 
41, 42, 43, 44, 45, 46 
 
5.14 Return to Fertility 
Each woman who discontinues the study due to a pregnancy wish will be followed-up after study treatment 
discontinuation to evaluate return of spontaneous menstruation, return of fertility, or initiation of hormonal 
contraception, whichever comes first.  
The date of the first spontaneous menstruation after study discontinuation will be recorded in the eCRF and 
follow-up will be continued. Once a pregnancy is reported or once a new contraceptive method has been 
started, the date of expected pregnancy term or of contraceptive treatment initiation will be recorded in the 
eCRF and no further follow-up contact will be done. The time from last dose of study medication to the 
return to menstruation will be calculated as the date of return of menses – the date of last dose of study 
medication. If the subject’s fertility information indicates that she had confirmation of pregnancy, then time 
from last dose of study medication to the estimated date of conception will be calculated as the estimated 
date of conception – the date of last dose of study medication. The estimated date of conception will be 
derived as the date of expected pregnancy term – 38 weeks (266 days). If the subject’s fertility information 
indicates that she received a new contraceptive method, then time from last dose of study medication to 
the date of the new contraceptive method will be calculated as the date of new contraceptive method – the 
date of last dose of study medication. 
5.15 Methods for Handling Missing Data 
5.15.1 Missing Data Related to the Pearl Index and Pill Intake 
In the derivation of the Pearl Index, if the subject did not respond to the question on other contraceptive 
methods in the subject diary, it will be assumed that another contraceptive method was used. The cycle will 
be classed as a not at-risk cycle and excluded from the denominator of the Pearl Index. If the subject did 
not respond to the question on sexual intercourse in the subject diary, it will be assumed that she did not 


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have sexual intercourse and that cycle will be classed as a not at-risk cycle and excluded from the 
denominator of the Pearl Index as appropriate. 
For compliance, if the number of active (pink) and inactive (white) pills is blank in the diary, then it will be 
assumed that no pills were taken on that day. 
If there is a partial start date for a cycle, then the start date will be imputed as the day after the date of Day 
28 of the previous cycle, providing the imputed date is consistent with the non-missing part of the date 
reported and that the duration of the cycle is consequently consistent with the expected 28 days. For rules 
around missing or partial start dates for Cycle 1, see Section 5.15.5. 
5.15.2 Missing Bleeding Data 
One or two consecutive days with missing bleeding information will be interpolated with the bleeding 
information from the previous day. For three or more consecutive days with missing bleeding information, 
missing data will be interpolated using the worst bleeding observation of the bordering days. If there are 3 
or more consecutive days with missing bleeding information at the end of the diary with no non-missing 
data reported afterwards, then the missing bleeding information will be interpolated with the bleeding 
information from the day immediately prior to the missing days. Data missing after withdrawal from the 
study will not be imputed.  
In the case of an ambiguous response for bleeding on a given day, the worst response recorded will be 
used. For example, if both bleeding and spotting are reported, then the response will be set to bleeding. If 
both bleeding and absence of vaginal bleeding or spotting are reported, then the response will be set to 
bleeding. If both spotting and absence of vaginal bleeding or spotting are reported, then the response will 
be set to spotting. If bleeding, spotting and absence of vaginal bleeding or spotting are reported, then the 
response will be set to bleeding. 
The first 7 days of Cycle 1 will be imputed with no bleeding. It will be assumed that the bleeding data for 
the 3 days after the end of Cycle 13 is the same as that of the last day of Cycle 13 where bleeding data 
were recorded.  
5.15.3 Missing or Partial Dates for Medications  
In the determination of whether a medication is taken during the On-Treatment Period, the following rules 
for missing and partial dates will be applied:  
 
If the end date is before the first dose of study medication, then the medication is a prior medication, 
regardless of whether or not the start date is missing or partially missing  
 
If the end date is on or after the date of first dose of study medication, then the following rules will 
be applied for missing or partially missing start dates: 
o 
If the start date is completely missing, then the medication will be assumed to be 
concomitant. 
o 
If only the year of the start date is recorded and the year is either before or the same year 
as the end of the safety On-Treatment Period, then the medication will be assumed to be 
concomitant.  
o 
If only the year of the start date is recorded and the year is after the year of the end of the 
safety On-Treatment Period, it will be considered to be a post-study treatment medication.  
o 
If only the year and the month of the start date is recorded and the month specified is either 
before or the same month as the end of the safety On-Treatment Period, then the 
medication will be assumed to be concomitant 
o 
If only the year and the month of the start date is recorded and the month specified is after 
the month of the end of the safety On-Treatment Period, it will be considered to be a post-
study treatment medication. 


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Rules for dealing with missing start and stop dates for study medication for the classification of medications 
are in Section 5.15.5. 
5.15.4 Missing or Partial Dates for AEs  
If the start date for an AE is missing and the end date is either missing or on or after the date of first dose 
of study medication, then the AE will be assumed to be treatment-emergent. However, if the start date for 
an AE is missing and the end date is recorded and is before the first dose of study medication, then the AE 
will be assumed to be non-treatment emergent. 
Rules for dealing with missing start and stop dates for study medication for the classification of AEs are in 
Section 5.15.5. 
5.15.5 Missing or Partial Treatment Start and Stop Dates 
5.15.5.1 Missing Treatment Start and Stop Dates 
If the subject has no diary data but has a pregnancy as per Principal Investigator’s assessment in the 
pregnancy narrative that is classified as on-treatment or post treatment, then the subject will be classed as 
treated. The treatment start date and treatment stop date would be unknown in this situation.  
In the case of post-treatment pregnancies, the cycle for censoring for the cumulative event rates for 
pregnancies cannot be determined and this will be missing. The subject will also consequently have no 
evaluable cycles for the Pearl Index. In the case of on-treatment pregnancies, the cycle of conception from 
the narrative will be used in the derivation of the cumulative event rates for pregnancies and in the derivation 
of the Pearl Index but for the Pearl Index no other cycles would be included in the denominator for that 
subject.  
When classifying concomitant, pre- and post medication and treatment emergent AEs and defining the 
Baseline assessments, the treatment start date will be assumed to be the first date in which the 
investigational product was dispensed and the treatment end date will be assumed to be the discontinuation 
or completion date for that subject. However, the start and stop dates for study medication will remain 
missing and the compliance and exposure will not be calculated. Similarly, the cycle of discontinuation of 
study medication cannot be determined and therefore this would remain missing for such subjects. The 
subject will have no evaluable cycles for the bleeding analysis.  
5.15.5.2 Partial Treatment Start Dates 
If the subject has a partial start date Cycle 1, and consequently a partial start date for study medication, 
then the partial start date will be presented in the listing. If the date of last dose cannot be derived as a 
result of the partial start date, then this will be blank in the listings as the end date is unknown.  
In the case of an on-treatment pregnancy, the cycle of conception will be estimated from the available data. 
If the subject does not have an on-treatment pregnancy, then for the cumulative event rates for pregnancy, 
the subject will be censored in the cycle where the last pill intake was reported per the diary data. Cycle 1 
will be included in the denominator for the Pearl Index following the rules in Section 5.1.1 and will be 
included in the bleeding analysis following the rules in Section 5.1.2.  
In this case, when classifying concomitant, pre- and post medication and treatment emergent AEs and 
defining the Baseline assessments, the treatment start date will be assumed to be the first date in which 
the investigational product was dispensed. If the treatment end date cannot be determined as a result of 
the partial start date, then the date of last dose will be derived for the day in the diary where the last pill is 
reported and by assuming that the start date is the latest possible day. For example, if the partial start date 
is January 2017 and the last day with a pill reported is Day 4 of Cycle 1, then the assumed start date would 
be 31 January 2017 and therefore Day 4 of Cycle 1 would be 3 February 2017 and this would be used as 
the date of last dose. The diary data for pill intake will be used to derive compliance and exposure per the 
rules in the SAP.  


