Clinical trial NCT02269241
Conditions: Contraception
Keywords: contraception hormonal oral contraceptive agents hormonal oral contraceptive oral contraceptive drospirenone LF111 birth control
Sponsor: Laboratories Leon Farma, S.A.
Start date: 2014-10-09; Completion date: 2017-10-04
Enrollment: 1552 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To demonstrate the contraceptive efficacy of LF111 . To demonstrate the safety and tolerability of LF111 and assessment of pharmacokinetics of LF111.

Detailed description:
This trial is a prospective, multicenter, open-label, non-controlled trial in female subjects, including adolescents between the ages of 15+(inclusive) who present to the clinic seeking contraception, who are postmenarcheal and premenopausal.

At screening, informed consent will be obtained and the screening procedures will be performed. After confirmation of the subject's eligibility, the subject will be provided with the investigational product and trained in the use of an electronic diary. Afterwards, the subjects will attend visit the clinical site on Day 20±2 of the 1st, 3rd, 6th and 9th cycles and on Day 29+2 of the 13th cycle. The last clinical site visit will occur 10-14 days after the 13th cycle visit.

The trial will include women who have never used hormonal contraceptives before consent (naïve users), women who have not used hormonal contraceptives in the past three months before consent or who have used hormonal contraceptives in the past but have a contraceptive-free time of less than three months before consent (previous users) as well as women directly switching from another hormonal method (switchers). Women who have used hormonal contraceptives in the past but have a contraceptive-free time of less than three months before consent are allowed to be included into the trial if they had at least one complete menstrual cycle before enrollment.

A population pharmacokinetic (PK) analysis planned in the whole subject population, will obtain sparse blood samples to determine plasma concentrations. In total, four blood samples will be collected: two samples each will be collected during the 1st cycle and during the 6th cycle of treatment.

Adverse events and safety information will be collected throughout the study.

Arms: arm 1: single treatment arm receives LF111
Interventions: intervention 1: LF111 (drospirenone)
Intervention descriptions: intervention 1: One LF111 tablet once per day for 24 days followed by 4 placebo tablets for 4 days equals one cycle.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol CF111/303 
Laboratorios León Farma S.A. 
Final Version 4.0, 16-NOV-2015 
CONFIDENTIAL 
Page 5 of 84 
2. 
PROTOCOL SYNOPSIS 
Name of sponsor/company: Laboratorios León Farma S.A. 
Name of active ingredient: Drospirenone (DRSP) 
Title of trial:  A Pivotal, Multicenter, Non-Comparative Trial on the Contraceptive 
Efficacy, Safety, Tolerability and Pharmacokinetics of LF111 (Drospirenone 
4.0 mg) During 13 Cycles 
Trial number: CF111/303 
IND number: 111347 
Coordinating investigator: Prof. David F. Archer, MD 
Trial center(s): Approximately 40 centers located in the United States of America  
Planned duration of the trial: 
 First subject first visit:  October 2014 
 Last subject last visit:  July 2017 
Subject recruitment: 20 months 
Phase of development: III 
Objectives: 
Primary:  
To demonstrate the contraceptive efficacy of LF111 
Secondary: To demonstrate the safety and tolerability of LF111 and assess the 
pharmacokinetics of LF111 
Methods / trial design: 
This trial is a prospective, multicenter, open-label, non-controlled trial in female subjects, 
age 15 and above who present to the clinic seeking contraception, who are postmenarcheal 
and premenopausal. Breastfeeding women are allowed to participate in the trial. 
At V1a (screening), informed consent/assent will be obtained and the screening procedures 
will be performed. At V1b, after the results of the laboratory tests have confirmed the 
subject’s eligibility, the subject will be provided with the investigational medicinal product 
(IMP) and an electronic diary and the subject will be instructed in their use. Afterwards, the 
subjects will attend Visits 2 to 5 at Day 20±2 of the 1st, 3rd, 6th and 9th cycle and Visit 6 at 
Day 29+2 of the 13th cycle. The follow-up (Visit 7) will take place 10-14 days after Visit 6. 
Once a month, on Day 10 (+ 2 days) of each cycle, the subjects will be contacted by the site 
staff to collect information on any adverse events which might have occurred. 
The trial will include women who have never used hormonal contraceptives before 
consent/assent (naïve users), women who have not used hormonal contraceptives in the past 
three months before consent/assent or who have used hormonal contraceptives in the past 
but have a contraceptive-free time of less than three months before consent/assent (previous 
users) as well as women directly switching from another hormonal method (switchers). 
Women who have used hormonal contraceptives in the past but have a contraceptive-free 
time of less than three months before consent/assent are allowed to be included into the trial 
if they had at least one complete menstrual cycle before enrollment. 
For naïve users and previous users, the first IMP intake will be on the first day of the next 
menstrual bleeding after Visit V1b. (If the menstrual bleeding starts in the evening, and the 
subject prefers to take her pill in the morning, then she may begin the first IMP intake the 
next day [Day 2 of the menstrual bleeding]). For a switcher, the first IMP intake will be on 


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Final Version 4.0, 16-NOV-2015 
CONFIDENTIAL 
Page 6 of 84 
the day following the last active pill of the previous hormonal contraceptive. The subject is 
free to choose an intake time in the morning or evening that suits her requirements. 
Breastfeeding women can start the first IMP any day starting six weeks after delivery. 
A population pharmacokinetic (PK) analysis planned in the whole subject population, will 
obtain sparse blood samples to determine plasma concentrations of LF111 at Visits 2 and 4. 
In total, four blood samples will be collected: two samples each will be collected during the 
1st cycle (Visit 2: Cycle 1, Week 3, Day 20±2) and during the 6th cycle (Visit 4: Cycle 6, 
Week 3, Day 20±2) of treatment.  
Number of subjects (planned):  
Screened (enrolled):  
Approximately 1500. Screening will continue until a sufficient 
number of subjects have been allocated to treatment. 
Allocated to treatment:  At least 995 non-breastfeeding subjects, including a minimum of 
75 subjects > 35 years. 
Note: Breastfeeding women are also allowed to be enrolled in the 
trial. 
 
Collected medication cycles:  At least 5000 evaluable cycles (cycles with intercourse 
without back-up contraceptive at least once per month based on electronic diary question 
’Did you have sexual intercourse since the beginning of the cycle?’) for non-breastfeeding 
subjects aged ≤ 35 years (at the time of trial enrollment). 
At least 200 women having completed 13 cycles of treatment will be analyzed for safety.  
Diagnosis and main criteria for inclusion: 
1. Sexually active, postmenarcheal and premenopausal female subjects at risk of 
pregnancy including breastfeeding women with no upper age limit.  
2. Female subjects at risk of pregnancy, between the ages of 15 and 17 (inclusive) 
provided that 
• Applicable national, state and local laws allow subjects in this age group to 
consent/assent to receive contraceptive services, and 
• All applicable laws and regulations regarding the informed consent/assent of the 
subjects to participate in clinical trials are observed. 
3. Regular cycles during the last six months before consent/assent when not using 
hormonal contraception. 
4. At least three complete menstrual cycles after delivery (only applicable for women who 
were pregnant within the last six months and for non-breastfeeding women). 
Breastfeeding women can be included six weeks after delivery irrespective of menstrual 
cycles post-delivery. 
5. At screening, maximum systolic blood pressure (median value of three values) 
≤ 159 mm Hg and diastolic blood pressure (median value of three values) ≤ 99 mm Hg. 
6. Be able and willing to provide written informed consent or assent if the subject is 
adolescent, prior to undergoing any trial-related procedure. 
7. Willing to use trial contraception for thirteen 28-day cycles. 
8. Be willing to have intercourse each cycle of trial without the need to use back-up 


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Laboratorios León Farma S.A. 
Final Version 4.0, 16-NOV-2015 
CONFIDENTIAL 
Page 7 of 84 
contraceptive. 
9. Be willing to state that, to her best knowledge, her male sexual partner(s): 
• Has not had a vasectomy or been previously diagnosed as infertile. 
• Has not been previously diagnosed or suspected of human immunodeficiency virus 
(HIV) unless he has subsequently had a negative HIV test. 
• Has not been known to have engaged in homosexual intercourse in the past five years 
unless he has had negative HIV test results since then.  
• Has not shared injection drug needles in the past unless he has had a negative HIV 
test at least six weeks since last use.  
10. Agree not to participate in any other clinical trials during the course of this trial. 
 
Exclusion criteria: 
1. Pregnant.  
2. Subject is known to or suspected of not being able to comply with the trial protocol, the 
use of the trial medication or the use of the trial diary. 
3. History of infertility. 
4. Abnormal finding on pelvic, breast or ultrasound examination that in the investigator’s 
opinion contraindicates participation in the trial. 
5. Unexplained amenorrhea. 
6. Known polycystic ovary syndrome. 
7. Women ≥21 years of age with a Papanicolaou (pap) smear reading LGSIL or higher at 
screening (or six months prior to screening date). Human papilloma virus (HPV) testing 
in subjects with atypical squamous cells of undetermined significance (ASC-US) can be 
used as an adjunctive test. 
• Subjects with ASC-US can be included if they are negative for high-risk HPV strains.
• Subjects <21 years of age do not require a pap smear. 
8. Known contraindication or hypersensitivity to ingredients or excipients of the IMP, 
including:  
a. Renal insufficiency 
b. Hepatic dysfunction 
c. Adrenal insufficiency 
d. Current or history of venous thrombophlebitis or thromboembolic disorders 
(venous thrombembolism, which includes deep vein thrombosis and pulmonary 
embolism) 
e. Current or history of cerebral-vascular or coronary-artery disease  
f. Valvular heart disease with thrombogenic complications 
g. Diabetes with vascular involvement 
h. Headaches with focal neurological symptoms 
i. Major surgery with prolonged immobilization 


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Final Version 4.0, 16-NOV-2015 
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j. Known or suspected carcinoma of the breast 
k. Known or suspected sex-steroid sensitive malignancies 
l. Undiagnosed abnormal genital bleeding 
m. Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive 
use 
n. Liver tumor (benign or malignant) or active clinically significant liver disease. 
9. Uncontrolled thyroid disorder (i.e., on stable dose of thyroid replacement for less than 
two months). 
10. Uncontrolled concomitant diseases (i.e., not on a stable treatment dose for at least two 
months). 
11. Evidence or history of alcohol, medication or drug abuse (within the last 12 months 
prior to consent/assent). 
12. Known inherited or acquired predisposition to venous thromboembolism or arterial 
thromboembolism (e.g., factor VLeiden, Prothrombin mutation, Antiphospholipid-
antibodies) or bruising within the last 12 months prior to consent/assent. 
13. Known or suspected HIV and/or hepatitis infection at screening. 
14. Received a dose of depot medroxyprogesterone acetate (DMPA or Depo-Provera®) 
during the 10 months prior to consent/assent, or received any combined injectable 
contraceptive (e.g., Cyclofem®) during the six months prior to consent/assent, or no 
spontaneous menses since last injection.  
15. Long-term treatment (longer than seven consecutive days within a month prior to V1b) 
of any medication that might interfere with the efficacy of hormonal contraceptives. 
Prohibited medication include:  
a. Anticonvulsants (e.g. phenytoin, carbamazepine, oxcarbazepine, topiramate, 
felbamate, primidone) 
b. Barbiturates 
c. Rifampin 
d. Bosentan 
e. Griseofulvin 
f. St. John’s wort (hypericum perforatum)  


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Laboratorios León Farma S.A. 
Final Version 4.0, 16-NOV-2015 
CONFIDENTIAL 
Page 9 of 84 
16. Administration of human chorionic gonadotropin (hCG) or intake of co-medication 
containing hCG within a month prior to V1b). 
17. Progestin-releasing intra-uterine device (IUD) or contraceptive implant received or in 
place within the last two months prior to consent/assent. 
18. Planned regular concomitant use of barrier contraceptive methods, spermicides, IUDs 
or other contraceptive measures (excepting occasional use for safety reasons, e.g., to 
reduce risk of infection). 
19. Evidence or history of clinically significant psychiatric illness or suicide risk. 
20. Participation in another trial of an investigational drug or device parallel to the current 
trial or less than 90 days before consent/assent, or previous participation in the current 
trial and dispensed trial medication. 
21. Subject is a member of the investigator’s or Sponsor’s staff or a relative or family 
member thereof. 
22. Any condition that, in the opinion of the investigator, may jeopardize protocol 
compliance or the scientific integrity of the trial. 
Duration of treatment for the individual subject: 13 sequential cycles of 28 days  
 
Test product, dose and mode of administration:  
LF111 coated tablets (4.0 mg drospirenone), oral administration 
Reference therapy, dose and mode of administration: Not applicable. 
Criteria for evaluation:  
Efficacy: 
Primary: 
• Pearl index (PI) from evaluable cycles in non-breastfeeding women aged ≤ 35 years 
(at the time of trial enrollment) 
Secondary:  
• Pearl Index based on overall cycles (overall PI) in women aged ≤ 35 years (at the 
time of trial enrollment) 
• PI for method failures in women aged ≤ 35 years (at the time of trial enrollment) 
• Pregnancy ratio in women aged ≤ 35 years (at the time of trial enrollment) 
• Overall PI, PI for method failures, PI (using evaluable cycles) and pregnancy ratio 
(life table analysis) in all women 
• Overall PI, PI for method failures, PI (using evaluable cycles) and pregnancy ratio 
(life table analysis) in women aged > 35 years 
Data from breastfeeding women will be excluded from the efficacy analyses but included in 
the analyses regarding safety and tolerability. 
 
Safety/Tolerability:  
• Adverse events (AEs) 


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• Vital signs 
• Clinical laboratory parameters 
• Vaginal bleeding pattern 
• IMP acceptability 
Pharmacokinetics: 
• DRSP plasma concentrations 
• Area under the curve (AUC) 
• Volume of distribution 
• Apparent clearance 
Statistical methods: 
Statistical analysis: 
Analysis of the primary efficacy variable defined as PI based on evaluable cycles in non-
breastfeeding women aged ≤ 35 years (at the time of trial enrollment) will be performed for 
the Full Analysis Set (FAS). Two-sided 95% confidence interval (CI) for the PI will be 
calculated assuming that events of pregnancy have a Poisson distribution. 
Secondary efficacy analysis will be based on the FAS. Two-sided 95% CIs will be calculated 
for the overall PI and the method failures PI. 
Life table analysis: The pregnancy rate at each cycle and the cumulative pregnancy rate will 
be calculated (95% CI). 
Analysis of safety endpoints will be conducted using the Safety Set only. 
All adverse events (AEs) and treatment-emergent AEs (TEAEs) will be summarized by 
calculating the number and percent of subjects with AEs by preferred term and system organ 
class. Also TEAEs will be summarized by severity and relationship to treatment. Number 
and percent of TEAEs leading to trial termination will be provided.  
Laboratory parameters will be summarized by calculating summary statistics on the absolute 
values and on the change from V1a to V3, V4, V5 and V6. Shift tables will be provided to 
illustrate changes with respect to the laboratory normal ranges between V1a and V6 (or 
EDV). The number and percent of subjects with values outside the limits of clinical 
significance will be summarized. 
Analysis of tolerability will be based on FAS. 
Number and percent of subjects with bleeding and spotting, scheduled bleeding, scheduled 
spotting, unscheduled bleeding and unscheduled spotting will be presented for each cycle. 
The Clopper-Pearson 95% confidence interval for rate of subjects will be calculated. 
Cumulative rate of subjects for reference periods (summary of cycles 2-4, 5-7, 8-10 and 11-
13) will be provided. Cumulative rates only for reference periods will also be presented for 
number and percent of subjects with prolonged bleeding and spotting > nine days/ > 14 days 
and the number of bleeding and spotting episodes. 
Number and percent of days per cycle and reference period with bleeding and spotting, 
scheduled bleeding, scheduled spotting and unscheduled bleeding, unscheduled spotting and 
duration of scheduled bleeding, scheduled spotting, unscheduled bleeding and unscheduled 
spotting will be analyzed descriptively. 


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Final Version 4.0, 16-NOV-2015 
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IMP acceptability will be summarized by default frequency tabulation. Shift tables will be 
provided to illustrate change from V3 to V6/EDV. Additionally for subjects who switched 
from another oral contraceptive to the IMP default frequency tables will be summarized to 
present change of subject wellbeing. 
Pharmacokinetics analyses of LF111 will be conducted using a population pharmacokinetic 
method to determine individual estimates of LF111 pharmacokinetic parameters. In addition, 
a model-based covariate analysis will be performed to explore the effect of pre-defined 
covariates, including body weight/body mass index, on the apparent clearance of DRSP, and 
the influence of any significant covariates on the exposure over the dose interval assessed. 
Sample size calculation: 
At least 920 subjects will be allocated to treatment to have at least 5000 evaluable cycles for 
the PI calculation in non-breastfeeding women aged ≤ 35 years (at the time of trial 
enrollment). Additionally, a minimum of 75 subjects aged > 35 years will be allocated to 
treatment. The calculations are based on empirical values including firstly a rate of 24.8% of 
subjects using back-up contraception or not having intercourse. Secondly, 45% of subjects 
are assumed to drop out of the trial. The prime target is to collect at least 5000 evaluable 
cycles. 
 

SAP_001.pdf: 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of León 
Farma S.A. or a nominated representative. 
A PIVOTAL, MULTICENTER, NON-COMPARATIVE TRIAL ON THE CONTRACEPTIVE 
EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF LF111 
(DROSPIRENONE 4.0 MG) DURING 13 CYCLES 
Sponsor Project Code: CF111/303 
Scope Project Code: 183LE07.MMB 
STATISTICAL ANALYSIS PLAN 
Sponsor: 
Laboratorios León Farma S.A. 
La Vallina s/n 
Polígono Industrial de Navatejera 
24008 Navatejera (León) 
Spain 
Phone: + 34 987 878 000 
Fax: 
+34 978 278 524 
leonfarma@chemogroup.com 
Author: 
Tadas Zvirblis  
Statistician 
Scope International AG 
Kalvariju 300 
LT-08318 Vilnius, Lithuania 
tzvirblis@scope-international.com 
Phone: +370 5 2360 348 
Fax: 
+370 5 2388 533 
Version: 
v1.0 (14-DEC-2017) 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 2 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
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SOP effective date: 18.04.2016 
Version 6 
DOCUMENT REVISION HISTORY 
Version Draft 0.1 (13-JAN-2017): Document created. 
Version Draft 0.2 (27-FEB-2017): Document updated after sponsor comments on SAP version draft 
0.1. 
Version Draft 0.3 (10-MAY-2017): 
Section 
Updates 
2.2.2 Secondary Efficacy Endpoints 
Deleted sentence “Additionally, only evaluable cycles will be included 
in analysis.”. 
3.1 Analysis Sets 
Sites 104 and 120 were excluded from the main analysis. Analysis sets 
were corrected accordingly. 
3.1 Analysis Sets 
Included Additional Analysis Set. 
4.6 Trial Periods 
Added Baseline value definition. 
5.5 Efficacy Analysis 
Added Confirmed and non-confirmed pregnancy definition. 
5.5 Efficacy Analysis 
Evaluable cycle definition was adopted according to scenario IV. 
5.5.3 Additional Efficacy Analysis 
Added new section “5.5.3 Additional Efficacy Analysis”. 
5.7 Tolerability Analysis 
Tables of bleeding and spotting episodes were merged into 
bleeding/spotting episodes tables. 
3.1 Analysis Sets 
Rule for partial pregnancy determination date added. 
Version Draft 0.4 (11-SEP-2017): 
Section 
Updates 
2.2.2 Secondary Efficacy Endpoints 
Updated pregnancy ratio analysis definition. 
3.1 Analysis Sets 
Safety tables will not consist of data from 104 and 120 sites. 
3.2 Subgroups 
Overweight category was included. 
3.3 Data Review 
Category of impact on cycles was deleted for criterions which cannot be 
checked through EDC data. 
5.2.1 Demographics 
New age category was included. 
5.4.1 Exposure to IMP 
Two consecutive missing entries was changes to gap between two active 
table intakes more than 48 hours. 
5.4.2 Efficacy Analysis 
Definitions of Method failure pregnancy, Evaluable cycle and Perfect 
cycle was updated. 
5.6.1 Adverse Events 
Safety tables will not consist of data from 104 and 120 sites. 
Version Draft 0.5 (10-NOV-2017): 
Section 
Updates 
2.2.4 Tolerability Endpoints 
Period 2-13 was added. 
3.3 Data Review 
DRM listings were updated. 
4.6 Trial Periods 
Definitions of Date of the first/last IMP intake and baseline value were 
updated. 
5.2.3 Medical History 
Definition of current medical history condition was updated. 
Version Draft 0.6 (22-NOV-2017): 
Section 
Updates 
All 
New tables were added: 
15.1.4.1.2, 15.2.1.2.4, 15.2.1.2.5, 15.2.1.2.6, 15.2.1.2.7, 15.2.1.4.3, 
15.2.1.4.4, 15.2.1.4.5, 15.2.1.4.6, 15.2.1.4.7, 15.2.1.4.8, 15.2.1.4.9, 
15.3.1.8.1, 15.3.1.8.2, 15.3.1.8.3, 15.3.1.8.4, 15.3.1.8.5, 15.3.1.8.6, 
15.3.6.1.2, 15.3.7.1.2, 15.3.8.1.2, 15.3.9.1.2, 15.4.4.1.1, 15.4.4.2.1, 
15.4.4.3.1, 15.4.5.1.1, 15.4.6.1.1, 15.4.6.2.1, 15.4.6.3.1. 
All 
Analysis set for Table 15.1.3.1.1 and Listing 16.2.1.2, 16.2.1.14, 
16.2.1.15 was changed. 
3.1 Analysis Sets 
Definition of allocated to treatment set was deleted. 
Definition of Full analysis and modified full analysis sets were changed. 
3.2 Subgroups 
Median weight subgroup was updated. 
4.6 Trial Periods 
Definitions of Date of the first/last IMP intake and baseline value were 
updated 
5.1.1 Disposition and Withdrawals 
New subcategories (“IMP related”, “non-IMP related” and 
“Uncategorized”) were included. 
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Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
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SOP effective date: 18.04.2016 
Version 6 
Analysis of withdrawn reasons were expanded. 
5.5 Efficacy Analysis 
Suspected, subject confirmed not pregnant definition was added. 
Non-confirmed pregnancy definition and perfect cycle definitions were 
updated. 
Tables titles were updated. 
Version Draft 0.7 (08-DEC-2017): 
Section 
Updates 
All 
New tables were added: 
15.2.1.2.8_add, 15.2.1.2.9_add, 15.2.1.2.10_add, 15.2.1.2.11_add, 
15.2.1.4.10_add, 15.2.1.4.11_add, 15.2.1.4.12_add, 15.2.1.4.13_add, 
15.4.7.1.1_add, 15.4.7.2.1_add, 15.4.7.3.1_add. 
 
New figures were added: 
15.2.1.1_add, 15.2.1.2_add, 15.2.1.3_add, 15.2.1.4_add, 15.2.2.1_add, 
15.2.2.2_add, 15.2.2.3_add, 15.2.2.4_add, 15.4.9.1_add, 15.4.9.2_add, 
15.4.9.3_add, 15.4.10.1_add, 15.4.10.2_add, 15.4.11.1_add, 
15.4.11.2_add 
INTRODUCTION 
Explanatory legend was included. 
2.2 Trial Endpoints 
Additional endpoints were added. 
5.2.1 Demographics 
Age subgroups were corrected. 
5.5 Efficacy Analysis 
Exposure and perfect cycle definition was updated. 
 
