A Phase 3, Open-label, Multi-center, Single-arm Study to Assess Contraceptive Efficacy and Safety of the Nomegestrol Acetate + 17β-estradiol Combined Oral Contraceptive (OG-8175A) in Premenopausal Females Aged 14 to 35 Years (Inclusive)
Phase: PHASE3
Conditions: Contraception
Sponsor: Organon and Co

Protocol 
Title:  A Phase 3, Open-label, Multi-center, Single-arm Study to Assess 
Contraceptive Efficacy and Safety of the Nomegestrol Acetate + 17β-estradiol 
Combined Oral Contraceptive (OG-8175A) in Premenopausal Females Aged 14 
to 35 Years (Inclusive) 
NCT Number:  NCT05264506  
Document Date:  30 August 2022 
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TITLE PAGE 
Protocol Title: A Phase 3, Open-label, Multi-center, Single-arm Study to Assess Contraceptive 
Efficacy and Safety of the Nomegestrol Acetate + 17β-estradiol Combined Oral Contraceptive 
(OG-8175A) in Premenopausal Females Aged 14 to 35 Years (Inclusive) 
Protocol Number: OG-8175A-023 
Amendment Number: Amendment 2 
Product: OG-8175A (Nomegestrol acetate and 17β-estradiol) 
Short Title: Contraceptive Efficacy and Safety of the NOMAC-E2 Combined Oral 
Contraceptive 
Study Phase: Phase 3 
Sponsor Name: Organon LLC., a subsidiary of Organon & Co. 
Legal Registered Address: 
Organon & Co. 
30 Hudson Street 
33rd floor 
Jersey City, NJ USA 
07302 
Regulatory Agency Identifying Number(s): 
Date of Protocol: 30 August 2022 
STATEMENT OF CONFIDENTIALITY 
This confidential information about an investigational product is provided for the exclusive use of 
Investigators of this product and is subject to recall at any time. The information in this document 
may not be disclosed unless such disclosure is required by law or regulation. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have 
a need to know, with the obligation not to disseminate this information further. These restrictions 
on disclosure will apply equally to all further oral or written information supplied to you by 
Organon LLC. and its affiliates (collectively, “Organon”) and representatives of Organon, which 
is designated as “Privileged” or “Confidential”. 
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Sponsor Signatory: 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
This document is signed electronically. See the last page of the protocol for Sponsor signature. 
 
 
Date 
Investigator Agreement Page is provided in Appendix 7. The Investigator should retain the 
original in the study site study files and return a copy to the Sponsor or Contract Research 
Organization for archiving. 
Each Investigator should be sent a copy of the Investigator Agreement Page for completion. 
Signatures are obtained after the Sponsor has finalized and approved the protocol. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 2 
30 August 2022 
No 
Global 
Amendment 1 
01 December 2021 
Yes 
Global 
Original Protocol 
28 July 2021 
- 
- 
Amendment 2 (30 August 2022) 
Rationale for the Amendment: This amendment was prepared to describe the potential splitting 
of Visit 1 into two separate days, to clarify study procedures for pregnancy testing and reporting 
in relation to the first tablet intake, the starting advice for non-users of hormonal contraception, 
the PAP test exclusion criterion #7, tests to be done at local and/or central laboratory, and to add 
tablet-intake advice in case of gastrointestinal disturbance. 
Table 2 
Description of Changes in Amendment 2 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 Schema 
Schema updated. 
To include an additional phone visit 
before treatment and a minimum 
visit window for screening. 
Section 1.3 Schedule of Activities 
Added phone visit (P1) before the 
start of treatment. 
To inform the participant of the 
results of the serum β-hCG test 
performed at the V2 visit and to 
review e-Diary instructions. 
Added AE assessment for P1 Visit. 
To collect pre-treatment AEs. 
Additional assessment added at V2 
for contraception history. 
Contraception status to be evaluated 
at V2 before treatment is allocated. 
Footnote ‘a’ added to clarify that the 
screening visit can be split into two 
separate days, if required, and to 
clarify the duration between V1 and 
V2. 
To allow the participant to complete 
the Screening Visit if they cannot 
complete all assessments on the 
same day and to prevent enrollment 
of participants without all the 
eligibility criteria confirmed. 
Footnote ‘b’ added. 
To clarify the purpose of phone 
contact P1. 
Footnote ‘f’ revised. 
To indicate that drug intake will not 
occur at V2. 
A new footnote ‘h’ was added 
corresponding to the row for serum 
β-hCG. 
To reference that the V2 serum 
β-hCG test result will be 
communicated to the participant at 
P1 and that a negative V2 serum β-
hCG test result and a negative urine 
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Section # and Name 
Description of Change 
Brief Rationale 
home pregnancy test result on the 
intended day of tablet intake are 
both required prior to the first tablet 
intake. 
Footnote ‘i’ revised. 
To clarify that urine pregnancy tests 
must be performed at the site before 
treatment allocation and at all other 
visits as well as at home just before 
the intake of the first tablet of study 
drug and before the start of all 
subsequent blisters. 
Footnote ‘k’ revised. 
P5 changed to P6 due to additional 
phone contact P1 being added to the 
schedule. 
Footnote ‘n’ revised. 
To add that BMI should also be 
calculated at enrollment, in addition 
to the Screening Visit, and that cm 
and 
kg 
should 
be 
used 
as 
measurement units. 
The following text was added to 
footnote ‘p’: 
“Testing for STIs must be 
performed by a local laboratory.” 
To clarify that STI panel must be 
tested in a local laboratory. 
Deleted superscript associated with 
urinary pregnancy test for 
assessments corresponding to V3, 
V4, V5, V6. EOT and V7. 
Footnotes reordered. 
Section 1.1 Synopsis (Objectives 
and Endpoints) 
Section 3.0 (Objectives and 
Endpoints) 
Section 8.2.3.2 Study Treatment 
Compliance 
Section 9.3.4 Per-Protocol Analysis 
and Protocol Deviations 
Rephrased the following wording:  
“protocol violations” changed to 
“protocol deviations”. 
For consistency. 
Section 1.1 Synopsis (Overall 
Design) 
Section 4.1 Overall Design 
Text added to clarify the time to 
schedule V2 (between 7 and 42 
days after V1) andclarify that the 
screening visit can be split into two 
separate days, if required. 
To allow the participant to complete 
the Screening Visit if they cannot 
complete all assessments on the 
same day. 
A paragraph was revised, and the 
following text was added: 
“Participants will also receive urine 
home pregnancy tests, the first of 
which should be performed just 
before the first study drug intake of 
the first cycle. A serum pregnancy 
test will also be performed at V2, 
To describe that negative urine 
pregnancy tests will be required for 
the first study drug intake and at the 
beginning 
of 
each 
subsequent 
treatment cycle, to reference that the 
V2 serum β-hCG test result will be 
communicated to the participant at 
P1, and that a negative V2 serum 
β-hCG test result and a negative 
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Section # and Name 
Description of Change 
Brief Rationale 
and 
the 
results 
will 
be 
communicated to the participant via 
phone 
contact 
(P1). 
Before 
participants may begin study drug, a 
negative V2 serum β-hCG test 
result, in combination with a 
negative urine home pregnancy test 
result just before the first tablet 
intake, are both required. At P1 the 
e-Diary 
instructions 
will 
be 
reviewed too, in particular to ensure 
adequate recording of the home 
pregnancy test and start of the first 
blister at first tablet intake. […] 
Participants must also perform a 
urine home pregnancy test at the 
beginning 
of 
each 
subsequent 
treatment cycle, which must be 
negative in order to continue tablet 
intake.”. 
urine home pregnancy test result on 
the intended day of tablet intake are 
both required prior to the first tablet 
intake. 
On-treatment phone contact visits 
were updated from “P1 to P5” to “P2 
to P6”. 
Text 
correction 
to 
incorporate 
additional phone contact (P1) before 
treatment. 
Section 5.2. Exclusion Criteria 
The following text was added to 
exclusion criterion #7: 
“The presence of atypical squamous 
cells of undetermined significance 
(ASCUS) will require HPV reflex 
testing; ASCUS in an HPV-negative 
patient is not exclusionary.”. 
To clarify the interpretation of PAP 
results 
with 
respect 
to 
trial 
eligibility. 
Section 5.4 Screen Failures 
Table 8 
8.2.1.2 Pregnancy 
Rephrased the following wording: 
“data entry guidelines” changed to 
“eCRF completion guidelines”. 
For accuracy. 
Section 6.4.1 Timing of the first 
dose 
The bold text was added: 
“Before participants can begin study 
drug, a negative Visit 2 serum β-
hCG test result, in combination 
with a negative urine home 
pregnancy test result, are both 
required. 
The 
urine 
home 
pregnancy test must be performed 
on the same day as the (intended) 
first tablet intake and must be 
performed before the first tablet 
intake of study drug.”. 
To clarify the importance of the 
serum pregnancy test performed at 
V2. 
The following advice was added: 
“If the first dose is delayed until the 
start of a subsequent menstrual 
cycle, a condom must be used until 
start of study drug on Day 1 of the 
To clarify the requirements and 
timing of first dose. 
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Section # and Name 
Description of Change 
Brief Rationale 
subsequent menstrual period.”. 
 
Note revised (bold text was added): 
“Participants using a non-hormone 
medicated 
intrauterine 
device 
should have the device removed 
prior to starting study drug. They 
should start the study drug on the 
first day of the next menstrual 
period. A condom must be used 
until start of study drug. Starting 
between Days 2 and 5 of the next 
menstrual period is also allowed, 
but in this case a condom must be 
used until the participant has 
completed 7 days of uninterrupted 
active study treatment”. 
Section 6.4.2 Management of 
Missed NOMAC-E2 Tablets 
Advice was added for GI 
disturbances. 
To provide guidance for managing 
a condition that was not yet 
described in the protocol. 
Section 6.7 Treatment After the 
End of Study 
Sentence rephrased (text added in 
bold and deletions in strikethrough): 
 
An additional barrier method (ie, 
condoms) 
or 
abstinence 
is 
recommended (ie, condoms) for 1 
week (or longer if indicated by the 
labeling of the newly started 
method) 
to 
minimize 
risk 
of 
conception during the switch in 
methods of contraception. 
For clarity. 
Section 8.1.5.1 Prior Medications 
Updated the definition of prior 
medications (text added in bold and 
deletions in strikethrough): 
All prior medication taken by the 
participant 
(defined 
as 
any 
medications reported up to the 
first study drug intake) within the 
2 months before V2 should be 
recorded. 
For correction. 
Section 8.2.1.2 Pregnancy 
The following sentence was edited 
(text added in bold and deletions in 
strikethrough): 
Information Data should be 
recorded on the Pregnancy Report 
appropriate pregnancy eCRF. 
Strikethrough text was deleted: 
Any AE related to the infant must be 
reported on the eCRF for capturing 
these data, not in the AEs eCRF for 
For accuracy. 
For correction. There is no specific 
AE eCRF for infants. 
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Section # and Name 
Description of Change 
Brief Rationale 
participants. 
8.2.3.1 Participant e Diary 
Moved the following text about data 
to be collected in the e-Diary from 
‘optional information’ to ‘monthly 
information’: “Start of a new blister, 
triggering 
recording 
of 
the 
information below”. 
Correction. 
8.2.3.1.2 Monthly e Diary 
Questions (Before Starting a New 
Blister) 
The following sentence was 
deleted: 
“The e Diary will allow these 
additional questions to be answered 
for a period of 4 days, after which, 
data entry will be locked out.”. 
Correction. 
8.2.3.3 Monitoring “at-risk” Cycle 
Compliance 
Revised sentence (text added in bold 
and deletions in strikethrough): 
“Sites will be notified if participants 
are non-compliant with the protocol 
(ie, cycles not at risk or entries 
missing such that a cycle is 
considered not at risk) on a per 
cycle basis for 2 consecutive cycles 
and are expected to contact the 
participant to reinforce compliance 
with the study protocol”. 
Correction. Sites are being contacted 
on a per cycle basis when issues with 
study compliance are identified. 
8.3.2 
Gynecologic and Breast 
Examinations 
Strikethrough text was deleted: 
“Only abnormal findings should be 
recorded on the appropriate eCRF; 
either as medical history (if obtained 
at screening and before treatment 
allocation [V2]) or an AE (if 
reported after treatment allocation 
[V2])”. 
Correction to be consistent with the 
current record period of AEs which 
will be from the time of signing ICF 
(not screening). 
8.3.4 
Clinical Safety Laboratory 
Assessments 
Sentence revised (text added in bold 
and deletions in strikethrough): 
“Screening 
may 
be 
performed 
between 7 days and 42 days up to 
6 weeks before V2”. 
To add a minimum visit window for 
the Screening Visit. 
8.4 
Adverse Events 
Revised paragraphs (text added in 
bold and deletions in strikethrough): 
“The definitions of an AE or SAE, 
as well as the method of recording, 
evaluating, and assessing causality 
of AE and SAE and the procedures 
for completing and transmitting AEs 
and SAEs, and other reportable 
safety event reports can be found in 
For consistency with the standard 
process of AE classification and 
reporting. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 4”. 
“The Investigator, who is a qualified 
physician, will assess events that 
meet the definition of an AE or SAE 
as well as other reportable safety 
events with respect to seriousness, 
intensity/toxicity and causality”. 
Section 8.4.1 Time Period and 
Frequency for Collecting AE and 
SAE information  
Revised text to clarify that the AE 
reporting 
period 
begins 
with 
‘signing of ICF’ and not ‘screening 
(V1)’ since the screening visit may 
be split into 2 days, if required. 
Revised the AE reporting period in 
Table 8.  
To clarify the reporting time period 
for adverse events. 
Deleted ‘study drug’ from the 
reporting criteria for AEs for V1 or 
V2 visit from Table 8. 
Added ‘or’. 
There 
is 
no 
study 
drug 
administration 
at 
V1 
or 
V2; 
therefore, there will be no AEs due 
to study drug on these visits. 
Section 9.4.3 Safety Analysis 
Text in strikethrough was deleted:  
“The on-treatment period will be 
defined as the period from the day of 
first tablet intake up to and including 
the day of last active study drug 
intake, extended by 14 days. 
However, any delayed events or 
diagnoses judged by the Investigator 
as well as Sponsor to be related to 
study drug will also be considered to 
have occurred on-treatment and will 
be included in the safety analysis”. 
To 
clarify 
that 
Sponsor’s 
assessments of delayed events or 
related events is not necessary for 
statistical analysis of safety. 
Section 9.4.3.2 Laboratory 
Parameters 
Bold text added: 
“Routine 
hematology 
and 
biochemistry parameters measured 
at V1 (screening) and V7 (EOS or 
ET) will be determined by a central 
laboratory, 
unless 
the 
central 
laboratory 
results 
are 
not 
available in time for 
either 
starting 
study 
treatment 
administration and/or response 
evaluation. 
The 
sexually 
transmitted infections (STI) panel 
testing will be performed by a 
local laboratory”. 
To accommodate sites’ request for 
documentation 
in 
protocol 
of 
laboratory assessments required to 
be performed locally. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 3 
Text was added to clarify that STI 
testing will be performed locally, 
and that urine pregnancy tests will 
be performed on-site or at the 
participant’s home. 
The sentence “The results of each 
test must be entered into the eCRF” 
was deleted. 
Table 12 was updated to indicate the 
STI assessment. 
To accommodate sites’ request for 
documentation 
in 
protocol 
of 
laboratory assessments required to 
be performed locally.  
 
Correction, since not all laboratory 
test results will be entered into the 
eCRF. 
Appendix 4 
A paragraph was added as an 
additional example of events not 
meeting the AE definition. 
‘Assessment 
of 
Intensity’ 
was 
changed 
to 
“Assessment 
of 
Severity”, and the text was revised 
accordingly. 
The text regarding SAE reporting to 
Sponsor via an Electronic Data 
Collection System or via Paper SAE 
Report Form was revised for clarity. 
For consistency with the standard 
process of AE classification and 
reporting. 
Appendix 5 
The following text was added:“In 
addition to the negative Visit 2 
serum β-hCG test result, it is 
required to have a negative urine 
home pregnancy test result on the 
day of the intended first tablet 
intake, just prior to the actual first 
tablet intake”. 
To clarify the importance of the 
serum pregnancy test performed at 
V2. 
Signature Page 
Updated the sponsor signatory. 
Administrative update. 
Deleted the text “Medical Monitor 
name and contact information can be 
found in Appendix 2”. 
Correction. 
Throughout 
Minor 
editorial 
and 
document 
formatting revisions. 
Minor, therefore, have not been 
summarized. 
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...........................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF CONTENTS ......................................................................................................10 
LIST OF TABLES .................................................................................................................14 
LIST OF FIGURES ...............................................................................................................15 
1.0 
PROTOCOL SUMMARY ........................................................................................16 
1.1 
Synopsis ...........................................................................................................16 
1.2 
Schema ............................................................................................................23 
1.3 
Schedule of Activities .....................................................................................24 
2.0 
INTRODUCTION......................................................................................................28 
2.1 
Study Rationale ..............................................................................................28 
2.2 
Background ....................................................................................................29 
2.3 
Benefit/Risk Assessment ................................................................................31 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................32 
4.0 
STUDY DESIGN ........................................................................................................34 
4.1 
Overall Design ................................................................................................34 
4.2 
Scientific Rationale for Study Design ...........................................................36 
4.3 
Justification for Dose .....................................................................................36 
4.4 
End of Study Definition .................................................................................36 
5.0 
STUDY POPULATION ............................................................................................37 
5.1 
Inclusion Criteria ...........................................................................................37 
5.2 
Exclusion Criteria ..........................................................................................37 
5.3 
Lifestyle Considerations ................................................................................40 
5.4 
Screen Failures ...............................................................................................40 
6.0 
STUDY TREATMENT .............................................................................................42 
6.1 
Study Treatment(s) Administered ................................................................42 
6.2 
Preparation/Handling/Storage/Accountability ...........................................42 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................43 
6.4 
Study Drug Intake..........................................................................................43 
6.4.1 
Timing of the First Dose ....................................................................43 
6.4.2 
Management of Missed NOMAC-E2 Tablets ...................................44 
6.5 
Dose Modification ..........................................................................................45 
6.6 
Concomitant Therapy ....................................................................................45 
6.6.1 
Prohibited Medications ......................................................................46 
6.6.2 
Rescue Medicine ...............................................................................47 
6.7 
Treatment After the End of the Study .........................................................47 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................49 
7.1 
Strategies to Minimize Participant Discontinuation/Withdrawal .............49 
7.2 
Discontinuation of Study Treatment ............................................................49 
7.3 
Participant Discontinuation/Withdrawal from the Study .........................51 
7.4 
Lost to Follow-up ...........................................................................................51 
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8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................52 
8.1 
General Assessments ......................................................................................53 
8.1.1 
Inclusion and Exclusion Criteria .......................................................53 
8.1.2 
Participant Identification Card ..........................................................53 
8.1.3 
Assignment of Screening Number .....................................................53 
8.1.4 
Assignment of Treatment Number ....................................................53 
8.1.5 
Prior and Concomitant Medications ..................................................53 
8.1.5.1 
Prior Medications ............................................................53 
8.1.5.2 
Concomitant Medications ................................................54 
8.1.6 
Medical and Contraceptive History ...................................................54 
8.1.7 
Gynecologic and Obstetric History ...................................................54 
8.2 
Efficacy Assessments .....................................................................................54 
8.2.1 
Assessment of On-treatment Pregnancy ............................................54 
8.2.1.1 
Pregnancy Testing ...........................................................54 
8.2.1.1.1 
Urine Home Pregnancy Test ...................55 
8.2.1.2 
Pregnancy ........................................................................55 
8.2.1.2.1 
Ultrasound Dating of Confirmed 
Pregnancies ..............................................56 
8.2.2 
Vaginal Bleeding Event .....................................................................56 
8.2.3 
Compliance ........................................................................................57 
8.2.3.1 
Participant e-Diary ...........................................................57 
8.2.3.1.1 
Daily e-Diary Questions ..........................58 
8.2.3.1.2 
Monthly e-Diary Questions 
(Before Starting a New Blister) ...............58 
8.2.3.1.3 
Monitoring e-Diary Compliance .............59 
8.2.3.2 
Study Treatment Compliance ..........................................59 
8.2.3.3 
Monitoring “at-risk” Cycle Compliance .........................60 
8.3 
Safety Assessments .........................................................................................60 
8.3.1 
Physical Examinations .......................................................................60 
8.3.2 
Gynecologic and Breast Examinations ..............................................60 
8.3.3 
Vital Signs, Body Weight, and Height ..............................................61 
8.3.4 
Clinical Safety Laboratory Assessments ...........................................61 
8.4 
Adverse Events ...............................................................................................62 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................62 
8.4.2 
Method of Detecting AEs and SAEs .................................................63 
8.4.3 
Follow-up of AEs and SAEs .............................................................64 
8.4.4 
Regulatory Reporting Requirements for SAEs .................................64 
8.4.5 
Events of Clinical Interest .................................................................64 
8.5 
Treatment of Overdose ..................................................................................65 
8.6 
Pharmacokinetics and Pharmacodynamics .................................................65 
8.7 
Genetics ...........................................................................................................66 
8.8 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................66 
8.9 
Changes to Study Procedures Due to COVID-19 Pandemic .....................66 
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9.0 
STATISTICAL CONSIDERATIONS .....................................................................68 
9.1 
Statistical Hypotheses ....................................................................................68 
9.2 
Sample Size Determination ...........................................................................68 
9.2.1 
Main Analysis ....................................................................................68 
9.2.2 
Pharmacokinetic Analysis .................................................................69 
9.3 
Populations for Analyses ...............................................................................70 
9.3.1 
Full Analysis Set ................................................................................70 
9.3.2 
Contraceptive Efficacy Analysis Populations ...................................70 
9.3.2.1 
Restricted Full Analysis Set ............................................70 
9.3.2.2 
Per Protocol 1 Population ................................................70 
9.3.3 
Vaginal Bleeding Analysis Populations ............................................70 
9.3.4 
Per-Protocol Analysis and Protocol Deviations ................................71 
9.3.5 
Safety Analysis Population ................................................................72 
9.3.6 
Pharmacokinetic Analysis Population ...............................................72 
9.4 
Statistical Analyses.........................................................................................72 
9.4.1 
General Considerations .....................................................................72 
9.4.2 
Efficacy Analyses ..............................................................................72 
9.4.2.1 
Contraceptive Efficacy Endpoints ...................................72 
9.4.2.1.1 
Definitions ...............................................72 
9.4.2.2 
Primary Contraceptive Efficacy Endpoint(s) ..................73 
9.4.2.3 
Secondary Contraceptive Efficacy Endpoint(s) ..............74 
9.4.2.4 
One-year Cumulative Pregnancy Rate ............................74 
9.4.2.5 
Vaginal Bleeding Endpoint(s) .........................................75 
9.4.2.5.1 
Cycle Control Analysis ............................75 
9.4.2.6 
Reference Period Analysis ..............................................77 
9.4.3 
Safety Analysis ..................................................................................79 
9.4.3.1 
Adverse Events ................................................................81 
9.4.3.2 
Laboratory Parameters .....................................................81 
9.4.3.3 
Vital Signs and Body Weight ..........................................82 
9.4.3.4 
Physical, Gynecological, and Breast 
Examinations ...................................................................82 
9.4.4 
Other Analysis ...................................................................................82 
9.4.4.1 
Pharmacokinetics .............................................................82 
9.4.4.2 
Demographics, Baseline Characteristics, and 
Disposition .......................................................................82 
9.4.4.3 
Prior and Concomitant Medication .................................83 
9.4.5 
Interim Analysis ................................................................................83 
9.4.6 
Sensitivity Analysis ...........................................................................83 
9.4.7 
Missing Data ......................................................................................83 
9.4.7.1 
Strategies to Minimize Missing Data ..............................83 
9.4.7.2 
How to Handle Missing Data ..........................................83 
10.0 
REFERENCES ...........................................................................................................84 
11.0 
APPENDICES ............................................................................................................86 
Appendix 1 
Abbreviations ...................................................................................86 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations ..........88 
Appendix 3 
Clinical Laboratory Tests ...............................................................94 
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Appendix 4 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................95 
Appendix 5 
Collection of Pregnancy Information ............................................99 
Appendix 6 
Protocol Amendment History .......................................................101 
Appendix 7 
Signature of Investigator ..............................................................108 
 