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6.0 Analysis Sets 
6.1 Screened Population 
The Screened Population includes all subjects who signed an informed consent (IC) form. 
The Screened Population will be used for disposition data and data will be displayed for subjects aged 16 
to 35 years and for all subjects in separate columns. 
6.2 Enrolled Population 
The Enrolled Population includes all enrolled subjects (i.e. subjects who had a non-missing enrollment date 
on the enrollment page of the CRF). 
The Enrolled Population will be used for summaries of enrollment per country. 
6.3 Safety Population 
The Safety Population includes all enrolled subjects who receive at least one dose of study medication.  
If a subject returns all study medication that was dispensed, then the subject will not be included in the 
Safety Population. If there is at least one pill that was dispensed but was not returned, but the subject diary 
has no pills recorded as taken, then it will be assumed that the subject has not taken any study medication 
and will not be included in the Safety Population. However, if the subject has no pills taken according to the 
diary but the subject has a pregnancy that is classified as per Principal Investigator’s assessment in the 
pregnancy narrative as either an on-treatment or post treatment pregnancy, then the subject will be included 
in the Safety Population. In the case of missing diary data, it will be assumed that no pills were taken for 
the corresponding days with missing data. If there was at least one pill that was dispensed but was not 
returned and the subject has taken at least one pill according the subject diary, then that subject will be 
included in the Safety Population.  
The Safety Population will be used for compliance and exposure data with data displayed for subjects aged 
16 to 35 years and for all subjects in separate columns. The Safety Population will also be used for safety 
presented for all subjects. 
Follow-up evaluations will be presented for subjects in the Safety Population who discontinued study 
medication with pregnancy wish as the reason for discontinuation. 
6.4 Intention-to-Treat (ITT) Population 
The ITT Population includes all enrolled subjects who receive at least one dose of study medication. The 
ITT Population is the same as the Safety Population for this study. 
The ITT Population will be used for baseline and contraceptive efficacy data with data displayed for 
subjects aged 16 to 35 years and for all subjects in separate columns. The ITT Population will also be 
used for protocol deviations, bleeding and quality of life data with data presented for all subjects.  
6.5 Per-Protocol (PP) Population 
The bleeding data cycle analysis will be presented in the PP Population. For the bleeding analysis, the PP 
Population will exclude cycles based on the rules in Section 5.1.2. Subjects in the ITT Population with at 
least one evaluable cycle for the bleeding analysis will be included in the PP Population and only their 
evaluable cycles will be included in the PP analysis for bleeding data. Subjects will be excluded from the 
PP Population entirely if they have no evaluable cycles for the bleeding analysis. 
6.6 Pharmacokinetics (PK) Population 
The PK Population includes all subjects enrolled in the PK Substudy who provide concentration data for at 
least one sample. 


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The PK Population will be used for all PK analysis described in Section 9.8. 
7.0 Interim Analyses 
There are no planned interim analyses for this study. 
8.0 Data Review 
8.1 Data Handling and Transfer 
Processes for data handling and transfer will be documented in the Data Management Plan. 
8.2 Data Screening 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed data issues will 
be output into SAS logs identified by the word “Problem” and extracted from the logs by a SAS macro and 
sent to Data Management. 
Review of a pre-freeze TFL run on clean subjects and a post-freeze TFL run on the frozen database allow 
for further data screening prior to lock. The post-freeze TFL will be discussed with the sponsor in a data 
review meeting to identify any final data issues and seek corrections prior to database lock. The PRA 
statistician and the sponsor must approve database lock. 
8.3 Data Review Meetings 
Data review meetings will be held during the course of the study prior to database lock and the following 
may be reviewed during these meetings: 
 
Important protocol deviations and exclusion from the PP Population 
 
Classification of at-risk and not at-risk cycles for the Pearl Index derivation where the classification 
is not clear based on the data collected and the rules in the SAP 
 
Classification of on-, pre- and post- treatment pregnancies for the Pearl Index derivation 
 
Classification of method failure and user failure pregnancies for the method failure Pearl Index 
derivation 
 
Classification of evaluable and non-evaluable cycles for the PP bleeding analysis where the 
classification is not clear based on the data collected and the rules in the SAP 
9.0 Statistical Methods 
All analyses will be conducted using SAS version 9.4 or higher. 
No formal statistical analyses will be performed in this study. 
The following conventions will be used when presenting summary statistics for study data: 
 
Continuous variables will be summarized using the following descriptive statistics: number of 
subjects (n), mean, standard deviation (SD), standard error of the mean (SEM), median, minimum 
(min), maximum (max), 25th percentile (lower quartile or Q1) and 75th percentile (upper quartile or 
Q3) 
 
Categorical and count variables will be summarized by the number of subjects (n) and the percent 
of subjects in each category. For AE tables, m may also be presented which represents the number 
of events. Percentages will be presented to 1 decimal place 


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 
The number of subjects or observations will be presented as an integer 
 
Mean, median, lower quartile and upper quartile will be presented to 1 decimal place more than the 
raw value 
 
Min and max will be presented to the same number of decimal places as the raw value 
 
Standard deviation will be presented to 2 decimal places more than the raw value, up to a 
reasonable number of decimal places (i.e., rarely more than 3 decimal places unless the nature of 
the data suggests this) 
 
The denominator for percentage calculations will be the number of non-missing observations at 
that visit. Where this isn’t appropriate, the number of subjects in the relevant population will be used 
9.1 Subject Disposition 
All summaries in this Section will be presented for subjects aged 16 to 35 years and for all subjects. This 
will be based on the Screened Population. 
The number and percentage of subjects treated in the study will be presented, together with the number 
and percentage of subjects who completed the study and the number and percentage of subjects who 
withdrew from the study prematurely with a breakdown of the corresponding reasons for withdrawal. If a 
subject returns all study medication that was dispensed, then the subject will not be classed as treated. If 
there is at least one pill that was dispensed but was not returned, but the subject diary has no pills recorded 
as taken, then it will be assumed that the subject has not taken any study medication and will not be classed 
as treated. However, if the subject has no pills taken according to the diary but the subject has a pregnancy 
that is classified as either an on-treatment or post treatment pregnancy based on the Principal Investigator’s 
assessment in the pregnancy narrative, then the subject will be classed as treated. In the case of missing 
diary data, it will be assumed that no pills were taken for the corresponding days with missing data. If there 
was at least one pill that was dispensed but was not returned and the subject has taken at least one pill 
according the subject diary, then that subject will be classed as treated.  
Tabulations of the number and percentage of subjects included in each analysis set will be provided. The 
percentage will not be presented for the Screened and Enrolled Populations. Percentages will be derived 
based on the number of subjects enrolled. 
A tabulation of the number and percentage of subjects enrolled at each site and country will be summarized 
in the Enrolled Population. 
Disposition data and the site and country will be listed in the Enrolled Population. Information on inclusion 
in each of the analysis sets will be listed in the Screened Population. Screening failures will be listed with 
the reason for the screening failure. 
The cumulative discontinuation rate, as determined by life-table methods, together with the corresponding 
95% CIs will be presented in the ITT population for all subjects and for subject’s aged 16 to 35 years 
inclusive at Screening. The life-table analysis will evaluate the cumulative probability of discontinuation from 
the study by cycle using PROC LIFETEST in SAS where the time variable is the cycle where the 
discontinuation occurred for subjects who discontinued from the study prematurely. Subjects who did not 
discontinue from the study prematurely will be censored in Cycle 13. The rate of discontinuation and 95% 
CIs will be calculated based on Kaplan-Meier estimates for each cycle. Additionally, the estimated survival 
function against time (cycle) will be provided.  
9.2 Protocol Deviations and Violations 
The important protocol deviations for this study will be specified in the Protocol Deviation Guidance 
Template. Per PRA processes, protocol deviations will be entered into PRA’s Clinical Trials Management 
System (CTMS). The study team and the sponsor will conduct ongoing reviews of the protocol deviations 
from CTMS to identify deviations which meet the criteria for important.  