 
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Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
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Version 6 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND KEY TERMS ............................................................................ 7 
INTRODUCTION ................................................................................................................................. 9 
1. FLOW CHART AND VISIT SCHEDULE ................................................................................. 10 
2. OBJECTIVES AND DESIGN ...................................................................................................... 12 
2.1 TRIAL OBJECTIVES ................................................................................................................... 12 
2.1.1 Primary Objective ....................................................................................................... 12 
2.1.2 Secondary Objectives .................................................................................................. 12 
2.2 TRIAL ENDPOINTS .................................................................................................................... 12 
2.2.1 Primary Efficacy Endpoints ........................................................................................ 12 
2.2.2 Secondary Efficacy Endpoints .................................................................................... 12 
2.2.3 Safety Endpoints ......................................................................................................... 14 
2.2.4 Tolerability endpoints ................................................................................................. 14 
2.2.5 Pharmacokinetic endpoints ......................................................................................... 15 
2.3 OVERALL TRIAL DESIGN .......................................................................................................... 15 
2.4 RANDOMIZATION ..................................................................................................................... 16 
2.5 TREATMENTS ............................................................................................................................ 16 
2.6 SAMPLE SIZE ............................................................................................................................ 16 
2.7 BLINDING ................................................................................................................................. 16 
3. ANALYSIS SETS AND SUBGROUPS ....................................................................................... 17 
3.1 ANALYSIS SETS ........................................................................................................................ 17 
3.2 SUBGROUPS .............................................................................................................................. 17 
3.3 DATA REVIEW .......................................................................................................................... 18 
4. GENERAL DEFINITIONS AND NAMING CONVENTIONS ................................................ 24 
4.1 GENERAL METHODOLOGY AND PRESENTATION OF THE RESULTS .......................................... 24 
4.2 STATISTICAL OUTPUT LAYOUT ................................................................................................ 24 
4.3 TREATMENT GROUP NAMES AND LABELS ............................................................................... 24 
4.4 VISIT NAMES AND LABELS....................................................................................................... 25 
4.5 DAYS NUMBERING ................................................................................................................... 25 
4.6 TRIAL PERIODS ......................................................................................................................... 25 
4.7 VISIT WINDOWS ....................................................................................................................... 26 
4.8 COMPLETE AND CORRECT TREATMENT DIARY RECORDS ......................................................... 26 
4.9 CODING SYSTEMS AND CONVENTIONS .................................................................................... 26 
4.9.1 Coding of adverse events and medical history ............................................................ 26 
4.9.2 Coding of medications ................................................................................................ 26 
4.10 HANDLING OF MISSING DATA .................................................................................................. 26 
5. STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY ........................................................................................................................ 27 
5.1 SUBJECTS DISPOSITION ............................................................................................................ 27 
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5.1.1 Disposition and Withdrawals ...................................................................................... 27 
5.1.2 Protocol Deviations ..................................................................................................... 28 
5.1.3 Inclusion/Exclusion ..................................................................................................... 29 
5.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................................... 29 
5.2.1 Demographics ............................................................................................................. 29 
5.2.2 Substance Use ............................................................................................................. 31 
5.2.3 Medical History ........................................................................................................... 32 
5.2.4 Gynecological History and VTE Risk Factors ............................................................ 33 
5.2.5 Menstrual History ........................................................................................................ 34 
5.3 PRIOR AND CONCOMITANT MEDICATIONS, CONTRACEPTIVE DEVICES .................................. 34 
5.4 EXPOSURE TO IMP AND COMPLIANCE ..................................................................................... 36 
5.4.1 Exposure to IMP.......................................................................................................... 36 
5.4.2 Compliance to IMP ..................................................................................................... 37 
5.5 EFFICACY ANALYSIS ................................................................................................................ 37 
5.5.1 Primary Efficacy Analysis .......................................................................................... 39 
5.5.2 Secondary Efficacy Analysis ...................................................................................... 39 
5.6 SAFETY ANALYSIS ................................................................................................................... 45 
5.6.1 Adverse Events ............................................................................................................ 45 
5.6.2 Vital Signs ................................................................................................................... 49 
5.6.3 Clinical Laboratory Evaluation ................................................................................... 51 
5.6.4 Physical Examination Findings ................................................................................... 52 
5.6.5 Gynecological Examinations ....................................................................................... 53 
5.6.6 Cervical Cytology ....................................................................................................... 55 
5.7 TOLERABILITY ANALYSIS ........................................................................................................ 55 
5.7.1 Bleeding Pattern .......................................................................................................... 55 
5.7.2 IMP Acceptability ....................................................................................................... 59 
6. INTERIM ANALYSIS .................................................................................................................. 60 
7. REFERENCES............................................................................................................................... 61 
8. APPENDICES ................................................................................................................................ 62 
1. SPECIFICATION OF TABLES .......................................................................................................... 62 
2. SPECIFICATION OF LISTINGS ........................................................................................................ 62 
3. SPECIFICATION OF FIGURES ......................................................................................................... 62 
4. TABLES 62 
5. LISTINGS 68 
6. FIGURES 69 
 
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LIST OF ABBREVIATIONS AND KEY TERMS 
Abbreviation 
Description of abbreviation 
ACE 
Angiotensin-converting-enzyme 
AE 
Adverse event 
AGUS 
Atypical glandular cells of undetermined significance 
ALAT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ASAT 
Aspartate aminotransferase 
ASC-H 
Atypical squamous cells High-grade 
ASC-US 
Atypical squamous cells of undetermined significance 
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body mass index  
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CI 
Confidence interval 
CIN 
Cervical intraepithelial lesion 
CPK 
Creatine phosphokinase 
DBP 
Diastolic blood pressure  
DMPA 
Depot medroxyprogesterone acetate 
DRM 
Data review meeting  
DRSP 
Drospirenone 
DVT 
Deep vein thrombosis 
eCRF 
Electronic case report form 
EDV 
Early discontinuation visit 
ES 
Enrolled Set 
MFAS 
Modified Full analysis set 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HLGT 
High level group term 
HLT 
High level term  
HPV 
Human papilloma virus 
IMP 
Investigational medicinal product 
IUD 
Intra-uterine device 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LGSIL 
Low grade squamous intraepithelial lesion 
LLT 
Lowest level term  
LOCF 
Last observation carried forward 
Max 
Maximum 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume  
MedDRA 
Medical Dictionary for Regulatory Activities  
Min 
Minimum 
mmHg 
Millimeters of mercury 
n 
Number 
OTC 
Over-the-counter  
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PE 
Pulmonary embolism 
PI 
Pearl index  
PPS 
Per protocol set 
PT 
Preferred term  
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SBP 
Systolic blood pressure  
SD 
Standard deviation 
SOC 
System organ class  
SS 
Safety set 
TEAE 
Treatment emergent adverse event  
TLFs 
Tables, Listings and Figures 
VTE 
venous thromboembolism  
WHO-DDE 
World Health Organization-Drug Dictionary 
 
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INTRODUCTION 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the clinical trial protocol and its amendments: 
Final Protocol: 
7 February 2014; Final Version 1.0 
Final Protocol: 
16 May 2014; Final Version 2.0 
Final Protocol: 
27 May 2014; Final Version 3.0 
Final Protocol: 
16 November 2015; Final Version 4.0 
Protocol versions 1.0 and 2.0 were never effective. 
The SAP includes detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data, and it is structured according to different data types. 
Pharmacokinetic analysis will be described in a separate SAP. 
All analysis data sets and statistical output will be produced by the statistics department at Kalvariju 
300 Vilnius, Lithuania of Scope International AG using the SAS system version 9.4 for Windows (SAS 
Institute Inc., Cary, NC, USA) [1]. 
 
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1. FLOW CHART AND VISIT SCHEDULE 
Table 1: Schedule of Trial Procedures 
Visits 
V1a (Screening) 
V1b (Medication Dispensation) 
V2 
V3 
V4 
V5 
V6/EDV 
V7 (Follow-Up) 
Medication cycle 
3 to 4 
weeks 
 
1 
3 
6 
9(15) 
13(1) 
10 to 14 
days 
after 
V6(2) 
 
Day 20 ± 2  
of medication cycle 
Day 
29 +2 
Informed consent/assent 
x 
 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
 
Medical and gynecological 
history(3) 
x 
 
 
 
 
 
 
 
Prior medication/ 
contraceptive devices 
x 
 
 
 
 
 
 
 
Concomitant medication/ 
contraceptive devices 
x 
 
x 
x 
x 
x 
x 
 
Wish of pregnancy(13) 
x 
x 
x 
x 
x 
x 
x 
 
Physical examination 
x 
 
 
 
x 
 
x 
 
Vital signs(4, 11), body weight 
and height(7)  
x 
x 
x 
x 
x 
x 
x 
 
Gynecological examination 
x 
 
 
 
x 
 
x 
 
Transvaginal ultrasound 
x 
 
 
 
 
 
x 
 
Cervical cytology (Pap 
smear) 
x(19) 
 
 
 
 
 
x(19) 
 
Routine laboratory 
parameters(5) 
x 
 
x(17) 
x(10) 
x 
x(10) 
x 
 
Pharmacokinetic analysis(12) 
 
 
x 
 
x 
 
 
 
Urinalysis(6) 
x 
 
 
 
x 
 
x 
 
Serum pregnancy test 
x 
 
 
 
 
 
 
 
Urine pregnancy test(8) 
 
x 
x 
x 
x 
x 
x 
x 
In-/exclusion criteria 
x 
x 
 
 
 
 
 
 
Dispensing of IMP 
 
x(20) 
x 
x 
x 
x 
 
 
Drug accountability 
 
 
x(18) 
x 
x 
x 
x 
 
IMP acceptability(16) 
 
 
 
x 
 
 
x 
 
Discuss consecutive 
contraceptive method 
 
 
 
 
 
x 
 
 
Dispense/collect e-diary 
 
x(14) 
 
 
 
 
x 
 
Review e-diary(9) 
 
 
x 
x 
x 
x 
x 
 
Adverse events(9) 
x 
x 
x 
x 
x 
x 
x 
x 
1 Assessments are to be performed after completion of cycle 13 and also in case of early discontinuation. 
2 The post treatment evaluation is to be performed by interviewing the subjects. Inquiries are to be made 
regarding menstrual cycle, possible return of fertility, and possible use of contraceptive. 
3 Including check of venous thromboembolism (VTE) risk. 
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4 Blood pressure and pulse. 
5 Laboratory parameters: hematology, biochemistry. 
Hematology: hemoglobin, red blood cell count, mean corpuscular volume (MCV) and associated parameters, 
hematocrit, MCH, white blood cell count, differential white blood cell count including neutrophils, 
lymphocytes, eosinophils, basophils and monocytes, platelet count. 
Biochemistry: sodium, potassium, chloride, creatinine, blood urea nitrogen (BUN), calcium, glucose, total 
proteins, albumin, total cholesterol (HDL, LDL cholesterol), triglycerides, gamma glutamyl transferase, total 
and direct bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALAT), aspartate 
aminotransferase (ASAT), creatine phosphokinase (CPK), lactate dehydrogenase (LDH).  
6 Urinalysis: leukocytes, nitrite, protein, glucose, ketones, blood, pH, urobilinogen, bilirubin, hemoglobin – 
dipstick.  
7 V1a: Height has to be determined for all subjects. V1b to V6: Height has only to be determined in adolescent 
subjects (i.e. < 18 years of age). 
8 In addition, each subject will perform a urine dipstick pregnancy test at home at the beginning of each new 
medication cycle. In case of an equivocal or positive urine pregnancy test, a quantitative serum pregnancy test 
has to be performed for confirmation.  
9 On Day 10 + 2 days of each cycle, the subjects will be called by the site staff to collect information on adverse 
events which might have occurred, and to confirm e-diary compliance. Throughout each cycle, subjects will 
be called by site staff to review e-diary compliance as needed. 
10 Only electrolytes. 
11 Measurements of vital signs will be repeated twice with a break of one minute between them at each visit in 
sitting position, after at least five minutes of rest. The subject should not talk. 
12 Two blood samples per visit will be collected to determine plasma concentrations of LF111 at Visits 2 and 4 
and should ideally be one hour apart (between 45 and 120 minutes after the first sample) without a LF111 
administration in between. 
13 The subject will be asked if she has a wish of pregnancy at each visit. In case of a positive answer, the subject 
will be discontinued. 
14 Once the e-diary has been assigned to a subject, a practice diary (training section in e-diary) has to be actively 
completed. 
15 The investigator should arrange for the subject’s further contraceptive treatment or make an appropriate 
referral, as needed, at V5. Consecutive contraceptives should be started after last IMP intake and should be 
used at least until V7/Follow-up. This arrangement is outside the trial and costs will not be covered by the 
Sponsor. 
16 The subject will be asked by the investigator: Are you satisfied with this method? Answer options: strongly 
agree, agree, undecided, disagree, strongly disagree, no answer. Furthermore, for women who switched from 
another oral contraceptive method to the IMP will be asked by the investigator: How was your wellbeing 
during the intake of the IMP in comparison to the time when you took your former oral contraceptive? Answer 
options: better, unchanged, worse, no answer. 
17 Serum potassium will only be evaluated for subjects that take medications that may increase serum potassium 
(ACE inhibitors, angiotensin – II receptor antagonists, potassium-sparing diuretics, potassium 
supplementation, heparin and aldosterone antagonists). 
18 Drug accountability will only be performed in case a subject is discontinued prematurely or the IMP was 
collected from the subject. Otherwise the IMP will be counted by the investigator or designee at each visit and 
will be documented in the source documents only. 
19 Pap smear not performed in subjects < 21 years of age. 
20 On anticipated start date of Cycle 1 +2 days, the subject will be called by the site staff to confirm start date of 
IMP and e-diary compliance. 
 
 
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2. 
OBJECTIVES AND DESIGN 
2.1 
Trial Objectives 
2.1.1 
Primary Objective 
The primary objective of this trial is to demonstrate the contraceptive efficacy of LF111. 
2.1.2 
Secondary Objectives 
The secondary objectives of this trial are to demonstrate the safety and tolerability of LF111 and to 
assess the pharmacokinetics of LF111. 
2.2 
Trial Endpoints 
2.2.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint will be the Pearl Index (PI) based on evaluable cycles in non-
breastfeeding women aged ≤ 35 years (at the time of trial enrolment). 
PI = number of pregnancies*1300/number of evaluable medication cycles 
An evaluable cycle is a cycle with intercourse without back-up contraceptive at least once per month 
based on the electronic diary question ’Did you have sexual intercourse since the beginning of the 
cycle?’ and will be included in the primary analysis. If the cycle is not evaluable but the subject became 
pregnant in this cycle, the cycle has to be included in the analysis. 
Pregnancies following premature termination of IMP will be excluded from the calculations if the 
estimated date of conception occurs later than seven days after the last tablet intake (active or placebo). 
Date of conception will be determined by using the following information: 
1. Ultrasound (the date of conception must be based on the most accurate method i.e. the first 
trimester ultrasound. Subsequent ultrasounds will not be allowed to change dating based on this 
initial assessment). 
2. Ultrasound (in case the first trimester ultrasound was not performed) 
3. Quantitative β-hCG 
4. Qualitative urine β-hCG determination 
5. Estimation of gestational age based on pelvic and/or abdominal examination or pregnancy 
outcome 
6. Investigator’s estimation in the absence of the above criteria 
Medication cycle will be defined as 28 days starting with the administration of the first tablet from the 
blister containing 28 tablets and ending with the last day of intake. 
2.2.2 
Secondary Efficacy Endpoints 
Cycles of breastfeeding women will be excluded from the efficacy analyses but included in the analyses 
regarding safety and tolerability. 
Secondary efficacy endpoints are: 
• Pearl Index based on overall cycles (overall PI) in women aged ≤ 35 years 
PI based on overall cycles will include all pregnancies which will occur during the trial in women 
aged ≤ 35 years (at the time of trial enrollment). 
• PI for method failures in women aged ≤ 35 years 
Method failures PI will include all pregnancies of women who used the IMP correctly. 
Pregnancies are to be excluded from the calculation if in medication cycles of conception or in 
the previous medication cycles depending on the date of conception:  
- not all active tablets are taken (based on returned medication, recordings in the e-diary and 
non-compliance based on DRSP levels, if necessary) 
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- there is a tablet free interval between the previous medication cycle and the medication cycle 
of conception 
- vomiting or diarrhea is documented 
- administration of prohibited prior or concomitant therapy as detailed in Section 10.7 of the 
Clinical Trial Protocol is documented  
• Pregnancy ratio in women aged ≤ 35 years (Life table analysis) 
In addition to PI analysis, method failure life table analysis and life table analysis on evaluable 
cycles will be performed in women aged ≤ 35 years (at the time of trial enrollment) in order to 
have the pregnancy rate at each cycle and cumulative pregnancy rates for 6 and 13 cycles. For 
life table analysis on evaluable cycles, only medication cycles of non-breastfeeding women will 
be considered as evaluable as defined in 2.2.1 and will be included in analysis. If the cycle is not 
evaluable but the subject became pregnant in this cycle, the cycle has to be included in the 
analysis. All pregnancies following premature termination of IMP will not be included in 
calculations if they occur later than seven days after the last tablet intake (active or placebo). 
Method failure pregnancy rates similar to method failure PI will include only those cycles of 
women who use the IMP correctly and include only perfect medication cycles as described in 
Section 5.5 of non-breastfeeding women. 
• Overall PI, PI for method failures, PI for evaluable cycles and pregnancy ratio (life table analysis) 
in all women 
All analyses described above in women aged ≤ 35 years (at the time of trial enrollment) will also 
be evaluated for the whole subject population. Included are only cycles of non-breastfeeding 
women with sexual activity without using back-up contraception.  
• Overall PI, PI for method failures, PI for evaluable cycles and pregnancy ratio (life table analysis) 
in women aged > 35 years  
All analyses described above in women aged ≤ 35 years (at the time of trial enrollment) will also 
be evaluated for women aged > 35 years at study enrollment. Included are only evaluable cycles 
of non-breastfeeding women with sexual activity without using back-up contraception. 
Overall PI will be based on exposure cycles. 
Efficacy Endpoints in Addition to the Protocol 
• Overall PI based on only confirmed and on confirmed and suspected, non-confirmed 
pregnancies (with and without sites 104 and 120) 
Overall PI based on exposure cycles will be evaluated for the whole subject population. 
Included are only cycles of non-breastfeeding women. The overall PI will be evaluated 
based on only confirmed pregnancies and on confirmed and suspected, non-confirmed 
pregnancies and in- and excluding sites 104 and 120. 
All analyses described above will be evaluated in addition by BMI subgroup and by 
weight subgroup. 
• PI for evaluable cycles in women aged ≤ 35 years in total and by BMI and weight groups (with 
and without sites 104 and 120) based on confirmed and on confirmed and suspected, non-
confirmed pregnancies 
PI based on evaluable cycles will be evaluated in women aged ≤ 35 years. Included are 
only cycles of non-breastfeeding women. The PI will be evaluated based on only 
confirmed pregnancies and on confirmed and suspected, non-confirmed pregnancies and 
in- and excluding sites 104 and 120. 
All analyses described above will be evaluated in addition by BMI subgroup and by 
weight subgroup. 
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2.2.3 
Safety Endpoints 
Analysis of safety endpoints will be conducted using the SS only. 
• AEs 
All AEs will be summarized by number and proportion of subjects and number of AEs. TEAEs 
will be summarized by calculating the number and percent of subjects with AEs by MedDRA 
primary system organ class (SOC) and preferred term (PT). Also, TEAEs will be summarized by 
severity and relationship to treatment. Number and percent of subjects with serious TEAEs, 
TEAEs leading to trial termination and TEAEs of special interest will be provided by MedDRA 
PT and SOC. 
• Vital signs 
Summary statistics for absolute values and absolute change from V1a (baseline) will be provided 
for each visit (V1b to V6/EDV). 
• Clinical laboratory parameters 
Laboratory parameters will be summarized by calculating summary statistics on the absolute 
values and on the change from V1a to V3, V4, V5 and V6. Shift tables will be provided to 
illustrate changes with respect to the laboratory normal ranges between V1a and V6/Early 
discontinuation visit (EDV). The number and percent of subjects with values outside the limits 
of clinical significance reference ranges will be summarized. 
2.2.4 
Tolerability endpoints 
The tolerability endpoints are based on vaginal bleeding pattern and include the following variables: 
Bleeding: 
• Number of subjects with bleeding by treatment day, treatment cycle and reference period 
(summary of cycles 2-4, 5-7, 8-10, 11-13 and 2-13) 
• Number of subjects with unscheduled bleeding days by treatment cycle and reference period 
• Number of subjects with scheduled bleeding days by treatment cycle and reference period 
• Number of subjects with prolonged bleeding >nine days/ >14 days by reference period 
• Number of bleeding episodes during treatment and by reference period 
• Number of days with bleeding by cycle and reference period 
• Number of days with unscheduled bleeding by cycle and reference period 
• Number of days with scheduled bleeding by cycle and reference period 
• Mean length of bleeding episodes by cycle and reference period 
Spotting: 
• Number of subjects with spotting by treatment day, treatment cycle and reference period 
(summary of cycles 2-4, 5-7, 8-10, 11-13 and 2-13) 
• Number of subjects with unscheduled spotting days by treatment cycle and reference period 
• Number of subjects with scheduled spotting days by treatment cycle and reference period 
• Number of subjects with prolonged spotting >nine days/ >14 days by reference period 
• Number of spotting episodes during treatment and by reference period 
• Number of days with spotting by cycle and reference period 
• Number of days with unscheduled spotting by cycle and reference period 
• Number of days with scheduled spotting by cycle and reference period 
• Mean length of spotting episodes by cycle and reference period 
Only cycles of women with complete and correct diary entries will be taken into account in the analysis. 
All tolerability variables will be evaluated over 13 cycles. 
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Another tolerability endpoint is the IMP acceptability. 
Tolerability Endpoints in Addition to the Protocol 
In addition, tolerability endpoints that are based on vaginal bleeding pattern and on combined variables 
(bleeding/spotting) will be evaluated: 
• Number of subjects with bleeding/spotting by treatment day, treatment cycle and reference period 
• Number of subjects with unscheduled bleeding/spotting days by treatment cycle and reference 
period 
• Number of subjects with scheduled bleeding/spotting days by treatment cycle and reference 
period 
• Number of subjects with no bleeding/spotting days by treatment cycle and reference period 
• Number of days with bleeding/spotting by cycle and reference period by BMI subgroup 
• Number of days with unscheduled bleeding/spotting by cycle and reference period by BMI 
subgroup 
• Number of days with scheduled bleeding/spotting by cycle and reference period by BMI 
subgroup 
• Number of days with bleeding/spotting by cycle and reference period by weight subgroup 
• Number of days with unscheduled bleeding/spotting by cycle and reference period by weight 
subgroup 
• Number of days with scheduled bleeding/spotting by cycle and reference period by weight 
subgroup 
2.2.5 
Pharmacokinetic endpoints 
Pharmacokinetic endpoint analysis will be described in a separate SAP. 
2.3 
Overall Trial Design 
This trial is a prospective, multicenter, open-label, non-controlled trial in female subjects, age 15 or 
above who present to the clinic seeking contraception, who are postmenarcheal and premenopausal. 
Breastfeeding women are allowed to participate in the trial. 
At V1a (screening), informed consent/assent will be obtained and the screening procedures will be 
performed. At V1b, after the results of the laboratory tests have confirmed the subject’s eligibility, the 
subject will be provided with the investigational medicinal product (IMP) and an electronic diary and 
the subject will be instructed in their use. On anticipated start date of Cycle 1+2 days, the trial staff will 
call the subject for the confirmation of IMP start date. Afterwards, the subjects will attend Visits 2 to 5 
at Day 20±2 of the 1st, 3rd, 6th and 9th cycle and Visit 6 at Day 29+2 of the 13th cycle. The follow-up 
(Visit 7) will take place 10-14 days after Visit 6. Once a month, on Day 10 (+ 2 days) of each cycle, the 
subjects will be contacted by the site staff to collect information on any adverse events which might 
have occurred. 
The trial will include women who have never used hormonal contraceptives before consent/assent 
(naïve users), women who have not used hormonal contraceptives in the past three months before 
consent/assent or who have used hormonal contraceptives in the past but have a contraceptive-free time 
of less than three months before consent/assent (previous users) as well as women directly switching 
from another hormonal method (switchers). Women who have used hormonal contraceptives in the past 
but have a contraceptive-free time of less than three months before consent/assent are allowed to be 
included into the trial if they had at least one complete menstrual cycle before enrollment. 
For naïve users and previous users, the first IMP intake will be on the first day of the next menstrual 
bleeding after Visit V1b. (If the menstrual bleeding starts in the evening, and the subject prefers to take 
her pill in the morning, then she may begin the first IMP intake the next day [Day 2 of the menstrual 
bleeding]). For a switcher, the first IMP intake will be on the day following the last active pill of the 
previous hormonal contraceptive. The subject is free to choose an intake time in the morning or evening 
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that suits her requirements. Breastfeeding women can start the first IMP any day starting six weeks after 
delivery.  
2.4 
Randomization 
Not applicable. Subjects will be allocated to treatment only if they satisfy all the inclusion criteria and 
are not precluded from participation by any of the exclusion criteria. 
2.5 
Treatments  
The study product is LF111, which consists of coated tablets containing 4.0 mg DRSP. One package 
includes 24 active (white) tablets followed by 4 placebo (green) tablets. The dose for each subject is 
one tablet per day. During each medication cycle, the subjects will take 24 active tablets (each 
containing 4.0 mg DRSP) followed by 4 placebo tablets. 
2.6 
Sample Size 
At least 920 subjects will be allocated to treatment to have at least 5000 evaluable cycles for the PI 
calculation in non-breastfeeding women aged ≤ 35 years (at the time of trial enrollment). Additionally, 
a minimum of 75 subjects aged > 35 years will be allocated to treatment. The calculations are based on 
empirical values including firstly a rate of 24.8% of subjects using back-up contraception or not having 
intercourse. Secondly, 45% of subjects are assumed to drop out of the trial. The prime target is to collect 
at least 5000 evaluable cycles. 
2.7 
Blinding 
Not applicable to this trial. 
 