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LIST OF TABLES  
Table 1 
Document History ..............................................................................................3 
Table 2 
Description of Changes in Amendment 2 ..........................................................3 
Table 3 
Schedule of Activities ......................................................................................24 
Table 4 
Study Objectives and Endpoints ......................................................................32 
Table 5 
Study Treatment Details ..................................................................................42 
Table 6 
Prohibited Medications, Supplements, and Other Substances .........................47 
Table 7 
Blood Volume ..................................................................................................52 
Table 8 
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events .......................................................................63 
Table 9 
Number of at-risk Cycles and Number of Treated Participants 
Required Depending on Expected PI to Achieve an Assumed 80%, 
85% or 90% Power ..........................................................................................69 
Table 10 
Analysis Strategy for Safety Parameters ..........................................................80 
Table 11 
Timeframe Used in the Analysis of Vital Signs and Laboratory 
Parameters ........................................................................................................80 
Table 12 
Protocol-required Safety Laboratory Assessments ..........................................94 
Table 13 
Description of Changes in Amendment 1 ......................................................102 
 
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LIST OF FIGURES  
Figure 1 
Study Schema...................................................................................................23 
 
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1.0 PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: A Phase 3, Open-label, Multi-center, Single-arm Study to Assess Contraceptive 
Efficacy and Safety of the Nomegestrol Acetate + 17β-estradiol Combined Oral Contraceptive 
(OG-8175A) in Premenopausal Females Aged 14 to 35 Years (Inclusive).  
Short Title: Contraceptive Efficacy and Safety of NOMAC-E2 Combined Oral Contraceptive 
Rationale: 
Nomegestrol Acetate + 17β-estradiol (NOMAC-E2; OG-8175A) is a monophasic combined oral 
contraceptive (COC) containing nomegestrol acetate (NOMAC), a nor-progesterone-derived 
progestogen, and 17β-estradiol (E2), an estrogen that is identical to the predominant endogenous 
human estrogen (E2). NOMAC is a highly selective progestogen derived from, and structurally 
similar to, the naturally occurring steroid hormone, progesterone. NOMAC has a strong affinity 
for the human progesterone receptor and has strong anti-gonadotropic activity, moderate 
anti-androgenic activity, and is devoid of any estrogenic, androgenic, glucocorticoid, or 
mineralocorticoid activity. The estrogen contained in NOMAC-E2 is 17β-estradiol, an estrogen 
identical to the predominant endogenous human estrogen. This estrogen differs structurally from 
the estrogen ethinylestradiol (EE) used in other combined hormonal contraceptives (CHC) by the 
lack of the ethinyl group in the 17-α position. 
Phase 2 and 3 clinical studies have shown that NOMAC-E2 has robust contraceptive efficacy, a 
stable vaginal bleeding profile, and a good overall safety and tolerability profile, as compared with 
the COC containing drospirenone (DRSP) 3.0 mg and EE 30 µg. NOMAC-E2 has less pronounced 
effects on metabolic parameters than the levonorgestrel (LNG)-EE 150/30 µg COC. NOMAC-E2 
was first registered in July 2011 and is currently registered and marketed in over 50 countries 
worldwide, including the member states of the European Union, the United Kingdom, and 
Australia. 
 
 
 
 
 
 
 
 
. Mainly, this is a single-arm clinical study that will include the following: 
• A total of 1,878 participants to yield: a) >1,000 participants who will complete 1 year (thirteen 
28-day cycles) of treatment and b) >16,500 28-day cycles of exposure to assess the safety and 
contraceptive efficacy of NOMAC-E2. 
• The demographic characteristics (age, weight, body mass index [BMI; see exclusion criterion 
#15], racial distribution, etc.) as per inclusion/exclusion criteria are targeted to be 
representative of females of childbearing potential in the US. 
• The study assessments are designed to capture all information related to the concomitant use 
of condoms and other forms of contraception during the Treatment Period. 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the contraceptive efficacy of the 
NOMAC-E2 COC based on the number of 
on-treatment pregnancies 
• 
 
 
 
 
 
 
• 
To assess the safety and tolerability of the 
NOMAC-E2 COC 
• 
 
 
• 
 
 
• 
 
 
 
Secondary 
 
• 
To assess the perfect use contraceptive efficacy of 
the NOMAC-E2 COC based on the number of 
on-treatment pregnancies conceived during perfect 
use 
• 
 
 
 
 
 
 
 
• 
To assess the typical use contraceptive efficacy of 
the NOMAC-E2 COC based on the number of 
on-treatment pregnancies conceived during typical 
use 
• 
 
 
 
 
 
 
 
• 
To assess the contraceptive efficacy of the 
NOMAC-E2 COC based on the number of 
on-treatment pregnancies by BMI subgroup 
• 
 
 
 
 
 
• 
To assess the cumulative 1-year pregnancy rates of 
the NOMAC-E2 COC under at-risk, perfect use, 
and typical use circumstances, using Life Table 
Analysis  
• 
 
 
• 
To describe the bleeding profile associated with 
the use of the NOMAC-E2 COC, assessed by 
cycle analysis 
• 
 
 
• 
 
 
• 
 
 
• 
To describe the bleeding occurrence associated 
with the use of the NOMAC-E2 COC, assessed by 
91-day Reference Period Analysis 
• 
 
 
• 
 
 
 
 
 
 
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Objectives 
Endpoints 
 
 
• 
 
 
 
• 
To determine the effects of covariates (body 
weight and BMI) on the PK of NOMAC 
• 
 
 
 
Abbreviations: BMI=body mass index; COC=combined oral contraceptive; NOMAC-E2=nomegestrol acetate + 
17β-estradiol; PI=Pearl Index; PK=pharmacokinetic/s. 
Overall Design: 
This is an open-label, single-arm, multi-center study to assess the contraceptive efficacy and safety 
of the NOMAC-E2 COC in postmenarcheal premenopausal women aged 14 to 35 years (inclusive) 
at the time of study entry. Potential participants must be sexually active and engage in heterosexual 
vaginal intercourse at least once per month with a partner who is not known to be subfertile, 
sterilized, or infertile, and should not routinely use any other form of contraception. 
 
 
 
. It is estimated that 
2,680 women need to be screened. Additionally, primary and secondary contraceptive efficacy 
endpoints will be analyzed 
 
. To evaluate the 
potential for body weight and/or BMI to influence NOMAC exposure, contraceptive efficacy, and 
safety endpoints, the population pharmacokinetics (PK) of NOMAC will be investigated in a 
subset of participants, including covariate and exposure-response analyses.  
During the Screening Visit or Visit 1 (V1), after written informed consent has been obtained, 
participants will have their relevant medical history assessed; undergo a focused physical 
examination as well as breast and gynecological examinations, including sexually transmitted 
infection testing (specifically, gonorrhea and chlamydia, as per guideline recommendations, and 
trichomonas and bacterial vaginosis if clinically indicated) and a PAP smear if indicated. In 
addition, participants will have their height, body weight, and vital signs (heart rate, blood 
pressure) checked; a blood sample taken for evaluation of pregnancy, blood biochemistry and 
hematology; and a urine sample taken for urinalysis. Participants will also be instructed on the use 
of the electronic diary (e-Diary), which will have to be completed on a daily basis, to document 
their vaginal bleeding experience and their intake of study drug (to be documented after treatment 
allocation). Participants’ compliance to complete the e-Diary daily will be monitored for at least 
7 days prior to treatment allocation to determine their ability to complete the e-Diary daily. 
Depending on receipt of laboratory results and the participants’ current contraceptive method or 
the timing of the participants’ menstrual cycle, eligible participants will visit the site for allocation 
to treatment, which is to be scheduled between 7 and 42 days after V1. The Screening Visit may 
be split into 2 separate days if the participant is not able to complete all assessments on the same 
day. 
At the Treatment Allocation Visit (V2), the participant will receive the study drug after a negative 
on-site urine pregnancy test and if she meets eligibility criteria related to e-Diary completion (see 
inclusion criterion #6). Participants will also receive urine home pregnancy tests, which should be 
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performed just before the first study drug intake of each cycle. A serum pregnancy test will also 
be performed at V2, and the results will be communicated to the participant via phone contact (P1). 
Before participants may begin study drug, a negative V2 serum β-hCG test result, in combination 
with a negative urine home pregnancy test result just before the first tablet intake, are both required. 
At the beginning of each subsequent treatment cycle, participants must document in the e-Diary 
whether they have been involved in heterosexual vaginal intercourse during the preceding cycle 
and whether contraceptive methods other than the study drug have been used. Participants must 
also perform a urine home pregnancy test at the beginning of each subsequent treatment cycle, 
which must be negative in order to continue tablet intake. A urine home pregnancy test should also 
be performed within 48 hours after the last tablet from the last blister of study drug has been taken. 
During the Treatment Period, participants will visit the site shortly following completion of 
Cycles 1, 4, 7, 10 and 13 (V3-V7). At each of these visits, a blood sample for serum β-hCG will 
be taken, body weight and vital signs will be measured, and the use of concomitant medication 
and occurrence of adverse events (AEs) will be assessed. Testing for gonorrhea and chlamydia 
will be conducted at V6 (in addition to V1). Testing for trichomonas and bacterial vaginosis may 
be repeated during the study, if clinically indicated (ie, if abnormal vaginal discharge is present). 
Pre- and post-dose PK samples will be taken in a subset of the study population (approximately 
200 participants) during V3 and V4 and are to be scheduled between Day 7 and Day 12 of the 
corresponding cycle (ie, within the +5-day window for Cycle 2 and Cycle 5, respectively). 
Sufficient amount of study drug will be provided to cover treatment until one cycle after the next 
scheduled study visit. In addition, compliance with e-Diary entries and study drug use will be 
reviewed, and additional training provided as needed for participants who continue to incorrectly 
or incompletely fill out the e-Diary or who use the study drug incorrectly. Participants who are 
repeatedly non-compliant with study drug use or with e-Diary entries may be discontinued at the 
discretion of the Investigator. Phone contacts (P2 to P6) between the on-site visits are planned to 
monitor the participants’ compliance with the use of study drug and completion of e-Diaries, assess 
the at-risk status of their cycles, provide additional training when needed, and answer any 
questions. 
The Post-Treatment Visit (Visit 7/End of Study [EOS]) is the last site visit and includes the EOS 
assessments and is conducted either at study completion or after Early Termination (ET), 14 days 
after completion of the last treatment cycle. Participants will undergo a focused physical 
examination as well as breast and gynecological examinations, have their body weight and vital 
signs measured, and have a blood sample taken for evaluation of blood biochemistry including 
β-hCG, and hematology. The use of concomitant medication, including the initiation of post-study 
contraception, and occurrence of AEs will be assessed. 
The total duration of study participation will be up to 60 weeks, which includes a Pre-treatment 
Period of maximally 6 weeks, a Treatment Period of 52 weeks, and a Follow-up Period of 2 weeks 
after the last intake of study drug. 
Key Inclusion/Exclusion Criteria 
Healthy, postmenarcheal, premenopausal female, aged 14 to 35 years (inclusive) at the time of 
informed consent signing who is at risk for pregnancy (heterosexual vaginal intercourse at least 
once a month and not sterilized), with a partner who is not known to be subfertile, sterilized, or 
infertile, and who does not desire a pregnancy within 1 year following screening and is not 
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intending to use any other form of contraception (eg, condoms) including withdrawal, during the 
study. Participants must have a history of regular menstrual cycles of 21 to 35 days prior to the use 
of any hormonal contraceptive. 
Number of Investigators and Study Sites: 
Approximately 120 Investigators and study sites are expected to participate in this study. 
Number of Participants: 
A total of 2,680 fertile premenopausal women aged 14 to 35 years (inclusive) will be screened to 
achieve about 1,878 being allocated to study treatment. Over 1,000 total participants are expected 
to complete 1 year of treatment (13 cycles). 
Treatment Groups and Duration: 
All participants will receive the NOMAC-E2 COC. Participants will take one tablet of study drug 
per day for a period of thirteen 28-day treatment cycles. Each 28-day treatment cycle consists of 
24 days of active medication intake, followed by 4 days of placebo. The total duration of study 
participation will be up to 60 weeks, which includes a Pre-treatment Period of maximally 6 weeks, 
a Treatment Period of 52 weeks, and a Follow-up Period of 2 weeks after the last intake of study 
drug. 
Statistical Methods: 
 
 
 
 
 
 
 
 
 
 
 
 
A PI of 3.0 is assumed for the NOMAC-E2 COC, which is similar to the values observed for low 
dose COCs such as LoLoestrin™ (norethindrone/EE) and Quartette™ (LNG/EE). This is 
considered to be a conservative estimation, as previous clinical study data suggest that the 
NOMAC-E2 COC is associated with a lower PI than higher dosed COCs such as DRSP/EE 
3.0 mg/30 µg (Yasmin™), while recent large scale observational study data suggest that the 
NOMAC-E2 COC may also have a PI much lower than the LNG/EE 150/30 µg COC (eg, Levora). 
 
 
 
 
 
 
 
 
 
 
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 (see Section 9.2). 
Primary and Secondary Efficacy Analyses: 
Contraceptive Efficacy: 
The estimated PI with associated 95% CI will be calculated for the primary and secondary 
contraceptive efficacy endpoints of on-treatment pregnancies PI at-risk, PI perfect use, and PI typical use. 
The PIs will be estimated by means of the maximum likelihood estimate of the mean parameter in 
a Poisson distribution. The PIs will also be summarized by BMI subgroup. 
A time-to-pregnancy analysis under at-risk, perfect use, and typical use circumstances will be 
performed using the Kaplan-Meier approach. Participants who do not become pregnant will be 
censored at the last day of the on-treatment period. The cumulative probabilities of in-treatment 
pregnancies after thirteen 28-day treatment cycles will be estimated. 
Bleeding Profile: 
The main vaginal bleeding endpoints in the Cycle Control Analysis are: 
• Proportion of participants who experienced unscheduled bleeding-spotting 
• Proportion of participants who experienced absence of scheduled bleeding-spotting 
• Proportion of participants who experienced no scheduled or unscheduled bleeding-spotting at 
all 
Point estimates with associated 95% CIs will be estimated for these main vaginal bleeding outcome 
proportions and presented by treatment cycle. The 95% CIs will be based on the method of Clopper 
and Pearson. 
Additional vaginal bleeding endpoints in the Cycle Control Analysis include: 
• Number of bleeding days 
• Number of spotting days 
• Number of bleeding-spotting days 
• Mean duration of bleeding-spotting episodes 
Frequency tables and/or summary statistics for continuous variables will be calculated for all 
primary and secondary parameters and presented per cycle. The number and percentage of 
participants with a bleeding day and the number and percentage of participants with a 
bleeding/spotting day will be presented per cycle and within cycle per cycle day, with a 
denominator based on the number of participants who are considered evaluable for the complete 
cycle. 
Reference Period Analysis will be also conducted on the following vaginal bleeding endpoints: 
• Number of bleeding days, spotting days, and bleeding-spotting days 
• Proportion of participants with the following: 
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− Amenorrhea; 
− Infrequent, frequent, or normal frequency bleeding-spotting; and 
− Prolonged bleeding-spotting. 
• Mean duration of bleeding-spotting episodes defined as abnormal uterine bleeding that occur 
between periods. 
Continuous variables will be summarized using the number of observations, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized with 
counts and percentage for each category. 
Primary Safety Analyses: 
The proportions of participants who experienced 
• A treatment-emergent AE, 
• Abnormalities in clinical laboratory assessments, vital signs, or physical examination during 
the on-treatment period. 
The proportion of participants who prematurely discontinued study treatment due to an AE will be 
presented along with a corresponding 95% CI. 
Pharmacokinetic Analysis: 
Sparse sampling and population PK modeling will be used to estimate the effect of covariates 
(body weight and BMI) on NOMAC PK in premenopausal women aged 14 to 35 years (inclusive) 
after 1.5 mg E2 and 2.5 mg NOMAC. Results will be reported separately from the clinical study 
report. 
Data Monitoring Committee: No
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1.2 
Schema  
Figure 1 
Study Schema  
 
 
Abbreviations: EOS=End of Study; ET=Early Termination; Min=minimum; Max=maximum. 
* Time between Visit 2 and Day 1 will depend on the onset of menstruation or the completion of the pre-study contraceptive. 
 