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The number and percentage of subjects who had an important protocol deviation will be summarized in the 
ITT Population. 
All important protocol deviations will be listed in the ITT Population. 
The important protocol deviations will be reviewed and their potential to impact the analysis of the bleeding 
data will be assessed against the rules specified in Sections 5.1.2. If there is a potential for a specific 
important protocol deviation to impact this analysis, then the impacted cycles for that subject will be 
excluded from the PP analysis for bleeding data. Subjects with no evaluable cycles will be excluded from 
the PP Population for the analysis of bleeding data. The PP Population and the cycles to be excluded from 
the PP analysis must be finalized at the post-freeze data review meeting (or earlier), prior to database lock. 
9.3 Treatments 
All summaries described in this Section will be presented for subjects aged 16 to 35 years and for all 
subjects in the Safety Population.  
9.3.1 Extent of Study Drug Exposure 
The overall duration of total exposure and actual exposure will be summarized using descriptive statistics. 
In addition, the total extent of exposure and total extent of actual exposure across all subjects will be 
summarized in years. 
Additionally, the number and percentage of subjects exposed for at least 26 weeks and at least 52 weeks 
based on actual exposure will be presented. The denominators for calculating the percentages will be based 
on the number of subjects. 
The number of cycles as defined in Section 5.1 will also be summarized using descriptive statistics. The 
number and percentage of subjects who had at least 1, 2, 3, etc. cycles will be summarized.  
Exposure data will be listed for all subjects in the Safety Population. 
9.3.2 Treatment Compliance 
Treatment compliance by cycle and overall will be summarized using descriptive statistics including the 
following information: 
 
The number of pills taken 
 
The compliance  
The number and percentage of subjects missing no pills, 1 pill, 2 pills and more than 2 pills will be 
summarized for each cycle where the cycle is defined as per Section 5.1. The denominator will be the 
number of subjects in the Safety Population who started that cycle. 
The total number of pills taken across all subjects will be presented. Compliance data will be listed for all 
subjects in the Safety Population. Drug accountability data will be listed only in the Safety Population. 
9.3.3 Prior, Post-Study Treatment and Concomitant Medications 
Medications received prior to or concomitantly with study drug, categorized by preferred term according to 
WHODRUG Jun 2017 will be summarized in the Safety Population. The number and percentage of subjects 
using each medication will be displayed. This will be repeated for prior medications. 
All prior, post-study treatment and concomitant medications will be listed in the Safety Population. 
9.4 Demographic and Baseline Characteristics 
All summaries described in this Section will be presented for subjects aged 16 to 35 years and for all 
subjects. 


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The following demographic data and baseline characteristics will be summarized in the ITT and PP 
Populations: 
 
Age at Screening 
 
Age group (≥16 to ≤25 years, >25 to ≤35 years, >35 to ≤50 years) at Screening 
 
Highest education level 
 
Ethnicity 
 
Race 
 
Height  
 
Weight at Baseline 
 
BMI at Baseline 
 
BMI categories (<30kg/m2, ≥30kg/m2) at Baseline 
If subjects record more than one race, then for the summary table, these subjects will be included in the 
Other Race group. BMI will be derived programmatically from the height and weight collected. 
The subject’s previous contraceptive method used will be summarized in terms of the number and 
percentage of switchers, starters and true new users in the ITT Population. Note: subjects who are true 
new users are a subset of the starters. 
The following information will be summarized for gynecological history in the ITT Population: 
 
Gravidity and parity status 
 
Menstrual cycle length for starters 
 
Dysmenorrhea 
 
Previous contraceptive method used 
 
History of pregnancy during accurate hormonal contraceptive use 
Smoking status, including the following information for current smokers will be presented in the ITT 
Population:  
 
The number of days per week where the subject smokes  
 
The number of tobacco products per day that the subject smokes 
All demographic data, baseline characteristics, gynecological history, contraceptive use and smoking status 
will be listed in the ITT Population. In the demography listing, if a subject has more than one race recorded, 
then all races selected will be listed for that subject. 
Medical history will be summarized in the ITT. Medical history will be classified into a standardized 
terminology using the Medical Dictionary for Regulatory Activities (MedDRA) system organ classifications 
and preferred terms. Version 20.0 of MedDRA will be used as coding dictionary.  
Surgical history will not be summarized. 
All medical and surgical history recorded will be listed in the ITT Population. 
9.5 Efficacy Analyses 
9.5.1 Primary Variable 
The primary variable will be summarized using the Pearl Index in the ITT population aged 16 to 35 years 
inclusive at Screening with at-risk cycles. Subjects in this age group will not be censored on their 36th 


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birthday for the pregnancy assessment. The Pearl Index will be presented with corresponding 95% CIs. No 
formal statistical analyses will be conducted for the primary variable. 
The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment, will be 
calculated as 
Pearl Index = 
1300 x number of on −treatment pregnancies
number of women −28 day equivalent cycles of treatment 
Only at-risk cycles will be included in the denominator of the Pearl Index calculation. At-risk cycles will be 
defined as cycles in which the following criteria are met: 
1. No other methods of birth control (including condoms and emergency contraception) are used by 
the subject as confirmed in the subject diary  
2. The subject confirmed that sexual intercourse occurred during the cycle in the subject diary 
Note that if conception occurs in a cycle, then that cycle will be included as an at-risk cycle in the 
denominator even if other methods of birth control were used during that cycle or the subject did not confirm 
that they had had sexual intercourse. Cycles after the cycle of conception will not be included as at-risk 
cycles and will be excluded from the denominator. 
The number of women-28 day equivalent cycles of treatment is the sum of the number of at-risk cycles 
across all subjects. The total number of at-risk cycles will be presented in the table.  
All on-treatment pregnancies will be included in the numerator for the Pearl Index (see Section 5.9.1 for 
definition of on-treatment pregnancies).  
For calculation purposes a cycle will be defined as per Section 5.1.1.  
The 95% CI for Pearl Indices will be calculated using a Poisson distribution. The confidence interval limits 
are calculated by the following equations: 
𝐶𝐼𝐿𝑂𝑊𝐸𝑅= 1300 ×
1
2 𝜒0.025; 2𝑥
2
𝑡ℎ𝑒 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑤𝑜𝑚𝑒𝑛−28 𝑑𝑎𝑦 𝑒𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑐𝑦𝑐𝑙𝑒𝑠 𝑜𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡  
 
𝐶𝐼𝑈𝑃𝑃𝐸𝑅= 1300 ×
1
2 𝜒0.975; 2(𝑥+1)
2
 
𝑡ℎ𝑒 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑤𝑜𝑚𝑒𝑛−28 𝑑𝑎𝑦 𝑒𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑐𝑦𝑐𝑙𝑒𝑠 𝑜𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 
where x is the number of on-treatment pregnancies. 
The Pearl Index and corresponding 95% CIs will be presented by the subgroups described in Section 4.3 
for subjects aged 16 to 35 years. All subject diary data, pregnancy information and at-risk cycles for each 
analysis will be listed. 
9.5.2 Secondary Variables 
9.5.2.1 Pearl Index 
The Pearl Index and corresponding 95% CIs will be presented for all subjects in the ITT Population (see 
Section 9.5.1 for details) including only at-risk cycles in the denominator. At-risk cycles will be defined as 
cycles in which no other methods of birth control (including condoms and emergency contraception) are 
used by the subject as confirmed in the subject diary, and the subject confirmed that sexual intercourse 
occurred during the cycle in the subject diary. The number of on-treatment pregnancies and at-risk cycles 
will be presented. 