 
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3. ANALYSIS SETS AND SUBGROUPS 
3.1 
Analysis Sets 
As described in the “CF111303: Site 104: Addendum to Investigation Report Signed 18-August-2016 
by Cristin Barrett, SCOPE CRA Manager”, “CF111303: Site 120: Addendum to Serious Breach 
Reporting Form Signed 23-August-2016 by Amy O’Sullivan, SCOPE Project Manager” and sponsor 
letter “RE: Clinical Trial CF111-303: exclude data from analysis for sites 104 and site 120” data from 
sites 104 and 120 will not be included in any statistical summary or analysis tables. Data from these 
sites will only be included in the Appendix 4 tables (Tables 15.1.1.1.1, 15.1.2.1.1, 15.1.3.1.1, 15.2.1.2.5, 
15.2.1.2.7, 15.2.1.4.3, 15.2.1.4.5, 15.2.1.4.7, 15.2.1.4.9, 15.2.3.1.1 and 15.2.3.1.2), Appendix 5 listings 
and Appendix 6 figures (Figures 15.1.1.1, 15.1.2.1). 
The analyses will be based on the following analysis sets: 
Enrolled Set (ES) will consist of all subjects who signed informed consent/assent.  
Safety Set (SS) will consist of all subjects who: 
• took at least one dose of IMP. 
Full Analysis Set (FAS) will consist of all subjects who: 
• took at least one dose of IMP; 
• were not pregnant at the date of first IMP intake. 
Modified Full Analysis Set (MFAS) will consist of all subjects who: 
• took at least one dose of IMP; 
• were not pregnant at the date of first IMP intake; 
• were non-breastfeeding. 
Per Protocol Set (PPS) will not be defined since PI will be calculated using three methods therefore 
protocol violations will be taken into account. 
Data of centers 104 and 120 will be excluded for SS and FAS calculations. Data of these centers will 
also be excluded for MFAS calculations unless it will be specified in the header of the respective tables 
that data of these centers are included. 
3.2 
Subgroups 
The following subgroups will be defined: 
• Weight subgroups, defined as  
- < median weight of the safety set 
- ≥ median weight of the safety set 
• Body mass index (BMI) subgroups, defined as  
- BMI < 30 kg/m2 
- BMI ≥ 30 kg/m2 
- 25 kg/m2 < BMI < 30 kg/m2 1 
• Blood pressure subgroups, defined as 
- Systolic blood pressure (SBP) < 130 mmHg and diastolic blood pressure (DBP) < 85 mmHg 
- Systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 85 mmHg 
• Race subgroups, defined as 
- American Indian or Alaska Native 
- Asian 
- Black or African-American 
                                                     
1 25 kg/m2 < BMI < 30 kg/m2 category is in addition to the protocol. 
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- Native Hawaiian or Other Pacific Islander 
- White 
- Other 
• Ethnicity subgroups, defined as 
- Hispanic or Latino 
- Not Hispanic or Latino 
3.3 
Data Review 
A data review meeting (DRM) will be held after database lock, prior to the final SAP and clinical 
database closure. 
The following aims are defined for the DRM: 
- to assign pregnancies to their category and cycle; 
- to identify protocol deviations which may have impact on cycles; 
- to assign subjects to each of the analysis sets; 
- to check that there are no data issues that are outstanding or need resolution; 
- to define complete and correct diary entry; 
- to solve any outstanding issues in the SAP. 
Appropriate trial team, including a physician, will review certain potential protocol deviations and will 
review relevant information regarding those deviations to determine whether each of them have an 
impact on a perfect cycle. Protocol deviations will be not categorized into major and minor rather they 
will be categorized according to their impact to the perfect medication cycle. 
Inclusion criterion related deviations will be classified as follows: 
Inclusion criteria 
(At Visit 1 (Screening) and at Visit 1b (Medication Dispensation), subjects must 
meet ALL of the following criteria) 
Impact on 
the cycle 
DRM 
listing 
no. 
1. Sexually active, postmenarcheal and premenopausal female subjects at 
risk of pregnancy with no upper age limit. 
 
Since Protocol Final Version 4.0: 
Sexually active, postmenarcheal and premenopausal female subjects at 
risk of pregnancy including breastfeeding women with no upper age limit. 
Case by 
case 
decision 
IN01, 
IN02 
2. Female subjects at risk of pregnancy, between the ages of 15 and 17 
(inclusive) provided that  
• Applicable national, state and local laws allow subjects in this age 
group to consent to receive contraceptive services, 
• All applicable laws and regulations regarding the informed consent 
of the subjects to participate in clinical trials are observed, and 
• Subjects in this age group will also be encouraged to consistently 
and correctly use male condoms with every event of sexual 
intercourse. 
 
Since Protocol Final Version 4.0: 
Female subjects at risk of pregnancy, between the ages of 15 and 17 
(inclusive) provided that  
• Applicable national, state and local laws allow subjects in this age 
group to consent/assent to receive contraceptive services, and 
All cycles 
IN03 
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• All applicable laws and regulations regarding the informed 
consent/assent of the subjects to participate in clinical trials are 
observed. 
3. Regular cycles during the last six months before consent when not 
using hormonal contraception. 
 
Since Protocol Final Version 4.0: 
Regular cycles during the last six months before consent/assent when not 
using hormonal contraception. 
Case by 
case 
decision 
IN04 
4. Menstruation restarted since last pregnancy (only applicable for 
women that were pregnant within the last six months), i.e., at least 
three complete menstrual cycle after delivery. 
 
Since Protocol Final Version 4.0: 
At least three complete menstrual cycles after delivery (only applicable 
for women who were pregnant within the last six months and for non-
breastfeeding women). Breastfeeding women can be included six weeks 
after delivery irrespective of menstrual cycles post-delivery. 
Case by 
case 
decision 
IN05 
5. At screening, maximum systolic blood pressure (median value of three 
values) less than or equal to 159 mm Hg and diastolic blood pressure 
(median value of three values) less than or equal to 99 mm Hg 
 
Since Protocol Final Version 4.0: 
At screening, maximum systolic blood pressure (median value of three 
values) ≤ 159 mmHg and diastolic blood pressure (median value of three 
values) ≤ 99 mmHg. 
No impact 
IN06 
6. Be able and willing to provide written informed consent/assent, or 
assent if the subject is adolescent, prior to undergoing any trial related 
procedure. 
- 
- 
7. Willing to use trial contraception for thirteen 28-day cycles. 
- 
- 
8. Be willing to have intercourse each cycle of trial. 
 
Since Protocol Final Version 4.0: 
Be willing to have intercourse each cycle of trial without the need to use 
back-up contraceptive. 
- 
- 
9. Be willing to state that, to her best knowledge, her male sexual 
partner(s): 
• Has not had a vasectomy or been previously diagnosed as infertile.  
• Has not been previously diagnosed or suspected of human 
immunodeficiency virus (HIV) unless he has subsequently had a 
negative HIV test. 
• Has not been known to have engaged in homosexual intercourse in 
the past five years unless he has had negative HIV test results since 
then. 
• Has not shared injection drug needles in the past unless he has had 
a negative HIV test at least six weeks since last use. 
- 
- 
10. Agree not to participate in any other clinical trials during the course of 
this trial. 
- 
- 
Exclusion criterion related deviations will be classified as follows: 
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Exclusion criteria 
(Subjects are to be excluded from the trial for ANY ONE of the following 
reasons) 
Impact on 
the cycle 
DRM 
listing 
no. 
1. Pregnant or breastfeeding. 
 
Since Protocol Final Version 4.0: 
Pregnant. 
All cycles 
DRM01 
2. Subject is known to or suspected of not being able to comply with the 
trial protocol, the use of trial medication or the use of the trial diary. 
- 
- 
3. History of infertility. 
All cycles 
EX02 
4. Abnormal finding on pelvic, breast or ultrasound examination that in 
the investigator’s opinion contraindicates participation in the trial. 
Case by 
case 
decision 
EX03 
5. Unexplained amenorrhea. 
Case by 
case 
decision 
EX04 
6. Known polycystic ovary syndrome. 
Case by 
case 
decision 
EX05 
7. Abnormal Papanicolaou (Pap) smear (ASC-US or more severe 
finding) at screening. (Pap smear results from within the previous three 
months prior to consent are acceptable if the report is available to the 
trial investigator). 
 
Since Protocol Final Version 4.0: 
Women ≥ 21 years of age with a Papanicolaou (pap) smear reading 
LGSIL or higher at screening (or six months prior to screening date). 
Human papilloma virus (HPV) testing in subjects with atypical squamous 
cells of undetermined significance (ASC-US) can be used as an 
adjunctive test. 
• Subjects with ASC-US can be included if they are negative for 
high-risk HPV strains. 
• Subjects < 21 years of age do not require a pap smear. 
Case by 
case 
decision 
EX06 
8. Known contraindication or hypersensitivity to ingredients or excipients 
of the IMP, including: 
a. Renal insufficiency 
b. Hepatic dysfunction 
c. Adrenal insufficiency 
d. Current or history of venous thrombophlebitis or thromboembolic 
disorders (venous thrombembolism; which includes deep vein 
thrombosis and pulmonary embolism) 
e. Current or history of cerebral-vascular or coronary-artery disease 
f. Valvular heart disease with thrombogenic complications 
g. Diabetes with vascular involvement 
h. Headaches with focal neurological symptoms 
i. Major surgery with prolonged immobilization 
j. Known or suspected carcinoma of the breast 
k. Known or suspected sex-steroid sensitive malignancies 
l. Undiagnosed abnormal genital bleeding 
Case by 
case 
decision 
EX07 
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m. Cholestatic jaundice of pregnancy or jaundice with prior hormonal 
contraceptive use 
n. Liver tumor (benign or malignant) or active clinically significant 
liver disease. 
9. Uncontrolled thyroid disorder (i.e., on stable dose of thyroid 
replacement for less than two months). 
Case by 
case 
decision 
EX08 
10. Uncontrolled concomitant diseases (i.e., not on a stable treatment dose 
for at least two months). 
Case by 
case 
decision 
EX09 
11. Evidence or history of alcohol, medication or drug abuse (within the 
last 12 months). 
 
Since Protocol Final Version 4.0: 
Evidence or history of alcohol, medication or drug abuse (within the last 
12 months prior to consent/assent). 
Case by 
case 
decision 
EX10 
12. Known inherited or acquired predisposition to VTE or ATE (e.g. 
factor VLeiden, Prothrombin mutation, Antiphospholipid-antibodies) or 
bruising within the last 12 months prior to consent. 
 
Since Protocol Final Version 4.0: 
Known inherited or acquired predisposition to venous thromboembolism 
or arterial thromboembolism (e.g., factor VLeiden, Prothrombin mutation, 
Antiphospholipid-antibodies) or bruising within the last 12 months prior 
to consent/assent. 
No impact 
EX11, 
EX12 
13. Known or suspected HIV and/or hepatitis infection at screening. 
All cycles 
EX13 
14. Received a dose of depot medroxyprogesterone acetate (DMPA or 
Depo-Provera) during the 10 months prior to consent, or received any 
combined injectable contraceptive (e.g., Cyclofem) during the six 
months prior to consent, or no spontaneous menses since last injection. 
 
Since Protocol Final Version 4.0: 
Received a dose of depot medroxyprogesterone acetate (DMPA or Depo-
Provera®) during the 10 months prior to consent/assent, or received any 
combined injectable contraceptive (e.g., Cyclofem®) during the six 
months prior to consent/assent, or no spontaneous menses since last 
injection. 
Case by 
case 
decision 
EX14 
15. Long-term treatment (longer than seven consecutive days) within a 
month prior to V1b of any medication that might interfere with the 
efficacy of hormonal contraceptives. Prohibited medication include:  
a. Anticonvulsants (e.g. Phenytoin, carbamazepine, oxcarbazepine, 
topiramate, felbamate, primidone) 
b. Barbiturates 
c. Rifampin 
d. Atorvastatin 
e. Bosentan 
f. Griseofulvin 
g. Phenylbutazon 
h. St. John’s wort (hypericum perforatum)  
 
Since Protocol Final Version 4.0: 
Case by 
case 
decision 
EX15 
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Long-term treatment (longer than seven consecutive days within a month 
prior to V1b) of any medication that might interfere with the efficacy of 
hormonal contraceptives. Prohibited medication include: 
a. Anticonvulsants (e.g. phenytoin, carbamazepine, oxcarbazepine, 
topiramate, felbamate, primidone) 
b. Barbiturates 
c. Rifampin 
d. Bosentan 
e. Griseofulvin 
f. St. John’s wort (hypericum perforatum) 
16. Administration of human chorionic gonadotropin (hCG) or intake of 
co-medication containing hCG within a month prior to V1b. 
Case by 
case 
decision 
EX16 
17. Progestin-releasing IUD or contraceptive implant received or in place 
within the last two months prior to consent. 
 
Since Protocol Final Version 4.0: 
Progestin-releasing intra-uterine device (IUD) or contraceptive implant 
received or in place within the last two months prior to consent/assent. 
Case by 
case 
decision 
EX17 
18. Planned regular concomitant use of barrier contraceptive methods, 
spermicides, IUDs or other contraceptive measures (excepting 
occasional use for safety reasons, e. g. reduce risk of infection). 
 
Since Protocol Final Version 4.0: 
Planned regular concomitant use of barrier contraceptive methods, 
spermicides, IUDs or other contraceptive measures (excepting occasional 
use for safety reasons, e. g. reduce risk of infection). 
- 
- 
19. Evidence or history of clinically significant psychiatric illness or 
suicide risk. 
No impact 
EX18 
20. Participation in another trial of an investigational drug or device 
parallel to the current trial, or less than 90 days before consent, or 
previous participation in the current trial and dispensed trial 
medication. 
 
Since Protocol Final Version 4.0: 
Participation in another trial of an investigational drug or device parallel 
to the current trial or less than 90 days before consent/assent, or previous 
participation in the current trial and dispensed trial medication. 
- 
- 
21. Subject is a member of the investigator’s or Sponsor’s staff or a 
relative or family member thereof. 
- 
- 
22. Any condition that, in the opinion of the investigator, may jeopardize 
protocol compliance or the scientific integrity of the trial. 
- 
- 
Listings related to Inclusion/Exclusion criterions: 
Number 
Name 
Listing IN01 
Subjects with Missing Age at Menarche 
Listing IN02 
Sexually Non-Active Subjects. 
Listing IN03 
Subjects with Missing Consent/Assent Date 
Listing IN04 
Subjects with Non-Regular Menstrual Bleeding During the Last 6 Cycles Before 
Visit 1a 
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Listing IN05 
Non-Breastfeeding Subjects Who Had Delivery Within the Last Six Months or 
Breastfeeding Subjects Who Had Delivery Within Less than Six Weeks Before Visit 
1a 
Listing IN06 
Subjects with Maximum SBP ≥ 159 mmHg or DBP ≥ 99 mmHg at Visit 1a 
Listing EX02 Subjects with History of Infertility 
Listing EX03 Subjects with Abnormal Finding on Pelvic, Breast or Ultrasound Examination 
Listing EX04 Subjects with Unexplained Amenorrhea 
Listing EX05 Subjects with Known Polycystic Ovary Syndrome 
Listing EX06 Subjects ≥ 21 Years of Age with Abnormal Papanicolaou Smear Reading or Positive 
Human Papilloma Virus Test 
Listing EX07 Subjects with Known Contraindication or Hypersensitivity to Ingredients or 
Excipients of the IMP 
Listing EX08 Subjects with Uncontrolled Thyroid Disorder 
Listing EX09 Subjects with Uncontrolled Concomitant Diseases 
Listing EX10 Excessive Drinkers 
Listing EX11 Subjects with Known Inherited Predisposition to Thromboembolic Illness 
Listing EX12 Subjects with Acquired Predisposition to Thromboembolic Illness or Bruising 
Within the Last 12 Months Prior to Visit 1a 
Listing EX13 Subjects with Known or Suspected HIV and/or Hepatitis Infection at Visit 1a 
Listing EX14 Subjects Who Received a Dose of Depot Medroxyprogesterone Acetate During the 
10 Months Prior to Visit 1a, or Received Any Combined Injectable Contraceptive 
During the 6 Months Prior to Visit 1a 
Listing EX15 Subjects with Long-Term Treatment of Any Medication That Might Interfere with 
the Efficacy of Hormonal Contraceptives Prior to Visit 1b 
Listing EX16 Subjects Who Received Human Chorionic Gonadotropin or Co-Medication 
Containing Human Chorionic Gonadotropin Within a Month Prior to V1b 
Listing EX17 Subjects with Progestin-Releasing Intra-Uterine Device or Contraceptive Implant 
Received or in Place within the Last 2 Months Prior to Visit 1a 
Listing EX18 Subjects with history of clinically significant psychiatric illness or suicide risk 
Additional trial conduct criteria deviations will be classified as follows: 
Number 
Name 
Listing DRM01 
Subjects Who Became Pregnant During the Study 
Listing DRM02 
Cycles when Vomiting or Diarrhea is Documented 
Listing DRM03 
Cycles with Administration of Prohibited Concomitant Therapy 
Listing DRM04 
Subjects Who did not Meet Inclusion/Exclusion Criterions 
Listing DRM05 
Listing and Chart with Treatment Cycles 
Listing DRM06 
IMP Gaps of More Than 48 Hours 
Listing DRM07 
Adverse Events of Special Interest 
Listing DRM08 
Non-Complete or Non-Correct Treatment Diary Records 
Listing DRM09 
Specification of Subject Withdrawn During Treatment 
Listing DRM10 
Specification of Subject Withdrawn During Screening 
Listing DRM11 
Protocol Deviation from eCRF 
Listing DRM12 
Scenarios for first IMP intake preceding V1b 
Listing DRM13 
Subjects with Partial Date of Last IMP Intake in eCRF 
Listing DRM14 
Treatment Compliance According to Drug Accountability 
Listing DRM15 
Subjects for Whom IMP Was Dispensed but Have No eDiary Records 
Listing DRM16 
Subjects Who Have Cyst Larger Than 30 mm 
All decisions made during DRM will be documented in the DRM report. 
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4. GENERAL DEFINITIONS AND NAMING CONVENTIONS 
In order to avoid ambiguity during the analysis, a number of definitions and conventions for data 
handling are described here. 
4.1 
General Methodology and Presentation of the Results 
The default summary statistics for quantitative (continuous) variables will be  
- 
the number of subjects with data available (n), 
- 
mean, 
- 
standard deviation (SD), 
- 
median, 
- 
minimum (Min) and maximum (Max), 
- 
1st and 3rd quartiles (Q1 and Q3) for continuous demographic and laboratory data. 
Mean and median will be presented to one more decimal place than the raw value. SD will be reported 
to two decimal places greater than the original value. The minimum, maximum, 1st and 3rd quartiles and 
95% CI values will be presented with the same decimal precision as the raw value.  
For qualitative (categorical) variables, the frequency count (n) and percentage (%) of subjects with non-
missing data per category will be presented. “Missing” classification without percentage will be 
presented only if missing data will be in respective category. 
Percentage values will be presented to one decimal place. 
The denominator used for calculation of the percentages will be specified in a footnote to the tables for 
clarification. 
4.2 
Statistical Output Layout 
All titles and column headers (consisting of one or several words) will be capitalized; articles, 
prepositions, and conjunctions, and “To” in infinitives will not be capitalized, except they are at the 
beginning of titles or headers. 
All pages will be numbered according to the table/listing/figure to which the page belongs to. Every 
table/listing/figure will be numbered from page 1, “Page X of Y” at the bottom of each page. 
The definition of baseline and endpoint value will be described in a footnote in every TLF where 
applicable. Other important definitions will also be presented if necessary. 
Dates will be listed in the format: <yyyy>-<mm>-<dd> (e.g. 2003-11-20). Times will be listed in the 
format: <hh>:<mm> (e.g. 09:15) or in the format <hh>:<mm>:<ss> if seconds are collected. When date 
and time are collected, these are listed in the format: <yyyy>-<mm>-<dd>T<hh>:<mm> (e.g. 2003-11-
20T09:15), <yyyy>-<mm>-<dd>T<hh>, or <yyyy>-<mm>-<dd>T<hh>:<mm>:<ss>.  
Partial missing dates will be listed in the format <yyyy>-<mm> (e.g. 2013-11) if only day is missing or 
in the format <yyyy> (e.g. 2013) if month and day are missing. 
Missing data including missing dates or times will be displayed in listings as blank fields, unless 
otherwise specified. 
Listings will be sorted by subject’s number and visit number where applicable, unless specified 
otherwise. 
4.3 
Treatment Group Names and Labels 
Since there is only one treatment group in this trial, statistical output will be presented only for the 
overall group. The labels to be used in the tables, listings and figures are defined in the table below. 
Treatment Group Description 
Treatment Group Label, which will appear in the TLFs 
DRSP 4.0 mg 
DRSP 4.0 mg 
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4.4 
Visit Names and Labels 
The names to be used in the analysis datasets and the labels to be used in the tables, listings and figures 
for the different trial visits are defined below. 
Visit 
number 
Visit name 
Visit label, which will 
appear in the TLFs 
10 
Visit 1a (V1a, Screening Visit)  
Visit 1a or V1a 
11 
Visit 1b (V1b, Medication Dispensation Visit, as soon as the 
results of the routine laboratory tests from V1a are available)  
Visit 1b or V1b 
20 
Visit 2 (V2, Day 20 ± 2 of Medication Cycle 1)  
Visit 2 or V2 
30 
Visit 3 (V3, Day 20 ± 2 of Medication Cycle 3)  
Visit 3 or V3 
40 
Visit 4 (V4, Day 20 ± 2 of Medication Cycle 6)  
Visit 4 or V4 
50 
Visit 5 (V5, Day 20 ± 2 of Medication Cycle 9)  
Visit 5 or V5 
60 
Visit 6 (V6, Day 29 + 2 of Medication Cycle 13) or EDV  
Visit 6/EDV or V6/EDV 
70 
Visit 7 (V7, Follow-Up Visit, 10 to 14 days after V6)  
Visit 7 (Follow-Up) or V7 
(FU) 
4.5 
Days Numbering 
All assessment dates will be related to the first day of IMP intake. This first day of IMP intake is referred 
to as Day 1. Day -1 is the day that is preceding Day 1 and Day 0 will not be defined. The assessment 
series is built up so that Day -2 is the day before Day -1 in the pre-treatment period, and Day 2 the 
second day on trial medication, etc. 
4.6 
Trial Periods 
Date of the first IMP intake 
The date of the first IMP intake will be defined as the date of the first IMP intake recorded in the 
treatment diary. 
If such date is not available and subject did not return all IMP pills, Visit 1b date will be taken into 
account. 
Date of the last IMP intake 
The date of last IMP intake will be defined as the date of the last IMP intake provided in the eCRF 
“Trial Termination” section.  
If such date is incomplete the following will be imputed: 
- 
The date of the last day of the month, if month and year is available but the day is missing. 
If such date is not available or only year is provided, last date of IMP administration recorded in 
subject’s diary will be taken into account. If last date of IMP administration recorded in subject’s diary 
is not available and subject did not return all IMP pills, the subject's last visit date will be taken into 
account. 
Treatment period 
The treatment period is defined as the period from the first IMP intake up to the last IMP intake. 
Baseline value  
Baseline value for a variable will be defined as Visit 1a value. 
Absolute change 
Absolute change from Visit 1a to each visit will be calculated as 
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 <𝑋𝑋> = 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 <𝑋𝑋> − 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉. 
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Treatment cycle  
Treatment cycles will be defined as 28 days periods starting on the day of the first IMP intake from the 
blister containing 28 tablets. No more than 13 completed cycles will be used for analysis. 
Reference period 
The treatment period will be grouped into reference periods as: 
- 
Cycles 2-4 
- 
Cycles 5-7 
- 
Cycles 8-10 
- 
Cycles 11-13 
Overall period 
- 
Cycles 2-13 
4.7 
Visit Windows 
No windowing will be done, that is, the data will be analyzed with the nominal visit numbers. 
4.8 
Complete and correct treatment diary records 
Treatment diary records will be defined as correct and complete if the following information will be 
non-missing: 
• 
Reference date (REFDTC), 
• 
Vaginal bleeding or spotting (VAGBLEEX), 
• 
Bleeding amount (BLEEDAMX). 
4.9 
Coding Systems and Conventions 
4.9.1 
Coding of adverse events and medical history 
Adverse event and medical history investigator terms are assigned to a lowest level term (LLT) and a 
preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) and 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 17.0 [2]. 
4.9.2 
Coding of medications 
Medications are classified according to active drug substance using the World Health Organization-
Drug Dictionary (WHO-DD), version 2014 [3]. The WHO drug code has 11 digits. The generic name 
is defined by the first 6 of the 11 digits. In addition, the Anatomical Therapeutic Chemical (ATC) classes 
are assigned to the drug code. In this trial, ATC codes are defined to the 4th level. 
4.10 Handling of Missing Data 
Handling of missing data, if applicable, is discussed in the relevant sub-sections of Section 5. 
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5. 
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY 
5.1 
Subjects Disposition  
5.1.1 
Disposition and Withdrawals 
Disposition and withdrawal data will be collected at Visit 1a and Visit 6/EDV in eCRF and will include 
the following: 
• Date of informed consent/assent; 
• Reason for screening failure; 
• Date of trial termination; 
• Did the subject complete the trial as scheduled (yes, no); 
• Reason for the premature trial termination; 
• Date of last contact. 
Screening failures will be subjects who have been enrolled in the trial (i.e. informed consent form 
signed/assent form signed), but discontinue the trial before first IMP intake due to the following reasons:  
• Inclusion/exclusion criteria 
• Withdrew consent 
• Lost to follow-up 
• Adverse event 
• Other 
One additional attempt to enroll a subject at screening may be permitted for screening failures if the 
subject fulfils the eligibility criteria. Both disposition events will be included in the analysis for subjects 
who were rescreened, i.e., the first disposition event (screening failure with reason) will be included 
into analysis. 
The Trial Termination form must be completed for all subjects that have participated in at least one visit 
starting from Visit 1b, including subjects dropping out before any IMP intake. The subject information 
eCRF must be updated to indicate the subject status as Completed or Withdrawn. 
Subjects may withdraw or may be withdrawn from the trial for the following reasons:  
• at subject’s own request (withdrawal of consent/assent) 
• if in the investigator’s opinion, for reasons of safety or ethics, continuation in the trial would be 
detrimental to the subject’s well-being  
• major protocol deviations (rules to consider deviations as minor/major will be documented in the 
data review report)  
• pregnancy  
• wish for pregnancy  
• development of an exclusion criterion if clinically significant  
• adverse event 
• at the specific request of the sponsor 
• lost to follow-up 
• other 
In addition to protocol, withdrawn reasons (for subjects who were withdrawn) “At subject’s own request 
(withdrawal of consent)”, “If in the investigator’s opinion, for reasons of safety or ethics, continuation 
in the trial would be detrimental to the subject's well-being” and “Other” will be subcategorized as “IMP 
related”, “non-IMP related” and “Uncategorized” by data management. Final decision for 
subcategorization will be approved by sponsor. 
 