 
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1.3 
Schedule of Activities  
The Schedule of Activities (SoA) is presented in Table 3. 
Table 3 
Schedule of Activities  
Study Period 
Pre-treatmenta 
Treatment: 52 weeks 
Follow-up 
2 weeks 
Study Visit 
Screening 
Treatment 
Allocation 
Before 
Cycle 1 
After Cycle 1 
After Cycle 4 
After Cycle 7 
After Cycle 10 
After 
Cycle 13 
EOT 
V7/EOS 
or ET 
V1 
V2 
P1b 
V3 
P2 
V4 
P3 
V5 
P4 
V6 
P5 
P6 
Timing 
 
 
 
1st 
week 
Cycle 2 
3rd 
week 
Cycle 3 
1st 
week 
Cycle 5 
3rd 
week 
Cycle 6 
1st week 
Cycle 8 
3rd week 
Cycle 9 
1st week 
Cycle 11 
3rd week 
Cycle 12 
1st day 
after 
Cycle 13 
14 days 
after last 
intake of 
study 
drug 
Window (days) 
 
 
 
+5 
+/-3 
+5 
+/-3 
+5 
+/- 3 
+5 
+/- 3 
+3 
+5 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
allocation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Contraceptive 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Gynecological and 
obstetric historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect 
e-Diary 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
e-Diary (re-) 
traininge 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Study Period 
Pre-treatmenta 
Treatment: 52 weeks 
Follow-up 
2 weeks 
Study Visit 
Screening 
Treatment 
Allocation 
Before 
Cycle 1 
After Cycle 1 
After Cycle 4 
After Cycle 7 
After Cycle 10 
After 
Cycle 13 
EOT 
V7/EOS 
or ET 
V1 
V2 
P1b 
V3 
P2 
V4 
P3 
V5 
P4 
V6 
P5 
P6 
Timing 
 
 
 
1st 
week 
Cycle 2 
3rd 
week 
Cycle 3 
1st 
week 
Cycle 5 
3rd 
week 
Cycle 6 
1st week 
Cycle 8 
3rd week 
Cycle 9 
1st week 
Cycle 11 
3rd week 
Cycle 12 
1st day 
after 
Cycle 13 
14 days 
after last 
intake of 
study 
drug 
Window (days) 
 
 
 
+5 
+/-3 
+5 
+/-3 
+5 
+/- 3 
+5 
+/- 3 
+3 
+5 
e-Diary 
compliance 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense study 
drugf 
 
Xf 
 
X 
 
X 
 
X 
 
X 
 
 
 
Study drug 
accountability 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
Study drug 
complianceg 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-study 
contraceptive 
counseling 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum β-hCG 
X 
Xh 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Urinary pregnancy 
test 
 
Xi,j 
 
X 
 
X 
 
X 
 
X 
 
Xkk 
X 
Check cycles at 
riskl 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaginal bleeding 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationm 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weightn 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Vital signs (HR, 
BP) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
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Study Period 
Pre-treatmenta 
Treatment: 52 weeks 
Follow-up 
2 weeks 
Study Visit 
Screening 
Treatment 
Allocation 
Before 
Cycle 1 
After Cycle 1 
After Cycle 4 
After Cycle 7 
After Cycle 10 
After 
Cycle 13 
EOT 
V7/EOS 
or ET 
V1 
V2 
P1b 
V3 
P2 
V4 
P3 
V5 
P4 
V6 
P5 
P6 
Timing 
 
 
 
1st 
week 
Cycle 2 
3rd 
week 
Cycle 3 
1st 
week 
Cycle 5 
3rd 
week 
Cycle 6 
1st week 
Cycle 8 
3rd week 
Cycle 9 
1st week 
Cycle 11 
3rd week 
Cycle 12 
1st day 
after 
Cycle 13 
14 days 
after last 
intake of 
study 
drug 
Window (days) 
 
 
 
+5 
+/-3 
+5 
+/-3 
+5 
+/- 3 
+5 
+/- 3 
+3 
+5 
Gynecological 
exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Breast exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PAP testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STI panelp 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Routine 
laboratoryq 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokineticsr 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: β-hCG=β-human chorionic gonadotropin; ACOG=American Congress of Obstetricians and Gynecologists; BMI=body mass index; BP=blood 
pressure; e-Diary=electronic diary; EOS=End of Study; EOT=End of Treatment; ET=Early Termination; HR=heart rate; P=phone contact; 
PK=pharmacokinetic/s; STI=sexually transmitted infections; V=visit. 
a. The Screening Visit may be split into 2 separate days if the participant is not able to complete all assessments on the same day. The duration between V1 and V2 
should be no less than 7 days and no greater than 42 days.  
b. The purpose of the phone contact (P1) is to communicate the results of the serum β-hCG test performed at V2 and to reinforce e-Diary instructions. 
c. Includes medical history regarding illicit drugs, alcohol, and tobacco use. 
d. Includes pregnancy history and menstrual bleeding history (6 months prior to V1). 
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e. Participants will use the e-Diary for at least 1 week during screening to conduct daily assessments of vaginal bleeding/spotting. Participants will receive e-Diary 
training at V1. Investigators or designees should explain the importance of completing the e-Diary daily. Investigators are to evaluate participant compliance 
with the e-Diary during screening to assess eligibility. Additional study visits may also be scheduled to provide additional training as needed for participants 
who continue to fill out the e-Diary incorrectly or incompletely. Participants who are not compliant should be re-trained. 
f. Dispensing only; the first dose will actually be taken at home after Visit 2 (see Section 6.4.1). 
g. See Section 6.4 for information regarding timing of the first dose and management of missed study drug doses. 
h. A negative Visit 2 serum β-hCG test result, to be communicated at P1, in combination with a negative urine home pregnancy test result on the intended day of 
tablet intake, are both required prior to the first tablet intake. 
i. Urine pregnancy test must be performed at the site before treatment allocation and at all other visits. Urine pregnancy tests must also be performed at home just 
before the intake of the first tablet of study drug and before the start of all subsequent blisters. Participants must document a negative home pregnancy test in the 
e-Diary prior to starting each blister.  
j. Additional urine pregnancy tests to be conducted at home as needed for suspected pregnancies. If a positive result is obtained with a urine pregnancy test, a 
confirmatory serum β-hCG test must be performed within 24 hours. Note, a local laboratory can perform the serum pregnancy test used to confirm a positive 
urine pregnancy test.  
k. The scheduled urine pregnancy test indicated at P6 is to be conducted by the participant at home, within 48 hours after the last tablet intake. 
l. Assess for heterosexual vaginal intercourse during that cycle and whether contraceptive methods other than the study drug have been used. 
m. At a minimum, examination for abnormalities of the heart, lungs, abdomen, and extremities should be performed. 
n. Participants’ BMI should be calculated at screening and enrollment (using cm and kg as measurement units). 
o. In the absence of a documented result within the timeline per current ACOG standard of care guidelines. 
p. All participants must be tested for gonorrhea and chlamydia. Testing for trichomonas and bacterial vaginosis will only be required if abnormal vaginal discharge 
is present, and may be repeated during the study as needed. Testing for STIs must be performed by a local laboratory. 
q. Includes biochemistry and hematology. Liver function testing may be repeated once prior to V2 at the discretion of the Investigator if results are inconsistent with 
the participant’s clinical status or recent laboratory results. 
r. Sparse sampling for PK analysis to be performed in a subset of the study population during V3 and V4, to be scheduled between Day 7 and Day 12 of the 
corresponding cycle (ie, within the +5-day window for Cycle 2 and Cycle 5, respectively). At each visit, 2 PK plasma samples will be taken; the first sample 
within 1 hour prior to, and the second sample between 1 and 2 hours after, the observed dose administration. The dosing date and time for the doses 
administered prior to and during the V3 and V4 visits will be recorded in the respective electronic case report form (eCRF) pages. 
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2.0 INTRODUCTION  
2.1 
Study Rationale  
Nomegestrol Acetate + 17β-estradiol (NOMAC-E2; OG-8175A) is a monophasic combined oral 
contraceptive (COC) containing nomegestrol acetate (NOMAC), a nor-progesterone-derived 
progestogen, and 17β-estradiol (E2), an estrogen that is identical to the predominant endogenous 
human estrogen. NOMAC is a highly selective progestogen derived from, and structurally similar 
to, the naturally occurring steroid hormone, progesterone. NOMAC has a strong affinity for the 
human progesterone receptor and has strong anti-gonadotropic activity, moderate anti-androgenic 
activity, and is devoid of any estrogenic, androgenic, glucocorticoid, or mineralocorticoid activity. 
The estrogen contained in NOMAC-E2 is E2, an estrogen identical to the predominant endogenous 
human estrogen. This estrogen differs structurally from the estrogen ethinylestradiol (EE) used in 
other combined hormonal contraceptives (CHC) by the lack of the ethinyl group in the 17-α 
position. 
Phase 2 and 3 clinical studies have shown that NOMAC-E2 has robust contraceptive efficacy, a 
stable vaginal bleeding profile, and a good overall safety and tolerability profile, as compared with 
the COC containing drospirenone 3.0 mg and EE 30 µg. NOMAC-E2 has less pronounced effects 
on metabolic parameters than the levonorgestrel (LNG)-EE 150/30 µg COC. NOMAC-E2 was 
first registered in July 2011 and is currently registered and marketed in over 50 countries 
worldwide, including the member states of the European Union (EU), the United Kingdom (UK), 
and Australia. 
A large post-authorization safety study (
) has been 
conducted in over 50,000 women having been prescribed NOMAC-E2 in comparison to an equally 
sized group having been prescribed LNG-EE. The study has been conducted in 12 countries 
(Australia, Austria, Colombia, France, Germany, Hungary, Italy, Mexico, Poland, Russia, Spain, 
and Sweden). A pre-final interim analysis has shown that after women had been followed for up 
to 24 months, NOMAC-E2 is safe and well tolerated, associated with a numerically lower risk of 
venous thromboembolism (VTE) than LNG-EE (hazard ratio: 0.6; 95% confidence interval [CI], 
0.2 – 1.5) and with a statistically significantly lower pregnancy rate than LNG-EE, ie, 0.13 per 100 
woman-years (WY) (95% CI, 0.10 – 0.17) for NOMAC-E2 versus 0.39 per 100 WY (95% CI, 
0.33 – 0.45) for LNG-EE. 
Post-marketing surveillance data collected from more than 4 million WY of exposure have 
confirmed the favorable benefit-risk profile of NOMAC-E2. 
 
 
 
 
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 Mainly, this is a single-arm clinical study that will include the following: 
• A total of 1,878 participants to yield: a) >1,000 participants who will complete 1 year 
(thirteen 28-day cycles) of treatment and b) >16,500 28-day cycles of exposure to assess the 
safety and contraceptive efficacy of NOMAC-E2. 
• The demographic characteristics (age, weight, body mass index [BMI; see exclusion criterion 
#15], racial distribution, etc.) as per inclusion/exclusion criteria are targeted to be 
representative of females of childbearing potential in the US. 
• The study assessments are designed to capture all information related to the concomitant use 
of condoms and other forms of contraception during the Treatment Period. 
2.2 
Background  
Combined hormonal oral contraceptives are one of the most common birth control methods used 
by women. Most COCs in use today are a combination of a synthetic progestin, which is most 
commonly a 19-nortestosterone derivative, and a synthetic estrogen, EE. 
The main goal of the development of CHCs is the demonstration of inhibition of ovulation, good 
vaginal bleeding pattern, and safety. The first contraceptives had a relatively high steroid content, 
the preparations showed good contraceptive efficacy, but also produced some rare but serious 
adverse events (SAEs). Based on laboratory and epidemiological findings of the association 
between the estrogen dose and the risk of thrombosis, the dose of EE has been progressively 
reduced over the years and most pills now contain 20 μg to 35 µg of EE. A further reduction is 
considered not possible without compromising the vaginal bleeding pattern. Furthermore, a new 
generation of selective progestins has been introduced with the goal of maximizing progestational 
effects and minimizing symptoms or metabolic effects associated with androgenic activity. The 
use of highly selective progestogens might also allow the replacement of EE by the predominant 
endogenous human estrogen, E2. It is generally perceived that an E2 containing CHC will be 
associated with a more favorable safety profile than EE containing COCs (1-3). In the past, several 
attempts have been made to replace EE in COCs by E2. However, for a long time E2-containing 
combinations or regimens have been explored but have not resulted in an acceptable clinical 
profile, ie, providing both contraceptive efficacy and an acceptable vaginal bleeding pattern for 
the target population. 
Nonclinical and clinical studies that have been conducted with NOMAC-E2 are outlined in the 
Investigator’s Brochure (IB) (4) and Summary of Product Characteristics (5). A brief summary of 
the clinical studies is provided below. 
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Dose-finding studies were initially performed with NOMAC alone and identified 2.5 mg NOMAC 
as the minimum effective dose for ovulation inhibition 
. Subsequently, 2 dose 
finding studies were performed with combinations of 1.5 mg E2 and 3 doses of NOMAC, with the 
meanwhile established minimum effective dose of NOMAC as the highest dose (
. These studies led to the selection of NOMAC-E2 
(2.5 mg-1.5 mg), being the combination providing the optimum balance between ovulation 
inhibition and cycle control. Finally, the selected dose combination was investigated in a study 
comparing a 21/7 regimen to a 24/4 regimen for 3 cycles (
). On the 
basis of a better bleeding profile as judged by a shorter duration of withdrawal bleeding and a 
lower overall number of days with vaginal bleeding over 3 cycles of use and increased 
contraceptive robustness, the 24/4 regimen was selected for further development in Phase 3 
studies. 
The clinical Phase 3 program was initiated in May 2006. The program included 2 (twin) pivotal 
efficacy and safety studies, 
. These 2 studies together provided a 
sufficient number of at-risk cycles of exposure to obtain evidence of contraceptive efficacy and 
sufficient general safety data (6-9). In addition, the clinical Phase 3 program included 3 clinical 
pharmacology studies, ie, one metabolic safety study of NOMAC-E2 versus LNG-EE that 
evaluated effects on hemostasis, lipid metabolism, carbohydrate metabolism, adrenal function, 
thyroid function, and androgens (10, 11); a pharmacodynamic study into the contraceptive 
mechanism of action of NOMAC-E2 versus drospirenone (DRSP)-EE (12); and a bone mineral 
density study (13). 
Six additional Phase 1 clinical pharmacology studies within the Phase 3 development program 
were initiated to complete the clinical development for the contraceptive application of NOMAC-
E2. These 6 studies were: (1) a study to establish pharmacokinetics of NOMAC and E2 after single 
and repeated dose administration (14), (2) a study to compare the pharmacokinetics of NOMAC 
after single-dose oral administration of different NOMAC-E2 batches 
, (3) a study 
to compare the pharmacokinetics of NOMAC after single-dose administration of NOMAC-E2 
between healthy female adolescents and female adults (15), (4) a study to investigate the effect of 
multiple therapeutic and supra-therapeutic oral doses of NOMAC-E2 on the QT/QTc interval in 
healthy women (16), (5) a bioequivalence study comparing the batches used in the pivotal studies 
with the batch prepared using the commercial production process 
, and (6) a food 
effect study to complete the characterization of the commercial film-coated tablet formulation 
. 
In addition to the studies above, this Phase 3 study will provide 1 year of efficacy and safety data 
for NOMAC-E2 and will support the regulatory submission for NOMAC-E2 in the US. 
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2.3 
Benefit/Risk Assessment  
It cannot be guaranteed that participants in clinical studies will directly benefit from treatment 
during participation, as clinical studies are designed to provide information about the safety and 
effectiveness of a study drug. The NOMAC-E2 COC has demonstrated contraceptive efficacy and 
is generally well tolerated. Eligible participants in this study will be monitored for safety 
throughout their participation. 
Participants may benefit from 12 months of contraception and from the clinical care provided as 
part of study participation, including gynecologic and breast examinations, screening for 
gonorrhea/chlamydia, and trichomonas, bacterial vaginosis, and cervical cytology (if indicated). 
As with all contraceptives, there is a risk of getting pregnant, but this risk is considered small if 
the NOMAC-E2 COC is used according to the instructions. Participants may experience 
discomfort during the gynecological and breast examinations. Participants may have bruising, 
experience lightheadedness, and rarely, infection, from drawing blood. 
Additional details regarding specific benefits and risks for participants participating in this clinical 
study may be found in the IB and informed consent/assent documents. 
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3.0 OBJECTIVES AND ENDPOINTS  
This is an open-label, single-arm, multi-center study aimed to assess the contraceptive efficacy 
and safety of the NOMAC-E2 COC in postmenarcheal premenopausal women aged 14 to 35 years 
(inclusive). The study objectives and endpoints are outlined in Table 4. 
Table 4 
Study Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To assess the contraceptive efficacy of the 
NOMAC-E2 COC based on the number of 
on-treatment pregnancies 
• 
 
 
 
 
 
 
• 
To assess the safety and tolerability of the 
NOMAC-E2 COC 
• 
 
 
• 
 
 
• 
 
 
 
Secondary 
 
• 
To assess the perfect use contraceptive efficacy of 
the NOMAC-E2 COC based on the number of 
on-treatment pregnancies conceived during perfect 
use. 
• 
 
 
 
 
 
 
 
• 
To assess the typical use contraceptive efficacy of 
the NOMAC-E2 COC based on the number of on-
treatment pregnancies conceived during typical 
use 
• 
 
 
 
 
 
 
 
• 
To assess the contraceptive efficacy of the 
NOMAC-E2 COC based on the number of 
on-treatment pregnancies by BMI subgroup 
• 
 
 
 
 
 
• 
To assess the cumulative 1-year pregnancy rates of 
the NOMAC-E2 COC under at-risk, perfect use, 
and typical use circumstances, using Life Table 
Analysis  
• 
 
 
• 
To describe the bleeding profile associated with 
the use of the NOMAC-E2 COC, assessed by 
cycle analysis 
• 
 
 
• 
 
 
• 
 
 
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Objectives 
Endpoints 
• 
To describe the bleeding occurrence associated 
with the use of the NOMAC-E2 COC, assessed by 
91-day Reference Period Analysis 
• 
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
To determine the effects of covariates (body 
weight and BMI) on the PK of NOMAC 
• 
 
 
 
Abbreviations: BMI=body mass index; COC=combined oral contraceptive; NOMAC-E2=nomegestrol acetate + 
17β-estradiol; PI=Pearl Index; PK=pharmacokinetic/s. 
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4.0 STUDY DESIGN  
4.1 
Overall Design  
This is an open-label, single-arm, multi-center study to assess the contraceptive efficacy and safety 
of the NOMAC-E2 COC in postmenarcheal premenopausal women aged 14 to 35 years (inclusive) 
at the time of study entry. Potential participants must be sexually active and engage in heterosexual 
vaginal intercourse at least once per month with a partner who is not known to be subfertile, 
sterilized, or infertile, and should not routinely use any other form of contraception. 
 