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The Pearl Index and corresponding 95% CIs will be presented for subjects aged 16 to 35 years and for all 
subjects in the ITT Population including all cycles in the denominator with the exception of cycles after the 
cycle of conception in the case of pregnancy.  
The Pearl Index and corresponding 95% CIs will also be presented for subjects aged 16 to 35 years and 
for all subjects in the ITT Population employing a modified at-risk definition. With this definition, at-risk 
cycles will be defined as cycles in which no other methods of birth control (including condoms and 
emergency contraception) are used by the subject while cycles with and without confirmed intercourse are 
being included in the denominator.  
9.5.2.2 Method Failure Pearl Index 
The method failure Pearl Index is calculated using the same method as the Pearl Index (see Section 9.5.1 
for details), but includes only those pregnancies that were classified as method failure (see Section 5.9.4 
for details). Pregnancies due to user failure will be excluded from the numerator. 
The method failure Pearl Index and corresponding 95% CIs will be presented for subjects aged 16 to 35 
years at Screening in the ITT Population and for all subjects in the ITT Population including only at-risk 
cycles in the denominator. The number of on-treatment pregnancies and at-risk cycles will be presented. 
This will be derived in 4 ways: 
 
Including all at-risk cycles in the denominator where at-risk cycles will be defined as cycles in which 
no other methods of birth control (including condoms and emergency contraception) are used by 
the subject as confirmed in the subject diary and the subject confirmed that sexual intercourse 
occurred during the cycle in the subject diary. 
 
Including all at-risk cycles in the denominator employing a modified at-risk definition. With this 
definition, at-risk cycles will be defined as cycles in which no other methods of birth control 
(including condoms and emergency contraception) are used by the subject while cycles with and 
without confirmed intercourse are being included in the denominator.  
 
Including only at-risk cycles in the denominator where at-risk cycles will be defined as cycles in 
which no other methods of birth control (including condoms and emergency contraception) are 
used by the subject as confirmed in the subject diary and the subject confirmed that sexual 
intercourse occurred during the cycle in the subject diary where the subject was compliant with the 
dosing rules 3 to 8 in Section 5.1.1.  
 
Including only modified at-risk cycles in the denominator where at-risk cycles will be defined as 
cycles in which no other methods of birth control (including condoms and emergency contraception) 
are used by the subject as confirmed in the subject diary where the subject was compliant with the 
dosing rules 3 to 8 in Section 5.1.1 while cycles with and without confirmed intercourse are being 
included in the denominator.  
9.5.2.3 Life-Table Rates 
In addition, the cumulative pregnancy rate, as determined by life-table methods, together with the 
corresponding 95% CIs will be presented for all pregnancies and for all method failure pregnancies in the 
ITT population for all subjects and for subject’s aged 16 to 35 years inclusive at Screening. 
Life-table analyses will provide one-year life-table pregnancy rates for each efficacy endpoint (i.e. for all 
pregnancies as used in the Pearl Index and for all method failure pregnancies as used in the method failure 
Pearl Index). The life-table analysis will evaluate the cumulative probability of pregnancy by cycle using 
PROC LIFETEST in SAS where the time variable is the cycle where the estimated conception occurred for 
subjects who had an on-treatment event of pregnancy. Subjects who did not have an on-treatment event 
of pregnancy will be censored on the cycle prior to the cycle in which they discontinued from the study. The 
rate of pregnancy and 95% CIs will be calculated based on Kaplan-Meier estimates for each cycle. 
Additionally, the estimated survival function against time (cycle) will be provided. 


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9.5.3 Bleeding and Spotting 
Bleeding patterns will be analyzed using data from the subject diary. A cycle analysis and an analysis by 
RP will be performed (see Section 5.1.2 for details). Derived data for bleeding and spotting will be listed in 
the ITT Population.  
9.5.3.1 Cycle Analysis  
The cycle analysis will be performed following two approaches: a classical (for details see Section 5.10.2.2) 
and a modified cycle analysis (for details see Section 5.10.2.3).  
The classical analysis will be performed in the ITT and PP Population. This analysis will also be repeated 
for the following populations: 
 
The PP analysis excluding cycles where there is at least 1 day where an active pill was missed 
 
The ITT analysis including only cycles where 1 active pill was missed 
 
The ITT analysis including only cycles where 2 or more active pills were missed.  
The number of subjects with evaluable cycles for each population will be summarized by cycle.  
The modified cycle analysis where early and continued withdrawal bleeding are classed as unscheduled 
bleeding will be performed in the ITT Population, PP Population and the PP Population excluding cycles 
where there is at least 1 day where an active pill was missed.  
Details of the exclusion of cycles from the PP Population are provided in Section 5.1.2. Vaginal bleeding 
will be classified as spotting or bleeding and scheduled or unscheduled based on the definitions in Section 
5.10.1 and 5.10.2. Rules for handling missing data are provided in Section 5.15.2. The inclusion of cycles 
in ITT Population, PP Population and PP Population excluding cycles with at least 1 active pill missed in 
the cycle will be listed by subject and cycle along with reasons for exclusion of the cycle from the PP 
Population analysis and the number of missed pills. 
The following information will be summarized for bleeding and spotting for the cycle analysis: 
 
Number and percentage of subjects with unscheduled bleeding and/or spotting episodes for each 
cycle (classical analysis + modified cycle analysis) 
 
Number and percentage of subjects with unscheduled bleeding only episodes for each cycle 
(classical analysis + modified cycle analysis)  
 
Number and percentage of subjects with unscheduled spotting only episodes for each cycle 
(classical analysis + modified cycle analysis)  
 
Number and percentage of subjects with absence of a scheduled bleeding and/or spotting episode 
for each cycle (classical analysis + modified cycle analysis) 
 
Number and percentage of subjects with early withdrawal bleeding and/or spotting for each cycle  
 
Number and percentage of subjects with continued withdrawal bleeding and/or spotting for each 
cycle  
 
Number and percentage of subjects with absence of any bleeding and/or spotting for each cycle  
 
Descriptive statistics (e.g., mean, SD, median, minimum, and maximum) for the number of days of 
bleeding and/or spotting, bleeding only, and spotting only within a cycle for (classical and modified 
cycle analysis): 
o 
Total Days (Unscheduled + Scheduled) 
o 
Unscheduled Days 
o 
Scheduled Days 


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 
Cumulative number and percentage of subjects with absence of withdrawal bleeding and/or 
spotting in the ITT Population only (classical analysis) 
o 
The number of subjects who have no withdrawal bleeding and/or spotting that started in at 
least 1 cycle, at least 2 cycles, at least 3 cycles and so on up to at least 13 cycles. The 
denominator is the number of subjects with at least 1 evaluable cycle, at least 2 evaluable 
cycles, at least 3 evaluable cycles and so on up to at least 13 evaluable cycles, 
respectively, for the specified population  
Note that the denominator for the percentages listed above will be the number of subjects with an evaluable 
cycle unless otherwise specified. 
The percentage of subjects with bleeding, the percentage of subjects with spotting and the percentage of 
subjects with absence of bleeding and/or spotting for each day will be presented in a bar chart over time 
for the ITT, PP Populations and Populations based on active pill counts. The plot will start on Day 4 of Cycle 
1 because Days 1-3 of Cycle 1 are not assigned to a shifted cycle so cannot be assigned to the specified 
analysis populations. The 3 days imputed for the days included in shifted Cycle 13 after Day 28 of Cycle 
13 in the diary will not be included in the plot as these do not reflect the true bleeding pattern. Day will be 
the day from the diary data i.e. pill intake days (examples: Day 4 = Cycle 1 Day 4 or Day 118 = Cycle 5 Day 
6). The denominator will be the number of subjects with an evaluable cycle for the specified population on 
that day.  
The descriptive statistics (e.g., mean, SD, median, minimum, and maximum) for the number of unscheduled 
bleeding and/or spotting days, bleeding days, and spotting days within a cycle will also be summarized in 
subjects who experienced an unscheduled bleeding and/or spotting episode within that cycle. This will be 
presented for the classical and modified analysis in the ITT and PP Populations. Additionally, unscheduled 
bleeding and spotting and the absence of scheduled bleeding will be summarized for all subgroups 
specified in Section 4.3 by cycle for the classic cycle analysis for the ITT, PP Population and the PP 
Population excluding cycles with at least 1 missed active pill and the modified cycle analysis for the ITT 
Population. 
The number and percentage of subjects with a scheduled bleeding episode starting on each day in the 
scheduled bleeding period in the shifted cycle (i.e. Day 25, 26, 27, 28 and Day 1, 2 and 3 of the next cycle 
in the diary) will be summarized by Cycle. If there is more than one scheduled bleeding episode, then the 
only the earliest start date of the scheduled bleeding episodes starting within the cycle will be counted. This 
will be presented for the classical and modified analysis in the ITT Population. 
9.5.3.2 Reference Period Analysis 
All RP analysis will be performed in the ITT Population only. The following information will be summarized 
for bleeding and spotting for the RP analysis: 
 
Descriptive statistics (e.g., mean, SD, median, minimum, and maximum) for the number of days of 
bleeding and/or spotting, bleeding only, and spotting only within a RP. 
 