 
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Subjects’ disposition table for withdrawals will include further summaries: 
• 
Overall withdrawn reasons; 
• 
Withdrawn reasons by visits; 
• 
Withdrawn reasons by cycles; 
• 
Withdrawn reasons by education level 
• 
Withdrawn reasons by race; 
• 
Withdrawn reasons by ethnicity; 
• 
Withdrawn reasons by BMI groups. 
Also, Subjects’ disposition table without data from site 140 will be prepared. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.1.1.1 
Analysis Sets 
Enrolled 
Number and percentage of subjects included into each 
analysis set will be presented. Percentage will be based on 
number of subjects in the ES. 
Table 
15.1.2.1.1 
Screen Failures 
Enrolled 
Number and percentage of subjects who were enrolled and 
failed screening will be presented and summarized by 
reasons associated with the discontinuation. Percentage will 
be based on number of subjects in the ES. 
Table 
15.1.3.1.1 
Reasons for Exclusion from 
Analysis Sets 
Enrolled 
Number and percentage of subjects excluded from SS, FAS 
and MFAS together with reason(s) for exclusion will be 
summarized. Percentage will be based on number of 
subjects in the ES. 
Table 
15.1.4.1.1 
Subjects’ Disposition 
Safety 
The number and percentage of subjects who completed or 
discontinued study will be summarized. Reasons associated 
with the termination will be included. Percentage will be 
based on number of subjects in the SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.1.4.1.2 
Subjects’ Disposition 
(Excluding Site 140) 
Safety 
The number and percentage of subjects who completed or 
discontinued study will be summarized excluded data from 
site 140. Reasons associated with the termination will be 
included. Percentage will be based on number of subjects in 
the SS. Data of centers 104 and 120 will be excluded. 
Table 
15.1.5.1.1 
Disposition by Attended Visit 
Safety 
The number and percentage of subjects attended at each 
visit will be summarized. Percentage will be based on 
number of subjects in the number of subjects in the SS. 
Table 
15.1.6.1.1 
Disposition by Sites 
Safety 
The number and percentage of subjects by sites will be 
summarized. Percentage will be based on number of 
subjects in the number of subjects in the SS. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.1 
Reasons for Exclusion from 
Analysis Sets 
Enrolled 
Subjects excluded from any analysis set and corresponding 
reasons for exclusion will be listed. 
Listing 
16.2.1.2 
Subject’s Disposition 
Safety 
Disposition information from trial termination page will be 
listed. 
Listing 
16.2.1.3 
Subject Visits 
Enrolled 
Visits’ dates will be listed for the subjects from ES. 
Figures 
No. 
Name 
Analysis set 
Comments 
Figure 
15.1.1.1 
Flow Chart of Subject 
Disposition 
Enrolled 
- 
Figure 
15.1.2.1 
Flow Chart of Analysis Sets 
Enrolled 
- 
5.1.2 
Protocol Deviations 
A Per-Protocol analysis will not be carried out and therefore no Per-Protocol population is defined. 
However, protocol deviations which may have impact on method failure PI will be reviewed during 
DRM and will be classified as according to their impact. 
 
 
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Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.7.1.1 
Deviations Leading to 
Pregnancies Exclusion from 
the Method Failure Analysis 
Modified 
Full 
Analysis 
Number and percentage of pregnancies which were 
excluded from method failure analysis will be presented. 
Percentage will be based on total number of subjects in 
MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.1.7.1.2 
Deviations Leading to Cycles 
Exclusion from Analyses 
Modified 
Full 
Analysis 
Number and percentage of cycles which were excluded 
from some analysis will be presented. Percentage will be 
based on total number of cycles from subjects in MFAS. 
Data of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.4 
Protocol Deviations Reported 
by Investigators 
Enrolled 
Protocol deviation from eCRF will be listed for the subjects 
from ES. 
5.1.3 
Inclusion/Exclusion 
The trial specific inclusion/exclusion criteria are presented in the Sections 9.2 and 9.3 of the Clinical 
Trial Protocol. For each criterion, as appropriate, a response of “Yes/No” is to be obtained at Visit 1a 
(Screening) and at Visit 1b (Medication Dispensation). 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.5 
Screening Failures 
Enrolled 
Subjects who discontinued the trial during the screening 
phase prior to enrolment to the treatment phase will be 
listed. Reasons associated with the discontinuation will be 
displayed. 
Listing 
16.2.1.6 
Inclusion Criteria Not Met 
and Exclusion Criteria Met 
Enrolled 
Listing of inclusion criteria which were not met and 
exclusion criteria which were met will be presented per 
subject. 
5.2 
Demographic and Other Baseline Characteristics 
5.2.1 
Demographics 
Demographic data collected at Visit 1a will include the following: 
• Date of birth 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Other) 
• Highest level of education completed (No high school diploma, high school diploma or 
equivalent, some college, college degree or higher) 
• Years of education completed for subjects who have no high school diploma 
• Sexual activity. 
Age in years 
Age in years will be calculated as the difference between the date of birth and the date of informed 
consent/assent using the following SAS function:  
𝐴𝐴𝐴𝐴𝐴𝐴= 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹(𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌(< 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑐𝑐𝑐𝑐𝑐𝑐s𝑒𝑒𝑒𝑒𝑒𝑒>, < 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏ℎ>, ′𝐴𝐴𝐴𝐴𝐴𝐴/𝐴𝐴𝐴𝐴𝐴𝐴′)) 
Breastfeeding 
With Protocol Final Version 4.0, 16 November 2015 exclusion criteria have been changed and 
breastfeeding women were allowed to enter the study. Information on whether the subject is 
breastfeeding will be collected in the eCRF only on Protocol Final Version 4.0, 16 November 2015. 
Additional categories which will be presented in demographic and subgroup tables: 
• Breastfeeding status, defined as 
- Breastfeeding 
- Non-breastfeeding 
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• Age categories (the 1st rule), defined as 
- ≤35 years (at study enrollment) 
- >35 years (at study enrollment) 
• Age categories (the 2nd rule), defined as 
- 15-17 years (at study enrollment) 
- 18-35 years (at study enrollment) 
- >35 years (at study enrollment) 
• Non-breastfeeding women and race, defined as: 
- Non-breastfeeding women, American Indian or Alaska Native 
- Non-breastfeeding women, Asian 
- Non-breastfeeding women, Black or African-American 
- Non-breastfeeding women, Native Hawaiian or Other Pacific Islander 
- Non-breastfeeding women, White 
- Non-breastfeeding women, Other 
• Non-breastfeeding women and BMI, defined as: 
- Non-breastfeeding women, BMI < 30 kg/m2 
- Non-breastfeeding women, BMI ≥ 30 kg/m2 
- Non-breastfeeding women, 25 kg/m2 < BMI < 30 kg/m2 2 
• Sexual activity status, defined as: 
- Active 
- Non-active 
Baseline characteristics of the subjects include: 
• 
Body height (cm) at screening visit 
• 
Body weight (kg) at screening visit  
• 
BMI (kg/m2) at screening visit 
• 
Systolic blood pressure (mmHg) at screening visit 
• 
Diastolic blood pressure (mmHg) at screening visit  
• 
Pulse rate (bpm) at screening visit.  
Median value from the 1st, 2nd and 3rd measurements for systolic, diastolic blood pressure and pulse rate 
will be summarized. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.8.1.1 
Demographics 
Safety 
Default descriptive statistics for age (years) and years of 
education completed for subjects who have no high school 
diploma will be presented. Frequency tabulations for 
categories defined in Section 5.2.1 will be included. 
Percentage will be based on the number of subjects with 
non-missing data in the SS. Data of centers 104 and 120 will 
be excluded. 
Table 
15.1.8.1.2 
Demographics 
Modified 
Full 
Analysis 
Default descriptive statistics for age (years) and years of 
education completed for subjects who have no high school 
diploma will be presented. Frequency tabulations for 
categories defined in Section 5.2.1 will be included. 
Percentage will be based on the number of subjects with 
non-missing data in the MFAS. Data of centers 104 and 120 
will be excluded. 
                                                     
2 25 kg/m2 < BMI < 30 kg/m2 category is in addition to the protocol. 
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Table 
15.1.9.1.1 
Subgroups 
Safety 
Number and percentage of subjects included all subgroups 
from Section 3.2 will be provided. Percentage will be based 
on the number of subjects with non-missing data in the SS. 
Data of centers 104 and 120 will be excluded 
Table 
15.1.9.1.2 
Subgroups 
Modified 
Full 
Analysis 
Number and percentage of subjects included all subgroups 
from Section 3.2 will be provided. Percentage will be based 
on the number of subjects with non-missing data in the 
MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.1.10.1.1 
Baseline Characteristics at 
Screening 
Safety 
Body height, weight, BMI, systolic and diastolic blood 
pressure, pulse rate will be summarized for subjects in the 
SS. Data of centers 104 and 120 will be excluded. 
Table 
15.1.10.1.2 
Baseline Characteristics at 
Screening 
Modified 
Full 
Analysis 
Body height, weight, BMI, systolic and diastolic blood 
pressure, pulse rate will be summarized for subjects in the 
MFAS. Data of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.7 
Demographics 
Enrolled 
Demographics will be listed for the subjects in the ES. 
5.2.2 
Substance Use 
Substance use for the subjects include: 
• Smoking status at screening visit (Non-smoker, Current smoker, Ex-Smoker, Nicotine 
replacement therapy) 
• Smoking start date 
• Number of cigarettes per day 
• Date of smoking cessation 
• Alcohol status (Abstainer, Moderate drinker, Excessive drinker) 
Smoking duration (years)  
Smoking duration in years for current smokers will be calculated as the difference between the start 
date of smoking and the date of Visit 1a using the following SAS function: 
𝐼𝐼𝐼𝐼𝐼𝐼(𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌(< 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑡𝑡𝑒𝑒>, < 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 1𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑>, ′𝐴𝐴𝐴𝐴𝐴𝐴/𝐴𝐴𝐴𝐴𝐴𝐴′)) 
Non-smoking duration (years)  
Non-smoking duration in years for ex-smokers will be calculated as difference between smoking 
cessation date and the date of Visit 1a using the following SAS function: 
𝐼𝐼𝐼𝐼𝐼𝐼(𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌(< 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>, < 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 1𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑>, ′𝐴𝐴𝐴𝐴T/𝐴𝐴𝐴𝐴𝐴𝐴′)) 
Imputation of missing/incomplete dates:  
Incomplete dates will be imputed in the following way: 
for incomplete/missing smoking start date:  
• the first day of the month, if only day is missing  
• 1st of January, if the year is available but the day and month are missing 
• if date is completely missing smoking duration will be set to missing 
for incomplete/missing smoking cessation date: 
• the last day of the month if only the day is missing, unless the year and the month of smoking 
cessation and Visit 1a are the same then the day of Visit 1a will be imputed 
• 31st of December if only the year is available unless Visit 1a was performed at the same year 
then the day of Visit 1a will be imputed 
• for completely missing dates Visit 1a date will be imputed. 
 
 
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Pack years smoking history: 
A pack year is a unit for measuring the amount a subject has smoked over a long period of time. It will 
be calculated as follows:  
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦= 𝑛𝑛𝑛𝑛𝑚𝑚𝑏𝑏𝑏𝑏𝑏𝑏 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑
20 (1 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 ℎ𝑎𝑎𝑎𝑎 20 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑒𝑒𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡)  × 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦) 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.11.1.1 
Substance Use 
Safety 
Smoking duration, number of cigarettes per day, pack-years 
and non-smoking duration will be summarized as 
continuous data. Smoking status and alcohol status will be 
presented by means of default frequency tabulation. 
Percentage will be based on the number of subjects with 
non-missing data in the SS. Data of centers 104 and 120 will 
be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.8 
Substance Use 
Enrolled 
Information about subjects’ smoking and alcohol use will 
be listed for the subjects in the ES. 
5.2.3 
Medical History 
Medical history includes any previous relevant illnesses, conditions and hospitalization during the last 
6 months (longer in case of gynecological relevance) or any relevant ongoing (concomitant) diseases at 
Visit 1a. 
Medical history of the subjects includes: 
• Diagnosis 
• Start date 
• Stop date 
• Ongoing tick box 
• Treatment used (yes, no) 
Medical history conditions will be classified as follows: 
Prior medical history conditions are conditions which ended prior to Visit 1a. 
Current medical history conditions are conditions which are ongoing at Visit 1a, i.e. “Ongoing” was 
ticked in eCRF at screening visit or stop date is after Visit 1a. In case of partial missing stop dates, a 
disease will be considered as ongoing at Visit 1a, unless the partial date information clearly indicates 
that the disease stopped prior to Visit 1a. 
Also, medical history will be classified as current medical history condition if it stop date is 
completely missing and “Ongoing” status is not ticked. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.1.12.1.1 
Prior Medical History 
Conditions 
Safety 
Prior medical history conditions will be summarized by 
displaying counts and percentages of subjects having at 
least one prior medical history condition and will be 
presented by SOC and PT. Subjects with two or more 
occurrences of the same disease/condition (as qualified by 
its PTs) will be counted only once for the respective PT. 
Percentage will be based on the number of subjects in the 
SS. Data of centers 104 and 120 will be excluded. 
Table  
15.1.12.2.1 
Current Medical History 
Conditions 
Safety 
Current medical history conditions will be summarized by 
displaying counts and percentages of subjects having at 
least one current medical history condition and will be 
presented by SOC and PT. Subjects with two or more 
occurrences of the same disease/condition (as qualified by 
its PTs) will be counted only once for the respective PT. 
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Percentage will be based on the number of subjects in the 
SS. Data of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.9 
Medical History 
Enrolled 
Medical history conditions will be listed for the subjects 
from ES. 
5.2.4 
Gynecological History and VTE Risk Factors 
Gynecological history of the subjects includes: 
• 
Subject’s age at menarche (years) 
• 
Had the subject any deliveries (yes, no) 
• 
Date of delivery 
• 
Subject is currently breastfeeding tick 
• 
Had the subject any miscarriages (yes, no) 
• 
Date of miscarriage 
• 
Had the subject any abortions (yes, no) 
• 
Date of abortion 
Deliveries, miscarriages and abortions calcification 
Deliveries, miscarriages and abortions will be classified as follows: 
• 
No delivery/miscarriage/abortion 
• 
1 delivery/miscarriage/abortion 
• 
2 deliveries/miscarriages/abortions 
• 
3 and more deliveries/miscarriages/abortions 
Number of VTE risk factors classification 
In addition to gynecological history findings a check of individual VTE risk factors will be performed 
at screening visit: 
• Family history of thromboembolic illness (yes, no) 
• Evidence of predisposing conditions for a vascular or metabolic disease (yes, no) 
• Current smoker older than 35 years or non-smoker over 40 years old (yes, no) 
• Body weight so that BMI > 30 kg/m2 (yes, no) 
Number of VTE risk factors per subject will be classified as follows: 
• No risk factor 
• 1 risk factor 
• 2 risk factors 
• 3 and more risk factors 
• Missing 
Missing category will be set if at least one of individual VTE risk factors will be missing. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.13.1.1 
Gynecological History 
Safety 
Subject’s age at menarche will be summarized as 
continuous data. Frequency tabulations for subject with any 
deliveries/miscarriages/abortions and subjects with “No”, 1, 
2 or 3 deliveries/miscarriages/ abortions will be presented. 
Percentage will be based on the number of subjects with 
non-missing data in the SS. Data of centers 104 and 120 will 
be excluded. 
Table 
15.1.14.1.1 
VTE Risk Factors 
Safety 
Frequency tabulations for subject with or without 
corresponding VTE risk factor and subjects with “No”, 1, 2 
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SOP effective date: 18.04.2016 
Version 6 
or 3 corresponding number of VTE risk factors will be 
presented. Percentage will be based on the number of 
subjects with non-missing data in the SS. Data of centers 
104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing  
16.2.1.10 
Gynecological History 
Enrolled 
Gynecological history will be listed for the subjects from 
ES. 
Listing  
16.2.1.11 
VTE Risk Factors 
Enrolled 
VTE risk factors will be listed for the subjects from ES. 
5.2.5 
Menstrual History 
Menstrual history of the subjects includes (depending on the subject category some questions are not 
applicable): 
• Subject category (Naive User, Previous User (No hormonal contraceptives for three months or 
more), Previous user (no hormonal contraceptives for less than three months), Switcher) 
Subcategories ‘Prior users of progestin-only methods(s)’, ‘Prior user of combination hormonal 
contraception only’ will be included for “Previous User” categories. Subcategories ‘Prior users 
of progestin-only methods(s)’, ‘Prior user of combination hormonal contraception only’ will be 
reviewed by Medical Monitor. 
• Date of the first day of last menstrual bleeding before Visit 1a 
• Was menstrual bleeding during last 6 cycles before V1a regular (yes, no) 
• Mean intensity of menstrual bleeding during the last 6 cycles before Visit 1a (Light, Moderate, 
Heavy) 
• Occurrence of spotting during the last 6 cycles before Visit 1a (yes, no) 
• Occurrence of any unscheduled bleeding during the last 6 cycles before Visit 1a (yes, no) 
• Intensity of unscheduled bleeding during the last 6 cycles before Visit 1a (Light, Moderate, 
Heavy) 
• Occurrence of more than one menstrual bleeding absent during the last 6 cycles before Visit 1a 
(yes, no) 
• Occurrence of at least one complete menstrual cycle before Visit 1a (yes, no) 
Time since last menstrual bleeding (days) 
Time since the last menstrual bleeding will be calculated as follows: 
𝑇𝑇𝑖𝑖𝑖𝑖𝑖𝑖 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑)
= 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 1𝑎𝑎−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.15.1.1 
Menstrual History 
Safety 
Default summary statistics for time since last menstrual 
bleeding (days) will be summarized. Frequency tabulations 
for the rest of menstrual history variables will be presented. 
Percentage will be based on the number of subjects with 
non-missing data in the SS. Data of centers 104 and 120 will 
be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.12 
Menstrual History 
 
Menstrual history will be listed for the subjects from SS. 
5.3 
Prior and Concomitant Medications, Contraceptive Devices 
Medications in current use, relevant medications used within six months before consent/assent and 
newly started medications during the trial are to be documented including over-the-counter (OTC) 
medications and herbal remedies. In addition, changes of therapy (including changes of frequency) 
during the trial are to be documented in the eCRF. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 36 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 35 of 71 
SOP effective date: 18.04.2016 
Version 6 
The following information is collected: 
• Drug unique number 
• Medication (trade name)/Therapy/Device 
• Indication (if medication is used as a contraceptive, a checkbox “Contraceptive (incl. device)” is 
checked) 
• Dose per intake 
• Units 
• Frequency 
• Route 
• Start Date 
• Stop Date/Ongoing (checkbox “Ongoing” is checked) 
For subjects with at least 1 intake of IMP, medications and therapies are classified as ‘prior’ or 
‘concomitant’ based on start/stop dates: 
Prior medications 
Prior medications are defined as medications which stopped before the first intake of IMP (Day 1 of 
Cycle 1). 
Concomitant medications 
Concomitant medications are defined as medications taken during the treatment period. This includes 
any medication when: 
• the start date is on or after the first IMP intake and on or before the last IMP intake 
or 
• the start date is before the first IMP intake and the stop date is after or on the first IMP intake day 
or 
• the start date is before the first IMP intake and the tick box “Ongoing” is marked. 
Where only partial dates are present, the month and/or year may be sufficient alone for classification of 
therapies but in cases where this is not possible it will be treated as concomitant. 
The number and percentage of subjects with at least one medication within each ATC 2nd level 
subgroup and preferred drug name will be presented for the respective set. The ATC 2nd level 
subgroups and preferred drug name within ATC 2nd level subgroup will be ordered alphabetically. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.16.1.
1 
Prior Medications, Therapies 
and Contraception 
Safety 
The number and percentage of subjects taking prior 
medications will be presented by ATC 2nd level subgroup 
and preferred medication name for subjects in the SS. Data 
of centers 104 and 120 will be excluded. 
Table 
15.1.16.2.
1 
Concomitant Medications, 
Therapies and Contraception 
Safety 
The number and percentage of subjects taking concomitant 
medications will be presented by ATC 2nd level subgroup 
and preferred medication name for subjects in the SS. Data 
of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing  
16.2.1.13 
Prior and Concomitant 
Medications, Therapies and 
Contraception 
Enrolled 
Prior and concomitant medications, therapies and 
contraception will be listed for the subjects from ES. 
 
 
 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 37 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
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SOP effective date: 18.04.2016 
Version 6 
5.4 
Exposure to IMP and Compliance 
5.4.1 
Exposure to IMP 
Exposure data include:  
• Date of the first IMP intake (subject's diary) 
• Date of the last IMP intake 
• Date of IMP dispensation 
• Number of white tablets dispensed 
• Number of green tablets dispensed 
• Date of IMP collection 
• Number of white tablets collected 
• Number of green tablets collected 
• Numbers of tablets taken (subject's diary) 
• Date of IMP intake with time in hours and minutes (subject's diary) 
Exposure data are derived from appropriate eCRF pages and diary. If the 1st regular IMP intake (variable 
PILDTC in subject's diary) was not entered, but the first IMP intake (variable BPILDTC in subject's 
diary) was entered then the 1st regular IMP intake will be derived from BPILDTC by adding time 
“T00:00”. 
Derived variables: 
Overall treatment duration will be calculated as follows: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
= 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝐼𝐼𝐼𝐼𝐼𝐼 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝐼𝐼𝐼𝐼𝐼𝐼 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖+ 1. 
Cumulative exposure will be categorized as: 
- 
≥ 28 days 
- 
≥ 84 days 
- 
≥ 168 days 
- 
≥ 252 days 
Missing Entries of IMP Intake in Treatment Diary 
Missing IMP intake entries will be classified as total number of missing entries and consecutive missing 
entries per respective cycle. Total and consecutive number of missing entries will be categorized as: 
• Total missing entries over up to 13 cycles 
- 
0-2 missing entries 
- 
3-5 missing entries 
- 
6-8 missing entries 
- 
9 or more missing entries 
• Total missing entries per separate cycle 
- 
0 missing entries 
- 
1 missing entries 
- 
2 missing entries 
- 
3 missing entries 
- 
4 or more missing entries 
• Active tablet free interval. Active tablet free interval is >48h tablet free interval during the second 
IMP intake till day 24 of each cycle or >144h interval between the last IMP intake and the first 
IMP intake in consecutive cycles. Tablet free interval calculation will not take into account cycle 
days 25-28. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 38 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 37 of 71 
SOP effective date: 18.04.2016 
Version 6 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.17.1.1 
Exposure to Investigational 
Medicinal Product 
Safety 
Default summary statistics for the overall treatment 
duration in days will be presented. Default frequency 
tabulation for cumulative overall treatment duration will be 
displayed. Percentage will be based on the number of 
subjects in the SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.1.18.1.1 
Number of Subjects with at 
Least One Missing Entry of 
IMP Intake in Treatment 
Diary by Treatment Cycle 
and Overall 
Safety 
Numbers and percentages of subjects having at least one 
missing IMP intake will be presented. Number of missing 
IMP intakes will be presented by treatment cycle and 
overall. Percentage will be based on the number of subjects 
in respective cycle. Data of centers 104 and 120 will be 
excluded. 
Table 
15.1.19.1.1 
Number of Subjects with 
Gaps between Two Active 
Tablet Intakes of More Than 
48/144 Hours by Treatment 
Cycle and Overall 
Safety 
Numbers and percentages of subjects having >48h (or 144h 
for the 1st IMP intake) active tablet free interval. Number of 
>48h (or 144h for the 1st IMP intake) active tablet free 
interval will be presented by treatment cycle and overall. 
Percentage will be based on the number of subjects in 
respective cycle. Data of centers 104 and 120 will be 
excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.14 
Drug Accountability 
Enrolled 
Dispensation and collection of IMP will be listed for the 
subjects from ES. 
5.4.2 
Compliance to IMP 
Subject’s compliance to the IMP will be checked throughout the trial by the investigator. It will be 
based on the dispensation and retrieval of medication and subjects’ records in treatment diary. 
Subjects will record their tablet intakes in the treatment diary. 
The subject’s overall treatment compliance according to eCRF records will be assessed by the tablet 
count and will be calculated according to the following formula: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒) (%)
= 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
𝑂𝑂𝑣𝑣𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
 × 100%. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.1.20.1.1 
Compliance to 
Investigational Medicinal 
Product 
Safety 
Default summary statistics for overall treatment compliance 
according to eCRF records will be presented. Data of 
centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.1.15 
Treatment Compliance 
According to Drug 
Accountability 
Enrolled 
Treatment compliance will be listed for the subjects from 
ES. 
5.5 
Efficacy Analysis 
Primary and secondary efficacy analysis will be based on calculations of the PI in several different cases 
for non-breastfeeding women. The general formula of PI is 
𝑃𝑃𝑃𝑃 (< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>) = ∑𝑜𝑜𝑜𝑜-𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}
#{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}
 × 1300. 
A two-sided 95% CI for the PI will be calculated assuming that events of pregnancy have a Poisson 
distribution. The CI will be calculated using the following equations from Gerlinger et al. [4]: 
𝐶𝐶𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙൫𝑃𝑃𝑃𝑃(< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>)൯
=
1300
#{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>} × 𝐶𝐶𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙൫#൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ൯, 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 39 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 38 of 71 
SOP effective date: 18.04.2016 
Version 6 
𝐶𝐶𝐶𝐶𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢൫𝑃𝑃𝑃𝑃(< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>)൯
=
1300
#{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>} × 𝐶𝐶𝐶𝐶𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢൫#൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ൯, 
where 
𝐶𝐶𝐶𝐶𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙൫#൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ൯
= 0.5𝜒𝜒2൫0.025; 2 × #൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ൯, 
 