 
 
 It is estimated that 2,680 
women need to be screened. Additionally, primary and secondary contraceptive efficacy endpoints 
will be analyzed 
 
. To evaluate the potential for 
body weight and/or BMI to influence NOMAC exposure, contraceptive efficacy, and safety 
endpoints, the population pharmacokinetics (PK) of NOMAC will be investigated in a subset of 
participants, including covariate and exposure-response analyses.  
During the Screening Visit or Visit 1 (V1), after written informed consent has been obtained, 
participants will have their relevant medical history assessed; undergo a focused physical 
examination as well as breast and gynecological examinations, including sexually transmitted 
infection testing (specifically, gonorrhea and chlamydia, as per guideline recommendations 
(17, 18), and trichomonas and bacterial vaginosis if clinically indicated) and a PAP smear if 
indicated. In addition, participants will have their height, body weight, and vital signs (heart rate, 
blood pressure) checked; a blood sample taken for evaluation of pregnancy, blood biochemistry 
and hematology; and a urine sample taken for urinalysis. Participants will also be instructed on the 
use of the electronic diary (e-Diary), which will have to be completed on a daily basis, to document 
their vaginal bleeding experience and their intake of study drug (to be documented after treatment 
allocation). Participants’ compliance to complete the e-Diary daily will be monitored for at least 7 
days prior to treatment allocation to determine their ability to complete the e-Diary daily. 
Depending on receipt of laboratory results and the participants’ current contraceptive method or 
the timing of the participants’ menstrual cycle, eligible participants will visit the site for allocation 
to treatment, which is at the latest 6 weeks after V1. The screening visit may be split into 2 separate 
days if the participant is not able to complete all assessments on the same day. 
At the Treatment Allocation Visit (V2), the participant will receive the study drug after a negative 
on-site urine pregnancy test and if she meets eligibility criteria related to e-Diary completion (see 
inclusion criterion #6). Participants will also receive urine home pregnancy tests, the first of which 
should be performed just before the first study drug intake of the first cycle. A serum pregnancy 
test will also be performed at V2 and the results will be communicated to the participant via phone 
contact (P1). Before participants may begin study drug, a negative V2 serum β-hCG test result, in 
combination with a negative urine home pregnancy test result just before the first tablet intake, are 
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both required. At P1 the e-Diary instructions will be reviewed too, in particular to ensure adequate 
recording of the home pregnancy test and start of the first blister at first tablet intake. At the 
beginning of each subsequent treatment cycle, participants must document in the e-Diary whether 
they have been involved in heterosexual vaginal intercourse during the preceding cycle and 
whether contraceptive methods other than the study drug have been used. Participants must also 
perform a urine home pregnancy test at the beginning of each subsequent treatment cycle, which 
must be negative in order to continue tablet intake. A urine home pregnancy test should also be 
performed within 48 hours after the last tablet from the last blister of study drug has been taken. 
During the Treatment Period, participants will visit the site shortly following completion of Cycles 
1, 4, 7, 10 and 13 (V3-V7). At each of these visits, a blood sample for serum β-human chorionic 
gonadotropin (β-hCG) will be taken, body weight and vital signs will be measured, and the use of 
concomitant medication and occurrence of adverse events (AEs) will be assessed. Testing for 
gonorrhea and chlamydia will also be conducted at V6 (in addition to V1). Testing for trichomonas 
and bacterial vaginosis may be repeated during the study as needed, if clinically indicated (ie, if 
abnormal vaginal discharge is present). Pre- and post-dose PK samples will be taken in a subset of 
the study population (approximately 200 participants) during V3 and V4 and are to be scheduled 
between Day 7 and Day 12 of the corresponding cycle (ie, within the +5-day window for Cycle 2 
and Cycle 5, respectively). 
Sufficient amount of study drug will be provided to cover treatment until one cycle after the next 
scheduled study visit. In addition, compliance with e-Diary entries and study drug use will be 
reviewed, and additional training provided as needed for participants who continue to incorrectly 
or incompletely fill out the e-Diary or who use the study drug incorrectly (see Section 8.2.3 for 
more information; per-protocol defined use of study drug is outlined in Section 9.3.4). Participants 
who are repeatedly non-compliant with study drug use or with e-Diary entries may be discontinued 
at the discretion of the Investigator. Phone contacts (P2 to P6) between the on-site visits are 
planned to monitor the participants’ compliance with the use of study drug and completion of 
e-Diaries, assess the at-risk status of their cycles, provide additional training when needed, and 
answer any questions. 
The Post-Treatment Visit (Visit 7/End of Study [EOS]) is the last site visit and includes the EOS 
assessments and is conducted either at study completion or after Early Termination (ET), 14 days 
after completion of the last treatment cycle. Participants will undergo a focused physical 
examination as well as breast and gynecological examinations, have their body weight and vital 
signs measured, and have a blood sample taken for evaluation of blood biochemistry including 
β-hCG and hematology. The use of concomitant medication, including the initiation of post-study 
contraception, and occurrence of AEs will be assessed. 
The total duration of study participation will be up to 60 weeks, which includes a Pre-treatment 
Period of maximally 6 weeks, a Treatment Period of 52 weeks, and a Follow-up Period of 2 weeks 
after the last intake of study drug. 
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4.2 
Scientific Rationale for Study Design  
This is a Phase 3, single-arm, multi-center, open-label study to assess the contraceptive efficacy 
and safety of the NOMAC-E2 COC. The study has been designed to meet the regulatory 
requirements for registration within the US in accordance with the 2019 FDA Guidance 
Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy 
(19) and it has also taken into account multiple interactions between the FDA and the Sponsor (ie, 
incorporation of FDA’s recommendations into the study design and assessments). 
The study has a duration of 1 year (thirteen 28-day cycles) and primarily aims to establish the 
contraceptive efficacy of the NOMAC-E2 COC in women aged 14 to 35 years (inclusive), at risk 
of pregnancy. The assessment of efficacy is based on the point estimate and the upper bound of 
the corresponding 95% CI for the PI. To be considered a very effective COC, the upper bound of 
the 95% CI for the PI should not exceed 5 in an adequately designed and conducted study. The 
anticipated exposure of >14,000 cycles at risk in 1,878 participants expected to complete 1 year of 
treatment (thirteen 28-day cycles) has been calculated to provide a PI conforming to this 
requirement (see Section 9.4.2 for additional information). In addition to the post-marketing data, 
the results from this study will also provide additional support to the clinical safety of the 
NOMAC-E2 COC. This study is open label and does not have a comparator arm, as this is not 
needed to meet regulatory requirements for registration. 
4.3 
Justification for Dose  
The NOMAC-E2 COC active tablets contain 2.5 mg NOMAC and 1.5 mg E2 and will be used in 
a 24/4 regimen, ie, 28-day cycles with 24 days of active tablet intake followed by 4 days of placebo 
tablet intake. The doses and regimen have been selected based on providing strong ovulation 
inhibition and good cycle control and are currently the marketed approved dose and regimen in 
countries wherein NOMAC-E2 is approved. 
4.4 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if she has completed all phases of the 
study, including the last scheduled procedure indicated at the EOS Visit shown in the Schedule of 
Activities (SoA); Section 1.3. 
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5.0 STUDY POPULATION  
Prospective approval of protocol deviations to eligibility criteria, also known as protocol waivers 
or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Demographics 
1. Is a postmenarcheal, premenopausal female, aged 14 to 35 years (inclusive) at the time of 
informed consent signing. 
2. Is at risk for pregnancy (heterosexual vaginal intercourse at least once a month and not 
sterilized), with a partner who is not known to be subfertile, sterilized, or infertile. 
3. Does not desire a pregnancy within 1 year following screening and is not intending to use any 
other form of contraception (eg, condoms) including withdrawal. 
4. Is in good physical and mental health, based upon the medical judgment of the Investigator. 
5. Has a history of regular menstrual cycles of 21 to 35 days prior to the use of any hormonal 
contraceptive. 
6. Is able and willing (in the opinion of the Investigator) to adhere to all required study 
procedures, including study visits and e-Diary entries, and not planning to relocate during the 
study (such that the participant would not be able to continue participation at the study site). 
Note: Participants are eligible to participate in the study, if they have demonstrated 
capability to independently complete the e-Diary and have completed the questions related 
to bleeding at least 6 out of 7 days of the last week preceding treatment allocation (V2). 
Informed Consent 
7. The participant (or legally acceptable representative, if applicable) provides written informed 
consent (and assent, if applicable) for the study. 
 
5.2 
Exclusion Criteria  
The participant is excluded from the study if the participant: 
Recent or Current Pregnancy 
1. Has a known or suspected pregnancy. 
Note: A negative serum β-hCG test at V1 and a negative urine pregnancy test at V2 are 
required for a participant to be eligible in this study. 
2. Has a history of subfertility or infertility. 
3. Has not had at least 2 normal menstrual cycles following a recent pregnancy regardless of 
gestational age. 
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4. Is breastfeeding or has been breastfeeding within 2 months prior to start of study drug. 
Gynecologic Conditions 
5. Has a known human immunodeficiency virus (HIV) infection. 
Note: This condition requires the use of condoms, which is not allowed per protocol. 
6. Has untreated gonorrhea, chlamydia, or trichomonas. 
Note: These conditions require the use of condoms, which is not allowed per protocol. 
Participants may be rescreened 3 weeks after completing treatment for these conditions if 
not at risk for reinfection as deemed by the Investigator. 
7. Has no documented normal PAP test within the timeline of current standard of care guidelines 
or has a significantly abnormal PAP test at Screening (V1) (ie, ASC-H, low grade squamous 
intraepithelial lesion, high grade squamous intraepithelial lesion, atypical glandular cells [any 
type], squamous cell carcinoma, or adenocarcinoma [in situ or invasive]). The presence of 
high-risk human papillomavirus (HPV), regardless of PAP result, is exclusionary.  
Note: The presence of atypical squamous cells of undetermined significance (ASCUS) will 
require HPV reflex testing; ASCUS in an HPV-negative patient is not exclusionary. 
8. Has had any unexplained abnormal vaginal bleeding or abnormal vaginal bleeding attributable 
to underlying pathology (ie, cervical/endometrial polyp, uterine fibroids, endometriosis, etc.) 
which has not been treated/resolved. 
Cardiovascular Risks and Disorders: 
9. Has a presence or history of VTE (ie, deep vein thrombosis, pulmonary embolism), a history 
of arterial thrombotic or thromboembolic events (ATE) (ie, myocardial infarction, stroke, or 
peripheral arterial disease), or a history of transient ischemic attack, angina pectoris, or 
claudication. 
10. Is at a higher risk of VTE due to major surgery, any surgery to the legs or pelvis, neurosurgery, 
major trauma, recent prolonged immobilization (within 2 weeks before screening, eg, due to 
trauma, surgery, or other illness markedly limiting mobility); is planning surgery requiring 
prolonged immobilization; or has a hereditary or acquired predisposition or elevated risk for 
venous or arterial thrombosis, such as Activated Protein C resistance, antithrombin-III-
deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, or 
antiphospholipid antibodies (eg, anticardiolipin antibodies, lupus anticoagulant); or has 
thrombogenic cardiac valve or rhythm abnormalities of the heart associated with 
thromboembolism (eg, atrial fibrillation). 
Note: Routine screening through laboratory tests for thrombophilia is not required. 
Exclusion from participation is based on reported medical history. 
11. Has uncontrolled or severe hypertension (systolic blood pressure ≥160 mmHg or diastolic 
blood pressure ≥100 mmHg) at Screening (V1). 
Note: if hypertension can be controlled with medications and is no longer severe at 
treatment allocation (V2), the participant may be eligible. 
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12. Has severe dyslipoproteinemia. 
Note: Routine screening is not required. A lipid panel may be performed at V1 at the 
discretion of the Investigator. 
13. Has a history of migraine with aura or focal neurological symptoms. 
14. Has diabetes mellitus with end-organ involvement (nephropathy, retinopathy, neuropathy, or 
vascular involvement) or has diabetes for >20 years duration. 
15. Has multiple cardiovascular risk factors such as obesity (BMI >30 kg/m2), inadequately 
controlled hypertension, use of tobacco/nicotine products, or inadequately controlled diabetes 
which, in the opinion of the Investigator, in composite pose an unacceptable risk of study 
participation.  
Note: A participant who has a BMI >30 kg/m2 only is not exclusionary. The Investigator 
should consider the severity of each risk factor in determining whether study participation 
is appropriate. 
Gastrointestinal Disorders: 
16. Has a history of pancreatitis associated with severe hypertriglyceridemia. 
17. Has a presence or history of clinically significant liver disease, including active viral hepatitis 
or cirrhosis. Participants with a prior history of liver disease which is now inactive or 
successfully treated may be eligible if liver function values (ie, aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], total bilirubin) have been normal for the past year and 
are within the normal range (per central laboratory) at V1. Liver function testing may be 
repeated once prior to V2 at the discretion of the Investigator if results are inconsistent with 
the participant’s clinical status or recent laboratory results. 
18. Has a history of malabsorptive surgical procedures (eg, Roux-en-Y gastric bypass, jejunoileal 
bypass, biliopancreatic diversion). 
Other Medical Disorders: 
19. Has a history of malignancy ≤5 years before signing the informed consent except for 
adequately treated basal cell or squamous cell skin cancer. 
Note: Participants with a history or presence of liver tumors (benign or malignant) or sex 
steroid-influenced malignancies (eg, genital organs, breasts) are excluded regardless of the 
interval since the history of the malignancy. 
20. Has a history or presence of meningioma. 
21. Has any disease that may worsen under hormonal treatment such as disturbances in the bile 
flow (presence of or history of cholestasis, presence of gallstones), systemic lupus 
erythematosus, pemphigoid gestationis or idiopathic icterus during a previous pregnancy, 
middle-ear deafness (otosclerosis), Sydenham chorea, or porphyria. 
Note: History of cholecystectomy does not exclude a participant. 
22. Has a current or previous history of medically diagnosed severe depression unless the 
potential participant is determined to be clinically stable and asymptomatic. 
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23. Has a known allergy/sensitivity or contraindication to NOMAC-E2. 
24. Has a history (current or within the past 2 years) of drug or alcohol abuse or dependence. 
25. Has any clinically relevant abnormal laboratory result at Screening (V1) as judged by the 
Investigator. 
26. Has a history or current evidence of any condition, therapy, or other circumstance that in the 
opinion of the Investigator might confound the results of the study, affect participant’s 
well-being, or interfere with the participant’s participation for the full duration of the study (ie, 
approximately 1 year). 
Prior/Concomitant Therapy 
27. Has received any treatment listed in Table 6 more recently than the “last allowable use” 
indicated in Table 6 and/or needs to continue to receive any treatment listed in Table 6. 
Note: Contraceptives are allowed beginning the day following the last placebo tablet 
intake. 
Prior/Concurrent Clinical Study Experience 
28. Has used an investigational drug and/or participated in any other clinical study within 
2 months before V2. 
Other Exclusions 
29. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) 
who is part of the investigational site or Sponsor staff directly involved with this study. 
5.3 
Lifestyle Considerations  
There are no restrictions related to lifestyles, including diet or alcohol restrictions. 
5.4 
Screen Failures  
Screen failures are defined as participants who consent (and assent, if applicable) to participate in 
the clinical study, but are not subsequently allocated to treatment in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, reason for screen 
failure, and any pre-treatment AEs or SAEs (for definition, see Section 8.4.1) as outlined in the 
electronic case report form (eCRF) completion guidelines. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened, except for those participants who were diagnosed with chlamydia, gonorrhea, or 
trichomonas, which may be rescreened once 3 weeks after completing treatment for these 
conditions if not at risk for reinfection. Rescreened participants retain the same screening number. 
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If the rescreening is outside the 42-day window since V1, all screening assessments must be 
repeated. 
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6.0 STUDY TREATMENT  
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a participant according to the study protocol. 
6.1 
Study Treatment(s) Administered  
All participants will receive NOMAC-E2 COC. Participants will take one tablet of study drug per 
day for thirteen 28-day treatment cycles. Each 28-day treatment cycle consists of 24 days of active 
study drug, followed by 4 days of placebo. Details regarding the study drug are provided in Table 5. 
Table 5 
Study Treatment Details  
Study Treatment Name: 
Nomegestrol acetate / estradiol 
Nomegestrol Acetate + 17β-estradiol combined oral contraceptive, NOMAC-E2 
COC, OG-8175A 
Dosage Formulation: 
Film-coated Tablet 
Unit Dose Strength: 
Nomegestrol acetate (NOMAC) 2.5 mg and estradiol (E2) 1.5 mg; Each blister 
stripa contains 28 tablets: 24 tablets with the active drug (number 1 to 24) and 4 
tablets with placebo (number 25 to 28). 
Route of Administration  
Oral 
Dosing Instructions: 
 
Take 1 tablet daily at about the same time as directed. 
 
Packaging and Labeling 
 
Study treatment will be provided in blister stripsa, packaged in tamper sealed 
boxes. Each box will be labeled as required per country requirement. 
A day label will be supplied for application to the blister stripa to designate the first 
day of dosing for each cycle and subsequent daily dosing. 
Manufacturer 
 
 
 