Descriptive statistics for the number of bleeding and/or spotting episodes in each RP  
 
Descriptive statistics for the mean duration of the bleeding and/or spotting episodes in each RP  
 
Descriptive statistics for the number of bleeding and/or spotting free episodes in each RP 
 
Descriptive statistics for the mean duration of the bleeding and/or spotting free episodes in each 
RP 
Note that the denominator for the percentages listed above will be the number of subjects with an evaluable 
RP.  
The number of subjects with evaluable reference periods for each population will be summarized by 
reference period. The inclusion of reference periods in ITT Population will be listed by subject and reference 
period along with reasons for exclusion of the reference period. 


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9.6 Safety Analyses 
9.6.1 Adverse Events 
TEAEs will be classified into a standardized terminology using the MedDRA system organ classifications 
and preferred terms. Version 20.0 of MedDRA will be used as coding dictionary. The incidence of TEAEs 
will be summarized for the Safety Population. 
A summary of TEAEs including the number of events reported, the annual rate and the number and 
percentage of subjects reporting the following will be presented: 
 
Any TEAE 
 
Any TEAE leading to death 
 
Any treatment-emergent SAE 
 
Any TEAE leading to premature discontinuation from the study 
 
Any SAE related to study medication 
TEAEs are defined in Section 5.11. The annual rate will be derived as the number of events divided by the 
total exposure across all subjects in years. 
A breakdown of the number and percentage of subjects reporting each TEAE with the corresponding 
number of events, categorized by body system and preferred term coded according to the MedDRA 
dictionary, will be presented. Note that subjects are only counted once within each body system or preferred 
term but subjects with multiple events of a specific type will be counted once for each occurrence in the 
number of events column. 
A further tabulation of these data, categorized by relationship to study drug, will be presented. Subjects 
with multiple events within a particular body system or preferred term will be counted under the category of 
their most drug-related event within that body system or preferred term in column for the number of subjects. 
In the column for the number of events, multiple events of a specific type and relationship will be counted 
once for each occurrence. Relationship to study drug is categorized as not related (not related and unlikely 
on the CRF) and related (possible, probable and highly probable on the CRF). This will be repeated for 
TEAEs leading to premature discontinuation from the study. 
TEAEs will also be presented by severity. For each system organ class and preferred term, subjects are 
included only once, at the maximum severity. In the column for the number of events, multiple events of a 
specific type and severity will be counted once for each occurrence.  
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed. The 
following listings will be generated in the Screened Population: 
 
All AEs 
 
AEs leading to premature discontinuation from the study 
9.6.2 Deaths and Serious Adverse Events 
A tabulation of SAEs, categorized by relationship to study drug, will be presented. Subjects with multiple 
events within a particular body system or preferred term will be counted under the category of their most 
drug-related event within that body system or preferred term in column for the number of subjects. In the 
column for the number of events, multiple events of a specific type and relationship will be counted once 
for each occurrence. Relationship to study drug is categorized as not related (not related and unlikely on 
the CRF) and related (possible, probable and highly probable on the CRF).  
The following listings will be generated including non-treatment emergent events in the Screened 
Population: 


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 
All SAEs 
 
All AEs leading to death 
 
All SAEs related to treatment (includes SAEs where the relationship to study drug is possible, 
probable and highly probable) 
9.6.3 Laboratory Data 
Central laboratory data will be used for the tables and listings. The scheduled laboratory assessments will 
be included in the tables where data are available. If a specific parameter is missing at the scheduled 
assessment and there is an unscheduled assessment collected at the same visit where this parameter is 
not missing, then the value at the unscheduled assessment will be used in the table. Otherwise 
unscheduled assessments will not be included in the tables. Note that unscheduled pregnancy tests will be 
used in the assessment of pregnancies for the primary endpoint. The parameters listed in Table 4 will be 
summarized. Separate outputs will be provided for hematology, serum chemistry and lipid profile. 
Table 4: Laboratory Parameters 
Hematology 
Hemoglobin  
Mean cell volume 
Hematocrit  
White blood cell & Differential 
Red blood cell count  
Platelet count 
Serum Chemistry 
Albumin  
Total protein 
Alanine aminotransferase (ALAT)  
Serum creatinine 
Aspartate aminotransferase (ASAT) 
Sodium 
Blood urea nitrogen  
Potassium 
Gamma glutamyl transferase (GGT)  
Calcium 
Glucose  
Chloride 
Glycated hemoglobin  
Bicarbonate 
Lactate dehydrogenase (LDH) 1 and LDH 2  
Phosphorus 
Total bilirubin 
Choriogonadotropin Beta (Serum Pregnancy Test) 
Estimated Glomerular Filtration Rate (eGFR) 
 
Lipid Profile 
Total cholesterol  
Triglycerides 
High density lipoprotein cholesterol  
Low density lipoprotein cholesterol 
 
For continuous clinical laboratory analytes, the absolute value and change from baseline will be 
summarized by analyte and visit using descriptive statistics for the Safety Population.  
Shifts to values outside of the normal range will be presented by analyte and visit and will be summarized 
by the number and percentage of subjects with evaluable shifts. The denominators for calculating the 
percentages will be the number of subjects in the Safety Population with both the Baseline value and the 
value at the specified visit recorded. 
If the value is below the lower limit of quantification, then half the lower limit of quantification will be used in 
the summary tables to calculate the descriptive statistics. If the value is above the upper limit of 
quantification, then the upper limit of quantification will be used in the summary tables to calculate the 
descriptive statistics. In the listings, values will be listed as collected without the imputation applied.  
All clinical laboratory values, abnormal clinical laboratory values, and clinical significant laboratory values 
will also be provided in data listings in the Safety Population including data collected at any unscheduled 
assessments. 


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Chlamydia and gonorrhea test results will be listed. 
9.6.4 Vital Signs 
Unscheduled vital signs assessments will be excluded from the tables. 
Vital sign measurements (systolic blood pressure, diastolic blood pressure and heart rate) for the Safety 
Population will be summarized using descriptive statistics by visit. The change from Baseline will also be 
summarized in the same manner. 
Weight and BMI measurements for the Safety Population will be summarized using descriptive statistics by 
visit. The change from Baseline will also be summarized in the same manner. BMI will be derived 
programmatically from the height and weight collected. 
All vital signs, weight and BMI measurements will be listed in the Safety Population including data collected 
at any unscheduled assessments. 
9.6.5 Physical and Gynecological Examinations 
Physical and gynecological examination assessments will be summarized for the Safety population by visit. 
For each body system and assessment category, the number and percentage of subjects will be presented. 
The denominators for calculating the percentages will be based on the number of subjects evaluated for a 
particular body system. Unscheduled physical examinations will not be summarized. 
All physical and gynecological examination data will be listed in the Safety Population. 
9.7 Other Secondary Endpoints (Excluding PK) 
9.7.1 Quality of Life 
Quality of life data will be summarized in the ITT Population. Summaries will be provided overall and by 
switchers and starters separately. 
For the Q-LES-Q-SF, the absolute values and change from baseline of the percentage maximum, how 
satisfied have you been with your medication and how would you rate your overall life satisfaction and 
contentment during the past week will be summarized descriptively by visit. 
For the Menstrual Distress Questionnaire, the absolute values and change from baseline for the scores for 
pain, water retention, autonomic reactions, negative affect, impaired concentration, behaviour change, 
arousal and control will be summarized descriptively by visit and by phase. The phases are menstrual (most 
recent flow), premenstrual (four days before) and intermenstrual (remainder of cycle).  
All quality of life data will be listed in the ITT Population. 
9.7.2 Follow-Up Evaluations 
The number and percentage of subjects who had pregnancy confirmation, return to menses and received 
a new contraceptive method after discontinuation of study treatment will be summarized. The denominator 
used for the percentages will be the number of subjects in the Safety Population who discontinued study 
medication due to a pregnancy wish. 
The time from last dose of study medication to return of menses will be summarized using descriptive 
statistics in the Safety Population. 
The following will be summarized using descriptive statistics for subjects in the Safety Population who 
discontinued study medication due to a pregnancy wish who selected the corresponding fertility information: 
 