𝐶𝐶𝐶𝐶𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢൫#൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ൯
= 0.5𝜒𝜒2൫0.025; 2 × #൛𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{< 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐>}ൟ+ 1൯, 
where 𝜒𝜒2(𝛼𝛼; 𝑛𝑛) = 𝛼𝛼-𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄 𝑜𝑜𝑜𝑜 𝜒𝜒2-𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑝𝑝𝑝𝑝r𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑛𝑛. 
The following information from Pregnancy Notification forms will be taken: 
- Subject ID number 
- Estimated date of conception 
- Method(s) Used to Estimate Conception Date 
Efficacy analysis definitions 
Term 
Definition 
Confirmed 
pregnancy 
Subject reported a positive urine home pregnancy test and the pregnancy was 
confirmed by qualitative urine pregnancy test (ß-hCG) and quantitative serum 
pregnancy test (ß-hCG). 
Suspected, non-
confirmed 
pregnancy 
Subject reported a positive urine home pregnancy test but confirmatory 
qualitative urine pregnancy test (ß-hCG) and/or quantitative serum pregnancy test 
(ß-hCG) are missing. 
Suspected, 
subject 
confirmed not 
pregnant 
Subject reported a positive urine home pregnancy test but confirmatory 
qualitative urine pregnancy test (ß-hCG) and/or quantitative serum pregnancy test 
(ß-hCG) are negative. 
On-drug 
pregnancy 
An on-drug pregnancy includes all conceptions that occur from Day 1 (the 
initiation of study medication) through seven days after the final tablet (active or 
placebo) is taken.  
Method failure 
pregnancy* 
All on-drug pregnancies of women who used the IMP correctly. 
Pregnancies are to be excluded from the calculation if in medication cycles of 
conception or in the previous medication cycles depending on the date of 
conception: 
- not all active tablets are taken (based on returned medication, recordings in 
the e-diary and non-compliance based on DRSP levels, if necessary) 
- there is an active tablet free interval between the previous medication cycle 
and the medication cycle of conception. Tablet free interval will be 
determined by record from treatment diary. 
- vomiting or diarrhea is documented 
- administration of prohibited prior or concomitant therapy as detailed in 
Section 10.7 of the Clinical Trial Protocol is documented 
Exposure cycles 
28-day cycles, where at least one treatment diary entry of IMP intake is available. 
In addition, a cycle will be an exposure cycle if the subject become pregnant 
during this cycle regardless this cycle was a 28-day cycle or not. 
Evaluable cycle 
Cycles are exposure cycles with intercourse without back-up contraceptive at 
least once per cycle based on electronic diary question ’Did you have sexual 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 40 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 39 of 71 
SOP effective date: 18.04.2016 
Version 6 
intercourse since the beginning of the cycle?’ and answered with: ’Yes I had 
sexual intercourse without additional contraception’. 
Also, cycle is to be defined as evaluable if: 
- Subject become pregnant at the respective cycle regardless back-up 
contraception was used or not. 
- Cycle has missing answer about intercourse or answered “I had NO sexual 
intercourse at all” but subject become pregnant at the respective cycle. 
Cycle will not be defined as evaluable if subject did not become pregnant and: 
- The question was answered with ‘Yes I had sexual intercourse with 
additional contraception’. 
- Cycles with NO intercourse. 
- Cycle has missing answer about intercourse. 
Perfect cycle* 
Evaluable cycles which have no: 
- >48h tablet free interval during the second IMP intake till day 24 of each 
cycle or >144h interval between the last IMP intake and the first IMP intake 
in consecutive cycles. Tablet free interval calculation will not take into 
account cycle days 25-28. 
- 4 or more days with forgotten tablets intake during 1-24 cycle days. 
- Protocol deviations having effect on this cycle. 
* Method failure pregnancies will be only those which occurred during the perfect cycles, e.g., if 
pregnancy will contradict method failure definition then the cycle in which pregnancy occurred could 
not be called perfect cycle and vice versa. 
5.5.1 
Primary Efficacy Analysis 
Analysis of the primary efficacy variable defined as PI based on evaluable cycles in non-breastfeeding 
women aged ≤ 35 years will be performed for the MFAS. 
𝑃𝑃𝑃𝑃 (𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐) = ∑𝑜𝑜𝑜𝑜-𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
#{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
 × 1300. 
Respective two-sided 95% CI for PI based on evaluable cycles will be calculated according to formula 
in Section 5.5. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.2.1.1.1 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented. Table analysis will be based on MFAS. Data of 
centers 104 and 120 will be excluded. 
5.5.2 
Secondary Efficacy Analysis 
Secondary Efficacy Analysis will be based on non-breastfeeding women. Also, analysis will be 
performed in BMI subgroups. 
Overall PI 
Overall PI will be calculated based on exposure cycles for all women, aged ≤ 35 years and aged > 35 
years: 
𝑃𝑃𝑃𝑃 (𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐) = ∑𝑜𝑜𝑜𝑜-𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
#{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
 × 1300. 
Respective two-sided 95% CI for overall PI will be calculated according to formula in Section 5.5. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 41 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 40 of 71 
SOP effective date: 18.04.2016 
Version 6 
PI for method failures 
PI for method failures will be calculated based on perfect cycles for all women, aged ≤ 35 years and 
aged > 35 years. Number of pregnancies will be calculated according to method failure definition: 
𝑃𝑃𝑃𝑃 (𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓) = ∑𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
#{𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
 × 1300. 
Respective two-sided 95% CI for PI for method failures will be calculated according to formula in 
Section 5.5. 
Evaluable cycles PI 
Evaluable cycles PI will be calculated based on evaluable cycles for all women and women aged > 35 
years: 
𝑃𝑃𝑃𝑃 (𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐) = ∑𝑜𝑜𝑜𝑜-𝑑𝑑𝑑𝑑𝑑𝑑𝑔𝑔 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝∈{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
#{𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐}
 × 1300. 
Respective two-sided 95% CI for PI based on evaluable cycles will be calculated according to formula 
in Section 5.5. 
Life table analysis for pregnancy rate 
Method failure life table analysis and life table analysis on evaluable cycles will be performed in 
all women, women aged ≤ 35 and > 35 years in order to have the pregnancy rate at each cycle and 
cumulative pregnancy rates for 6 and 13 cycles. 
Cumulative pregnancy rate will be calculated by using the PROC LIFETEST procedure: 
PROC LIFETEST DATA=<data set> METHOD=KM OUTSURV=CL CONFTYPE=LOG; 
TIME <time variable>*< censorship flag>(1); 
RUN; 
The Kaplan-Meier method will be used to estimate the cumulative pregnancy ratio. Logarithmic 
transformation will be used for 95% CI of the pregnancy rate. The period from the start of treatment 
until the pregnancy will be the time variable in this analysis. Subjects who did not become pregnant 
will be censored at their time of the last intake of IMP. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.2.1.2.1 
Overall Pearl Index in Non-
Breastfeeding Women (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented. Table analysis will 
be based on MFAS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.1.2.2 
Overall Pearl Index in Non-
Breastfeeding Women Aged 
≤ 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented. Table analysis will 
be based on MFAS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.1.2.3 
Overall Pearl Index in Non-
Breastfeeding Women Aged 
> 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented. Table analysis will 
be based on MFAS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.1.2.4
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI Subgroup (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented by BMI subgroup. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be excluded. 
Table 
15.2.1.2.5
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI Subgroup (Only 
Confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented by BMI subgroup. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be included. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 42 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 41 of 71 
SOP effective date: 18.04.2016 
Version 6 
Table 
15.2.1.2.6
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI Subgroup (Confirmed 
and Suspected, Non-
confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented by BMI subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.1.2.7
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI Subgroup (Confirmed 
and Suspected, Non-
confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented by BMI subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be included. 
Table 
15.2.1.2.8
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
Weight Subgroup (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented by weight 
subgroup. Table analysis will be based on MFAS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.2.1.2.9
_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
Weight Subgroup (Only 
Confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented by weight 
subgroup. Table analysis will be based on MFAS. Data of 
centers 104 and 120 will be included. 
Table 
15.2.1.2.1
0_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
Weight Subgroup (Confirmed 
and Suspected, Non-
confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented by weight subgroup. Table analysis will be 
based on MFAS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.1.2.1
1_add 
Overall Pearl Index in Non-
Breastfeeding Women by 
Weight Subgroup (Confirmed 
and Suspected, Non-
confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented by weight subgroup. Table analysis will be 
based on MFAS. Data of centers 104 and 120 will be 
included. 
Table 
15.2.1.3.1 
Pearl Index for Method 
Failures in Non-Breastfeeding 
Women (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed pregnancies in the 
perfect cycles will be presented. Number of perfect cycles 
as well as PI and two-sided 95% CI will be presented. Table 
analysis will be based on MFAS. Data of centers 104 and 
120 will be excluded. 
Table 
15.2.1.3.2 
Pearl Index for Method 
Failures in Non-Breastfeeding 
Women Aged ≤ 35 Years 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed pregnancies in the 
perfect cycles will be presented. Number of perfect cycles 
as well as PI and two-sided 95% CI will be presented. Table 
analysis will be based on MFAS. Data of centers 104 and 
120 will be excluded. 
Table 
15.2.1.3.3 
Pearl Index for Method 
Failures in Non-Breastfeeding 
Women Aged > 35 Years 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed pregnancies in the 
perfect cycles will be presented. Number of perfect cycles 
as well as PI and two-sided 95% CI will be presented. Table 
analysis will be based on MFAS. Data of centers 104 and 
120 will be excluded. 
Table 
15.2.1.4.1 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed pregnancies in the 
evaluable cycles will be presented. Number of evaluable 
cycles as well as PI and two-sided 95% CI will be presented. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be excluded. 
Table 
15.2.1.4.2 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
> 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed pregnancies in the 
evaluable cycles will be presented. Number of evaluable 
cycles as well as PI and two-sided 95% CI will be presented. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be excluded. 
Table 
15.2.1.4.3
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years (Only Confirmed 
Pregnancies, Including Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented. Table analysis will be based on MFAS. Data of 
centers 104 and 120 will be included. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 43 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 42 of 71 
SOP effective date: 18.04.2016 
Version 6 
Table 
15.2.1.4.4
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years (Confirmed and 
Suspected, Non-confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented. Table analysis will be 
based on MFAS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.1.4.5
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years (Confirmed and 
Suspected, Non-confirmed 
Pregnancies, Including Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented. Table analysis will be 
based on MFAS. Data of centers 104 and 120 will be 
included. 
Table 
15.2.1.4.6
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by BMI Subgroup 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented by BMI subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.1.4.7
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by BMI Subgroup 
(Only Confirmed 
Pregnancies, Including Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage confirmed of on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented by BMI subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be included. 
Table 
15.2.1.4.8
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by BMI Subgroup 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented by BMI subgroup. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be excluded. 
Table 
15.2.1.4.9
_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by BMI Subgroup 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented by BMI subgroup. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be included. 
Table 
15.2.1.4.1
0_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by Weight 
Subgroup (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented by weight subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.1.4.1
1_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by Weight 
Subgroup (Only Confirmed 
Pregnancies, Including Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage confirmed of on-drug pregnancies 
in the evaluable cycles will be presented. Number of 
evaluable cycles as well as PI and two-sided 95% CI will be 
presented by weight subgroup. Table analysis will be based 
on MFAS. Data of centers 104 and 120 will be included. 
Table 
15.2.1.4.1
2_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by Weight 
Subgroup (Confirmed and 
Suspected, Non-confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented by weight subgroup. 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be excluded. 
Table 
15.2.1.4.1
3_add 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women Aged 
≤ 35 Years by Weight 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies in the evaluable cycles will 
be presented. Number of evaluable cycles as well as PI and 
two-sided 95% CI will be presented by weight subgroup. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 44 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 43 of 71 
SOP effective date: 18.04.2016 
Version 6 
Subgroup (Confirmed and 
Suspected, Non-confirmed 
Pregnancies, Including Sites 
104 and 120) 
Table analysis will be based on MFAS. Data of centers 104 
and 120 will be included. 
Table 
15.2.2.1.1 
Overall Pregnancy Rate Life 
Table in Non-Breastfeeding 
Women (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the confirmed on-drug pregnancy rate at 
each cycle and cumulative pregnancy rates for 6 and 13 
cycles will be presented. Table analysis will be based on 
MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.2.1.2 
Overall Pregnancy Rate Life 
Table in Non-Breastfeeding 
Women Aged ≤ 35 Years 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the confirmed on-drug pregnancy rate at 
each cycle and cumulative pregnancy rates for 6 and 13 
cycles will be presented. Table analysis will be based on 
MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.2.1.3 
Overall Pregnancy Rate Life 
Table in Non-Breastfeeding 
Women Aged > 35 Years 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the confirmed on-drug pregnancy rate at 
each cycle and cumulative pregnancy rates for 6 and 13 
cycles will be presented. Table analysis will be based on 
MFAS. Data of centers 104 and 120 will be excluded. 
Table 
15.2.2.2.1 
Evaluable Cycles Pregnancy 
Rate Life Table in Non-
Breastfeeding Women (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Life table with the evaluable cycle pregnancy rate at each 
cycle and cumulative pregnancy rates for 6 and 13 cycles 
will be presented. Table analysis will be based on MFAS 
and confirmed pregnancies. Data of centers 104 and 120 
will be excluded. 
Table 
15.2.2.2.2 
Evaluable Cycles Pregnancy 
Rate Life Table in Non-
Breastfeeding Women Aged 
≤ 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the evaluable cycle pregnancy rate at each 
cycle and cumulative pregnancy rates for 6 and 13 cycles 
will be presented. Table analysis will be based on MFAS 
and confirmed pregnancies. Data of centers 104 and 120 
will be excluded. 
Table 
15.2.2.2.3 
Evaluable Cycles Pregnancy 
Rate Life Table in Non-
Breastfeeding Women Aged 
> 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the evaluable cycle pregnancy rate at each 
cycle and cumulative pregnancy rates for 6 and 13 cycles 
will be presented. Table analysis will be based on MFAS 
and confirmed pregnancies. Data of centers 104 and 120 
will be excluded. 
Table 
15.2.2.3.1 
Method Failure Life Table in 
Non-Breastfeeding Women 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full analysis 
Life table with the perfect cycle pregnancy rate at each cycle 
and cumulative pregnancy rates for 6 and 13 cycles will be 
presented. Table analysis will be based on MFAS and 
confirmed pregnancies. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.2.3.2 
Method Failure Life Table in 
Non-Breastfeeding Women 
Aged ≤ 35 Years (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Life table with the perfect cycle pregnancy rate at each cycle 
and cumulative pregnancy rates for 6 and 13 cycles will be 
presented. Table analysis will be based on MFAS and 
confirmed pregnancies. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.2.3.3 
Method Failure Life Table in 
Non-Breastfeeding Women 
Aged > 35 Years (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Life table with the perfect cycle pregnancy rate at each cycle 
and cumulative pregnancy rates for 6 and 13 cycles will be 
presented. Table analysis will be based on MFAS and 
confirmed pregnancies. Data of centers 104 and 120 will be 
excluded. 
Table 
15.2.3.1.1
_add 
Overall Pearl Index in Non-
Breastfeeding Women 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented. Table analysis will be based on MFAS. Data 
of centers 104 and 120 will be included. 
Table 
15.2.3.1.2
_add 
Overall Pearl Index in Non-
Breastfeeding Women (Only 
Confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed on-drug pregnancies 
will be presented. Number of exposure cycles as well as PI 
and two-sided 95% CI will be presented. Table analysis will 
be based on MFAS. Data of centers 104 and 120 will be 
included. 
Table 
15.2.3.1.3
_add 
Overall Pearl Index in Non-
Breastfeeding Women 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full analysis 
Number and percentage of confirmed and suspected, non-
confirmed on-drug pregnancies will be presented. Number 
of exposure cycles as well as PI and two-sided 95% CI will 
be presented. Table analysis will be based on MFAS. Data 
of centers 104 and 120 will be excluded. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
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Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
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Version 6 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.2.1 
Pregnancy Determination 
Enrolled 
All on study pregnancies will be listed. 
Listing 
16.2.2.2 
Pregnancy Outcome 
Enrolled 
All on study pregnancies with the outcome results will be 
listed. 
Listing 
16.2.2.3 
Subjects’ Decision to Become 
Pregnant 
Enrolled 
Information about subjects’ decision to become pregnant 
will be listed. 
Figures 
No. 
Name 
Analysis set 
Comments 
Figure 
15.2.1.1_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Race (Black or 
African-American vs White) 
(Only Confirmed 
Pregnancies, Excluding Sites 
104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed on-drug 
pregnancies will be presented by race and BMI subgroups. 
Data of centers 104 and 120 will be excluded. 
Figure 
15.2.1.2_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Race (Black or 
African-American vs White) 
(Only Confirmed 
Pregnancies, Including Sites 
104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed on-drug 
pregnancies will be presented by race and BMI subgroups. 
Data of centers 104 and 120 will be included. 
Figure 
15.2.1.3_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Race (Black or 
African-American vs White) 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed and 
suspected, non-confirmed on-drug pregnancies will be 
presented by race and BMI subgroups. Data of centers 104 
and 120 will be excluded. 
Figure 
15.2.1.4_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Race (Black or 
African-American vs White) 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed and 
suspected, non-confirmed on-drug pregnancies will be 
presented by race and BMI subgroups. Data of centers 104 
and 120 will be included. 
Figure 
15.2.2.1_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Ethnicity (Only 
Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed on-drug 
pregnancies will be presented by ethnicity and BMI 
subgroups. Data of centers 104 and 120 will be excluded. 
Figure 
15.2.2.2_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Ethnicity (Only 
Confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed and 
suspected, non-confirmed on-drug pregnancies will be 
presented by ethnicity and BMI subgroups. Data of centers 
104 and 120 will be included. 
Figure 
15.2.2.3_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Ethnicity 
(Confirmed and Suspected, 
Non-Confirmed Pregnancies, 
Excluding Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed and 
suspected, non-confirmed on-drug pregnancies will be 
presented by ethnicity and BMI subgroups. Data of centers 
104 and 120 will be included. 
Figure 
15.2.2.4_a
dd 
Overall Pearl Index in Non-
Breastfeeding Women by 
BMI and Ethnicity 
(Confirmed and Suspected, 
Non-confirmed Pregnancies, 
Including Sites 104 and 120) 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed on-drug 
pregnancies will be presented by ethnicity and BMI 
subgroups. Data of centers 104 and 120 will be excluded. 
Figure 
15.2.3.1_a
dd 
Pearl Index Based on 
Evaluable Cycles in Non-
Breastfeeding Women by 
BMI and Race (Black or 
African-American vs White) 
(Only Confirmed 
Modified 
Full 
Analysis 
Diagram showing the PI and 95%CI of confirmed on-drug 
pregnancies will be presented by race and BMI subgroups. 
Data of centers 104 and 120 will be excluded. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 46 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
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Page 45 of 71 
SOP effective date: 18.04.2016 
Version 6 
Pregnancies, Excluding Sites 
104 and 120) 
5.6 
Safety Analysis 
Analysis of safety endpoints will be conducted using the SS only. 
5.6.1 
Adverse Events 
AE data includes:  
• AE ID number 
• AE name 
• Start date 
• Stop date  
• Severity (mild, moderate, severe) 
• Outcome (recovered/resolved, recovered/resolved with sequelae, not recovered/not resolved, 
recovering/resolving, fatal, unknown) 
• Action taken with IMP (dose not changed, drug interrupted, drug withdrawn, not applicable, 
unknown) 
• Relationship to IMP (unrelated, unlikely, possible, probable, definite) 
• Other actions (none, medication required, tests required, hospitalization required or prolonged, 
other) 
• Serious (yes, no) 
The maximum severity (intensity) of the AE will be categorized by the investigator as follows:  
• Mild: a type of AE that is usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living.  
• Moderate: a type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
• Severe: a type of AE that requires intensive therapeutic intervention. The event interrupts usual 
activities of daily living, or significantly affects clinical status. The event possesses a significant 
risk of harm to the research participant and hospitalization may be required. 
AEs severity will be defined as “Unknown” if severity assessment is missing. 
Drug relationship of adverse events 
The relationship of an AE to the IMP is a clinical decision by the investigator based on all available 
information and is graded as follows: 
• Unrelated: A clinical event with no evidence of any causal relationship. 
• Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to 
drug administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
• Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the drug, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
• Probable: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfil this definition. 
• Definite: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
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plausible. The event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
Related AEs include the categories “possible”, “probable” and “definite”. 
Unrelated AEs include the categories “unrelated” and “unlikely”. 
The relationship of an AE to the IMP will be defined as “Unknown” if relationship grade assessment is 
missing. 
Treatment Emergent Adverse Events 
An AE that emerges during treatment having been absent prior to treatment or worsens relative to the 
pre-treatment state is defined as treatment emergent adverse event (TEAE). All AEs with onset or 
worsening after first intake of IMP until 10 days after last intake of IMP are defined as treatment 
emergent. 
Where only partial dates are present, the month and/or year may be sufficient alone for assignment of 
treatment emergent AEs but in cases where this is not possible these AEs will be considered as treatment 
emergent. 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• Death 
• A life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• Congenital anomaly/birth defect 
Adverse Events of Special Interest 
Adverse events of special interest will be defined as hyperkalemia and venous thromboembolism 
events. Hyperkalemia will be identified as AEs with preferred terms “Hyperkalaemia” and “Blood 
potassium increased”. Venous thromboembolism will be identified as embolic and thrombotic venous 
events and assignments will be handled by Medical Monitors after database closure. 
Adverse events leading to trial termination  
Defined as those events where “Action taken with investigational medicinal product” is indicated as 
“drug withdrawn”. 
All AEs will be summarized by calculating the number and percent of subjects with AEs as well as 
number of events. TEAEs will be summarized by calculating the number and percent of subjects with 
AEs by preferred term and system organ class. Also, TEAEs will be summarized by severity and 
relationship to treatment. Number and percent of subjects with serious TEAEs, TEAEs leading to trial 
termination and TEAEs of special interest will be provided by MedDRA PT and SOC. 
Summaries of AEs will be repeated for defined subgroups. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.3.1.1.1 
Summary of Adverse Events 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.1.2 
Summary of Adverse Events 
by Weight Subgroup 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 48 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
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Version 6 
Table 
15.3.1.1.3 
Summary of Adverse Events 
by BMI Subgroup 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.1.4 
Summary of Adverse Events 
by Blood Pressure Subgroup 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.1.5 
Summary of Adverse Events 
by Race Subgroup 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.1.6 
Summary of Adverse Events 
by Ethnicity Subgroup 
Safety 
An overall summary of AEs will be provided for subjects in 
the SS. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.2.1 
Incidence of TEAEs 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.2.2 
Incidence of TEAEs by 
Weight Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.2.3 
Incidence of TEAEs by BMI 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.2.4 
Incidence of TEAEs by Blood 
Pressure Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.2.5 
Incidence of TEAEs by Race 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.2.6 
Incidence of TEAEs by 
Ethnicity Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
will be summarized by PT nested within SOC. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.1.3.1 
Incidence of TEAEs by 
Relationship 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.3.2 
Incidence of TEAEs by 
Relationship by Weight 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.3.3 
Incidence of TEAEs by 
Relationship by BMI 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.3.4 
Incidence of TEAEs by 
Relationship by Blood 
Pressure Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.3.5 
Incidence of TEAEs by 
Relationship by Race 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.3.6 
Incidence of TEAEs by 
Relationship by Ethnicity 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
relationship to study medication will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.4.1 
Incidence of TEAEs by Worst 
Severity 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.4.2 
Incidence of TEAEs by Worst 
Severity by Weight Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 49 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
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Version 6 
Table 
15.3.1.4.3 
Incidence of TEAEs by Worst 
Severity by BMI Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.4.4 
Incidence of TEAEs by Worst 
Severity by Blood Pressure 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.4.5 
Incidence of TEAEs by Worst 
Severity by Race Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.4.6 
Incidence of TEAEs by Worst 
Severity by Ethnicity 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs by 
worst severity will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.5.1 
Incidence of Serious TEAEs 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.5.2 
Incidence of Serious TEAEs 
by Weight Subgroup 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.5.3 
Incidence of Serious TEAEs 
by BMI Subgroup 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.5.4 
Incidence of Serious TEAEs 
by Blood Pressure Subgroup 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.5.5 
Incidence of Serious TEAEs 
by Race Subgroup 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.5.6 
Incidence of Serious TEAEs 
by Ethnicity Subgroup 
Safety 
The number and percentage of subjects reporting serious 
TEAEs will be summarized by PT nested within SOC. 
Percentage will be based on SS. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.1.6.1 
Incidence of TEAEs Leading 
to Trial Termination 
Safety 
The number and percentage subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.6.2 
Incidence of TEAEs Leading 
to Trial Termination by 
Weight Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.6.3 
Incidence of TEAEs Leading 
to Trial Termination by BMI 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.6.4 
Incidence of TEAEs Leading 
to Trial Termination by Blood 
Pressure Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.6.5 
Incidence of TEAEs Leading 
to Trial Termination by Race 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.6.6 
Incidence of TEAEs Leading 
to Trial Termination by 
Ethnicity Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs 
leading to trial termination will be summarized by PT 
nested within SOC. Percentage will be based on SS. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.1.7.1 
Incidence of TEAEs of 
Special Interest 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 50 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
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SOP effective date: 18.04.2016 
Version 6 
Table 
15.3.1.7.2 
Incidence of TEAEs of 
Special Interest by Weight 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.7.3 
Incidence of TEAEs of 
Special Interest by BMI 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.7.4 
Incidence of TEAEs of 
Special Interest by Blood 
Pressure Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.7.5 
Incidence of TEAEs of 
Special Interest by Race 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.7.6 
Incidence of TEAEs of 
Special Interest by Ethnicity 
Subgroup 
Safety 
The number and percentage of subjects reporting TEAEs of 
special interest will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.1 
Incidence of Related Serious 
TEAEs 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.2 
Incidence of Related Serious 
TEAEs by Weight Subgroup 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.3 
Incidence of Related Serious 
TEAEs by BMI Subgroup 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.4 
Incidence of Related Serious 
TEAEs by Blood Pressure 
Subgroup 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.5 
Incidence of Related Serious 
TEAEs by Race Subgroup 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Table 
15.3.1.8.6 
Incidence of Related Serious 
TEAEs by Ethnicity 
Subgroup 
Safety 
The number and percentage of subjects reporting related 
serious TEAEs will be summarized by PT nested within 
SOC. Percentage will be based on SS. Data of centers 104 
and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.3.1 
Adverse Event: General 
Enrolled 
All AEs information will be listed. 
Listing 
16.2.3.2 
Adverse Event: MedDRA 
Coding 
Enrolled 
All AEs will be listed by preferred term nested within 
system organ class. 
Listing 
16.2.3.3 
Serious Adverse Event 
Enrolled 
All SAEs information will be listed. 
Listing 
16.2.3.4 
TEAEs Leading to Trial 
Termination 
Enrolled 
All TEAEs Leading to Trial Termination information will 
be listed. 
Listing 
16.2.3.5 
TEAEs of Special Interest 
Enrolled 
All TEAEs of Special Interest information will be listed. 
5.6.2 
Vital Signs 
Vital signs include blood pressure, pulse, height, body weight and BMI data. 
Summary statistics for parameter values and absolute parameter change values from Baseline to Visit 
6/EDV will be provided for each visit as described in Sections 4.1 and 4.6. 
 