  
a. Referred to as “blister” throughout protocol. 
6.2 
Preparation/Handling/Storage/Accountability  
The Investigator, a member of the study site staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study drug using the Drug Accountability 
Form. These forms must be available for inspection at any time. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only eligible participants in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatment must be stored in a secure, 
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environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study treatment accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Study site personnel will be responsible for the assessment of drug accountability, by counting 
returned blisters and unused tablets during on-site visits, which must be documented in the source 
documents and relevant form.  
A record of the quantity of blisters dispensed to and blisters administered by each participant must 
be maintained and reconciled with study drug records. Study drug start and stop dates will also be 
recorded in the e-Diary and eCRF. 
For reporting of potential quality-related issues with blister, refer to the Pharmacy Manual. 
Further guidance and information for the final disposition of unused study drugs are provided in 
the Pharmacy Manual or other specified location. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
This is an open-label study; however, the treatment to be taken by a participant will be allocated 
using an Interactive Voice (Web) Response System (IVRS/IWRS). The study site will contact the 
IVRS/IWRS prior to the start of study treatment administration for each participant. 
6.4 
Study Drug Intake  
6.4.1 
Timing of the First Dose  
Participants will take their study drug at home. Before participants can begin study drug, a negative 
Visit 2 serum β-hCG test result, in combination with a negative urine home pregnancy test result, 
are required. The urine home pregnancy test must be performed on the same day as the (intended) 
first tablet intake and must be performed before the first tablet intake of study drug. Participants 
should begin study treatment only after a negative test result is obtained. 
The start of the study drug depends on the contraceptive status of the participant at Treatment 
Allocation Visit (V2), as follows: 
• No preceding hormonal contraceptive use: Participants not using a hormonal contraceptive 
should start the study drug on the first day of their menstrual period. Starting on Days 2 to 5 is 
allowed, but in this case a condom must be used until the participant has completed 7 days of 
uninterrupted active study treatment.  
− If the first dose is delayed until the start of a subsequent menstrual cycle, a condom 
must be used until start of study drug on Day 1 of the subsequent menstrual period. 
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Note: Participants using a non-hormone medicated intrauterine device should have the device 
removed prior to starting study drug. They should start the study drug on the first day of the 
next menstrual period. A condom must be used until start of study drug. Starting between Days 
2 and 5 of the next menstrual period is also allowed, but in this case a condom must be used 
until the participant has completed 7 days of uninterrupted active study treatment. 
• Changing from a CHC (COC, transdermal patch, or vaginal ring): 
− Participants switching from a COC should, after having completed at least 14 days of the 
active treatment phase, start the study drug within 4 or 7 days after the last active tablet, 
depending on whether the length of the progestin/estrogen active interval of the previous 
COC is 24 or 21 days, respectively. 
− Participants switching from a weekly transdermal patch should after having completed at 
least 2 patches (14 days) of a course, start study drug within 7 days after patch removal. 
− Participants switching from a contraceptive vaginal ring should after having completed at 
least 14 days of uninterrupted ring use, start study drug within 7 days after ring removal. 
• Changing from a progestogen-only method (minipill, implant, intrauterine system): 
− Participants switching from a progestogen-only pill (POP) should stop taking the POP and 
start the study drug on the next day (immediate switch). 
− Participants switching from a contraceptive implant or an intrauterine system (IUS) should 
start on the day of its removal. 
In these cases, a condom must be used until the participant has completed 7 days of 
uninterrupted active study drug intake. 
6.4.2 
Management of Missed NOMAC-E2 Tablets  
The NOMAC-E2 blister contains 28 tablets: 24 white tablets with the active substances (number 
1 to 24) and 4 yellow tablets without active substances (number 25 to 28). 
The participant should take one tablet every day at about the same time, without regard to meals 
and with some liquid if needed and in the order directed on the blister. Stickers marked with the 
7 days of the week are provided; the participant should choose the sticker that starts with the day 
the participant begins taking the study drug. 
If a participant misses a dose, the risk of pregnancy increases; this includes starting the pack late. 
The more tablets missed and the closer the missed tablets are to the 4 yellow placebo tablets, the 
higher the risk of a pregnancy. 
The following advice applies in case of missed white active tablets: 
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1 active white tablet missed 
The user should take the last missed tablet as soon as she remembers, even if this means taking 
2 tablets at the same time. She then continues to take tablets at her usual time. She does not need 
any additional contraceptive protection. 
2 or more active white tablets missed 
The user should take the last missed tablet as soon as she remembers, even if this means taking 
2 tablets at the same time. She then continues to take tablets at her usual time. A condom should 
be used until she has completed 7 days of uninterrupted white active tablet intake. This might 
continue into the next cycle. If intercourse took place in the preceding 7 days, the possibility of a 
pregnancy should be considered. The more tablets are missed and the closer to the regular placebo 
tablet interval, the higher the risk of a pregnancy. 
Finally, if the participant is not sure what to do about what advice to follow on the number of 
tablets missed, she should be advised to use a barrier method anytime. If the woman missed active 
white tablets and subsequently has no withdrawal bleed in the first normal placebo tablet interval, 
the possibility of a pregnancy should be considered. 
If yellow placebo tablets are missed contraceptive protection is not reduced. Yellow tablets from 
the last (4th) row of the blister can be disregarded. However, the missed tablets should be discarded 
to avoid unintentionally prolonging the placebo tablet phase. 
The following advice applies in case of GI disturbances: 
In case of severe gastrointestinal disturbances (e.g., vomiting or diarrhea), absorption of steroids 
from the COC tablet may not be complete and a condom should be used for protection during this 
timeframe and until the participant has completed 7 days of uninterrupted active study drug intake 
following the resolution of the severe gastrointestinal disturbance.   
If the symptoms persist, the participant should be advised to contact the Investigator. 
6.5 
Dose Modification  
Dose modification is not permitted during the course of the study. 
6.6 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements or other specific categories of interest) that the participant is receiving at the 
time of treatment allocation (V2) or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor or appropriate designee should be contacted if there are any questions 
regarding concomitant or prior therapy. 
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6.6.1 
Prohibited Medications  
Medications and herbal supplements such as St. John’s wort specifically prohibited (see Table 6) 
are not allowed during the ongoing study, including during time periods specified by this protocol 
for that medication. Note that contraceptives are allowed beginning the day after the last tablet 
intake of study drug from the last blister (last cycle). If there is a clinical indication for any 
medications specifically prohibited, discontinuation from study drug may be required. The 
Investigator should discuss any questions regarding this with the Sponsor Clinical Director or 
appropriate designee. The final decision on any supportive therapy rests with the Investigator 
and/or the participant’s primary physician. However, the decision to continue the participant on 
study drug requires the mutual agreement of the Investigator, the Sponsor, and the participant. 
Vaccination with live or non-live vaccines (including SARS-CoV-2 vaccines) can be administered 
according to local vaccination standards whenever medically appropriate. 
As discussed in Section 9.4.2.6, a supportive Reference Period Analysis (RPA) will be performed 
excluding cycles during which concomitant medications are used for treatment of vaginal bleeding. 
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Table 6 
Prohibited Medications, Supplements, and Other Substances  
Prohibited Medications, Supplements, and Other Substances 
Last Allowable Use 
Sex hormones (other than pre- and post-treatment contraceptives)  
2 months before V1 
Injectable hormonal contraception with 3-month duration 
9 months before V1 
Injectable hormonal contraception with 2-month duration 
6 months before V1 
Injectable hormonal contraception with 1-month duration 
3 months before V1 
Intrauterine Device, Hormonal Intrauterine System, Contraceptive Implant, 
Contraceptive Vaginal Ring, Contraceptive Patch 
Cycle 1 Day 1 
Oral contraceptives (other than study drug) 
Day before Cycle 1 Day 1 
Injectable gonadotropin-releasing hormone agonist with 1-month duration 
(eg, leuprolide) 
3 months before V1 
Injectable gonadotropin-releasing hormone agonist with 3-month duration 
(eg, leuprolide) 
10 months before V1 
Oral gonadotropin-releasing antagonist (eg, elagolix) 
2 months before V1 
Medicines that induce liver enzymes, affecting the bioavailability of 
steroids, including but not limited to the following: 
• 
Anti-epileptics (eg, phenytoin, barbiturates, primidone, 
carbamazepine, oxcarbazepine, topiramate, and felbamate) 
• 
Bosentan 
• 
Rifampicin, rifabutin 
• 
Anti-HIV or anti- Hepatitis C drugs which decrease serum exogenous 
hormone levels (eg, ritonavir, nelfinavir, nevirapine, efavirenz, 
darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, 
tipranavir/ritonavir, boceprevir, telaprevir) 
• 
Griseofulvin 
• 
Herbal remedies containing Hypericum perforatum (eg, St John's 
wort) 
2 months before study 
treatment allocation (V2) 
Medicines whose action may be affected by the use of CHCs 
• 
Lamotrigine 
One month prior to V1 
Abbreviations: CHC=combined hormonal contraceptive; HIV=Human Immunodeficiency Virus; V=visit. 
6.6.2 
Rescue Medicine  
No rescue or supportive medications are specified for use in this study. 
6.7 
Treatment After the End of the Study  
The Sponsor will not provide any additional care to participants after they leave the study because 
such care should not differ from what is normally expected. There will be no access to study drug 
after the participant has completed or discontinued treatment. 
Participants who do not wish to conceive after the last tablet intake of study drug should begin a 
new contraceptive method as soon as possible after the last intake of study drug. Post-study 
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contraceptive counseling will be provided by study site personnel in accordance with the SoA 
(Section 1.3). 
At V6, Investigators (or their appropriately trained designee) should begin to discuss a 
participant’s preferences for contraception (if desired) after their study participation is complete. 
The Investigator may provide a referral for continuing care if needed or may elect to prescribe an 
alternative contraceptive as appropriate. 
When scheduling V7 (EOS/ET Visit), the plan for post-study contraception should be confirmed. 
At V7, the post-study contraceptive medication should be recorded as concomitant therapy in the 
database. Expenses and procedures related to initiation of a new contraceptive method are not 
funded by the study. 
Participants should start their post-study contraceptive (if applicable), as soon as possible after the 
last tablet intake of study drug. An additional barrier method (ie, condoms) or abstinence is 
recommended for 1 week (or longer if indicated by the labeling of the newly started method) to 
minimize risk of conception during the switch in methods of contraception. 
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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
Strategies to Minimize Participant Discontinuation/Withdrawal  
To minimize the number of participants who discontinue participation prematurely or are lost to 
follow-up, the following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• As per inclusion criterion #6, participants must be able and willing (in the opinion of the 
Investigator) to adhere to all required study procedures, including study visits and e-Diary 
entries, and not planning to relocate during the study (such that the participant would not be 
able to continue participation at the study site). Additionally, participants are eligible to 
participate in the study, if they have demonstrated capability to independently complete the 
e-Diary and have completed the questions related to bleeding at least 6 out of 7 days of the last 
week preceding treatment allocation (V2). 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be made at a minimum of at least 3 times and documented in 
the participant’s medical record. 
• Study site personnel will remind the participants at each visit the importance of completing 
their scheduled visit (ie, site and phone call visits) and continuing with study participation. 
Re-training should be considered for participants who are non-compliant with e-Diary 
completion. 
7.2 
Discontinuation of Study Treatment  
If a participant who does not meet eligibility criteria is inadvertently included in the study, that 
participant must be discontinued from study treatment and the Sponsor or Sponsor designee must 
be contacted. An exception may be granted in rare circumstances for which there is a compelling 
safety reason to allow the participant to continue. In these rare cases, the Investigator must obtain 
documented approval from the Sponsor or Sponsor designee to allow the participant to continue 
in the study. 
Participants who discontinue study treatment will not be replaced. Discontinuation from study 
drug is permanent. 
Participants who discontinue study drug before completion of the protocol-specified Treatment 
Period should compleqte all study-related procedures specified for the EOS/ET Visit (V7). See the 
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SoA (Section 1.3) for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 
Participants may discontinue at any time for any reason or be discontinued from the study drug at 
the discretion of the Investigator should any untoward effect occur. In addition, a participant may 
be discontinued from study drug by the Investigator or the Sponsor if study drug is inappropriate, 
the study plan is violated, or for administrative and/or other safety reasons. 
A participant must be discontinued from study drug for any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue 
study treatment. 
• The participant has experienced a VTE or ATE (including myocardial infarction, stroke, or 
peripheral arterial events). 
• The participant has had or is likely to have prolonged immobilization due to illness, injury, 
major trauma, surgery to the legs, or any other major surgery(ies) known to have an elevated 
risk of thromboembolism. 
• The participant has a sufficiently significant adverse reaction to the NOMAC-E2 COC that, 
in the opinion of the Investigator and/or Sponsor, places the participant at unnecessary risk 
from continued study participation. 
• The participant has a medical condition or personal circumstance, which in the opinion of the 
Investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study drug. 
• The participant has a confirmed pregnancy (ie, positive serum pregnancy test or ultrasound). 
See Section 8.2.1.1 for further details. 
• The participant has a need for continued use (>1 month) of any of the medications listed in 
Table 6 including any sex steroids. 
Note: Interactions between hormonal contraceptives and enzyme-inducing drugs may lead 
to breakthrough bleeding and/or contraceptive failure. A back-up nonhormonal 
contraceptive method is recommended when enzyme inducers are used with hormonal 
contraceptives and should be continued for 28 days after discontinuing the enzyme inducer. 
• The participant is persistently not at risk for pregnancy (see Section 8.2.3.3). 
For participants who are discontinued from study drug, all procedures for V7 should be 
completed. 
Any AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.3. Contraceptive counseling, as applicable, should be 
performed (see Section 6.7). The participant will be permanently discontinued both from the study 
drug and from the study at that time. 
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The procedures to be performed should a participant repeatedly fail to return for scheduled visits 
and/or if the study site is unable to contact the participant are outlined in Section 7.4. 
7.3 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study at any time at her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, or compliance reasons. This 
is expected to be uncommon. 
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent (or assent, if applicable) from the study. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
At the time of withdrawal participants should be encouraged to complete the applicable activities 
scheduled for the EOS/ET Visit (V7). See the SoA (Section 1.3) for data to be collected at the time 
of treatment discontinuation and follow-up and for any further evaluations that need to be 
completed. 
A participant who discontinues from study drug or withdraws from the study will not be replaced. 
7.4 
Lost to Follow-up  
Strategies to minimize participant discontinuation/withdrawal are outlined in Section 7.1. A 
participant will be considered lost to follow-up if she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site. 
After employing the strategies outlined in Section 7.1, should the participant continue to be 
unreachable, she will be considered to have withdrawn from the study. 
The missing data for the participant will be managed via the prespecified statistical data handling 
and analysis considerations. 
Discontinuation of specific study sites or of the study as a whole are handled as part of Appendix 2. 
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8.0 STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the informed consent form (ICF) may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
The maximum amount of blood collected from each participant is displayed in Table 7. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
Table 7 
Blood Volume  
Sample Type 
Screening 
Treatment Period 
Number of 
Collections 
Volume 
(mL)/Collection 
Total Volume 
(mL)/Test 
V1 
V2 to V6 
V7 to EOS/ET 
Laboratory 
Safety Tests –
Hematology 
1 
- 
1 
2 
2 
4 mL 
Laboratory 
Safety Tests –
Chemistry 
1 
- 
1 
2 
3.5 
7 mL 
Serum β-hCG 
1 
5 
1 
7 
3.5 
24.5 mL 
Plasma PK 
- 
2a 
- 
4 
5 
20 mL 
Total Blood Volume per Participant 
35.5 mL 
Total Blood Volume per Participant in the PK subseta 
55.5 mL 
Abbreviations: β-hCG=beta human chorionic gonadotropin; EOS=end of study; ET=early termination; 
PK=pharmacokinetic/s; V=visit. 
a. Samples collected from participants in the PK subset only, during V3 and V4. 
 