Time from last dose of study medication to estimated date of conception  
 
Time from last dose of study medication to new contraceptive method 


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The estimated date of conception is derived as the expected date of pregnancy term – 38 weeks (266 
days).  
Data for follow-up evaluations will be listed for subjects in the Safety Population who discontinued study 
medication due to a pregnancy wish. 
9.8 Population Pharmacokinetics Analysis 
9.8.1 Data Included in Analysis  
Data from study MIT-Es0001-C302 are very sparse (two samples at each of two visits per subject, and 
collected relatively close together). These data alone will likely not support identification of many of the 
model parameters. To insure identifiability of parameters required to meet the objectives, rich data from 
study Es0001-C101 will be included in the data set. Additional data from study MIT-Es0001-C103 may be 
included in the population PK analysis if relevant parameters are not identifiable with data from only MIT-
Es0001-C302 and Es0001-C101.  
9.8.2 Objectives 
The objectives are to assess the effect of various individual characteristics/covariates (e.g., body weight, 
race, smoking, and fed vs fasted status) on the pharmacokinetics (PK) of 15 mg Estetrol (E4)/3 mg 
Drospirenone (DRSP). As data permit, PK parameters will include, but are not limited to: 
 
Primary parameters (i.e. model parameters): 
o 
Apparent clearance (CL/F). 
o 
Central volume of distribution (V/F). 
o 
Lag time of Absorption (Tlag), if necessary. 
o 
Relative bioavailability for fed vs fasted state. 
 
Secondary parameters (i.e. derived parameters): 
o 
Maximum concentration (Cmax). 
o 
Time to Cmax (Tmax). 
o 
Extent of exposure for the dosing interval (AUCtau) at steady state. 
o 
Terminal half-life (t½). 
o 
Predicted trough drug concentration (Ctrough) at steady state. 
o 
Distribution half-life (t½) (if applicable). 
9.8.3 Assumptions 
Missing covariates will be imputed as the most recent reported value (last value carried forward) if any are 
reported for that subject. If no value is available, missing covariates will be imputed as the median of all 
other subjects within the study. 
Patients will record time of the most recent dose prior to sample collection. This dose will be assumed to 
be at steady state, with a 24-hour dosing interval.  
Two separate models will be developed, one for E4 and one for DRSP. It is assumed these drugs do not 
interact. 
9.8.4 Prespecified Hypotheses  
Pre-specified hypotheses will be tested before any hypotheses that are based on diagnostic plots. Formal 
conclusions will be drawn only from these prespecified hypotheses. Results of other hypotheses (e.g., those 
based on diagnostic plots) will be considered exploratory and will not lead to conclusions.  
1. Effect of body weight on volume of distribution of E4. 
2. Effect of body weight on clearance of E4 
3. Effect of race on clearance for E4. 
4. Effect of smoking status on clearance for E4. 


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5. Effect of fed vs fasted state on rate (e.g. Ka) or extent (e.g., F) of absorption for E4. 
6. Effect of body weight on volume of distribution of DRSP.  
7. Effect of body weight on clearance of DRSP 
8. Effect of race on clearance of DRSP. 
9. Effect of smoking status on clearance of DRSP. 
10. Effect of fed vs fasted state on rate (e.g. Ka) or extent (e.g., F) of absorption for DRSP. 
 
9.8.5 Study MIT-Es0001-C302  
A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and Safety of a 
Combined Oral Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone. 
 
Two PK samples will be taken from the subjects in the Population PK Substudy at Visits 3 and 4. All subjects 
included in the Substudy will provide a sample for PK analysis at the time they check into the site (PK 
sampling 1). An additional blood sample (PK sampling 2) will be collected approximately two hours after 
the first sample.  
 
The following timings will be recorded by the site personnel in the eCRF: 
- 
The exact times of the last study medication dosing and the PK samplings 1 and 2.  
Depending on the time scheduled for the study site visit (Visit 3 & 4), subjects were instructed on 
when they need to take their medication – either as usually done at home or on site. One blood 
sample will be taken before dosing and the second blood sample will be taken within 2-hour 
postdose. The subjects were instructed to record the time of the dosing in the Diary.  
 
- 
The time of the last meal intake before the last study medication dosing before study visit. 
9.8.6 Study Es0001-C101  
A study to characterize the effect of food on the bioavailability of 15 mg Estetrol/3 mg Drospirenone 
tablets in healthy female volunteers. 
 
Es0001-C101 was an open-label, randomized, balanced, single-dose, two-treatment, two-period, two-
sequence crossover study conducted under medical supervision in 28 healthy female volunteers. All 
subjects entered the study site at least 12 hours before each dosing and fasted for at least 10 hours prior 
to each dose. All subjects received the following 2 treatments: 
 
Treatment A (Reference): a single 15 mg E4/3 mg DRSP tablet without food (fasted). 
 
Treatment B (Test): a single 15 mg E4/3 mg DRSP tablet with food (fed). 
All subjects received both Treatment A and Treatment B either at the first treatment period (Period 1) or the 
second treatment period (Period 2). Approximately half of the subjects were randomized to receive either 
Treatment A followed by Treatment B (Sequence AB), or Treatment B followed by Treatment A (Sequence 
BA) as described in Table 5. 
PK Sampling: Blood samples were collected prior to each dose and at 10, 20, 30 and 45 min, and then at 
1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours post-dose for pharmacokinetic (PK) 
analysis.  
Table 5.  
Treatment Sequences 


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Sequence 
Period 1  
Period 2 
AB  
Treatment A: 1 tablet 15 mg 
E4/3 mg DRSP in fasted conditions 
Treatment B: 1 tablet 15 mg 
E4/3 mg DRSP in fed conditions 
BA 
Treatment B: 1 tablet 15 mg 
E4/3 mg DRSP in fed conditions 
Treatment A: 1 tablet 15 mg 
E4/3 mg DRSP in fasted conditions 
 
9.8.7 Study MIT-Es0001-C103  
A Randomized, Double-Blind, Placebo-Controlled, Parallel, Single Center Study To Investigate The 
Pharmacokinetics, Safety, Tolerability, And QT Concentration-Effect Modelling Of Estetrol (E4) In 
Combination With Drospirenone (DRSP) After Single And Multiple Dosing In Healthy Women. 
 
MIT Es0001-C103 was a randomized, double-blind, placebo-controlled, parallel, single and multiple oral 
dose study to investigate the PK, safety and tolerability of therapeutic and supratherapeutic single and 
multiple doses of E4 in combination with DRSP in healthy female subjects. A total of 42 healthy female 
subjects were to be enrolled in 3 groups of 14 subjects each. 
Subjects received a single dose on Day 1 and after washout of at least 14 days, multiple doses during 14 
consecutive days from Days 15 to 28. 
 The following treatments in Table 6 were administered:  
Table 6.  
MIT-ES0001-C103 Treatments 
 
Dose Level E4 (mg) 
Dose Level DRSP 
(mg) 
Dosage 
Group 1 
15  
3 
Therapeutic E4/DRSP 
dose level 
Group 2 
30 
6 
2 times therapeutic 
E4/DRSP dose level 
Group 3 
60 
12 
4 times therapeutic 
E4/DRSP dose level 
E4 = Estetrol; DRSP = Drospirenone.  
Drug administration on Days 1 and 28 were under fasted conditions. Drug administration on Days 15 to 27 
were at the same time of day as on Days 1 and 28, without regard to meals; however, subjects will be 
fasted before all clinical laboratory assessments. 
PK sampling: Samples for pharmacokinetic analysis were collected at the following times: 
On Day 1 and Day 28: at pre-dose and at 15 and 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 
96, 120, 144, and 168 hours post-dose.  
On Days 17, 19, 21, 23, 25 and 27: at pre-dose. 
9.8.8 Data management 
A NONMEM data set will be created from source data files provided by PRA for study MIT-Es0001-C302 
and by Estetra for Es0001-C101 and (if used) MIT-Es0001-C103 and will undergo quality control (QC) 
review according to SOPs at the time of the finalization of the analysis plan. 
The data manager will create one or more code files to automate the process of formatting the source 
dataset into the popPK dataset. No manual editing of the data will be done. The code file for the creation 
of the popPK datasets will be in R version 3.3.1 or later (R Foundation for Statistical Computing, Vienna, 
Austria).  