 
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Blood pressure and pulse 
Blood pressure and pulse data include: 
• Time of first/second/third measurement 
• Pulse (bpm) 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
Blood pressure and pulse will be measured in a sitting position at all visits from V1a to V6/EDV, after 
the subject has rested for at least five minutes. 
Median value from the 1st, 2nd and 3rd measurements for systolic, diastolic blood pressure and pulse rate 
will be summarized in analysis tables. All values from the 1st, 2nd and 3rd measurements for systolic, 
diastolic blood pressure and pulse rate will be provided in a listing. 
Height, body weight and body mass index 
Height, body weight and body mass index data include: 
• Weight (kg) 
• Height (cm) 
• Body mass index (kg/m2) 
At V1a, height will be measured in all subjects. At V1b to V6 height only has to be determined in 
adolescent subjects. Body weight will be measured at all visits from V1a to V6/EDV, lightly dressed 
and without shoes. The determined body weight has to be calculated as BMI. The BMI as a measure 
for the physical constitution of a ≥18-year-old subject is defined as follows: 
𝐵𝐵𝑀𝑀𝑀𝑀 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑋𝑋 (𝑘𝑘𝑘𝑘/𝑚𝑚2) = 
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑋𝑋 (𝑘𝑘𝑘𝑘)
(𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡 𝑎𝑎𝑎𝑎 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 1𝑎𝑎 (𝑐𝑐𝑐𝑐)/100)2 . 
The BMI as a measure for the physical constitution of a <18-year-old subject is defined as follows: 
BMI at Visit X (kg/m2) = 
Body weight at Visit X (kg)
(Body height at Visit X (cm)/100)2 . 
Summary of vital signs will be repeated for defined subgroups. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.3.2.1.1 
Summary of Vital Signs 
Safety 
Vital signs parameters will be summarized descriptively 
including change from baseline at each visit where 
assessments were made. Data of centers 104 and 120 will 
be excluded. 
Table 
15.3.2.1.2 
Summary of Vital Signs by 
Weight Subgroup 
Safety 
Vital signs parameters will be summarized descriptively by 
weight subgroup including change from baseline at each 
visit where assessments were made. Data of centers 104 and 
120 will be excluded. 
Table 
15.3.2.1.3 
Summary of Vital Signs by 
BMI Subgroup 
Safety 
Vital signs parameters will be summarized descriptively by 
BMI subgroup including change from baseline at each visit 
where assessments were made. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.2.1.4 
Summary of Vital Signs by 
Blood Pressure Subgroup 
Safety 
Vital signs parameters will be summarized descriptively by 
blood pressure subgroup including change from baseline at 
each visit where assessments were made. Data of centers 
104 and 120 will be excluded. 
Table 
15.3.2.1.5 
Summary of Vital Signs by 
Race Subgroup 
Safety 
Vital signs parameters will be summarized descriptively by 
race subgroup including change from baseline at each visit 
where assessments were made. Data of centers 104 and 120 
will be excluded. 
Table 
15.3.2.1.6 
Summary of Vital Signs by 
Ethnicity Subgroup 
Safety 
Vital signs parameters will be summarized descriptively by 
ethnicity subgroup including change from baseline at each 
visit where assessments were made. Data of centers 104 and 
120 will be excluded. 
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Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.4.1 
Vital Signs (EN) 
Enrolled 
All vital signs records will be listed. 
5.6.3 
Clinical Laboratory Evaluation 
Clinical laboratory values are collected as described in Section 1. The following parameters are 
collected: 
Hematology: hemoglobin, red blood cell count, mean corpuscular volume (MCV) and associated 
parameters, hematocrit, MCH, white blood cell count, differential white blood cell count 
including neutrophils, lymphocytes, eosinophils, basophils and monocytes, platelet count. 
Biochemistry: sodium, potassium, chloride, creatinine, blood urea nitrogen (BUN), calcium, 
glucose, total proteins, albumin, total cholesterol (HDL, LDL cholesterol), triglycerides, gamma 
glutamyl transferase, total and direct bilirubin, alkaline phosphatase (ALP), alanine 
aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine phosphokinase (CPK), 
lactate dehydrogenase (LDH). 
Pregnancy tests: serum β-hCG and urine dipstick tests. 
Urinalysis (dipstick test): leukocytes, nitrite, protein, glucose, ketones, blood, pH, urobilinogen, 
bilirubin, hemoglobin. 
All laboratory test results are assigned an LNH classification according to whether the value is lower 
than (L), within (N) or higher than (H) the reference range for that parameter as provided by the 
corresponding laboratory. Clinical significance of laboratory values is evaluated by the investigator. 
According to CRF investigator will evaluate only total cholesterol (not separate cholesterol fractions) 
deviation as clinically significant or not. 
If both absolute and percent values of eosinophils, basophils, monocytes or neutrophils will be out of 
range then clinical significance evaluation will be assigned for absolute value of respective parameter. 
Laboratory parameters will be summarized by calculating summary statistics on the absolute values and 
on the change from baseline V4 and V6/EDV (hematology and urinalysis variables) and from baseline 
to V3, V4, V5 and V6/EDV (biochemistry variables). The number and percent of subjects with values 
outside the limits of reference range will be summarized. Shift tables will be provided to illustrate 
changes with respect to the laboratory normal ranges between V1a and V4 and V6/EDV (hematology 
variables) and between V1a and V3, V4, V5 and V6/EDV (biochemistry variables). 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.3.3.1.1 
Summary of Clinical 
Laboratory Tests: 
Hematology 
Safety 
Default summary statistics of absolute and absolute change 
results at V1a, V4 and V6/EDV will be presented. Data of 
centers 104 and 120 will be excluded. 
Table 
15.3.3.1.2 
Summary of Clinical 
Laboratory Tests: 
Biochemistry 
Safety 
Default summary statistics of absolute and absolute change 
results at V1a, V3, V4, V5 and V6/EDV will be presented. 
Data of centers 104 and 120 will be excluded. 
Table 
15.3.3.1.3 
Summary of Clinical 
Laboratory Tests: Urinalysis 
dipstick 
Safety 
Number and percentage of subjects for each parameter 
based on the number of subjects with non-missing data at 
will be presented. Data of centers 104 and 120 will be 
excluded. 
Table 
15.3.3.1.4 
Clinical Laboratory Tests: 
Incidence of Hematology 
Abnormalities 
Safety 
Number and percentage of subjects for each parameter will 
be presented in normal, abnormal NCS and abnormal CS 
categories at specified visit. Percentage will be based on the 
number of subjects with non-missing data. Data of centers 
104 and 120 will be excluded. 
Table 
15.3.3.1.5 
Clinical Laboratory Tests: 
Incidence of Biochemistry 
Abnormalities 
Safety 
Number and percentage of subjects for each parameter will 
be presented in normal, abnormal NCS and abnormal CS 
categories at specified visit. Percentage will be based on the 
number of subjects with non-missing data. Data of centers 
104 and 120 will be excluded. 
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Table 
15.3.3.1.6 
Clinical Laboratory Tests: 
Shift Table of Hematology 
Results 
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to the normal range 
between Visit 1a and V4, V6/EDV will be presented. 
Subjects with missing data will be presented as part of a 
“missing” category. Percentage will be based on SS. Data 
of centers 104 and 120 will be excluded. 
Table 
15.3.3.1.7 
Clinical Laboratory Tests: 
Shift Table of Biochemistry 
Results 
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to the normal range 
between Visit 1a and V2, V3, V4, V5 and V6/EDV will be 
presented. Subjects with missing data will be presented as 
part of a “missing” category. Percentage will be based on 
SS. Data of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.5.1 
Laboratory Data: Hematology 
Enrolled 
Values of laboratory tests will be listed. 
Listing 
16.2.5.2 
Laboratory Data: 
Biochemistry 
Enrolled 
Values of laboratory tests will be listed. Pregnancy test 
results will be listed in the separate listing. 
Listing 
16.2.5.3 
Laboratory Data: Urinalysis 
Enrolled 
Urinalysis dipstick data will be listed. Pregnancy test results 
will be listed in the separate listing. 
Listing 
16.2.5.4 
Laboratory Data: Pregnancy 
tests 
Enrolled 
Pregnancy test serum β-hCG and urine dipstick tests results 
will be listed. 
5.6.4 
Physical Examination Findings 
Physical examinations will be performed at V1a, V4 and V6/EDV and include the following data: 
• Date of physical examination 
• General appearance (normal, abnormal, not done) 
• Ears, eyes, nose and throat (normal, abnormal, not done) 
• Lungs/chest (normal, abnormal, not done) 
• Heart (normal, abnormal, not done) 
• Abdomen (normal, abnormal, not done) 
• Pelvic (normal, abnormal, not done) 
• Back (normal, abnormal, not done) 
• Thyroid (normal, abnormal, not done) 
• Lymph nodes (normal, abnormal, not done) 
• Skin (normal, abnormal, not done) 
• Extremities including an inspection of the lower extremities for deep vein thrombosis (normal, 
abnormal, not done) 
• Other abnormal observations 
Abnormal values are assessed as clinically significant or not clinically significant. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.3.4.1.1 
Physical Examination 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.6.1 
Physical Examination 
Enrolled 
Physical examination results will be listed. 
 
 
 
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5.6.5 
Gynecological Examinations 
5.6.5.1 
Gynecological Examination 
Gynecological examinations will be performed at V1a, V4 and V6/EDV.  
The gynecological examinations will be described by the following data: 
• Date of gynecological examination 
• External genitalia (normal, abnormal, not done) 
• Speculum examination (normal, abnormal, not done) 
• Palpation of the internal genitalia (normal, abnormal, not done) 
• Breasts (normal, abnormal, not done) 
Gynecological examination abnormal values are assessed as clinically significant or not clinically 
significant. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.3.5.1.1 
Gynecological Examination 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.7.1 
Gynecological Examination 
Enrolled 
Gynecological examination results will be listed. 
5.6.5.2 
Transvaginal Ultrasound Examination 
Transvaginal ultrasound examinations will be performed at V1a and V6/EDV. The transvaginal 
ultrasound examination data will be described by the following data: 
• Date of ultrasound  
• The reason why transvaginal ultrasound was not performed 
• Uterus (normal, abnormal, not done) 
• Endometrium (normal, abnormal, not done) 
• Ovaries (normal, abnormal, not done) 
• Were any follicles or cysts identified during the ultrasound procedure (yes, no) 
• Diameter of largest follicle (Right ovary) 
• Diameter of largest cyst (Right ovary) 
• Diameter of largest follicle (Left ovary) 
• Diameter of largest cyst (Left ovary) 
Transvaginal ultrasound examination abnormal values are assessed as clinically significant or not 
clinically significant. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.3.6.1.1 
Transvaginal Ultrasound 
Examination 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Table  
15.3.6.1.2 
Shift Table for Transvaginal 
Ultrasound Examination 
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to the normal test 
between baseline and EDV, V6 and V6/EDV will be 
presented. Subjects with missing data will be presented as 
part of a “missing” category. Percentage will be based on 
SS. Data of centers 104 and 120 will be excluded. 
 
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Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.7.2 
Transvaginal Ultrasound 
Examination 
Enrolled 
Transvaginal Ultrasound examination results will be listed. 
5.6.5.3 
Dysmenorrhea Characteristic 
Dysmenorrhea characteristic will be collected at V1a and V6 (or EDV) and include: 
• Suffering from dysmenorrhea within the last 6 cycles before Visit 1a (yes, no) 
• Suffering from dysmenorrhea since the previous assessment (yes, no) 
• Intensity of dysmenorrhea (slight, moderate, heavy) 
• Use of pain medication (yes, no) 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.3.7.1.1 
Dysmenorrhea Characteristic 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Table  
15.3.7.1.2 
Shift Table for Dysmenorrhea 
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to dysmenorrhea 
between baseline and EDV, V6 and V6/EDV will be 
presented. Subjects with missing data will be presented as 
part of a “missing” category. Percentage will be based on 
SS. Data of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.7.3 
Dysmenorrhea Characteristic 
Enrolled 
Dysmenorrhea characteristic will be listed. 
5.6.5.4 
Mastodynia/Mastalgia Characteristic 
Mastodynia/Mastalgia characteristic will be collected at V1a and V6/EDV and include: 
• Suffering from mastodynia/mastalgia within the last 6 cycles before Visit 1a (yes, no) 
• Suffering from mastodynia/mastalgia since the previous assessment (yes, no) 
• Intensity of mastodynia/mastalgia (slight, moderate, heavy) 
• Use of pain medication (yes, no) 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.3.8.1.1 
Mastodynia/Mastalgia 
Characteristic 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Table  
15.3.8.1.2 
Shift Table for 
Mastodynia/Mastalgia 
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to the suffering from 
mastodynia/mastalgia between baseline and EDV, V6 and 
V6/EDV will be presented. Subjects with missing data will 
be presented as part of a “missing” category. Percentage 
will be based on SS. Data of centers 104 and 120 will be 
excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.7.4 
Mastodynia/Mastalgia 
Characteristic 
Enrolled 
Mastodynia/Mastalgia characteristic will be listed. 
 
 
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5.6.6 
Cervical Cytology 
Cervical cytology will be taken at V1a and V6/EDV and the findings will include: 
• Date of cervical cytology assessment 
• Cervical cytology results (Normal/Inflammatory, ASC-US, ASC-H and AGUS – cannot exclude 
high-grade disease or cancer, CIN1, CIN2, CIN3 – carcinoma in situ, Carcinoma in situ – 
Microinvasive carcinoma, Microinvasive carcinoma – Invasive carcinoma) 
• HPV results (Negative, Positive)  
• The reason, why cervical cytology was not assessed 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.3.9.1.1 
Summary of Cervical 
Cytology 
Safety 
Number and percentage at each visit will be presented. 
Percentage will be based on the number of subjects with 
non-missing data. Data of centers 104 and 120 will be 
excluded. 
Table  
15.3.9.1.2 
Shift Table for Cervical 
Cytology Test  
Safety 
Number and percentage showing changes in the number and 
frequency of subjects with respect to the normal between 
baseline and EDV, V6 and V6/EDV will be presented. 
Subjects with missing data will be presented as part of a 
“missing” category. Percentage will be based on SS. Data 
of centers 104 and 120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.8.1 
Cervical Cytology Results 
Enrolled 
Cervical cytology results will be listed. 
5.7 
Tolerability Analysis 
The tolerability assessment includes the vaginal bleeding pattern and the IMP acceptability. Analysis 
of tolerability endpoints will be conducted using the FAS. 
All tolerability variables will be evaluated over 13 cycles. 
5.7.1 
Bleeding Pattern 
The number and rate of subjects with different bleeding and spotting patterns will be presented for each 
cycle. The Clopper-Pearson 95% CI for vaginal bleeding or spotting rate of subjects will be calculated 
using the PROC FREQ procedure: 
PROC FREQ DATA=<data set>; 
BY <by variable>; 
TABLES <endpoint variable> / BINOMIAL; 
RUN; 
The following definitions will be applied: 
Episode of bleeding/spotting – bleeding/spotting days bounded on either end by two days of no 
bleeding or spotting. Missing data will be considered as bleeding/spotting day if it is bounded on 
bleeding/spotting days or one days of no bleeding or spotting. 
Days of bleeding/spotting – presence of bleeding/spotting on actual day. 
Scheduled bleeding/spotting – any bleeding or spotting that occurs during hormone-free intervals 
(defined as Days 25-28 ± 1 day). Bleeding/spotting that starts during this period and continues for up 
to eight consecutive days is considered as scheduled bleeding/spotting. 
If scheduled bleeding starts in Cycle X but ends in Cycle (X+1) then bleeding episode will be assigned 
to Cycle X. 
Any bleeding or spotting that occurs during cycle Days [1-8) of the first treatment cycle and lasts up to 
8 consecutive bleeding/spotting days will also be considered as scheduled bleeding days. 
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Unscheduled bleeding/spotting – any bleeding/spotting that occurs outside the time window defined 
for scheduled bleedings. 
Cumulative rate of subjects with different bleeding and spotting patterns for reference periods 
(summary of cycles 2-4, 5-7, 8-10 and 11-13) will be provided. Cumulative rates only for reference 
periods will also be presented for number and percent of subjects with prolonged bleeding and spotting 
> 9 days/ > 14 days and the number of bleeding and spotting episodes. 
Number and percent of days per cycle and reference period with bleeding and spotting, scheduled 
bleeding, unscheduled bleeding, scheduled spotting or unscheduled spotting and duration of scheduled 
bleeding, scheduled spotting, unscheduled bleeding and unscheduled spotting will be analyzed 
descriptively. 
Cycles without consecutively missing diary entries and with less than five non-consecutive missing 
diary entries will be used in the bleeding pattern analysis. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table 
15.4.1.1.1 
Number of Subjects with 
Bleeding by Treatment Day, 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.1.2.1 
Number of Subjects with 
Unscheduled Bleeding Days 
by Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.1.3.1 
Number of Subjects with 
Scheduled Bleeding Days by 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.1.4.1 
Number of Days with 
Bleeding by Cycle and 
Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.1.5.1 
Number of Days with 
Unscheduled Bleeding by 
Cycle and Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.1.6.1 
Number of Days with 
Scheduled Bleeding by Cycle 
and Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.2.1.1 
Number of Subjects with 
Spotting by Treatment Day, 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage is based on subject with 
respective cycle available. Data of centers 104 and 120 will 
be excluded. 
Table 
15.4.2.2.1 
Number of Subjects with 
Unscheduled Spotting Days 
by Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.2.3.1 
Number of Subjects with 
Scheduled Spotting Days by 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.2.4.1 
Number of Days with 
Spotting by Cycle and 
Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.2.5.1 
Number of Days with 
Unscheduled Spotting by 
Cycle and Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.2.6.1 
Number of Days with 
Scheduled Spotting by Cycle 
and Reference Period 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
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SOP effective date: 18.04.2016 
Version 6 
Table 
15.4.3.1.1 
Number of Bleeding/Spotting 
Episodes During Treatment 
and by Reference Period 
Full 
Analysis 
Default 
descriptive 
statistics 
for 
number 
of 
bleeding/spotting episodes will be presented. Number of 
bleeding/spotting episodes will be based on the number of 
subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.3.2.1 
Duration of Bleeding/Spotting 
Episodes by Cycle and 
Reference Period 
Full 
Analysis 
Default 
descriptive 
statistics 
for 
duration 
of 
bleeding/spotting episodes will be presented. Duration of 
bleeding/spotting episodes will be based on the number of 
subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.3.3.1 
Number of Subjects with 
Prolonged Bleeding/Spotting 
>9 and >14 Days by 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.4.1.1
_add 
Number of Subjects with 
Bleeding/Spotting by 
Treatment Day, Treatment 
Cycle and Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.4.2.1
_add 
Number of Subjects with 
Unscheduled 
Bleeding/Spotting Days by 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.4.3.1
_add 
Number of Subjects with 
Scheduled Bleeding/Spotting 
Days by Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.5.1.1
_add 
Number of Subjects with no 
Bleeding/Spotting Days by 
Treatment Cycle and 
Reference Period 
Full 
Analysis 
Number and percentage of subjects in respective time point 
will be presented. Percentage will be based on the number 
of subjects with respective cycles available. Data of centers 
104 and 120 will be excluded. 
Table 
15.4.6.1.1
_add 
Number of Days with 
Bleeding/Spotting by Cycle 
and Reference Period in BMI 
Groups 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.6.2.1
_add 
Number of Days with 
Unscheduled 
Bleeding/Spotting by Cycle 
and Reference Period in BMI 
Groups 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.6.3.1
_add 
Number of Days with 
Scheduled Bleeding/Spotting 
by Cycle and Reference 
Period in BMI Groups 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.7.1.1
_add 
Number of Days with 
Bleeding/Spotting by Cycle 
and Reference Period by 
Weight Subgroup 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.7.2.1
_add 
Number of Days with 
Unscheduled 
Bleeding/Spotting by Cycle 
and Reference Period by 
Weight Subgroup 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Table 
15.4.7.3.1
_add 
Number of Days with 
Scheduled Bleeding/Spotting 
by Cycle and Reference 
Period by Weight Subgroup 
Full 
Analysis 
Number of days will be summarized as continuous data. 
Number of days will be based on the number of subjects 
with respective cycles available. Data of centers 104 and 
120 will be excluded. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.9.1 
Treatment Diary 
Full 
Analysis 
Treatment diary records will be listed. 
Figures 
No. 
Name 
Analysis set 
Comments 
Figure 
15.4.1.1 
Subjects with Bleeding by 
Treatment Day 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding by study days during treatment period will be 
provided. Data of centers 104 and 120 will be excluded. 
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Figure 
15.4.1.2 
Subjects with Bleeding by 
Treatment Cycle 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding by treatment cycle will be provided. Data of 
centers 104 and 120 will be excluded. 
Figure 
15.4.1.3 
Subjects with Bleeding by 
Reference Period 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding by reference period will be provided. Data of 
centers 104 and 120 will be excluded. 
Figure 
15.4.2.1 
Subjects with Scheduled and 
Unscheduled Bleeding Days 
by Treatment Cycle 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled bleeding days by Treatment 
cycle will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.2.2 
Subjects with Scheduled and 
Unscheduled Bleeding Days 
by Reference Period 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled bleeding days by reference 
period will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.4.1 
Scheduled and Unscheduled 
Bleeding Days by Treatment 
Cycle 
Full 
Analysis 
Histogram showing the number of bleeding days by cycle 
will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.4.2 
Scheduled and Unscheduled 
Bleeding Days by Reference 
Period 
Full 
Analysis 
Histogram showing the number of bleeding days by 
reference period will be provided. Data of centers 104 and 
120 will be excluded. 
Figure 
15.4.5.1 
Subjects with Spotting by 
Treatment Day 
Full 
Analysis 
Linear diagram showing the number of women reporting 
spotting by study days during treatment period will be 
provided. Data of centers 104 and 120 will be excluded. 
Figure 
15.4.5.2 
Subjects with Spotting by 
Treatment Cycle 
Full 
Analysis 
Linear diagram showing the number of women reporting 
spotting by treatment cycle will be provided. Data of centers 
104 and 120 will be excluded. 
Figure 
15.4.5.3 
Subjects with Spotting by 
Reference Period 
Full 
Analysis 
Linear diagram showing the number of women reporting 
spotting by reference period will be provided. Data of 
centers 104 and 120 will be excluded. 
Figure 
15.4.6.1 
Subjects with Scheduled and 
Unscheduled Spotting Days 
by Treatment Cycle 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled spotting days by Treatment 
cycle will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.6.2 
Subjects with Scheduled and 
Unscheduled Spotting Days 
by Reference Period 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled spotting days by reference 
period will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.7.1 
Bleeding/Spotting Episodes 
by Reference Period 
Full 
Analysis 
Histogram showing the number of spotting episodes by 
reference period will be provided. 
Figure 
15.4.8.1 
Scheduled and Unscheduled 
Spotting Days by Treatment 
Cycle 
Full 
Analysis 
Histogram showing the number of spotting days by cycle 
will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.8.2 
Scheduled and Unscheduled 
Spotting Days by Reference 
Period 
Full 
Analysis 
Histogram showing the number of spotting days by 
reference period will be provided. Data of centers 104 and 
120 will be excluded. 
Figure 
15.4.9.1_a
dd 
Subjects with 
Bleeding/Spotting by 
Treatment Day 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding/spotting by study days during treatment period 
will be provided. Data of centers 104 and 120 will be 
excluded. 
Figure 
15.4.9.2_a
dd 
Subjects with 
Bleeding/Spotting by 
Treatment Cycle 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding/spotting by treatment cycle will be provided. Data 
of centers 104 and 120 will be excluded. 
Figure 
15.4.9.3_a
dd 
Subjects with 
Bleeding/Spotting by 
Reference Period 
Full 
Analysis 
Linear diagram showing the number of women reporting 
bleeding/spotting by reference period will be provided. Data 
of centers 104 and 120 will be excluded. 
Figure 
15.4.10.1_
add 
Subjects with Scheduled and 
Unscheduled 
Bleeding/Spotting Days by 
Treatment Cycle 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled bleeding/spotting days by 
Treatment cycle will be provided. Data of centers 104 and 
120 will be excluded. 
Figure 
15.4.10.2_
add 
Subjects with Scheduled and 
Unscheduled 
Bleeding/Spotting Days by 
Reference Period 
Full 
Analysis 
Histogram showing the number of women reporting 
scheduled and unscheduled bleeding/spotting days by 
reference period will be provided. Data of centers 104 and 
120 will be excluded. 
Figure 
15.4.11.1_
add 
Scheduled and Unscheduled 
Bleeding/Spotting Days by 
Treatment Cycle 
Full 
Analysis 
Histogram showing the number of bleeding/spotting days 
by cycle will be provided. Data of centers 104 and 120 will 
be excluded. 
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Clinical Trial Report CF111/303
Final Version 2.0
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Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
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SOP effective date: 18.04.2016 
Version 6 
Figure 
15.4.11.2_
add 
Scheduled and Unscheduled 
Bleeding/Spotting Days by 
Reference Period 
Full 
Analysis 
Histogram showing the number of bleeding/spotting days 
by reference period will be provided. Data of centers 104 
and 120 will be excluded. 
5.7.2 
IMP Acceptability 
IMP acceptability will be summarized by default frequency tabulation. Shift tables will be provided to 
illustrate change from V3 to V6/EDV. Additionally, for subjects who switched from another oral 
contraceptive to the study medication default frequency tables will be summarized to present change of 
subject wellbeing. 
Tables 
No. 
Name 
Analysis set 
Comments 
Table  
15.4.7.1.1 
IMP Acceptability 
Assessment 
Full 
Analysis 
Number and percentage will be presented. Percentage will 
be based on the number of subjects with non-missing data. 
Table  
15.4.7.2.1 
Shift table for IMP 
Acceptability Assessment 
Full 
Analysis 
Number and percentage showing changes between Visit 3 
and Visit 6/EDV will be presented. Percentage will be based 
on FAS. 
Listings 
No. 
Name 
Analysis set 
Comments 
Listing 
16.2.10.1 
IMP Acceptability 
Assessment 
Full 
Analysis 
IMP acceptability assessment records will be listed. 
 