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8.1 
General Assessments  
8.1.1 
Inclusion and Exclusion Criteria  
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee at 
Screening (V1) and treatment allocation(V2) to ensure that the participant qualifies for the study. 
Prior to treatment allocation, the participant’s BMI will be calculated via IVRS/IWRS and 
participants will be categorized as having BMI <30 kg/m2 or ≥30 kg/m2. 
8.1.2 
Participant Identification Card  
All participants will be given a participant identification card identifying them as participants in a 
research study. The card will contain study site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The Investigator or qualified designee will 
provide the participant with a participant identification card immediately after the participant 
provides documented informed consent (and assent, if applicable). At the time of treatment 
allocation, site personnel will add the treatment number to the participant identification card. 
8.1.3 
Assignment of Screening Number  
All participants who consent (and assent, if applicable) will be given a unique screening number 
(also referred to as participant number) that will be used to identify the participant for all 
procedures that occur prior to treatment allocation (V2). Each participant will be assigned only 
1 screening number. Screening numbers must not be re-used for different participants. 
Any participant who is rescreened will retain the original screening number assigned at the initial 
Screening Visit. Specific details are provided in Section 5.4. 
8.1.4 
Assignment of Treatment Number  
All eligible participants will receive a treatment (allocation) number. Treatment numbers cannot 
be re-assigned to another participant. A single participant cannot be assigned more than one 
treatment number. In this study, all participants receive the same study drug treatment. 
8.1.5 
Prior and Concomitant Medications  
8.1.5.1 
Prior Medications  
The Investigator or qualified designee will review current medication use at the time of screening 
and prior medication use, as applicable based on the time of screening in relation to planned 
treatment allocation. All prior medication taken by the participant (defined as any medications 
reported up to the first study drug intake) should be recorded. The medication review should 
specifically address any treatment that would meet the protocol-specified requirement for 
prohibited medications (see Table 6). 
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8.1.5.2 
Concomitant Medications  
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Concomitant medications should be reviewed at every study visit or contact. The 
use of herbal supplements and nonprescription medications should be recorded as concomitant 
medications. Note, the use of any product containing St. John’s wort (Hypericum perforatum) must 
be documented as this prohibited herbal medication may decrease contraceptive efficacy. 
Participants are required to record in the e-Diary if they used any additional contraception (and 
specify the type used) at the end of every cycle throughout the study. These questions will be 
automatically administered by the e-Diary. If the participant indicates use of a hormonal 
contraceptive other than the NOMAC-E2 COC (eg, emergency contraceptive medication) in the 
e-Diary or verbally, this medication must be recorded as a concomitant medication in the database. 
8.1.6 
Medical and Contraceptive History  
A medical history, including medical history regarding illicit drugs, alcohol, and tobacco use as 
well as a contraceptive history will be obtained by the Investigator or qualified designee. 
8.1.7 
Gynecologic and Obstetric History  
A gynecological and obstetric history (including menstrual history, gravidity, and parity) will be 
obtained by the Investigator or qualified designee for all participants at V1 to ensure the participant 
meets entry criteria. For eligible (allocated to treatment) participants, the pregnancy history should 
be reported on the eCRF. Refer to the eCRF completion guidelines for details. 
8.2 
Efficacy Assessments  
8.2.1 
Assessment of On-treatment Pregnancy  
On-treatment pregnancies are those with an estimated date of conception between the day of first 
intake of study drug up to and including 7 days after the last intake of active study drug. For more 
information regarding contraceptive efficacy definitions, see Section 9.4.2.1.1. 
The contraceptive efficacy is expressed by the PI defined as the number of pregnancies per 
100 WY of study drug exposure. The PI will be calculated for at-risk cycles as well as under perfect 
and typical study drug use and will be analyzed as described in Section 9.4.2.2 and Section 9.4.2.3, 
respectively. 
8.2.1.1 
Pregnancy Testing  
Serum β-hCG will be determined at all scheduled study visits and performed by the central 
laboratory. See the laboratory/procedure manual for sample collection instructions. A negative 
serum β-hCG test at Screening (V1) and a negative urine pregnancy test at treatment allocation 
(V2) are both required for a participant to enter the study. Borderline results should be repeated 
with quantification of the serum results. 
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If pregnancy is suspected, urine pregnancy tests may be performed either by the participant 
at home (at any time) or at a study visit to achieve a rapid result; however, results should be 
confirmed by serum β-hCG within 24 hours. If a pregnancy is confirmed, the participant will 
be discontinued from study drug and from the study. Confirmed pregnancies must be reported 
to the Sponsor within 24 hours. See Section 8.2.1.2 for further details regarding pregnancy 
reporting.  
A urine pregnancy test must be performed at the site before treatment allocation at V2. Urine 
pregnancy test kits will be dispensed at V2 and at subsequent visits (as needed) for use by 
participants at home (see Section 8.2.1.1.1). 
8.2.1.1.1 
Urine Home Pregnancy Test  
Urine pregnancy test kits will be dispensed to all study participants at V2 and at subsequent visits, 
as needed, for use by participants at home prior to starting each blister, whenever a pregnancy is 
suspected, and within 48 hours after the last tablet from the last blister of study drug has been taken. 
Instructions for use should be reviewed with each participant. The lot number and expiration date 
of the test kit(s) provided to the participant should be documented in the study chart. Additional 
test kits will be dispensed at subsequent visits, as needed, to replace those that were used and 
ensure that test kits for future use will not expire between visits.  
If a positive result is obtained with a urine home pregnancy test, a confirmatory serum 
β-hCG test must be performed within 24 hours. Note, a local laboratory can perform the serum 
pregnancy test used to confirm a positive urine pregnancy test. 
The earliest positive pregnancy test should be entered into the e-Diary and into the database (even 
if performed at home) after confirming the results.  
Negative urine home pregnancy tests should be documented within the database when 
performed due to a missed visit. In the event of a missed visit, the site will contact the participant 
and request that the visit be rescheduled. If the participant is unable to return to the site, the 
participant should perform a urine home pregnancy test and results should be documented in the 
e-Diary. 
8.2.1.2 
Pregnancy  
Pregnancy is not considered an AE. It is an efficacy endpoint. If a pregnancy is confirmed, the 
participant will be discontinued from study drug and from the study. Any pregnancy in a 
participant that occurs during the study is to be reported to the Sponsor within 24 hours of 
confirmation and should follow the procedures outlined in Appendix 5. Refer to Section 8.2.1.2.1 
for determination of estimated conception date by ultrasound. 
Details of all pregnancies will be collected after the start of study treatment. Pregnancies 
potentially exposed to NOMAC-E2, ie, pre-treatment pregnancies diagnosed after the onset of 
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treatment and pregnancies with a conception date between first tablet intake and 7 days after the 
last active tablet intake, must be followed to the delivery/termination of the pregnancy (unless the 
participant withdraws consent [or assent, if applicable]). The site should obtain the necessary 
information such as the date of delivery/termination, type of delivery/termination, outcome (health 
of infant), and birth weight. Data should be recorded on the Pregnancy Report eCRF. 
Pregnancy outcomes such as spontaneous abortion, missed abortion, benign or malignant 
hydatidiform mole, fetal death, intrauterine death, ectopic pregnancy, and stillbirth must be 
reported as SAEs (important medical events). 
Any AE related to the infant must be reported on the eCRF. Refer to the eCRF completion 
guidelines for details. 
Information regarding exposure during breastfeeding is not applicable since participants who are 
pregnant or lactating would be excluded from study participation. 
Pregnancy follow-up and outcomes for participants that have been exposed to treatment may not 
yet be available at the time of preparing the clinical study report. Any follow-up information not 
available at the time of preparing the clinical study report will be reported separately. Only 
information collected up to and including the last assessment 14 days after end of treatment will 
be reported in the clinical study report.  
8.2.1.2.1 
Ultrasound Dating of Confirmed Pregnancies  
Ultrasound examination should be performed to determine the gestational age and estimated date 
of conception. First trimester ultrasound results are preferred for dating purposes as they are the 
most accurate. The estimated date of conception, date of the ultrasound, and gestational age of the 
fetus (in weeks and days) at the time of the ultrasound, should be recorded on the appropriate 
eCRF. This information is very important for determining the on-treatment pregnancies 
used in the calculation of the PI for the primary efficacy endpoints. A pregnancy wheel or date 
of last menstrual period is not acceptable when determining the date of conception. A first trimester 
ultrasound must be performed to determine the gestational age of the pregnancy. If a first trimester 
ultrasound is not performed, the earliest available ultrasound should be used to determine the 
gestational age of the pregnancy. 
8.2.2 
Vaginal Bleeding Event  
The vaginal bleeding events will be assessed and recorded daily in the e-Diary (Section 1.3). 
Participants are to record the presence of bleeding or spotting daily and any use of sanitary products 
for this purpose. Sanitary products used for other reasons other than for vaginal bleeding (eg, 
urinary incontinence or vaginal discharge), are not recorded. Participants will be trained in how to 
record vaginal bleeding and spotting in the e-Diary as per below: 
• No bleeding: no vaginal discharge containing blood. 
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• Bleeding: vaginal discharge containing blood that requires the use of a sanitary product (ie, 
pad, panty liner, tampon, or menstrual cup). 
• Spotting: vaginal discharge containing blood that requires no use of a sanitary product (ie, 
pad, panty liner, tampon, or menstrual cup). 
See Section 9.4.2.5.1 for definitions of expected (ie, scheduled) bleeding interval. Data will be 
analyzed according to the definitions noted in Section 9.4.2.5. 
8.2.3 
Compliance  
Participants will be assessed for compliance with the following in accordance to the time points 
specified in the SoA (Section 1.3): 
• e-Diary completion (see Section 8.2.3.1). 
• Study drug intake (see Section 8.2.3.2). 
• “at-risk” cycles (see Section 8.2.3.3). 
8.2.3.1 
Participant e-Diary  
Access to the e-Diary Application will be made available to participants at V1. Participants should 
begin using the e-Diary on the same day as V1, at home, and continue to complete the e-Diary at 
approximately the same time daily until the e-Diary is returned at EOS/ET or at V2 for participants 
who did not meet inclusion/exclusion criteria. Participants should complete the e-Diary entries 
before returning their device, if one was provided. 
Participants will use the e-Diary for at least 1 week during screening to conduct daily assessments 
of vaginal bleeding/spotting. Participants will receive e-Diary training at V1. Investigators or 
designees should explain the importance of completing the e-Diary daily. Investigators are to 
evaluate participant compliance with the e-Diary during screening to assess eligibility. At V2, 
participants should complete their e-Diary after the visit has been conducted. 
Participants should bring their e-Diary each time they visit the site. 
Site staff are responsible for: 
• Training participants on how to complete the e-Diary. 
• Ensuring participants understand the e-Diary questions. 
• Ensuring participants understand the importance of completing the e-Diary every day. 
• Contacting participants when alerted to missing e-Diary entries. 
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See the e-Diary manual for additional information, including e-Diary activation instructions and 
technical guidance and support.  
Data to be collected in the e-Diary include (but are not limited to) the following: 
• Daily information: 
− Study drug intake 
− Vaginal bleeding-spotting events and the use of sanitary products. 
• Monthly information (to be provided before starting a new blister): 
− Start of a new blister, triggering recording of the information below 
− Pregnancy testing and results 
− Heterosexual vaginal intercourse during previous cycle. 
− Concomitant use of condoms and other forms of contraception during previous cycle 
• Optional information: 
− Pregnancy testing and results as applicable. 
8.2.3.1.1 
Daily e-Diary Questions  
Every day, starting at V2, eligible participants are to record the intake of study drug during the 
past 24 hours. 
Every day, starting at V1, participants are to record vaginal bleeding-spotting events that occurred 
during the past 24 hours. The use of any sanitary products (ie, tampons, pads, panty liners, or 
menstrual cup), used for vaginal bleeding should be recorded. Other sanitary products that do not 
permit the estimation of the amount of bleeding (eg, superabsorbent undergarments) should not be 
used. Sanitary products that are used for any other reason (eg, for urinary incontinence or vaginal 
discharge) are not recorded in the e-Diary. The questions should be completed EVERY DAY until 
V7 to also cover the withdrawal period, so that scheduled bleeding after the last cycle can also be 
determined. 
Participants should alert the site immediately if they are experiencing technical difficulties with 
their e-Diary. The e-Diary will allow daily data entry up to 24 hours late, after which, data entry 
will be locked out. Participants should complete the e-Diary entry before returning their device at 
V7. 
8.2.3.1.2 
Monthly e-Diary Questions (Before Starting a New Blister)  
The e-Diary will include additional questions for the participant to answer just before starting a 
new blister of study drug. These questions ask about the occurrence of heterosexual vaginal 
intercourse at least once during the preceding cycle and the use of additional contraceptives (eg, 
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condoms). If additional contraception was used, the participant must specify the type of 
contraception used. 
Note: If additional use of hormonal contraceptives (other than the NOMAC-E2 COC) is recorded, 
details should be collected at the next study visit and recorded in the database as concomitant 
medications. 
8.2.3.1.3 
Monitoring e-Diary Compliance  
e-Diary entries will be uploaded daily and monitored for completion. The e-Diary is equipped with 
a sound alert to daily remind participants to complete the e-Diary. Participants will receive a daily 
reminder alert to complete the e-Diary. Participants will not receive a daily reminder to take study 
drug. Compliance will be remotely monitored by study staff on an ongoing basis and will be 
reviewed at each site visit and phone contact. 
Missing daily e-Diary entries will interfere with the interpretation of adherence to study drug 
intake and the vaginal bleeding profile. Sites will be contacted if 2 consecutive daily e-Diary 
entries are missing. When alerted to missing entries, the site is expected to contact the participant 
in a timely fashion and remind the participant to complete the e-Diary. Attempts to contact the 
participant should be documented within the study record. 
As the end of cycle questions (to be answered before starting a new blister) regarding heterosexual 
vaginal intercourse and additional contraceptive use are crucial to the primary efficacy endpoints 
(and missing data will result in the exclusion of a cycle from the primary endpoint PI calculation), 
at the time of the statistical analysis, missing end of cycle e-Diary entries will be imputed by ‘No’ 
for heterosexual vaginal intercourse and ‘Yes’ for use of additional contraception, making the 
cycle to be considered not at-risk, which will exclude the entire cycle for the primary contraceptive 
efficacy analysis (unless a pregnancy occurred). 
At all site visits, compliance with daily and end of cycle e-Diary entries will be reviewed by site 
staff. Reinforcement of e-Diary study requirements and additional e-Diary training will be 
provided to study participants, as needed. Additional study visits may also be scheduled to provide 
additional training as needed for participants who continue to fill out the e-Diary incorrectly or 
incompletely. Participants who are not compliant should be re-trained. 
8.2.3.2 
Study Treatment Compliance  
The prescribed dosage and mode of administration may not be changed. 
The intake of study drug will be recorded by the study participants daily in the e-Diary. The e-Diary 
data will be the primary source to measure study treatment compliance. Any deviations from the 
prescribed dosing regimen will be captured in the e-Diary. 
During both on-site and phone visits, compliance will be reviewed by the site using the e-Diary 
data. Participants exhibiting poor study drug intake compliance should be counseled on the 
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importance of good compliance to the study drug dosing regimen. These compliance checks by 
the site and the counseling on the importance of compliance to study drug intake must be 
documented by site personnel in the source documents. 
Non-compliance to study drug intake during the scheduled active cycle period (Days 1 to 24) is 
defined as 4 or more days with forgotten tablets, or 2 or more consecutive days with forgotten 
tablets. The remaining treatment cycles will be included in the Per-Protocol (PP) analysis unless 
excluded by other protocol deviations (see Section 9.3.4 for more information). 
8.2.3.3 
Monitoring “at-risk” Cycle Compliance  
Participants are expected to have heterosexual vaginal intercourse at least once a month and refrain 
from using additional methods of contraception. Compliance with these instructions are needed 
for a cycle to be included in the primary endpoint PI calculation. Compliance will be assessed by 
review of the end of cycle questions (Section 8.2.3.1.2) at study visits and on an ongoing basis by 
the Sponsor through medical monitoring reports. Sites will be notified if participants are non-
compliant with the protocol (ie, cycles not at risk or entries missing such that a cycle is considered 
not at risk) on a per cycle basis and are expected to contact the participant to reinforce compliance 
with the study protocol. Additionally, sites will be notified if participants are persistently non-
compliant with the protocol (ie, for 3 or more consecutive cycles) such that cycles are not at risk 
for pregnancy. Participants who are persistently non-compliant will be evaluated for 
appropriateness to continue in the study. 
8.3 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Details 
regarding specific safety procedures/assessments to be performed in this study are provided below. 
8.3.1 
Physical Examinations  
A focused physical examination will be conducted by an Investigator or medically qualified 
designee (consistent with local requirements) at the Screening (V1) and EOS (V7) Visits as per 
institutional standard. At a minimum, examination for abnormalities of the heart, lungs, abdomen, 
and extremities should be performed. Investigators should pay special attention to clinical signs 
related to previous serious illnesses. 
8.3.2 
Gynecologic and Breast Examinations  
A gynecological examination (including vulva, vagina, cervix, uterus, and adnexa) and a breast 
examination will be performed according to the SoA (see Section 1.3) and whenever clinically 
indicated. These examinations should be conducted by a licensed clinician (ie, Physician, 
Physician Assistant, or Nurse Practitioner). 
Only abnormal findings should be recorded on the appropriate eCRF. 
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8.3.3 
Vital Signs, Body Weight, and Height  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Blood pressure and pulse measurements: 
• Should be assessed with a completely automated device. Manual techniques will be used 
only if an automated device is not available. 
• Should be performed before performance of any study procedure that may cause discomfort 
(eg, gynecological examination, venipuncture) and preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions. 
Height and weight will be measured and recorded according to the SoA (see Section 1.3). The 
BMI will be calculated (weight/height2 in kg/m2) at each visit during data analysis. The study site 
should calculate BMI at the Screening Visit to assess participant eligibility, and the IVRS/IWRS 
will calculate BMI at baseline (V2) to support treatment allocation targets for BMI <30 kg/m2 and 
BMI ≥30 kg/m2. Baseline BMI subgroups used for primary and secondary contraceptive analyses 
will be defined based on screening height and baseline weight as captured on the eCRF. 
8.3.4 
Clinical Safety Laboratory Assessments  
See Appendix 3 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3) 
for the timing and frequency. 
The Investigator or medically qualified designee (consistent with local requirements) must review 
the laboratory report, document this review, and record any clinically relevant changes occurring 
during the study in the AE eCRF. The laboratory reports must be filed with the source documents. 
All protocol-required laboratory assessments, as defined in Appendix 3 must be conducted in 
accordance with the laboratory/procedure manual and the SoA. 
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE), then the results must be recorded in the 
appropriate eCRF. 
For any laboratory tests with values considered clinically significantly abnormal during 
participation up to EOS. Every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined by the 
Investigator. If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor notified. 
Screening laboratory safety tests may be repeated once before treatment allocation (V2) at the 
discretion of the Investigator if the initial results are inconsistent with the participant's clinical 
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status or recent laboratory results. Screening may be performed between 7 days and 42 days before 
V2. 
Laboratory safety tests (hematology and biochemistry) are scheduled to be repeated at V7 for all 
participants. If the participant discontinues early from the protocol-specified Treatment Period, 
those safety tests specified for the EOS Visit (V7) should be completed. 
Details on sampling, processing, and shipping of the materials to the central laboratory will be 
described in a separate laboratory/procedure manual. 
8.4 
Adverse Events  
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AEs and SAEs, can 
be found in Appendix 4. 
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally acceptable representative). 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events 
for outcome according to Section 8.4.3. The Investigator and any designees remain responsible for 
following up AEs that are serious, considered related to the study treatment or study procedures, 
or that caused the participant to discontinue the study treatment or withdraw from the study. 
The Investigator, who is a qualified physician, will assess events that meet the definition of an AE 
or SAE with respect to seriousness, intensity/toxicity and causality. 
For any guidance regarding AE/SAE reporting, the Investigator should contact the Medical 
Monitor. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs and SAEs will be collected from the signing of the ICF until EOS/ET (Section 1.3). 
From the time of signing ICF through EOS/ET(V7), which is 14 to 19 days after last intake of 
study drug, all AEs, SAEs, and other reportable safety events must be reported by the Investigator. 
For the analysis of AEs and SAEs, a distinction will be made between: 
• Pre-Treatment AEs: Events which occur after the ICF (or assent form, if applicable) is signed 
and before the first intake of study drug. 
• Treatment-emergent AEs: Events which occur in temporal association with intake of study 
drug, until 14 days after the last intake of active study drug. 
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Additionally, any SAE brought to the attention of an Investigator at any time outside the period 
specified in the previous paragraph must be reported immediately (within 24 hours of learning 
about the event) to the Sponsor if the event is considered related to study drug. 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in 
former study participants. However, if the Investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 8. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4. 
Table 8 
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events  
Type of Event 
Reporting Time Period: 
Signing of ICF to  
First Intake of Study 
Drug (Day 1) 
Reporting Time Period: 
First Intake of Study 
Drug (Day 1) through 
End of Study (V7) 
Time Frame to Report 
Event and Follow-up 
Information to Sponsor: 
Nonserious Adverse 
Event (NSAE) 
Report if: 
• 
Due to protocol-
specified procedure, or 
• 
Causes exclusion 
Report all 
Per eCRF completion 
guidelines 
Serious Adverse 
Event (SAE) 
Report if: 
• 
Due to protocol-
specified procedure, or  
• 
Causes exclusion 
Report all 
Within 24 hours of 
learning of event 
Pregnancy 
complications and 
outcomes/ 
Lactation Exposure 
Report if: 
• 
Participant has been 
exposed to any 
protocol-specified 
procedure 
Report all 
Within 24 hours of 
learning of event 
Event of Clinical 
Interest (ECI) 
Report if: 
• 
Causes exclusion 
Report all 
Within 24 hours of 
learning of event 
Tumor 
Report if: 
• 
Causes exclusion 
Report all 
Within 5 calendar days of 
learning of event (unless 
serious) 
8.4.2 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
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non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, including 
pregnancy complications/outcomes (see Appendix 5) and exposure during breastfeeding, events 
of clinical interests (ECIs), cancer, and overdose will be followed until resolution, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
7.4). In addition, the Investigator will make every attempt to follow all nonserious AEs that occur 
in eligible (allocated to treatment) participants for outcome. Further information on follow-up 
procedures is given in Appendix 4. 
8.4.4 
Regulatory Reporting Requirements for SAEs  
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
drug under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 
and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5 
Events of Clinical Interest  
Selected nonserious AEs and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interests for this study that require regulatory reporting within 24 hours of 
learning of the event include: 
• An elevated AST or ALT lab value that is greater than or equal to 3 × the upper limit of normal 
(ULN) and an elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at 
the same time, an alkaline phosphatase lab value that is less than 2 × ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
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*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent). 
• ATE (including myocardial infarction, stroke, or peripheral arterial events) and VTE 
(including pulmonary embolism and deep venous thrombosis). 
8.5 
Treatment of Overdose  
Multiple doses up to 5 times the daily dose of NOMAC-E2 and single doses up to 40 times the 
daily dose of NOMAC alone have been used in women without safety concern. For this study, any 
dose of 3 or more tablets per day will be considered an overdose. Based on general experience 
with COC, symptoms that may occur include nausea, vomiting, and slight vaginal bleeding. There 
are no antidotes, and further treatment should be symptomatic. See the IB for more information 
(4). 
In the event of an overdose, the Investigator/treating physician should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
8.6 
Pharmacokinetics and Pharmacodynamics  
Sparse plasma samples for NOMAC PK analysis will be collected in a subset of the study 
population (approximately 200 participants) during V3 and V4, to be scheduled between Day 7 
and Day 12 of the corresponding cycle (ie, within the +5 day window for Cycle 2 and Cycle 5, 
respectively). The subset will be representative of the study population in terms of BMI 
distribution. 
For each participant in the PK subset, PK plasma samples will be taken during V3 and V4. At each 
visit, two PK plasma samples will be taken; the first sample within 1 hour prior to, and the second 
sample between 1 and 2 hours after, the observed dose administration. 
Participants must take their daily dose at the visit so it can be observed and recorded by the site 
staff. The dosing time and date must be correctly recorded for the dose immediately preceding the 
V3 and V4 clinic visits along with the date and time of the dose administration during the V3 and 
V4 clinic visits, in the respective eCRF pages. The participant must also enter the dose taken in 
their e-Diary, as usual. The date and time for all PK samples, along with the corresponding labeled 
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accession number will be recorded in the eCRF page. This will result in the study participants 
staying in the clinic a maximum of 3 hours longer for a visit when PK is assessed.  
Pharmacokinetic visits must be scheduled to allow 16 to 30 hours between the dose taken by the 
participant on the day prior to the PK visit, and the dose taken on the day of the PK visit.  
The following dosing instructions and visit scheduling relative to PK sampling should be followed: 
• If the participant is routinely taking their dose in the morning, the dose should be held until 
instructed to take the dose during the V3 and V4 clinic visits. 
or 
• If the participant is routinely taking their dose in the afternoon or evening, the corresponding 
V3 and V4 daily dose will be administered in the clinic when instructed. Consequently, no 
additional dose (after the dose taken in the clinic) should be taken the afternoon or evening of 
the V3 or V4 clinic visit. 
Samples will be kept frozen at -20°C, or colder, prior to shipment. See the Central Laboratory 
Manual for details on sampling, processing, labeling, storage, and shipment of human biological 
samples used in the PK evaluation. 
Pharmacodynamics are not evaluated in this study. 
8.7 
Genetics  
Genetics are not evaluated in this study. 
8.8 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
8.9 
Changes to Study Procedures Due to COVID-19 Pandemic  
The following information provides guidance regarding changes to the study procedures that could 
be implemented for study participants or study sites affected by the Coronavirus Disease 2019 
(COVID-19) public health emergency. This guidance takes references from the FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency – 
Guidance for Industry, Investigators, and IRBs, March 2020, updated 03 June 2020, and the 
European Medicines Agency Guidance on the Management of Clinical Trials During the COVID 
19 (Coronavirus) Pandemic, Version 3 (28 April 2020). 
As the COVID-19 pandemic may peak in different regions at different times and restrictions 
implemented by local laws and recommendations may vary, any decision on procedural changes 
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should be made on a case-by-case basis by the Investigator in consultation with the study team and 
the medical team as needed, while maintaining patient safety and confidentiality as the priority. 
Procedural changes due to COVID-19 may include the following: 
• All visits except Screening, V2, and EOS/ET (V7) may be converted to virtual visits or phone 
calls to extend flexibility to participants during the COVID-19 public health emergency. 
Virtual visits/phone calls will be documented in the study records and eCRF. The data collected 
from virtual visits/phone calls may be handled differently in the final data analysis, with this 
documented in the Statistical Analysis Plan (SAP). All other planned in-clinic visits must be 
done with the participant present at the site. Upon discussion and agreement with the Sponsor, 
other options besides virtual visits/phone calls may be utilized. Any conversion of visits must 
be approved by the Sponsor. 
• For virtual visits/phone calls, collection of scheduled clinical laboratory samples (blood 
specimen collection or other diagnostic tests) will be performed by a qualified health care 
professional who can visit the participant at home. All laboratory samples should still be sent 
to the designated laboratory as outlined in the Laboratory Manual. 
• Missed clinic visits or participant withdrawals due to COVID-19 must be recorded on the 
eCRF. Participants who discontinued from screening due to COVID-19-related factors but 
were otherwise qualified to participate in the study may be rescreened. Any rescreening must 
be approved by Medical Monitor. 
• Allow electronic clinical outcomes assessments typically scheduled for completion at the clinic 
to be completed at home if a site visit cannot occur. 
• In specific circumstances and with Sponsor approval, it may be allowed to transfer participants 
to sites away from risk zones or closer to their homes (either to new sites or sites already 
participating in the study). 
• During the COVID-19 public health emergency, alternative study drug delivery to study 
participants may be necessary to avoid unnecessary visits to sites while providing needed study 
drug. If there is a high risk that an upcoming visit may be converted from an on-site to off-site 
visit, additional study drug may be dispensed during a scheduled study visit. If needed, study 
drug may also be shipped directly from investigational sites to participants’ residences by a 
contracted logistics provider or distributor (direct-to-participant shipment) in compliance with 
national laws or temporary national emergency measures and Sponsor processes. 
Deviations from the protocol-specified procedures (eg, laboratory assessments) will be recorded 
as related to COVID-19. 
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9.0 STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses  
In this study, point estimates and associated CIs will be calculated. No formal hypothesis tests 
will be conducted. 
9.2 
Sample Size Determination  
9.2.1 
Main Analysis  
 
 
 
 
 
 
 
 
 
 
 
 
A PI of 3.0 is assumed for the NOMAC-E2 COC, which is similar to the values observed for low 
dose COCs such as LoLoestrin (norethindrone/EE) and Quartette (LNG/EE). This is considered to 
be a conservative estimation, as previous clinical study data suggest that the NOMAC-E2 COC is 
associated with a lower PI than higher dosed COCs such as DRSP/EE 3.0 mg/30 µg (Yasmin), 
while recent large scale observational study data suggest that the NOMAC-E2 COC may also have 
a PI much lower than the LNG/EE 150/30 µg COC (eg, Levora). 
 
 
 
 
 
 
 (19). 
A summary of the number of at-risk cycles and number of treated participants required is presented 
in Table 9 for different scenarios of expected PIs ranging between 2.4 and 3.4 in order to achieve 
80%, 85%, or 90% power, respectively. 
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Table 9 
Number of at-risk Cycles and Number of Treated Participants Required 
Depending on Expected PI to Achieve an Assumed 80%, 85% or 90% Power  
PI Expected 
Powera (%) 
Number of At-risk 
Cycles 
Number of Treated Participants 
2.4 
80 
5557 
731 
2.4 
85 
5903 
776 
2.4 
90 
7060 
928 
2.6 
80 
6847 
900 
2.6 
85 
7212 
948 
2.6 
90 
8307 
1092 
2.8 
80 
8417 
1107 
2.8 
85 
8825 
1160 
2.8 
90 
9890 
1300 
3.0 
80 
10717 
1409 
3.0 
85 
11643 
1531 
3.0 
90 
12708 
1671 
3.2 
80 
12695 
1669 
3.2 
85 
14941 
1964 
3.2 
90 
16481 
2167 
3.4 
80 
16469 
2165 
3.4 
85 
18629 
2449 
3.4 
90 
20997 
2760 
Abbreviations: CI=confidence interval; PI=Pearl Index. 
a. The “probability of success” or “power” represents the probability that the upper CI limit of the PI will be no 
larger than 5.0, under the various assumptions of the PI and that the number of pregnancies follow a Poisson 
distribution. The power was derived, based on formula (14) and exact Poisson probabilities, computed in the R 
software. 
 