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A popPK data set can be very large. QC of the final NONMEM dataset will include manual comparison of 
a subset of the records to the source data (Sponsor or PRA provided datasets) as well as diagnostics on 
the entire dataset to identify errors. Diagnostics will also be performed to ensure that the dataset complies 
with the formatting standards for NONMEM. The QC may include review of the code used to generate the 
dataset, as appropriate. This QC will be done by personnel other than the data manager. Any discrepancies 
will be addressed. Revised datasets will undergo quality control to confirm that the expected changes (e.g., 
deleted data records) are correct. The scope of the QC will be dependent on the nature and complexity of 
the study, as well as the source data. Any unique or complicated formatting issues associated with the 
dataset will be flagged by the data manager for specific QC review. 
9.8.9 Data Deletion 
9.8.9.1 Missing Data  
Incomplete data (e.g., missing dosing times) is a frequent occurrence in population analysis data sets. 
Typically, data with a missing or clearly erroneous dose time will be imputed per protocol or deleted as 
appropriate.  
9.8.9.2 Erroneous Data  
Data in the Sponsor data set will occasionally be found to be inconsistent with the known pharmacokinetics 
of the drug or study procedures. These may be a result of recording errors in the database (e.g., dose 
administered prior to study start or after study completion) or unrealistic pharmacokinetic considerations. 
These data may be deleted if they cannot be corrected based on data review and site queries.  
9.8.9.3 Outliers  
Outliers will be distinguished from erroneous data as being unusual but not inconsistent with the known 
pharmacokinetics of the drug. Outlier data may include entire subjects, entire subject visits, or individual 
observations. Outliers will be deleted only after careful examination of possible causes.  
9.8.10 PopPK Model Development 
Population pharmacokinetic model development will be performed in compliance with SOPs at the time of 
the finalization of the analysis plan.  
9.8.10.1 Data Set Creation 
Prior to initiation of analysis, NONMEM and other population PK software require specifically formatted data 
sets. Creation of these data sets is addressed Section 9.8.6.  
9.8.10.2 Handling Data below the Limit of Quantification (BLQ) 
BLQ data will be handled according to the “M3” methodology (Beal, 2001). 
9.8.10.3 Model Development Procedures 
A Bayesian analysis will be used to fit concentration-time data. Model features (number of compartments, 
lag times, covariate effects) will be included based on goodness of fit statistics (e.g., log-likelihood) and 
diagnostic plots. These pharmacokinetic models will be evaluated and used to derive individual post hoc 
pharmacokinetic parameters for E4 and DRSP described in Objectives (9.8.2).  
Initial estimates of PK parameters (e.g., CL/F, V/F, Tlag) will be determined using exploratory 
compartmental analyses or previous PK analysis. These estimates will be employed to build an appropriate 
population PK model. The impact of individual characteristics on the PK parameters will be explored and 
included in the population model if significant.  


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9.8.11 PopPK Model Evaluation  
A traditional approach to model selection will be used. In this approach, an initial simple model is run. 
Additional features are sequentially added to this model (e.g., compartments, lag times, variance terms, 
covariates), testing each addition for statistical significance, improvement of diagnostic graphics and/or 
biological plausibility. Model features (e.g., lag times, compartments) will be added or removed based on 
evaluation of diagnostic plots, consideration of biological plausibility, and statistical tests. The goodness-
of-fit between hierarchical models is measured by the difference in the objective function value (OFV) 
produced by NONMEM. The difference in OFV between two hierarchical or nested models is approximately 
χ2 distributed, with n degrees of freedom. As such, the OFV is used to obtain the significance level for the 
difference between two nested models. The criteria for forward addition will be p<0.05 and the criteria for 
backward elimination will be p<0.001. Covariate analyses will be performed separately for the PK of E4 and 
DRSP. 
Assessment of model adequacy and decisions about increasing model complexity will be driven by the data 
and guided by goodness-of-fit criteria, including:  
1. Visual inspection of diagnostic plots (e.g.,observed vs. predicted concentration, residual/weighted 
residual versus predicted concentration or time, and histograms of individual random effects).  
2. Successful convergence of the minimization routine with at least 2 significant digits in parameter 
estimates. Successful minimization and covariance steps will be desired, but not required. 
3. Plausibility of parameter estimates.  
4. Precision of parameter estimates, if available.  
5. Correlation between model parameter estimation errors < 0.95.  
6. Likelihood ratio test.  
7. Asymptotic and or Bootstrap estimate of confidence interval for parameter estimates. 
Covariates to be considered during population pharmacokinetic model building include, but are not limited 
to, variables such as body weight, race, smoking, and fed vs fasted status. Pre-specified hypotheses will 
be examined first, followed by hypotheses generated from diagnostic plots. If applicable, this will be followed 
by an automated covariate search (SCM user guide). 
9.8.11.1 Visual Predictive Check  
In order to verify that the final model adequately predicts both the central tendency and the variability of the 
observed data, a visual predictive check (VPC) stratified by weight, race, smoking status, and fed/fasted 
status will be performed. VPC plots will be made for two or three strata for weight and each stratum for the 
categorical covariates. For the VPC, simulations will be performed using the final model and final model 
parameters. The original data set will be used as a template for simulation input. Simulations will be 
performed to generate approximately 1,000 simulated observations at each time point; if 1,000 simulated 
observations are not feasible based on the model run times, a reduced number of simulated observations 
will be used. A graphical comparison will be made between the observed data and the model predicted 
median and 95% prediction interval over time. Additional VPC plots may be generated to include confidence 
intervals for the median and prediction intervals of the simulated data. VPC will be conducted in PsN and 
the result will be summarized using Xpose (Jonsson and Karlsson, 1999). 
9.8.12 Reporting 
A submission ready report will be developed, as described below. 
9.8.12.1 Report Structure 
The popPK report will comprise the following sections: 
1. Summary  


Statistical Analysis Plan 
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2. Objectives and Hypotheses  
a. Statement of the objectives of the analysis and formal statement of any hypotheses to be 
tested. 
3. Assumptions 
a. List of assumptions, with supporting data, as applicable. Assumptions will not be formally 
tested.  
4. Materials and Methods 
a. Data: description of data, to include (as applicable and appropriate) the number of 
individuals, number of observations, and range of sample collection times.  
b. Data analysis methods: 
i. The methods (e.g., forward addition/backward elimination) and criteria for model 
selection (likelihood ratio test, diagnostic plots). 
5. Results 
a. PopPK results  
i. Data description: summary statistics including mean, median, and SD of 
continuous covariates, and distributions of discrete covariates.  
ii. Description of base model, including parameter estimates and model 
qualification/diagnostic plots.  
iii. Description of final model, including parameter estimates and model 
qualification/diagnostic plots.  
6. Conclusion 
Conclusions will be based on pre-specified hypotheses only. Hypotheses generated during 
analysis (e.g., from diagnostic plots) will be considered exploratory only.  
7. Discussion 
8. Figures 
a. Figures supporting model selection decisions will be included in the report.  
b. Typical diagnostic plots will include Conditional Weighted Residuals vs. Time, vs. 
Conditional Weighted Residuals vs. Prediction, and Observed Dependent Variable vs. 
Prediction/Individual Prediction.  
c. VPC (Visual Predictive Check). 
d. Histogram of post hoc ETAs. 
e. Observed values vs. individual predicted values. 
f. 
Observed values vs. population predicted values. 
9.8.13 Source Files 
The following documents will be provided as ASCII text files based on the final analysis: 
a. Source data used in the analysis (NONMEM data set). 
b. Base model control file. 
c. Base model output file. 
d. Final Model control file. 
e. Final model output file. 