 
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6. INTERIM ANALYSIS 
No interim analysis is planned. 
 
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Version 6 
7. 
REFERENCES 
1. SAS® Institute Inc., Cary, North Carolina, United States of America, Version 9.4. 
2. MedDRA – Medical Dictionary for Regulated Activities. International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, VAR1/8A/MSSO, 12011 
Sunset Hills Road, Reston, VA 20190-3285, USA, Version 17.0, 1 March 2014. 
3. WHO – Drug Dictionary. World Health Organization Collaborating Center for International 
Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden, version 2014. 
4. Gerlinger C et al. Recommendation for confidence interval and sample size calculation for the 
Pearl Index. Eur J Contracept Reprod Health Care. 2003; 8:87-92. 
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8. APPENDICES 
1. Specification of Tables 
2. Specification of Listings 
3. Specification of Figures 
4. Tables 
Appendix tables defined below will be provided in separate .rtf files for each output. 
Seq. 
No 
Table No and Title 
Output file name 
Baseline Characteristics 
1.  
Table 15.1.1.1.1 
Analysis Sets – Enrolled Set 
T15_01_01_01_01_anal_sets_es 
2.  
Table 15.1.2.1.1 
Screen Failures – Enrolled Set 
T15_01_02_01_01_scr_fail_es 
3.  
Table 15.1.3.1.1 
Reasons for Exclusion from Analysis Sets – 
Enrolled Set 
T15_01_03_01_01_excl_anal_es 
4.  
Table 15.1.4.1.1 
Subjects’ Disposition – Safety Set 
T15_01_04_01_01_dispos_ss 
5.  
Table 15.1.4.1.2 
Subjects’ Disposition (Excluding Site 140) – 
Safety Set 
T15_01_04_01_02_dispos_wo140_ss 
6.  
Table 15.1.5.1.1 
Disposition by Attended Visit – Safety Set 
T15_01_05_01_01_dispos_visit_ss 
7.  
Table 15.1.6.1.1 
Disposition by Sites – Safety Set 
T15_01_06_01_01_dispos_sites_ss 
8.  
Table 15.1.7.1.1 
Deviations Leading to Pregnancies Exclusion from 
the Method Failure Analysis – Modified Full 
Analysis Set 
T15_01_07_01_01_dev_met_fail_mfas 
9.  
Table 15.1.7.1.2 
Deviations Leading to Cycles Exclusion from 
Analyses – Modified Full Analysis 
T15_01_07_01_02_dev_cyc_mfas 
10.  
Table 15.1.8.1.1 
Demographics – Safety Set 
T15_01_08_01_01_demo_ss 
11.  
Table 15.1.8.1.2 
Demographics – Modified Full Analysis Set 
T15_01_08_01_02_demo_mfas 
12.  
Table 15.1.9.1.1 
Subgroups – Safety Set 
T15_01_09_01_01_subgr_ss 
13.  
Table 15.1.9.1.2 
Subgroups – Modified Full Analysis Set 
T15_01_09_01_02_subgr_mfas 
14.  
Table 15.1.10.1.1 Baseline Characteristics at Screening – Safety Set 
T15_01_10_01_01_base_char_ss 
15.  
Table 15.1.10.1.2 Baseline Characteristics at Screening – Modified 
Full Analysis Set 
T15_01_10_01_02_base_char_mfas 
16.  
Table 15.1.11.1.1 Substance Use – Safety Set 
T15_01_11_01_01_substance_ss 
17.  
Table 15.1.12.1.1 Prior Medical History Conditions – Safety Set 
T15_01_12_01_01_prior_mh_ss 
18.  
Table 15.1.12.2.1 Current Medical History Conditions – Safety Set 
T15_01_12_02_01_current_mh_ss 
19.  
Table 15.1.13.1.1 Gynecological History – Safety Set 
T15_01_13_01_01_gin_his_ss 
20.  
Table 15.1.14.1.1 VTE Risk Factors – Safety Set 
T15_01_14_01_01_vte_ss 
21.  
Table 15.1.15.1.1 Menstrual History – Safety Set 
T15_01_15_01_01_menstr_his_ss 
22.  
Table 15.1.16.1.1 Prior Medications, Therapies and Contraception – 
Safety Set 
T15_01_16_01_01_prior_cm_ss 
23.  
Table 15.1.16.2.1 Concomitant Medications, Therapies and 
Contraception – Safety Set 
T15_01_16_02_01_concom_cm_ss 
24.  
Table 15.1.17.1.1 Exposure to Investigational Medicinal Product – 
Safety Set 
T15_01_17_01_01_exp_ss 
25.  
Table 15.1.18.1.1 Number of Subjects with at Least One Missing 
Entry of IMP Intake in Treatment Diary by 
Treatment Cycle and Overall – Safety Set 
T15_01_18_01_01_mis_imp_ss 
26.  
Table 15.1.19.1.1 Number of Subjects with Gaps between Two 
Active Tablet Intakes of More Than 48 Hours by 
Treatment Cycle and Overall – Safety Set 
T15_01_19_01_01_48h_gap_intake_ss 
27.  
Table 15.1.20.1.1 Compliance to Investigational Medicinal Product – 
Safety Set 
T15_01_20_01_01_compl_ss 
Efficacy Data 
28.  
Table 15.2.1.1.1 
Pearl Index Based on Evaluable Cycles in Non-
Breastfeeding Women Aged ≤ 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_01_01_PI_eval_less_35_C
_E_mfas 
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Version 6 
29.  
Table 15.2.1.2.1 
Overall Pearl Index in Non-Breastfeeding Women 
(Only Confirmed Pregnancies, Excluding Sites 104 
and 120) – Modified Full Analysis Set 
T15_02_01_02_01_PI_over_C_E_mfa
s 
30.  
Table 15.2.1.2.2 
Overall Pearl Index in Non-Breastfeeding Women 
Aged ≤ 35 Years (Only Confirmed Pregnancies, 
Excluding Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_02_02_PI_over_less_35_
C_E_mfas 
31.  
Table 15.2.1.2.3 
Overall Pearl Index in Non-Breastfeeding Women 
Aged > 35 Years (Only Confirmed Pregnancies, 
Excluding Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_02_03_PI_over_more_35_
C_E_mfas 
32.  
Table 15.2.1.2.4_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI Subgroup (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_02_04_PI_over_BMI_C_
E_mfas 
33.  
Table 15.2.1.2.5_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI Subgroup (Only Confirmed 
Pregnancies, Including Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_02_05_PI_over_BMI_C_I
_mfas 
34.  
Table 15.2.1.2.6_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI Subgroup (Confirmed and 
Suspected, Non-confirmed Pregnancies, Excluding 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_01_02_06_PI_over_BMI_CS
_E_mfas 
35.  
Table 15.2.1.2.7_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI Subgroup (Confirmed and 
Suspected, Non-confirmed Pregnancies, Including 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_01_02_07_PI_over_BMI_CS
_I_mfas 
36.  
Table 15.2.1.2.8_add 
Overall Pearl Index in Non-Breastfeeding 
Women by Weight Subgroup (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_02_08_PI_over_weight_C
_E_mfas 
37.  
Table 15.2.1.2.9_add 
Overall Pearl Index in Non-Breastfeeding 
Women by Weight Subgroup (Only Confirmed 
Pregnancies, Including Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_02_09_PI_over_weight_C
_I_mfas 
38.  
Table 15.2.1.2.10_add 
Overall Pearl Index in Non-Breastfeeding 
Women by Weight Subgroup (Confirmed and 
Suspected, Non-confirmed Pregnancies, Excluding 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_01_02_10_PI_over_weight_C
S_E_mfas 
39.  
Table 15.2.1.2.11_add 
Overall Pearl Index in Non-Breastfeeding 
Women by Weight Subgroup (Confirmed and 
Suspected, Non-confirmed Pregnancies, Including 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_01_02_11_PI_over_weight_C
S_I_mfas 
40.  
Table 15.2.1.3.1 
Pearl Index for Method Failures in Non-
Breastfeeding Women (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_03_01_PI_mf_C_E_mfas 
41.  
Table 15.2.1.3.2 
Pearl Index for Method Failures in Non-
Breastfeeding Women Aged ≤ 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_03_02_PI_mf_less_35_C_
E_mfas 
42.  
Table 15.2.1.3.3 
Pearl Index for Method Failures in Non-
Breastfeeding Women Aged > 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_03_03_PI_mf_more_35_C
_E_mfas 
43.  
Table 15.2.1.4.1 
Pearl Index Based on Evaluable Cycles in Non-
Breastfeeding Women (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_04_01_PI_eval_C_E_mfa
s 
44.  
Table 15.2.1.4.2 
Pearl Index Based on Evaluable Cycles in Non-
Breastfeeding Women Aged > 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_04_02_PI_eval_more_C_
E_mfas 
45.  
Table 15.2.1.4.3_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years 
T15_02_01_04_03_PI_eval_less_35_C
_I_mfas 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
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Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
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Page 64 of 71 
SOP effective date: 18.04.2016 
Version 6 
(Only Confirmed Pregnancies, Including Sites 104 
and 120) – Modified Full Analysis Set 
46.  
Table 15.2.1.4.4_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years 
(Confirmed and Suspected, Non-confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_04_04_PI_eval_less_35_C
S_E_mfas 
47.  
Table 15.2.1.4.5_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years 
(Confirmed and Suspected, Non-confirmed 
Pregnancies, Including Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_01_04_05_PI_eval_less_35_C
S_I_mfas 
48.  
Table 15.2.1.4.6_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
BMI Subgroup (Only Confirmed Pregnancies, 
Excluding Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_04_06_PI_eval_less_35_B
MI_C_E_mfas 
49.  
Table 15.2.1.4.7_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
BMI Subgroup (Only Confirmed Pregnancies, 
Including Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_04_07_PI_eval_less_35_B
MI_C_I_mfas 
50.  
Table 15.2.1.4.8_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
BMI Subgroup (Confirmed and Suspected, Non-
confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_04_08_PI_eval_less_35_B
MI_CS_E_mfas 
51.  
Table 15.2.1.4.9_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
BMI Subgroup (Confirmed and Suspected, Non-
confirmed Pregnancies, Including Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_04_09_PI_eval_less_35_B
MI_CS_I_mfas 
52.  
Table 15.2.1.4.10_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
Weight Subgroup (Only Confirmed Pregnancies, 
Excluding Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_04_10_PI_eval_less_35_
weight_C_E_mfas 
53.  
Table 15.2.1.4.11_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
Weight Subgroup (Only Confirmed Pregnancies, 
Including Sites 104 and 120) – Modified Full 
Analysis Set 
T15_02_01_04_11_PI_eval_less_35_
weight_C_I_mfas 
54.  
Table 15.2.1.4.12_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
Weight Subgroup (Confirmed and Suspected, Non-
confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_04_12_PI_eval_less_35_
weight_CS_E_mfas 
55.  
Table 15.2.1.4.13_add 
Pearl Index Based on Evaluable Cycles 
in Non-Breastfeeding Women Aged ≤ 35 Years by 
Weight Subgroup (Confirmed and Suspected, Non-
confirmed Pregnancies, Including Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_01_04_13_PI_eval_less_35_
weight_CS_I_mfas 
56.  
Table 15.2.2.1.1 
Overall Pregnancy Rate Life Table in Non-
Breastfeeding Women (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_02_01_01_preg_rate_over_C_
E_mfas 
57.  
Table 15.2.2.1.2 
Overall Pregnancy Rate Life Table in Non-
Breastfeeding Women Aged ≤ 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_02_01_02_preg_rate_over_les
s_35_C_E_mfas 
58.  
Table 15.2.2.1.3 
Overall Pregnancy Rate Life Table in Non-
Breastfeeding Women Aged > 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_02_01_03_preg_rate_over_m
ore_35_C_E_mfas 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 66 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 65 of 71 
SOP effective date: 18.04.2016 
Version 6 
59.  
Table 15.2.2.2.1 
Evaluable Cycles Pregnancy Rate Life Table in 
Non-Breastfeeding Women (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_02_02_01_preg_rate_eval_C_
E_mfas 
60.  
Table 15.2.2.2.2 
Evaluable Cycles Pregnancy Rate Life Table in 
Non-Breastfeeding Women Aged ≤ 35 Years (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_02_02_02_preg_rate_eval_les
s_35_C_E_mfas 
61.  
Table 15.2.2.2.3 
Evaluable Cycles Pregnancy Rate Life Table in 
Non-Breastfeeding Women Aged > 35 Years 
(Only Confirmed Pregnancies, Excluding Sites 104 
and 120) – Modified Full Analysis Set 
T15_02_02_02_03_preg_rate_eval_mo
re_35_C_E_mfas 
62.  
Table 15.2.2.3.1 
Method Failure Life Table in Non-Breastfeeding 
Women (Only Confirmed Pregnancies, Excluding 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_02_03_01_preg_rate_mf_C_E
_mfas 
63.  
Table 15.2.2.3.2 
Method Failure Life Table in Non-Breastfeeding 
Women Aged ≤ 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_02_03_02_preg_rate_mf_less
_35_C_E_mfas 
64.  
Table 15.2.2.3.3 
Method Failure Life Table in Non-Breastfeeding 
Women Aged > 35 Years (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
T15_02_02_03_03_preg_rate_mf_mor
e_35_C_E_mfas 
65.  
Table 15.2.3.1.1_add 
Overall Pearl Index in Non-Breastfeeding 
Women (Confirmed and Suspected, Non-
confirmed Pregnancies, Including Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_03_01_01_PI_over_CS_I_mf
as 
66.  
Table 15.2.3.1.2_add 
Overall Pearl Index in Non-Breastfeeding 
Women (Only Confirmed Pregnancies, Including 
Sites 104 and 120) – Modified Full Analysis Set 
T15_02_03_01_02_PI_over_C_I_mfas 
67.  
Table 15.2.3.1.3_add 
Overall Pearl Index in Non-Breastfeeding 
Women (Confirmed and Suspected, Non-
confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
T15_02_03_01_03_PI_over_CS_E_mf
as 
Safety Data 
68.  
Table 15.3.1.1.1 
Summary of Adverse Events – Safety Set 
T15_03_01_01_01_ae_ss 
69.  
Table 15.3.1.1.2 
Summary of Adverse Events by Weight Subgroup 
– Safety Set 
T15_03_01_01_02_ae_weight_ss 
70.  
Table 15.3.1.1.3 
Summary of Adverse Events by BMI Subgroup – 
Safety Set 
T15_03_01_01_03_ae_bmi_ss 
71.  
Table 15.3.1.1.4 
Summary of Adverse Events by Blood Pressure 
Subgroup – Safety Set 
T15_03_01_01_04_ae_blood_ss 
72.  
Table 15.3.1.1.5 
Summary of Adverse Events by Race Subgroup – 
Safety Set 
T15_03_01_01_05_ae_race_ss 
73.  
Table 15.3.1.1.6 
Summary of Adverse Events by Ethnicity 
Subgroup – Safety Set 
T15_03_01_01_06_ae_ethnicity_ss 
74.  
Table 15.3.1.2.1 
Incidence of TEAEs – Safety Set 
T15_03_01_02_01_teae_ SS 
75.  
Table 15.3.1.2.2 
Incidence of TEAEs by Weight Subgroup – Safety 
Set 
T15_03_01_02_02_teae_weight_ss 
76.  
Table 15.3.1.2.3 
Incidence of TEAEs by BMI Subgroup – Safety 
Set 
T15_03_01_02_03_teae_bmi_ss 
77.  
Table 15.3.1.2.4 
Incidence of TEAEs by Blood Pressure Subgroup – 
Safety Set 
T15_03_01_02_04_teae_blood_ss 
78.  
Table 15.3.1.2.5 
Incidence of TEAEs by Race Subgroup – Safety 
Set 
T15_03_01_02_05_teae_race_ss 
79.  
Table 15.3.1.2.6 
Incidence of TEAEs by Ethnicity Subgroup – 
Safety Set 
T15_03_01_02_06_teae_ethnicity_ss 
80.  
Table 15.3.1.3.1 
Incidence of TEAEs by Relationship – Safety Set 
T15_03_01_03_01_teae_rel_ss 
81.  
Table 15.3.1.3.2 
Incidence of TEAEs by Relationship by Weight 
Subgroup – Safety Set 
T15_03_01_03_02_teae_rel_weight_ss 
82.  
Table 15.3.1.3.3 
Incidence of TEAEs by Relationship by BMI 
Subgroup – Safety Set 
T15_03_01_03_03_teae_rel_bmi_ss 
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Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 67 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
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SOP effective date: 18.04.2016 
Version 6 
83.  
Table 15.3.1.3.4 
Incidence of TEAEs by Relationship by Blood 
Pressure Subgroup – Safety Set 
T15_03_01_03_04_teae_rel_blood_ss 
84.  
Table 15.3.1.3.5 
Incidence of TEAEs by Relationship by Race 
Subgroup – Safety Set 
T15_03_01_03_05_teae_rel_race_ss 
85.  
Table 15.3.1.3.6 
Incidence of TEAEs by Relationship by Ethnicity 
Subgroup – Safety Set 
T15_03_01_03_06_teae_rel_ethnicity_
ss 
86.  
Table 15.3.1.4.1 
Incidence of TEAEs by Worst Severity – Safety 
Set 
T15_03_01_04_01_teae_sev_ss 
87.  
Table 15.3.1.4.2 
Incidence of TEAEs by Worst Severity by Weight 
Subgroup – Safety Set 
T15_03_01_04_02_teae_sev_weight_s
s 
88.  
Table 15.3.1.4.3 
Incidence of TEAEs by Worst Severity by BMI 
Subgroup – Safety Set 
T15_03_01_04_03_teae_sev_bmi_ss 
89.  
Table 15.3.1.4.4 
Incidence of TEAEs by Worst Severity by Blood 
Pressure Subgroup – Safety Set 
T15_03_01_04_04_teae_sev_blood_ss 
90.  
Table 15.3.1.4.5 
Incidence of TEAEs by Worst Severity by Race 
Subgroup – Safety Set 
T15_03_01_04_05_teae_sev_race_ss 
91.  
Table 15.3.1.4.6 
Incidence of TEAEs by Worst Severity by 
Ethnicity Subgroup – Safety Set 
T15_03_01_04_06_teae_sev_ethnicity
_ss 
92.  
Table 15.3.1.5.1 
Incidence of Serious TEAEs – Safety Set 
T15_03_01_05_01_saeteae_ss 
93.  
Table 15.3.1.5.2 
Incidence of Serious TEAEs by Weight Subgroup 
– Safety Set 
T15_03_01_05_02_saeteae_weight_ss 
94.  
Table 15.3.1.5.3 
Incidence of Serious TEAEs by BMI Subgroup – 
Safety Set 
T15_03_01_05_03_saeteae_bmi_ss 
95.  
Table 15.3.1.5.4 
Incidence of Serious TEAEs by Blood Pressure 
Subgroup – Safety Set 
T15_03_01_05_04_saeteae_blood_ss 
96.  
Table 15.3.1.5.5 
Incidence of Serious TEAEs by Race Subgroup – 
Safety Set 
T15_03_01_05_05_saeteae_race_ss 
97.  
Table 15.3.1.5.6 
Incidence of Serious TEAEs by Ethnicity 
Subgroup – Safety Set 
T15_03_01_05_06_saeteae_ethnicity_
ss 
98.  
Table 15.3.1.6.1 
Incidence of TEAEs Leading to Trial Termination 
– Safety Set 
T15_03_01_06_01_teae_term_ss 
99.  
Table 15.3.1.6.2 
Incidence of TEAEs Leading to Trial Termination 
by Weight Subgroup – Safety Set 
T15_03_01_06_02_teae_term_weight_
ss 
100. 
Table 15.3.1.6.3 
Incidence of TEAEs Leading to Trial Termination 
by BMI Subgroup – Safety Set 
T15_03_01_06_03_teae_term_bmi_ss 
101. 
Table 15.3.1.6.4 
Incidence of TEAEs Leading to Trial Termination 
by Blood Pressure Subgroup – Safety Set 
T15_03_01_06_04_teae_term_blood_s
s 
102. 
Table 15.3.1.6.5 
Incidence of TEAEs Leading to Trial Termination 
by Race Subgroup – Safety Set 
T15_03_01_06_05_teae_term_race_ss 
103. 
Table 15.3.1.6.6 
Incidence of TEAEs Leading to Trial Termination 
by Ethnicity Subgroup – Safety Set 
T15_03_01_06_06_teae_term_ethnicit
y_ss 
104. 
Table 15.3.1.7.1 
Incidence of TEAEs of Special Interest – Safety 
Set 
T15_03_01_07_01_teae_sp_int_ss 
105. 
Table 15.3.1.7.2 
Incidence of TEAEs of Special Interest by Weight 
Subgroup – Safety Set 
T15_03_01_07_02_teae_sp_int_weigh
t_ss 
106. 
Table 15.3.1.7.3 
Incidence of TEAEs of Special Interest by BMI 
Subgroup – Safety Set 
T15_03_01_07_03_teae_sp_int_bmi_s
s 
107. 
Table 15.3.1.7.4 
Incidence of TEAEs of Special Interest by Blood 
Pressure Subgroup – Safety Set 
T15_03_01_07_04_teae_sp_int_blood
_ss 
108. 
Table 15.3.1.7.5 
Incidence of TEAEs of Special Interest by Race 
Subgroup – Safety Set 
T15_03_01_07_05_teae_sp_int_race_s
s 
109. 
Table 15.3.1.7.6 
Incidence of TEAEs of Special Interest by 