 
 
 
 
 
 
 
 
9.2.2 
Pharmacokinetic Analysis  
For the PK evaluation described in Section 8.6, sparse sampling and population PK modeling will 
be used to estimate the effect of covariates (body weight and BMI) on NOMAC PK in 
premenopausal women aged 14 to 35 years (inclusive) after 1.5 mg E2 and 2.5 mg NOMAC. A 
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subset of approximately 200 participants, representative of the study population in terms of BMI 
distribution, will be selected for inclusion in the NOMAC PK evaluation.  
The number of participants for inclusion in the PK subset to substantiate clinical relevance was 
established by the evaluation of various clinical trial simulation scenarios based upon a prior 
NOMAC population PK modeling effort (data on file).  
9.3 
Populations for Analyses  
9.3.1 
Full Analysis Set  
The Full Analysis Set (FAS) is defined as all participants allocated to treatment who took at least 
one dose of study drug. 
The FAS is a supportive population to further characterize the contraceptive efficacy and the 
vaginal bleeding pattern. 
9.3.2 
Contraceptive Efficacy Analysis Populations  
9.3.2.1 
Restricted Full Analysis Set  
The restricted FAS (rFAS) is defined as the subset of all participants included in the FAS who 
have at least one at-risk treatment cycle of NOMAC-E2 COC, or participants with a treatment 
cycle (at-risk or not) of NOMAC-E2 COC in which a pregnancy has occurred (ie, treatment cycle 
containing an estimated conception date for a pregnancy). 
The rFAS will be used for the primary (contraceptive) efficacy analysis. 
9.3.2.2 
Per Protocol 1 Population  
The PP 1 population is defined as the subset of all participants in the rFAS, with at least one 
treatment cycle of NOMAC-E2 COC that occurs without specific protocol deviations, as defined 
in Section 9.3.4. 
The PP 1 is used to further characterize the contraceptive efficacy. 
9.3.3 
Vaginal Bleeding Analysis Populations  
The FAS evaluable for the Cycle Control Analysis (FAS CCA evaluable) is the primary analysis 
population for cycle-based vaginal bleeding analyses and is defined as the subset of all participants 
included in the FAS who have at least one treatment cycle evaluable for the CCA. 
The FAS reference period (RP) evaluable is the primary analysis population for reference 
period-based vaginal bleeding analysis and is defined as the subset of all participants included in 
the FAS who have at least one RP evaluable. 
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Details regarding the definition of evaluable cycles for FAS CCA evaluable analysis and 
evaluable RPs for FAS RP analysis, along with any PP population that may correspond to either 
FAS population, will be clarified in the SAP. 
9.3.4 
Per-Protocol Analysis and Protocol Deviations  
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in an approved protocol. 
The final determination of important or non-important protocol deviations, and thereby the 
composition of important deviations which would exclude participants or time periods from an 
associated PP population, will be made prior to the final database lock and will be documented in 
a separate memo. These deviations may include, but are not limited to, the presence of any of the 
following: 
• Treatment cycles in which the participant is non-compliant with study drug will be excluded. 
Non-compliance to tablet intake during the scheduled active cycle period (Days 1 to 24) is 
defined as either: 
− 4 or more days with forgotten tablets, or 
− 2 or more consecutive days with forgotten tablets. 
• Participant has >75% of treatment cycles in which either the participant was not considered 
at risk for pregnancy or was non-compliant with study drug or e-Diary completion will 
exclude the participant from the PP 1 set. 
• Treatment cycles from participant having used prohibited medication listed in Table 6. 
Treatment cycles will be excluded in which the medication was used, including treatment 
cycles started within 28 days after discontinuation of prohibited medication. The remaining 
treatment cycles of the participant will be included in the PP analysis unless excluded by other 
protocol deviations. 
Note: Treatment cycles in which hormonal contraception other than the NOMAC-E2 COC 
has been used are considered a protocol deviation for the purposes of the CCA or RPA, 
and to be excluded from the FAS evaluable. Such treatment cycles have already been 
excluded from the contraceptive efficacy calculation in the rFAS. Treatment cycles in 
which condoms (or other non-hormonal methods of back-up contraception) are used will 
be considered in the CCA and RPA, in contrast to the contraceptive efficacy analysis, as 
such use is not expected to affect the CCA and RPA outcomes. 
• Participant is pregnant or has taken study drug without a documented negative pregnancy test, 
on the day of first study drug intake. 
• Participant has undiagnosed (unexplained) abnormal vaginal bleeding or any other abnormal 
bleeding that meets exclusion criteria at screening as being attributable to underlying pathology 
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(ie, cervical/endometrial polyp, uterine fibroids, endometriosis, etc.) which has not been 
treated/resolved. 
• Participant is breastfeeding. 
9.3.5 
Safety Analysis Population  
The All-Participants-as-Treated (APaT) population will consist of all participants allocated to 
treatment who took at least one dose of study treatment. 
The APaT population will be used for the analysis of all safety data in this study. 
9.3.6 
Pharmacokinetic Analysis Population  
A subset of approximately 200 participants, representative of the study population in terms of BMI 
distribution, will be selected for inclusion in the NOMAC PK evaluation. 
9.4 
Statistical Analyses  
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. The SAP document will provide 
further details regarding the definition of analysis variables and analysis methodology to address 
all study objectives. The SAP will serve as a complement to the protocol and will supersede the 
protocol in case of differences. 
Statistical analysis will be performed using SAS® software (version 9.4 or higher) (SAS Institute 
Inc., Cary, NC, USA). 
9.4.1 
General Considerations  
All data will be listed, and summary tables will be provided. Summary statistics will be presented 
by treatment group. Continuous variables will be summarized for the measured values and change 
from baseline values using the number of observations, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized with counts and percentage 
for each category. Point estimates will be presented together with 95% CIs as appropriate. 
9.4.2 
Efficacy Analyses  
9.4.2.1 
Contraceptive Efficacy Endpoints  
9.4.2.1.1 
Definitions  
An on-treatment pregnancy is defined as a pregnancy with an estimated date of conception from 
the day of first intake of study drug up to and including 7 days after the last intake of active study 
drug. 
A pre-treatment pregnancy is defined as a pregnancy with an estimated date of conception after 
signing informed consent, but before the first intake of study drug. Also, all pregnancies in 
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participants in which all dispensed study drug is returned unused (per Investigator's record) will 
be considered pre-treatment pregnancies. 
A post-treatment pregnancy is defined as a pregnancy with an estimated date of conception more 
than 7 days after the last intake of active study drug. 
See Section 8.2.1.2.1 for confirming reported pregnancies and determining conception date. 
A treatment cycle is defined by the period between 2 start dates of a blister, as recorded in the 
participant’s e-Diary. The last treatment cycle ends by the last recorded day of tablet intake. 
An at-risk cycle for pregnancy is a treatment cycle in which the participant has used no 
contraceptives of any type other than the study drug and in which the participant has affirmed 
heterosexual vaginal intercourse. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 (20). 
9.4.2.2 
Primary Contraceptive Efficacy Endpoint(s)  
PI at-risk 
The PI at-risk analyzed in the rFAS population is selected as the primary efficacy endpoint. As 
specified by the FDA Draft Guidance on Contraceptive Efficacy Trials, the calculation of the PI 
for the primary efficacy evaluation should include only cycles during which (a) heterosexual 
vaginal intercourse occurred and (b) no back-up or emergency contraception was used based on 
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e-Diary data (19). The participants will be asked to record in the e-Diary each time a new 
medication blister is started whether during the preceding cycle heterosexual vaginal intercourse 
has taken place and whether any other form of contraception has been used, and if so, which form. 
For a treatment cycle to be included in the primary efficacy analysis, it must be confirmed that 
heterosexual vaginal intercourse did occur and that no other forms of contraception were used. 
Note: any cycle in which a pregnancy is conceived is included in the PI at-risk even when back-up 
contraception has been used and/or heterosexual vaginal intercourse has been claimed to not have 
occurred. Missing information regarding heterosexual vaginal intercourse or the use of additional 
contraception will result in exclusion of a cycle from the denominator of the PI calculation, except 
for a cycle in which a pregnancy has occurred. 
9.4.2.3 
Secondary Contraceptive Efficacy Endpoint(s)  
PI perfect use 
The PI perfect use is selected as a key secondary efficacy endpoint. The PI perfect use will be analyzed 
using the PP 1 population. The PP 1 population is a subset of the rFAS population; see 
Section 9.3.4. For a cycle to be included in this secondary efficacy analysis, it must be confirmed 
that heterosexual vaginal intercourse did occur, that no other forms of contraception were used and 
that there were no protocol deviations as defined in Section 9.3.4. This analysis, also known as 
method failure analysis, estimates the contraceptive efficacy of the method when used as directed 
and is considered to approach the inherent contraceptive properties of the NOMAC-E2 COC most 
closely. 
PI typical use 
The PI typical use analyzed using the FAS is selected as another secondary efficacy endpoint. The 
FAS contains all participants allocated to treatment who took at least one dose of study drug. All 
cycles, regardless of heterosexual vaginal intercourse, use of other forms of contraception, and 
protocol deviations are included in this supportive efficacy analysis. This analysis, also known as 
user failure analysis, estimates the contraceptive efficacy of the method under typical use 
conditions is considered to approach the real-life contraceptive properties of the NOMAC-E2 COC 
most closely. 
Subgroup Analysis 
 
 
 
 
9.4.2.4 
One-year Cumulative Pregnancy Rate  
A time-to-pregnancy analysis will be performed using the Kaplan-Meier approach and will be 
further defined in the SAP. Participants who do not become pregnant will be censored at the last 
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day of the on-treatment period. The cumulative probabilities of in-treatment pregnancies after 
thirteen 28-day treatment cycles will be estimated. 
9.4.2.5 
Vaginal Bleeding Endpoint(s)  
Participants will record daily their experience of vaginal bleeding-spotting over the last 24 hours 
in the e-Diary, defined as follows: 
No bleeding: no vaginal discharge containing blood. 
Bleeding: vaginal discharge containing blood that requires the use of a sanitary product (ie, pad, 
panty liner, tampon, or menstrual cup). 
Spotting: vaginal discharge containing blood that requires no use of a sanitary product (ie, pad, 
panty liner, tampon, or menstrual cup). 
Note: The routine use of a panty liner or other sanitary protection for other reasons such as vaginal 
discharge or urinary incontinence will not be counted as a bleeding-spotting day. 
Vaginal bleeding-spotting information collected prior to the date of V2 will be used to assess diary 
compliance and will not contribute to the study analysis. 
9.4.2.5.1 
Cycle Control Analysis  
In conventional contraceptives with a 21/7 regimen the expected bleeding interval is the 7-day 
period during which no active treatment is taken (ie, Day 22 to Day 28 of the cycle). A scheduled, 
or withdrawal, bleeding is expected to start during this hormone-free interval. No bleeding is 
expected during the period with active treatment, the expected non-bleeding interval. 
In this study, participants will be treated with a 24/4 regimen. Therefore, scheduled bleedings will 
start later and will likely continue into the next cycle. To perform the CCA with this different 
dosing regimen without introducing an a priori increased probability of unscheduled bleeding and 
an a priori decreased probability of scheduled bleeding, the following definitions for the expected 
non-bleeding and expected bleeding interval will be used: 
Expected bleeding interval: 7-day period starting on Day 25 of the cycle and ending on Day 3 of 
the next cycle. 
Expected non-bleeding interval: 21-day period starting on Day 4 of the cycle. 
In other words, the cycles will be “shifted” by 3 days in comparison to contraceptives with a 
traditional 21/7 regimen. To analyze all 13 cycles from this group, the 3 days following the very 
last tablet intake (scheduled at Day 364) will be included in the analysis of Cycle 13, irrespective 
of any use of (post-study) contraceptives on one of these days. 
The following definitions will be used in the CCA. 
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• Bleeding-spotting episode: one or more consecutive days during which bleeding or spotting 
occurred, bounded at each end by bleeding-spotting-free days. 
• Bleeding episode: one or more consecutive days during which bleeding occurred, bounded at 
each end by days on which no bleeding was recorded (with spotting allowed as boundary). 
• Bleeding-spotting-free interval: one or more consecutive days with no bleeding, bounded at 
each end by bleeding or spotting days. 
• Unscheduled bleeding-spotting: any bleeding that occurred during the expected non-bleeding 
interval that was neither an early nor a continued scheduled bleeding-spotting. 
• Scheduled bleeding-spotting: any bleeding-spotting that started during or continued into the 
expected bleeding interval 
• Continued scheduled bleeding-spotting: any scheduled bleeding-spotting that continued into 
the expected non-bleeding interval of the next treatment cycle. For the cycle analysis, 
continued scheduled bleeding-spotting is counted in the treatment cycle in which it originated 
and not in the treatment cycle into which it continued. 
• Early scheduled bleeding-spotting: any scheduled bleeding-spotting that started before the 
current expected bleeding interval and continued into the expected bleeding interval. 
• Absent scheduled bleeding-spotting: no scheduled bleeding-spotting episode during the 
expected bleeding interval. 
• Absence of any bleeding-spotting: no scheduled or unscheduled bleeding-spotting at all.  
The main vaginal bleeding endpoints in the CCA are: 
• Proportion of participants who experienced unscheduled bleeding-spotting 
• Proportion of participants who experienced absence of scheduled bleeding-spotting 
• Proportion of participants who experienced no scheduled or unscheduled bleeding-spotting at 
all 
Point estimates with associated 95% CIs will be estimated for these main vaginal bleeding outcome 
proportions and presented by treatment cycle. 
Additional vaginal bleeding endpoints in the CCA include: 
• Number of bleeding days 
• Number of spotting days 
• Number of bleeding-spotting days 
• Mean duration of bleeding-spotting episodes 
All CCA will be performed on the FAS evaluable, as the primary efficacy analyses, and on the 
PP 2 population as supporting analyses. 
Frequency tables and/or summary statistics for continuous variables will be calculated for all 
primary and secondary parameters and presented per cycle. The number and percentage of 
participants with a bleeding day and the number and percentage of participants with a 
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bleeding/spotting day will be presented per cycle and within cycle per cycle day, with a 
denominator based on the number of participants who are considered evaluable for the complete 
cycle. 
Data Handling Conventions 
Because of the possible influence of missing data for the bleeding variables, the following 
additional conventions will be used for the analysis of bleeding events: 
• Interpolation rule: In cases, where for one or 2 consecutive days bleeding information is 
missing, the bleeding information of the day immediately preceding will be imputed for these 
days. If bleeding information is missing for more than 2 consecutive days, no imputation will 
be carried out (non-evaluable cycle). 
• Irrespective of what was recorded in the e-Diaries, “no bleeding” will be imputed for the first 
7 days of Cycle 1 (before “shifting” of cycles for the NOMAC-E2 group). This imputation will 
be carried out because many women will start during their menstrual period. 
9.4.2.6 
Reference Period Analysis  
Because of the varying treatment cycle lengths allowed within the FAS evaluable (≥22 days and 
≤35 days, see Section 9.3.3), an RPA will also be conducted. The RPA is based on occurrence of 
vaginal bleeding within 91-day long RPs. In this analysis, all bleeding events are counted within 
consecutive 91-day periods that begin with the first intake of the study drug, regardless of their 
occurrence in relation to expected bleeding and expected non-bleeding intervals. 
The following RPs with a fixed length of 91 days will be defined from the first to the last day of 
study drug intake and will be defined in more details in the SAP: 
• RP 1: from Day 1 to Day 91. 
• RP 1.1: from Day 29 to Day 119. 
• RP 2: from Day 92 to Day 182. 
• RP 3: from Day 183 to Day 273. 
• RP 4: from Day 274 to Day 364. 
• RP 5: the last 91 days. 
The length of the RPs is defined as 91 days (4 × 91 days equal 13 treatment cycles of 28 days) in 
accordance with the minimum World Health Organization (WHO) requirement of 90 days and is 
considered to be sufficiently long to allow several bleeding events to occur in an RP. 
In some participants the timing of the first tablet intake is aligned with the first day of menstruation, 
which may result in the beginning of the first RP including days with bleeding events due to 
menstruation. As this could affect the derived indices of amenorrhea, infrequent, frequent, and 
prolonged bleeding-spotting, an additional RP designated RP 1.1 starting with treatment Cycle 2 
(Day 29), and covering Days 29 to 119, has also been defined. 
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With respect to the RPA the following definitions will be used: 
• Bleeding-spotting-free interval: One or more consecutive bleeding-free days which are 
bounded at each end by at least one bleeding/spotting day. 
• Bleeding-spotting episode: one or more consecutive days during which bleeding or spotting 
occurred, bounded at each end by bleeding-spotting-free days. 
• Bleeding-only episode: one or more consecutive days during which bleeding occurred, 
bounded at each end by days on which no bleeding was recorded (with spotting allowed as 
boundary). 
• 
Spotting-only episode: one or more consecutive days during which spotting occurred, bounded 
at each end by days on which no spotting and no bleeding was recorded. 
• Amenorrhea: No bleeding and/or spotting throughout the RP. 
• Infrequent bleeding: Less than 3 bleeding/spotting episodes starting within an RP, excluding 
amenorrhea. 
• Frequent bleeding: More than 5 bleeding/spotting episodes, starting within an RP 
• Prolonged bleeding (WHO definition): At least one bleeding/spotting episode starting within 
an RP, with a length of >14 days. 
• Prolonged bleeding (FDA definition): At least one bleeding/spotting episode starting within an 
RP, with a length of >7 days. 
The RPA will be conducted on the following endpoints for the FAS evaluable: 
• Number of bleeding days, spotting days, and bleeding-spotting days 
• Proportion of participants with the following: 
− Amenorrhea; 
− Infrequent, frequent, or normal frequency bleeding-spotting; and 
− Prolonged bleeding-spotting. 
• Mean duration of bleeding-spotting episodes defined as abnormal uterine bleeding that occur 
between periods. 
Data Handling Conventions 
The same data handling conventions as for the cycle analysis will be used concerning the 
interpolation rule for missing bleeding information and the imputation of “no bleeding” for the 
first 7 days of RP1. 
Bleeding-spotting episodes and bleeding-spotting-free intervals will be assigned to the RP in 
which they started and, therefore, counted only once even if they ended in a later RP. Their lengths 
will not be truncated if they overlapped 2 or more RPs. If for a participant and RP the number of 
episodes or intervals was zero, the corresponding length variable will be set to missing. If an 
episode or interval was right- or left-bounded by missing values (after application of the 
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interpolation rule), the length was excluded from the calculation of the mean length statistics; such 
bounds may result from the exclusion of non-evaluable RPs. The very last episode or interval in 
progress on the last day of tablet intake will be counted in the mean length statistics with its 
truncated (by the last day of tablet intake) length because other treatments may follow after the 
EOS drug administration. 
9.4.3 
Safety Analysis  
The APaT population will be used for all safety analyses. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, 
laboratory values, vital signs, and body weight. 
For the analysis of safety data, the following conventions will be used: 
• Baseline will be defined as the last measurement before the first study drug intake. 
• The on-treatment period will be defined as the period from the day of first tablet intake up to 
and including the day of last active study drug intake, extended by 14 days. However, any 
delayed events or diagnoses judged by the Investigator to be related to study drug will also be 
considered to have occurred on-treatment and will be included in the safety analysis. 
• Last measurement is the last value obtained during the on-treatment period. 
The proportion of participants with prespecified events listed as ECIs described in Section 8.4.5 
during the on-treatment period will be provided along with corresponding 95% Clopper-Pearson 
CIs. All ECIs will be summarized, even if the incidence is zero. 
In addition, the broad AE categories consisting of the percentage of participants with any AE, a 
drug-related AE, a serious AE, an AE, which is both drug-related and serious, and who 
discontinued study drug due to an AE will be summarized with corresponding 95% 
Clopper-Pearson CIs (Table 10). On-treatment AEs are those occurring from first intake of study 
drug to 14 days after intake of the last active tablet of study drug. AEs occurring during the 
designated pre-treatment (between V1 and first intake of study drug) and post-treatment (>14 days 
after last tablet intake of study drug) periods will be provided. 
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Table 10 
Analysis Strategy for Safety Parameters  
Safety Endpointa 
Within Group 
95% CIb 
Descriptive 
Statistics 
Any AE 
X 
X 
Any Serious AE 
X 
X 
Any Drug-Related AE 
X 
X 
Any Serious and Drug-Related AE 
X 
X 
Discontinuation due to AE 
X 
X 
Specific AEs, SOCs, ECIs, and PDLCs (incidence ≥4 participants) 
X 
Specific AEs, SOCs, ECIs, and PDLCs (incidence <4 participants) 
 
X 
Change from Baseline Results (laboratory tests, vital signs) 
 