Statistical Analysis Plan 
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Effective Date: 11-Dec-2018/Version 3.0 
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10.0 Validation 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. PRA’s quality 
control procedures will be documented separately in the study specific Quality Control Plan.  
11.0 References 
Beal S. L. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet 
Pharmacodyn 28(5), 481-504 (2001). 
Gerlinger, C., Endrikat, J., van der Meulen, E. A., Dieben, T. O. & Dusterberg, B. Recommendation for 
confidence interval and sample size calculation for the Pearl Index. Eur.J.Contracept.Reprod.Health Care 
8, 87-92 (2003). 
Jonsson E.N and Karlsson M.O. Xpose--an S-PLUS based population pharmacokinetic/ pharmacodynamic 
model building aid for NONMEM. Comput Methods Programs Biomed. Jan;58(1):51-64 (1999). 
Moos, R. H. The development of a menstrual distress questionnaire. Psychosom Med 30, 853-867 (1968). 
SCM user guide http://psn.sourceforge.net/pdfdocs/scm_userguide.pdf. Accessed 18 August 2016. 
12.0 Amendment to the Statistical Analysis Plan 
12.1 Amendment 1 from SAP dated 12 December 2016 
The key changes to the SAP in amendment 1 are as follows: 
 
Missing data rules moved to one section for missing data 
 
The addition of analyses for the Pearl Index to look at the rate of on-treatment pregnancies and 
on-treatment method failure pregnancies where the at-risk cycles are defined as cycles in which 
no other methods of birth control are used by the subject 
 
The addition of an analysis for the Pearl Index to look at the rate of method failure on-treatment 
pregnancies excluding at-risk cycles that were not compliant according to Section 9.4.4 of the 
protocol 
 
Clarification of the definition of the evaluable cycles for the bleeding analysis in the PP Population 
in cases where the post Screening biopsy was not performed during Cycle 13 
 
Addition of criteria for exclusion from the PP Population to exclude cycles within 28 days after 
prohibited mediations 
 
Clarification that the Baseline value for the Menstrual Distress Questionnaire is the value 
collected at Visit 3 as the date of collection is not collected 
 
Clarification added that compliance by cycle will be based on the cycles defined from the start 
dates of the cycles per Section 5.1 including detail on how gaps between cycles and overlapping 
cycles are handled 
 
Clarification added that for overall compliance only pills reported between the start and stop date 
for study medication will be included in the numerator 
 
The addition of actual exposure accounting for days where no pills were taken 
 
Addition of the number of subjects with bleeding only episodes and spotting only episodes by 
cycle as endpoints 
 
Change in the definitions of unscheduled and scheduled bleeding and spotting days to use the 
episodes  
 
Clarification added for imputation for missing bleeding data to cover scenarios where 3 or more 
days having missing data at the end of the diary data collected 
 
The definition of an evaluable reference period was updated to exclude reference periods where 
there are gaps between the cycles 
 
Cumulative absence of withdrawal bleeding rate added as an endpoint 


Statistical Analysis Plan 
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 
Bleeding analysis section restructured and split out into the classical cycle analysis (including 
early and continued withdrawal bleeding as scheduled) which is now classed as the primary 
definition and the modified analysis (including early and continued withdrawal bleeding as 
unscheduled) which is no longer classed as the primary definition 
 
Analyses of bleeding data added for cycles with exactly 1 missed active pill and for cycles with at 
least 2 missed active pills  
 
The bleeding analysis by reference period was simplified to no longer differentiate between 
scheduled and unscheduled bleeding 
 
Clarification on the scales derived for the Menstrual Distress Questionnaire added 
 
Enrolled Population definition corrected to use the enrollment date  
 
PP Population corrected to make it clear that only the PP Population for bleeding is being derived 
 
Reference to ATC classification removed as data are not coded to ATC in this study 
 
Clarification added to indicate that BMI will be programmatically derived from height and weight 
for the vital signs and demography tables 
 
Listing added for the at-risk cycles for each Pearl Index analysis 
 
Clarification added to categorize relationship to study medication as not related and related for 
AEs 
 
Change to the handling of unscheduled laboratory assessments and clarification added for values 
above the upper limit of quantification and values below the lower limit of quantification 
 
Choriogonadotropin beta and eGFR added as laboratory parameters to be summarized 
 
Addition of summaries and listings of evaluable cycles and reference periods for the bleeding 
analysis 
 
Bleeding and spotting analysis section moved to Section 9.5 
 
Correction to the definition of the alternative definition of at-risk cycles that will be used for the 
derivation of the Pearl Index for method failure pregnancies based on compliance to indicate that 
all 8 criteria need to be met for a cycle to be at-risk 
 
Correction to definition of the presence of a bleeding only unscheduled episode and the presence 
of a spotting only unscheduled episode for the cycle analysis for bleeding 
 
Addition of a section for missing or partial dates for AEs 
 
Addition of a new analysis of the method failure Pearl Index icluding only modified at-risk cycles in 
the denominator where at-risk cycles will be defined as cycles in which no other methods of birth 
control (including condoms and emergency contraception) are used by the subject as confirmed in 
the subject diary where the subject was compliant with the dosing rules 3 to 8 in Section 5.1.1 while 
cycles with and without confirmed intercourse are being included in the denominator 
 
Clarification added on how to handle pregnancies for the at-risk cycles when the cycle is not in the 
diary data 
 
Clarification added on the handling of partial dates in the diary data 
 
Addition of summary tables of unscheduled bleeding and spotting days in subjects who had 
unscheduled bleeding and/or spotting episodes 
 
Clarification added that the exclusion of cycles for unauthorized medications may be different 
between the bleeding analysis and contraceptive efficacy 
 
Clarification added on the inclusion of subjects with an on-treatment or post treatment pregnancy 
but no diary data in the Safety Population and rules were added on how to derive the start and stop 
dates for those subjects  
 
Clarification added that if the subject has an on-treatment pregnancy, then the On-Treatment 
Period for efficacy ends on the estimated date of conception for that subject  
 
Addition of summary tables for the number of subjects with a scheduled bleeding episodes starting 
on each day in the cycle for the classical and modified cycle analysis for bleeding data 
 
Clarification added that the day for figures of bleeding by day will be the day in the diary data as 
collected  
 
WHO drug dictionary version updated 
 
Update to the prior medications definition for contraceptives 


Statistical Analysis Plan 
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12.2 Amendment 2 from SAP dated 13 November 2018 
 
Update in the definition for TEAEs to be consistent with the protocol and include all AEs starting on 
or after the date of first dose of study medication 
 
 


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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ASAT 
Aspartate Aminotransferase 
AUC 
Area under the curve 
AUCtau 
Extent of exposure for the dosing interval 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum concentration 
COC 
Combined Oral Contraceptives 
CRF 
Case Report Form 
CTMS 
Clinical Trials Management System 
DRSP 
Drospirenone 
E4/3 
Estetrol 
eGFR 
estimated Glomerular Filtration Rate 
GGT 
Gamma Glutamyl Transferase 
IC 
Informed Consent 
ITT 
Intention-to-Treat 
LDH 
Lactate dehydrogenase 
LOCF 
Last Observation Carried Forward 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum 
n 
Number of subjects 
NONMEM 
Nonlinear mixed effects model 
OFV 
Objective function value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per Protocol 
Q1 
25th percentile or lower quartile 
Q3 
75th percentile or upper quartile 


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Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire Short Form 
RP 
Reference Period 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
Tlag 
 
Lag time of absorption 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures and Listings 
Tmax 
Time to maximum concentration 
Vc 
Central Volume of distribution 
V/F 
Central volume of distribution 
VPC 
Visual predictive check