Ethnicity Subgroup – Safety Set 
T15_03_01_07_06_teae_sp_int_ethnic
ity_ss 
110. 
Table 15.3.1.8.1 
Incidence of Related Serious TEAEs – Safety Set 
T15_03_01_08_01_rel_saeteae_ss 
111. 
Table 15.3.1.8.2 
Incidence of Related Serious TEAEs by Weight 
Subgroup – Safety Set 
T15_03_01_08_02_rel_saeteae_weight
_ss 
112. 
Table 15.3.1.8.3 
Incidence of Related Serious TEAEs by BMI 
Subgroup – Safety Set 
T15_03_01_08_03_rel_saeteae_bmi_s
s 
113. 
Table 15.3.1.8.4 
Incidence of Related Serious TEAEs by Blood 
Pressure Subgroup – Safety Set 
T15_03_01_08_04_rel_saeteae_bood_
ss 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 68 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 67 of 71 
SOP effective date: 18.04.2016 
Version 6 
114. 
Table 15.3.1.8.5 
Incidence of Related Serious TEAEs by Race 
Subgroup – Safety Set 
T15_03_01_08_05_rel_saeteae_race_s
s 
115. 
Table 15.3.1.8.6 
Incidence of Related Serious TEAEs by Ethnicity 
Subgroup – Safety Set 
T15_03_01_08_06_rel_saeteae_ethnici
ty_ss 
116. 
Table 15.3.2.1.1 
Summary of Vital Signs – Safety Set 
T15_03_02_01_01_vs_ss 
117. 
Table 15.3.2.1.2 
Summary of Vital Signs by Weight Subgroup – 
Safety Set 
T15_03_02_01_02_vs_weight_ss 
118. 
Table 15.3.2.1.3 
Summary of Vital Signs by BMI Subgroup – 
Safety Set 
T15_03_02_01_03_vs_bmi_ss 
119. 
Table 15.3.2.1.4 
Summary of Vital Signs by Blood Pressure 
Subgroup – Safety Set 
T15_03_02_01_04_vs_blood_ss 
120. 
Table 15.3.2.1.5 
Summary of Vital Signs by Race Subgroup – 
Safety Set 
T15_03_02_01_05_vs_race_ss 
121. 
Table 15.3.2.1.6 
Summary of Vital Signs by Ethnicity Subgroup – 
Safety Set 
T15_03_02_01_06_vs_ethnicity_ss 
122. 
Table 15.3.3.1.1 
Summary of Clinical Laboratory Tests: 
Hematology – Safety Set 
T15_03_03_01_01_hema_ss 
123. 
Table 15.3.3.1.2 
Summary of Clinical Laboratory Tests: 
Biochemistry – Safety Set 
T15_03_03_01_02_bioch_ss 
124. 
Table 15.3.3.1.3 
Summary of Clinical Laboratory Tests: Urinalysis 
dipstick – Safety Set 
T15_03_03_01_03_urin_ss 
125. 
Table 15.3.3.1.4 
Clinical Laboratory Tests: Incidence of 
Hematology Abnormalities – Safety Set 
T15_03_03_01_04_hema_abn_ss 
126. 
Table 15.3.3.1.5 
Clinical Laboratory Tests: Incidence of 
Biochemistry Abnormalities – Safety Set 
T15_03_03_01_05_bioch_abn_ss 
127. 
Table 15.3.3.1.6 
Clinical Laboratory Tests: Shift Table of 
Hematology Results – Safety Set 
T15_03_03_01_06_shift_hema_ss 
128. 
Table 15.3.3.1.7 
Clinical Laboratory Tests: Shift Table of 
Biochemistry Results – Safety Set 
T15_03_03_01_07_shift_bioch_ss 
129. 
Table 15.3.4.1.1 
Physical Examination – Safety Set 
T15_03_04_01_01_pe_ss 
130. 
Table 15.3.5.1.1 
Gynecological Examination – Safety Set 
T15_03_05_01_01_gyn_exam_ss 
131. 
Table 15.3.6.1.1 
Transvaginal Ultrasound Examination – Safety Set 
T15_03_06_01_01_transvag_exam_ss 
132. 
Table 15.3.6.1.2 
Shift Table for Transvaginal Ultrasound 
Examination – Safety Set 
T15_03_06_01_02_transvag_exam_shi
ft_ss 
133. 
Table 15.3.7.1.1 
Dysmenorrhea Characteristic – Safety Set 
T15_03_07_01_01_dysm_char_ss 
134. 
Table 15.3.7.1.2 
Shift Table for Dysmenorrhea – Safety Set 
T15_03_07_01_02_dysm_char_shift_s
s 
135. 
Table 15.3.8.1.1 
Mastodynia/Mastalgia Characteristic – Safety Set 
T15_03_08_01_01_mastodyn_char_ss 
136. 
Table 15.3.8.1.2 
Shift Table for Mastodynia/Mastalgia – Safety Set 
T15_03_08_01_02_mastodyn_char_sh
ift_ss 
137. 
Table 15.3.9.1.1 
Summary of Cervical Cytology – Safety Set 
T15_03_09_01_01_cytology_ss 
138. 
Table 15.3.9.1.2 
Shift Table for Cervical Cytology Test – Safety Set 
T15_03_09_01_02_cytology_shift_ss 
Tolerability Data 
139. 
Table 15.4.1.1.1 
Number of Subjects with Bleeding by Treatment 
Day, Treatment Cycle and Reference Period – Full 
Analysis Set 
T15_04_01_01_01_sub_bleed_day_cy
c_ref_fas 
140. 
Table 15.4.1.2.1 
Number of Subjects with Unscheduled Bleeding 
Days by Treatment Cycle and Reference Period – 
Full Analysis Set 
T15_04_01_02_01_sub_ubleed_cyc_re
f_fas 
141. 
Table 15.4.1.3.1 
Number of Subjects with Scheduled Bleeding Days 
by Treatment Cycle and Reference Period – Full 
Analysis Set 
T15_04_01_03_01_sub_sbleed_cyc_re
f_fas 
142. 
Table 15.4.1.4.1 
Number of Days with Bleeding by Cycle and 
Reference Period – Full Analysis Set 
T15_04_01_04_01_day_bleed_cyc_ref
_fas 
143. 
Table 15.4.1.5.1 
Number of Days with Unscheduled Bleeding by 
Cycle and Reference Period – Full Analysis Set 
T15_04_01_05_01_day_ubleed_cyc_r
ef_fas 
144. 
Table 15.4.1.6.1 
Number of Days with Scheduled Bleeding by 
Cycle and Reference Period – Full Analysis Set 
T15_04_01_06_01_day_sbleed_cyc_re
f_fas 
145. 
Table 15.4.2.1.1 
Number of Subjects with Spotting by Treatment 
Day, Treatment Cycle and Reference Period – Full 
Analysis Set 
T15_04_02_01_01_sub_spot_day_cyc
_ref_fas 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 69 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
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Page 68 of 71 
SOP effective date: 18.04.2016 
Version 6 
146. 
Table 15.4.2.2.1 
Number of Subjects with Unscheduled Spotting 
Days by Treatment Cycle and Reference Period – 
Full Analysis Set 
T15_04_02_02_01_sub_uspot_cyc_ref
_fas 
147. 
Table 15.4.2.3.1 
Number of Subjects with Scheduled Spotting Days 
by Treatment Cycle and Reference Period – Full 
Analysis Set 
T15_04_02_03_01_sub_sspot_cyc_ref
_fas 
148. 
Table 15.4.2.4.1 
Number of Days with Spotting by Cycle and 
Reference Period – Full Analysis Set 
T15_04_02_04_01_day_spot_cyc_ref_
fas 
149. 
Table 15.4.2.5.1 
Number of Days with Unscheduled Spotting by 
Cycle and Reference Period – Full Analysis Set 
T15_04_02_05_01_day_uspot_cyc_ref
_fas 
150. 
Table 15.4.2.6.1 
Number of Days with Scheduled Spotting by Cycle 
and Reference Period – Full Analysis Set 
T15_04_02_06_01_day_sspot_cyc_ref
_fas 
151. 
Table 15.4.3.1.1 
Number of Bleeding/Spotting Episodes During 
Treatment and by Reference Period – Full Analysis 
Set 
T15_04_03_01_01_epis_trt_ref_fas 
152. 
Table 15.4.3.2.1 
Duration of Bleeding/Spotting Episodes by Cycle 
and Reference Period – Full Analysis Set 
T15_04_03_02_01_epis_dur_cyc_ref_
fas 
153. 
Table 15.4.3.3.1 
Number of Subjects with Prolonged 
Bleeding/Spotting >9 and >14 by Reference Period 
– Full Analysis Set 
T15_04_03_03_01_sub_pblsp_9_14_r
ef_fas 
154. 
Table 15.4.4.1.1_add 
Number of Subjects with 
Bleeding/Spotting by Treatment Day, Treatment 
Cycle and Reference Period – Full Analysis Set 
T15_04_04_01_01_sub_blsp_fas 
155. 
Table 15.4.4.2.1_add 
Number of Subjects with Unscheduled 
Bleeding/Spotting Days by Treatment Cycle and 
Reference Period – Full Analysis Set 
T15_04_04_02_01_sub_ublsp_fas 
156. 
Table 15.4.4.3.1_add 
Number of Subjects with Scheduled 
Bleeding/Spotting Days by Treatment Cycle and 
Reference Period – Full Analysis Set 
T15_04_04_03_01_sub_sblsp_fas 
157. 
Table 15.4.5.1.1_add 
Number of Subjects with no 
Bleeding/Spotting Days by Treatment Cycle and 
Reference Period – Full Analysis Set 
T15_04_05_01_01_sub_no_blsp_fas 
158. 
Table 15.4.6.1.1_add 
Number of Days with Bleeding/Spotting 
by Cycle and Reference Period in BMI Subgroup – 
Full Analysis Set 
T15_04_06_01_01_days_blsp_BMI_fa
s 
159. 
Table 15.4.6.2.1_add 
Number of Days with Unscheduled 
Bleeding/Spotting by Cycle and Reference Period 
in BMI Subgroup – Full Analysis Set 
T15_04_06_02_01_days_ublsp_BMI_f
as 
160. 
Table 15.4.6.3.1_add 
Number of Days with Scheduled 
Bleeding/Spotting by Cycle and Reference Period 
in BMI Subgroup – Full Analysis Set 
T15_04_06_03_01_days_sblsp_BMI_f
as 
161. 
Table 15.4.7.1.1_add 
Number of Days with Bleeding/Spotting 
by Cycle and Reference Period in Weight 
Subgroup – Full Analysis Set 
T15_04_07_01_01_days_blsp_weight_
fas 
162. 
Table 15.4.7.2.1_add 
Number of Days with Unscheduled 
Bleeding/Spotting by Cycle and Reference Period 
in Weight Subgroup – Full Analysis Set 
T15_04_07_02_01_days_ublsp_weight
_fas 
163. 
Table 15.4.7.3.1_add 
Number of Days with Scheduled 
Bleeding/Spotting by Cycle and Reference Period 
in Weight Subgroup – Full Analysis Set 
T15_04_07_03_01_days_sblsp_weight
_fas 
164. 
Table 15.4.7.1.1 
IMP Acceptability Assessment – Full Analysis Set 
T15_04_07_01_01_imp_accept_fas 
165. 
Table 15.4.7.2.1 
Shift table for IMP Acceptability Assessment – 
Full Analysis Set 
T15_04_07_02_01_shift_imp_accept_f
as 
5. Listings 
Appendix tables defined below will be provided in separate .rtf files for each output. 
Seq. 
No 
Table No and Title 
Output file name 
Demographic and Study Population Data 
1.  
Listing 16.2.1.1 
Reasons for Exclusion from Analysis Sets – 
Enrolled Set 
L16_02_01_01_excl_es 
2.  
Listing 16.2.1.2 
Subject’s Disposition – Safety Set 
L16_02_01_02_disp_ss 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 70 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
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Page 69 of 71 
SOP effective date: 18.04.2016 
Version 6 
3.  
Listing 16.2.1.3 
Subject Visits – Enrolled Set 
L16_02_01_03_visits_es 
4.  
Listing 16.2.1.4 
Protocol Deviations Reported by Investigator – 
Enrolled Set 
L16_02_01_04_dev_inv_es 
5.  
Listing 16.2.1.5 
Screening Failures – Enrolled Set 
L16_02_01_05_scrn_fail_es 
6.  
Listing 16.2.1.6 
Inclusion Criteria Not Met and Exclusion Criteria 
Met 
L16_02_01_06_incl_excl_es 
7.  
Listing 16.2.1.7 
Demographics – Enrolled Set 
L16_02_01_07_demo_es 
8.  
Listing 16.2.1.8 
Substance Use – Enrolled Set 
L16_02_01_08_subst_use_es 
9.  
Listing 16.2.1.9 
Medical History – Enrolled Set 
L16_02_01_09_mh_es 
10.  
Listing 16.2.1.10 Gynecological History – Enrolled Set 
L16_02_01_10_gyn_his_es 
11.  
Listing 16.2.1.11 VTE Risk Factors – Enrolled Set 
L16_02_01_11_vte_es 
12.  
Listing 16.2.1.12 Menstrual History – Enrolled Set 
L16_02_01_12_menstr_his_es 
13.  
Listing 16.2.1.13 Prior and Concomitant Medications, Therapies and 
Contraception – Enrolled Set 
L16_02_01_13_cm_es 
14.  
Listing 16.2.1.14 Drug Accountability – Enrolled Set 
L16_02_01_14_drug_account_es 
15.  
Listing 16.2.1.15 Treatment Compliance According to Drug 
Accountability – Enrolled Set 
L16_02_01_15_compl_es 
Efficacy Data 
16.  
Listing 16.2.2.1 
Pregnancy Determination – Enrolled Set 
L16_02_02_01_preg_determ_es 
17.  
Listing 16.2.2.2 
Pregnancy Outcome – Enrolled Set 
L16_02_02_02_preg_out_es 
18.  
Listing 16.2.2.3 
Subjects’ Decision to Become Pregnant – Enrolled 
Set 
L16_02_02_03_decis_preg_es 
Safety Data 
19.  
Listing 16.2.3.1 
Adverse Event: General – Enrolled Set 
L16_02_03_01_ae_es 
20.  
Listing 16.2.3.2 
Adverse Event: MedDRA Coding – Enrolled Set 
L16_02_03_02_ae_meddra_es 
21.  
Listing 16.2.3.3 
Serious Adverse Event – Enrolled Set 
L16_02_03_03_sae_es 
22.  
Listing 16.2.3.4 
TEAEs Leading to Trial Termination - Enrolled 
Set 
L16_02_03_04_teae_term_es 
23.  
Listing 16.2.3.5 
TEAEs of Special Interest – Enrolled Set 
L16_02_03_05_teae_sp_int_es 
24.  
Listing 16.2.4.1 
Vital Signs – Enrolled Set 
L16_02_04_01_vs_es 
25.  
Listing 16.2.5.1 
Laboratory Data: Hematology – Enrolled Set 
L16_02_05_01_hema_es 
26.  
Listing 16.2.5.2 
Laboratory Data: Biochemistry – Enrolled Set 
L16_02_05_02_bioch_es 
27.  
Listing 16.2.5.3 
Laboratory Data: Urinalysis – Enrolled Set 
L16_02_05_03_urin_es 
28.  
Listing 16.2.5.4 
Laboratory Data: Pregnancy Test – Enrolled Set 
L16_02_05_04_preg_es 
29.  
Listing 16.2.6.1 
Physical Examination – Enrolled Set 
L16_02_06_01_pe_es 
30.  
Listing 16.2.7.1 
Gynecological Examination – Enrolled Set 
L16_02_07_01_gyn_exam_es 
31.  
Listing 16.2.7.2 
Transvaginal Ultrasound Examination – Enrolled 
Set 
L16_02_07_02_transv_exam_es 
32.  
Listing 16.2.7.3 
Dysmenorrhea Characteristic – Enrolled Set 
L16_02_07_03_dysm_char_es 
33.  
Listing 16.2.7.4 
Mastodynia/Mastalgia – Enrolled Set 
L16_02_07_04_mastod_char_es 
34.  
Listing 16.2.8.1 
Cervical Cytology Results – Enrolled Set 
L16_02_08_01_cytol_es 
Tolerability Data 
35.  
Listing 16.2.9.1 
Treatment Diary – Full Analysis Set 
L16_02_09_01_diary_fas 
36.  
Listing 16.2.10.1 IMP Acceptability Assessment – Full Analysis Set 
L16_02_10_01_imp_accept_fas 
6. Figures 
Appendix figures defined below will be provided in separate .rtf files for each output. 
Seq. 
No 
Table No and Title 
Output file name 
Demographic and Study Population Data 
1.  
Figure 15.1.1.1 
Flow Chart of Subject Disposition – Enrolled Set 
F15_01_01_01_disp_es 
2.  
Figure 15.1.2.1 
Flow Chart of Analysis Sets – Enrolled Set 
F15_01_02_01_anal_es 
Tolerability Data 
3.  
15.2.1.1_add 
Overall Pearl Index in Non-Breastfeeding Women 
by BMI and Race (Black or African-American vs 
White) (Only Confirmed Pregnancies, Excluding 
Sites 104 and 120) – Modified Full Analysis Set 
F15_02_01_01_PI_over_BMI_C_E_ra
ce_mfas 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 71 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 70 of 71 
SOP effective date: 18.04.2016 
Version 6 
4.  
Figure 15.2.1.2_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Race (Black or African-
American vs White) (Only Confirmed Pregnancies, 
Including Sites 104 and 120) – Modified Full 
Analysis Set 
F15_02_01_02_PI_over_BMI_C_I_rac
e_mfas 
5.  
Figure 15.2.1.3_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Race (Black or African-
American vs White) (Confirmed and Suspected, 
Non-confirmed Pregnancies, Excluding Sites 104 
and 120) – Modified Full Analysis Set 
F15_02_01_03_PI_over_BMI_CS_E_r
ace_mfas 
6.  
Figure 15.2.1.4_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Race (Black or African-
American vs White) (Confirmed and Suspected, 
Non-confirmed Pregnancies, Including Sites 104 
and 120) – Modified Full Analysis Set 
F15_02_01_04_PI_over_BMI_CS_I_r
ace_mfas 
7.  
Figure 15.2.2.1_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Ethnicity (Only Confirmed 
Pregnancies, Excluding Sites 104 and 120) – 
Modified Full Analysis Set 
F15_02_02_01_PI_over_BMI_C_E_et
hnicity_mfas 
8.  
Figure 15.2.2.2_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Ethnicity (Only Confirmed 
Pregnancies, Including Sites 104 and 120) – 
Modified Full Analysis Set 
F15_02_02_02_PI_over_BMI_C_I_eth
nicity_mfas 
9.  
Figure 15.2.2.3_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Ethnicity (Confirmed and 
Suspected, Non-Confirmed Pregnancies, Excluding 
Sites 104 and 120) – Modified Full Analysis Set 
F15_02_02_03_PI_over_BMI_CS_E_
ethnicity_mfas 
10.  
Figure 15.2.2.4_add 
Overall Pearl Index in Non-Breastfeeding 
Women by BMI and Ethnicity (Confirmed and 
Suspected, Non-confirmed Pregnancies, Including 
Sites 104 and 120) – Modified Full Analysis Set 
F15_02_02_04_PI_over_BMI_CS_I_e
thnicity_mfas 
11.  
Figure 15.2.3.1_add 
Pearl Index Based on Evaluable Cycles in 
Non-Breastfeeding Women by BMI and Race 
(Black or African-American vs White) (Only 
Confirmed Pregnancies, Excluding Sites 104 and 
120) – Modified Full Analysis Set 
F15_02_03_01_PI_eval_BMI_C_E_ra
ce_mfas 
12.  
Figure 15.4.1.1 
Subjects with Bleeding by Treatment Day – Full 
Analysis Set 
F15_04_01_01_sub_bleed_day_fas 
13.  
Figure 15.4.1.2 
Subjects with Bleeding by Treatment Cycle – Full 
Analysis Set 
F15_04_01_02_sub_bleed_cyc_fas 
14.  
Figure 15.4.1.3 
Subjects with Bleeding by Reference Period – Full 
Analysis Set 
F15_04_01_03_sub_bleed_ref_fas 
15.  
Figure 15.4.2.1 
Subjects with Scheduled and Unscheduled 
Bleeding Days by Treatment Cycle – Full Analysis 
Set 
F15_04_02_01_sub_subleed_cyc_fas 
16.  
Figure 15.4.2.2 
Subjects with Scheduled and Unscheduled 
Bleeding Days by Reference Period – Full Analysis 
Set 
F15_04_02_02_sub_subleed_ref_fas 
17.  
Figure 15.4.4.1 
Scheduled and Unscheduled Bleeding Days by 
Cycle – Full Analysis Set 
F15_04_04_01_subleed_day_cyc_fas 
18.  
Figure 15.4.4.2 
Scheduled and Unscheduled Bleeding Days by 
Reference Period – Full Analysis Set 
F15_04_04_02_subleed_day_ref_fas 
19.  
Figure 15.4.5.1 
Subjects with Spotting by Treatment Day – Full 
Analysis Set 
F15_04_05_01_sub_spot_day_fas 
20.  
Figure 15.4.5.2 
Subjects with Spotting by Treatment Cycle – Full 
Analysis Set 
F15_04_05_02_sub_spot_cyc_fas 
21.  
Figure 15.4.5.3 
Subjects with Spotting by Reference Period – Full 
Analysis Set 
F15_04_05_03_sub_spot_ref_fas 
22.  
Figure 15.4.6.1 
Subjects with Scheduled and Unscheduled Spotting 
Days by Treatment Cycle – Full Analysis Set 
F15_04_06_01_sub_suspot_cyc_fas 
23.  
Figure 15.4.6.2 
Subjects with Scheduled and Unscheduled Spotting 
Days by Reference Period – Full Analysis Set 
F15_04_06_02_sub_suspot_ref_fas 
24.  
Figure 15.4.7.1 
Bleeding/Spotting Episodes by Reference Period – 
Full Analysis Set 
F15_04_07_01_epis_ref_fas 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 72 of 256


Sponsor: Laboratorios León Farma S.A. 
Protocol no. CF111/303 
Statistical Analysis Plan, Version v1.0 
14-DEC-2017 
 
I-DM-011-06-A1(SAP_template).docx 
Page 71 of 71 
SOP effective date: 18.04.2016 
Version 6 
25.  
Figure 15.4.8.1 
Scheduled and Unscheduled Spotting Days by 
Cycle – Full Analysis Set 
F15_04_08_01_suspot_day_cyc_fas 
26.  
Figure 15.4.8.2 
Scheduled and Unscheduled Spotting Days by 
Reference Period – Full Analysis Set 
F15_04_08_02_suspot_day_ref_fas 
27.  
Figure 15.4.9.1_add 
Subjects with Bleeding/Spotting by 
Treatment Day – Full Analysis Set 
F15_04_09_01_sub_blsp_day_fas 
28.  
Figure 15.4.9.2_add 
Subjects with Bleeding/Spotting by 
Treatment Cycle – Full Analysis Set 
F15_04_09_02_sub_blsp_cyc_fas 
29.  
Figure 15.4.9.3_add 
Subjects with Bleeding/Spotting by 
Reference Period – Full Analysis Set 
F15_04_09_03_sub_blsp_ref_fas 
30.  
Figure 15.4.10.1_add 
Subjects with Scheduled and 
Unscheduled Bleeding/Spotting Days by Treatment 
Cycle – Full Analysis Set 
F15_04_10_01_sub_sublsp_cyc_fas 
31.  
Figure 15.4.10.2_add 
Subjects with Scheduled and 
Unscheduled Bleeding/Spotting Days by Reference 
Period – Full Analysis Set 
F15_04_10_02_sub_sublsp_ref_fas 
32.  
Figure 15.4.11.1_add 
Scheduled and Unscheduled 
Bleeding/Spotting Days by Cycle – Full Analysis 
Set 
F15_04_11_01_sublsp_day_cyc_fas 
33.  
Figure 15.4.11.2_add 
Scheduled and Unscheduled 
Bleeding/Spotting Days by Reference Period – Full 
Analysis Set 
F15_04_11_02_sublsp_day_ref_fas 
 
Laboratorios León Farma S.A.
Clinical Trial Report CF111/303
Final Version 2.0
Appendix 16.1.9 - Page 73 of 256