X 
Abbreviations: AE=adverse event; CI=confidence interval; ECI=event of clinical interest; PDLC=Predefined Limit 
of Change; SOC=System Organ Class; X=results will be provided. 
a. AE references refer to both clinical and laboratory AEs. 
b. 95% CIs will be calculated using the Clopper-Pearson method. 
For continuous measures such as changes from baseline in laboratory tests and vital sign 
parameters, summary statistics for on-treatment values will be provided in table format at V2 and 
V7. 
For summary statistics of laboratory parameters and vital signs per visit, visit windows as 
described in Table 11 will be used. 
Table 11 
Timeframe Used in the Analysis of Vital Signs and Laboratory Parameters  
Definition 
Visit 
Visit window (treatment day) 
Baseline 
V1 Screening 
<1 
In-treatmenta 
V3 After Cycle 1 
29 ± 28 days 
V4 After Cycle 4 
113 ± 28 days 
V5 After Cycle 7 
197 ± 28 days 
V6 After Cycle 10 
281 ± 28 days 
V7 After Cycle 13 
379 ± 28 days 
Last measurement 
>1 
Abbreviation: V=Visit 
a. From Day 1 until ≤28 days after last tablet intake; Day 1 is defined as day of first study drug intake 
Values outside these visit windows, or outside the defined in-treatment period for post-baseline 
assessments, will be excluded from the analysis of that particular visit. 
However, these visit windows will only be applied for analyses performed per visit; no values 
will be excluded from the determination of markedly abnormal laboratory or vital signs values 
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(unless outside the defined in-treatment period). If more than one observation is available within 
a specific visit window, the latest value will be used for analysis. 
9.4.3.1 
Adverse Events  
An overview table of the number (percentage) of participants with any AEs, SAE, drug-related 
AEs, any serious drug-related AEs, any discontinuation due to AE, any discontinuation due to a 
SAE, any discontinuation due to a drug-related AE, any discontinuation due to serious drug-related 
AE, and any deaths will be presented for the on-treatment period. Pre-treatment AEs/SAEs starting 
before the in-treatment period will be excluded from the AE analyses (unless there is an increase 
in Investigator assessed intensity or causality, or the AE meets SAE criteria post-treatment 
allocation) and reported in separate frequency tables with the methods described above. 
The number (percentage) of participants with at least one AE will be presented in a frequency table 
of Medical Dictionary for Regulatory Activities (MedDRA) system organ class (according to the 
primary path) and MedDRA preferred term. The same tables will be presented by relationship to 
study drug (“Related” and “Not related”) by the Investigator; and by severity of the AE (“mild”, 
“moderate”, “severe”). 
All participants who prematurely discontinue from treatment due to an AE will be summarized 
considering all their AEs for which the action taken on study drug was “drug withdrawn”. The 
summary will be performed by MedDRA system organ class, preferred term, and relationship. 
9.4.3.2 
Laboratory Parameters  
Routine hematology and biochemistry parameters measured at V1 (Screening) and V7 (EOS or 
ET) will be determined by a central laboratory, unless the central laboratory results are not 
available in time for either starting study treatment administration and/or response evaluation. The 
sexually transmitted infections (STI) panel testing will be performed by a local laboratory. The 
measurements of each laboratory parameter will be converted to Standard International units 
before the statistical analysis, unless otherwise specified. The conversion factors will be recorded 
in the database. 
For each parameter, normal reference ranges (including the date of effect) and safety ranges will 
be presented. Safety ranges are defined on the suggestions of the FDA. If safety ranges are not 
available for specific parameters, in-house criteria will be used and presented. 
Summary Statistics 
For each laboratory parameter, summary statistics will be calculated by assessment (V1, V7, and 
last measurement, respectively). In addition, summary statistics will be presented for the change 
from baseline. Shifts from baseline to V7 and last measurement will be presented based on shift 
categories to be identified in the SAP. The incidence of post-baseline markedly abnormal values 
will be presented based on categories to be identified in the SAP. 
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9.4.3.3 
Vital Signs and Body Weight  
Blood pressure and body weight measurements will be performed at screening (V1), treatment 
allocation (V2), and after Cycles 1, 4, 7, and 10 and at the EOS. 
Summary Statistics 
For each parameter (including calculated BMI), descriptive statistics will be calculated by visit 
(including last measurement). In addition, the summary statistics will be presented for the change 
from baseline. The incidence of post-baseline markedly abnormal values will be presented based 
on categories to be identified in the SAP. 
9.4.3.4 
Physical, Gynecological, and Breast Examinations  
Clinically significant findings of general physical, gynecological, and breast examinations 
performed at EOS will be recorded as AEs by the Investigator; these findings will be recorded in 
the AEs eCRF. 
9.4.4 
Other Analysis  
9.4.4.1 
Pharmacokinetics  
The population PK evaluation will be performed by the assigned Contract Research Organization. 
The methodology will be detailed in a separate, stand-alone population PK modeling and 
simulation analysis plan. Results will be reported separately from the clinical study report. 
9.4.4.2 
Demographics, Baseline Characteristics, and Disposition  
Demographics and baseline characteristics include age, race, ethnicity (Hispanic or Latin origin), 
body weight, height, BMI (kg/m2), general medical history, gynecological history, and previous 
use of contraceptives. To further characterize former contraceptive use, “starters” are defined as 
those who have not taken any hormonal contraceptive within 2 months before the start of treatment 
and “switchers” are defined as participants who have used any type of hormonal contraceptive 
within 2 months before the start of treatment (inclusive). 
All variables will be summarized by descriptive statistics. Demographics and baseline 
characteristics will be summarized for the ApaT, the rFAS, and the FAS evaluable populations. 
No statistical hypothesis tests will be performed on the demographics and baseline characteristics. 
The number and percentage (as applicable) of participants screened and allocated to study 
treatment, the primary reason for screening failure, and the primary reason for discontinuation 
from study treatment will be displayed. In addition, the primary reason why participants were 
allocated to study treatment but discontinued prior to study treatment (non-treated participants) 
will be presented in a table. 
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The number of participants who were treated and who completed the clinical study will also be 
tabulated. A disposition graph of participants will be provided. 
The number of participants with protocol deviations will be tabulated by deviation for the FAS. In 
addition, all deviations will be listed by participant. 
A cumulative discontinuation rate will be calculated using the Kaplan-Meier method for all reasons 
combined. The tables and analyses for premature discontinuations will be performed for the ApaT 
population. 
9.4.4.3 
Prior and Concomitant Medication  
All medications, as documented by the Investigator, will be coded using the latest version of the 
WHO Drug Dictionary. Prior medications are defined as any medications reported up to the first 
study drug intake. Concomitant medications are defined as any medications from the first study 
drug intake day onwards up to the day of last study drug intake, extended by 7 days. 
For the ApaT population, the number of participants taking prior medications and the number of 
participants taking concomitant medications will be summarized using frequency tables. 
9.4.5 
Interim Analysis  
No interim analysis is planned. 
9.4.6 
Sensitivity Analysis  
Additional sensitivity analyses to be used for handling missing data will be described in the SAP. 
9.4.7 
Missing Data  
Data from participants who withdraw from the study, including Aes and any follow-up, will be 
included in the analyses of primary and secondary outcomes. Further details regarding missing 
data will be provided in the SAP. 
9.4.7.1 
Strategies to Minimize Missing Data  
In order to minimize missing data, strategies to minimize participant premature 
discontinuation/withdrawal will be employed as outlined in Section 7.1. Additionally, participant 
compliance with e-Diary completion, study drug intake, and at-risk cycles will be monitored 
closely as outlined in Section 8.2.3. 
9.4.7.2 
How to Handle Missing Data  
Conventions for handling missing e-Diary data are described in Section 9.4.2. 
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10.0 REFERENCES  
1. Astedt B, Svanberg L, Jeppsson S, Liedholm P, Rannevik G. The natural oestrogenic hormone 
E2 as a new component of combined oral contraceptives. Br Med J 1977;6056:269. 
2. Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Silfverstolpe G. A comparison 
between effects of E2 valerate and low dose ethinyl E2 on haemostasis parameters. Thrombosis 
and Haemostasis 1989;61:65-69. 
3. Csemicsky G, Dieben T, Coelingh Bennink HJ, Landgren BM. The pharmacodynamic effects 
of an oral contraceptive containing 3 mg micronized 17β E2 and 0.150 mg desogestrel for 21 
days, followed by 0.030 mg desogestrel only for 7 days. Contraception 1996;54: 333-338. 
4. NOMAC-E2 Investigator’s Brochure version 28 July 2021. 
5. NOMAC-E2 
Summary 
of 
Product 
Characteristics. 
Accessed 
18 March 2021. 
https://www.ema.europa.eu/en/documents/product-information/zoely-epar-product-
information_en.pdf 
6. Mansour D, Verhoeven C, Sommer W, Weisberg W, Taneepanichskul S, Melis GB, 
Sundström-Poromaa I, Korver T. Efficacy and tolerability of a monophasic combined oral 
contraceptive containing nomegestrol acetate and 17beta-oestradiol in a 24/4 regimen, in 
comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 
regimen. Eur J Contracept Reprod Health Care 2011;16: 430-43. 
7. Westhoff C, Kaunitz AM, Korver T, Sommer W, Bahamondes L, Darney P, Verhoeven C. 
Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol 
acetate and 17beta-estradiol: A randomized controlled trial. Obstet Gynecol 2012;119:989-99. 
8. Mansour D, Westhoff C, Kher U, Korver T. Pooled analysis of two randomized, open-label 
studies comparing the effects of nomegestrol acetate/17β-estradiol and drospirenone/ethinyl 
estradiol on bleeding patterns in healthy women. Eur J Contracept Reprod Health Care 
2017;95:390-7. 
9. Witjes H, Creinin MD, Sundström-Poromaa I, Martin Nguyen A, Korver T. Comparative 
analysis of the effects of nomegestrol acetate/17 β -estradiol and drospirenone/ethinylestradiol 
on premenstrual and menstrual symptoms and dysmenorrhea. Eur J Contracept Reprod Health 
Care 2015;20: 296-307. 
10. Ågren UM, Anttila M, Mäenpää-Liukko K, Rantala ML, Rautiainen H, Sommer WF, 
Mommers E. Effects of a monophasic combined oral contraceptive containing nomegestrol 
acetate and 17 β-oestradiol compared with one containing levonorgestrel and ethinylestradiol 
on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 
2011;16:444-57. 
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11. Ågren UM, Anttila M, Mäenpää-Liukko K, Rantala ML, Rautiainen H, Sommer WF, 
Mommers E. Effects of a monophasic combined oral contraceptive containing nomegestrol 
acetate and 17 β -oestradiol in comparison to one containing levonorgestrel and 
ethinylestradiol on markers of endocrine function. Eur J Contracept Reprod Health Care 
2011;16:458-67. 
12. Duijkers IJM, Klipping C, Grob P, Korver T. Effects of a monophasic combined oral 
contraceptive containing nomegestrol acetate and 17b-oestradiol on ovarian function in 
comparison to a monophasic combined oral contraceptive containing drospirenone and 
ethinylestradiol. Eur J Contracept Reprod Health Care 2010;15:314–25. 
13. Sørdal T, Grob P, Verhoeven C. Effects on bone mineral density of a monophasic combined 
oral contraceptive containing nomegestrol acetate/17β-estradiol in comparison to 
levonorgestrel/ethinylestradiol. Acta Obstet Gynecol Scand 2012;91:1279-85. 
14. Gerrits M, Schnabel P G, Post T M, Peeters PAM. Pharmacokinetic profile of nomegestrol 
acetate and 17 β-estradiol after multiple and single dosing in healthy women. Contraception 
2013;87:193-200. 
15.  Post TM, Gerrits M, Kerbusch T, de Greef R. Prediction of nomegestrol acetate 
pharmacokinetics in healthy female adolescents and adults by whole-body physiology-based 
pharmacokinetic modelling and clinical validation. Contraception 2016;93:133-8. 
16. de Kam PJ, van Kuijk J, Lillin O, Post T, Thomsen T. The effect of therapeutic and 
supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17b-estradiol (E2) on QTcF 
intervals in healthy women: results from a randomized, double-blind, placebo- and positive-
controlled trial. Clin Drug Investig 2014;34:413-20. 
17. Lee KC, Ngo-Metzger Q, Wolff T, Chowdhury J, LeFevre ML, Meyers DS. Sexually 
transmitted infections: recommendations from the U.S. Preventive Services Task Force. Am 
Fam Physician 2016;94(11):907-15. 
18. Workowski KA, Bachmann LH, Chan PA, Johnston CM, Muzny CA, Park I, Reno H, 
Zenilman JM, Bolan GA. Sexually Transmitted Infections Treatment Guidelines, 2021. 
MMWR 
Recomm 
Rep 
2021;70(No. 
RR-4):1-187. 
DOI: http://dx.doi.org/10.15585/mmwr.rr7004a1  
19. FDA Guidance Establishing Effectiveness and Safety for Hormonal Drug Products Intended 
to 
Prevent 
Pregnancy. 
July 
2019. 
Accessed 
18 March 
2021. 
https://www.fda.gov/media/128792/download 
20. Benda N, Gerlinger C, van der Meulen E.A, Endrikat J. Sample size calculation for clinical 
studies on the efficacy of a new contraceptive method. Biometrical Journal 2004; 46:141-150.
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11.0 APPENDICES  
Appendix 1 
Abbreviations  
Abbreviation 
Definition 
β-hCG 
β-human chorionic gonadotropin 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ApaT 
All-Participants-as-Treated 
ASCUS 
Atypical squamous cells of undetermined significance 
AST 
Aspartate Aminotransferase (SGOT) 
ATE 
Arterial thrombotic or thromboembolic events 
BMI 
Body mass index 
CCA 
Cycle Control Analysis 
CFR 
Code of Federal Regulations 
CHC 
Combined hormonal contraceptives 
CI 
Confidence interval 
COC 
Combined oral contraceptive 
COVID-19 
Coronavirus Disease 2019 
DRSP 
drospirenone 
E2 
17β-estradiol 
ECI 
Event of clinical interest 
eCRF 
Electronic case report form 
e-Diary 
Electronic diary 
EE 
Ethinylestradiol 
EOS 
End of Study 
ET 
Early Termination 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV(W)RS 
Interactive voice (web) response system 
LNG 
Levonorgestrel 
MALV 
Markedly abnormal laboratory value 
NOMAC 
Nomegestrol acetate 
PI 
Pearl Index 
PK 
Pharmacokinetic/s 
POP 
Progestogen-only pill 
PP 
Per-Protocol 
QTL 
Quality tolerance limit 
rFAS 
Restricted Full Analysis Set 
RP 
Reference Period 
RPA 
Reference Period Analysis 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SoA 
Schedule of Activities 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
V 
Visit 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 
WY 
Woman-years 
 
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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations  
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences International 
Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC and regulatory authority approval, when 
applicable, before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
• Providing oversight of the conduct of the study at the study site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
After reading the protocol, each Investigator will sign the protocol signature page and send a copy 
of the signed page to the Sponsor or representative (Appendix 7). The study will not start at any 
study site at which the Investigator has not signed the protocol. 
Financial Disclosure  
Investigators, sub-Investigators, and any personnel listed on a Form FDA 1572 will provide the 
Sponsor with sufficient, accurate financial information as requested to allow the Sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate regulatory 
authorities. Investigators are responsible for providing information on financial interests during 
the course of the study and for 1 year after completion of the study. 
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Insurance  
The Sponsor has obtained liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the 
insurance will be kept in the study files. 
Informed Consent and Assent Process  
The Investigator or his/her representative will explain the nature of the study to the participant (or 
her legally acceptable representative, if applicable) and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants (or their legally 
acceptable representative, if applicable) will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
The Investigator or medically qualified designee (consistent with local requirements) must obtain 
documented informed consent, and assent if applicable, from each potential participant (or her 
legally acceptable representative, if applicable) prior to participating in this clinical study. If there 
are changes to the participant’s status during the study (eg, health or age of majority requirements), 
the Investigator or medically qualified designee must ensure the appropriate documented informed 
consent (and assent, if applicable) is in place. 
General Informed Consent and Assent  
Informed consent (and assent, if applicable) given by the participant or their legally acceptable 
representative must be documented on a consent form. The form must include the study protocol 
number, study protocol title, dated signature, and agreement of the participant (or her legally 
acceptable representative, if applicable) and of the person conducting the consent discussion. 
When a participant’s assent is obtained because the participant is a minor, consent must be obtained 
from a parent or legally acceptable representative. 
A copy of the signed and dated informed consent (and assent, if applicable) form should be given 
to the participant (or her legally acceptable representative if applicable) before participation in the 
study. 
The initial informed consent (and assent, if applicable) form, any subsequent revised informed 
consent (and assent, if applicable) form, and any written information provided to the participant 
must receive the IRB/IEC’s approval/favorable opinion in advance of use. The participant (or her 
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legally acceptable representative if applicable) should be informed in a timely manner if new 
information becomes available that may be relevant to the participant’s willingness to continue 
participation in the study. The communication of this information will be provided and 
documented via a revised consent (and assent, if applicable) form or addendum to the original 
consent (and assent, if applicable) form that captures the participant’s (or if applicable, 
participant’s legally acceptable representative’s) dated signature. 
Specifics about the study and the study population are to be included in the study informed consent 
(and assent, if applicable) form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, applicable 
laws and regulations and Sponsor requirements. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within 
30 days from the previous ICF signature date. A participant who is <18 years of age at the time of 
screening who turns 18 years of age during study participation must provide another informed 
consent documenting consent to continue study participation. 
Data Protection  
Participants will be assigned a unique identifier by the Sponsor. Any participant records or datasets 
that are transferred to the Sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Dissemination of Clinical Study Data  
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to the EU database a summary of the results 
of the clinical study within 1 year from the end of the clinical study. It shall be accompanied by a 
summary written in a manner that is understandable to laypersons. 
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Data Quality Assurance  
All participant data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the data entered 
in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Quality tolerance limits (QTLs) will be pre-defined in the Monitoring Plan to identify systematic 
issues that can impact participant safety and/or reliability of study results. These predefined 
parameters will be monitored during the study and deviations from the QTLs and remedial actions 
taken will be summarized in the clinical study report. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
Source Documents  
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study site’s participants. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study site. 
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Data reported on the CRF or entered in the eCRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the data entered 
in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being conducted 
in accordance with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
Study and Study Site Closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
For study termination: 
• Discontinuation of further study drug development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator. 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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Publication Policy  
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study site will be set forth in the Clinical Trial Agreement. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multi-center studies only in their entirety and not as individual study site data. In this case, a 
Coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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Appendix 3 
Clinical Laboratory Tests  
The tests detailed in Table 12 will be performed by the central laboratory, with the exception of 
STI panel testing, which will be performed by a local laboratory. Otherwise, local laboratory 
results are only required in the event that the central laboratory results are not available in time for 
either starting study treatment administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make either a study treatment decision or 
response evaluation, the results must be entered into the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5.0 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
All study-required laboratory assessments will be performed by a central laboratory, with the 
exception of STI panel testing which will be performed by a local laboratory, and of urine 
pregnancy tests which will be performed on-site or at the participant’s home. 
Investigators must document their review of each laboratory safety report. 
Table 12 
Protocol-required Safety Laboratory Assessments  
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Hemoglobin 
Platelet count 
WBC (total and 
differential) 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase  
Aspartate aminotransferase  
Bicarbonate 
Calcium 
Chloride 
Creatinine (for 
determination of eGFR) 
Glucose (nonfasting) 
Phosphorus 
Potassium 
Sodium 
Total bilirubin (and direct 
bilirubin, if total bilirubin 
is elevated above the ULN) 
Total protein 
Blood urea nitrogen 
Blood 
Glucose 
Protein 
Specific gravity 
pH 
Leukocyte esterase 
Nitrate 
Microscopic examination if 
abnormal results noted on 
urinalysis 
Cervical cytology  
Serum β-hCG  
STI panel (local laboratory) 
 
Abbreviations: β-hCG=beta human chorionic gonadotropin; eGFR=estimated glomerular filtration rate; ULN=upper 
limit of normal; WBC=white blood cell. 
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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
Definition of AE 
AE Definition 
• 
Any untoward medical occurrence in a patient or participant (clinical investigation participant) administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments 
(eg, electrocardiogram, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of study treatment. Overdose per se will not 
be considered as an AE/SAE but should be reported on the AE Form as an overdose without adverse effect. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
• 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been pre-
planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly during the study 
(e.g., surgery performed earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an AE. 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen. 
 
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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered 
an AE. 
d) Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
 
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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. Each event must be recorded 
separately. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Sponsor in 
lieu of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Sponsor. In this 
case, all participant identifiers, with the exception of the screening number, will be redacted on the copies of 
the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Severity 
The severity of an AE is an estimate of the relative severity of the event made by the Investigator based on his or 
her clinical experience and familiarity with the literature. The following definitions are to be used to rate the severity 
of an AE: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with 
everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not be 
confused with a SAE. Severe is a category utilized for rating the intensity of an event; and both AEs and SAEs 
can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of each 
AE/SAE. The AE must be characterized as unrelated, unlikely to be related, possibly related, probably related, 
or unknown (unable to judge). 
o 
“Probably related” conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship, rather than a relationship cannot be ruled out. 
o 
“Possibly related” suggests that the association of the AE with the study treatment is unknown; 
however, the AE is not reasonably supported by other conditions. 
o 
“Unlikely to be related” suggests that only a remote connection exists between the study treatment 
and the AE. Other conditions, including chronic illness, progression or expression of the disease state 
or reaction to concomitant therapy, appear to explain the reported AE. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the AE. 
o 
All efforts should be made to classify the AE according to the above categories. The category 
“unknown” (unable to judge) may be used only if the causality is not assessable, eg, because of 
insufficient evidence, conflicting evidence, conflicting data, or poor documentation. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study treatment administration will be considered and investigated. 
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• 
The Investigator will also consult the IB, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to include 
in the initial report to Sponsor. However, it is very important that the Investigator always make an assessment 
of causality for every event before the initial transmission of the SAE data to Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Sponsor to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the information. 
 
Reporting of SAEs 
SAE Reporting to Sponsor via an Electronic Data Collection System 
• 
The primary mechanism for reporting an SAE to the Sponsor or designee will be the electronic data collection 
system. The study site will enter the event into the electronic data collection system within 24 hours of the 
Investigator’s awareness of the event. 
• 
If the electronic system is unavailable, then the study site will use the paper SAE report form (see next section) 
to report the event and will enter the event into the electronic data collection system as soon as the system 
becomes available. 
• 
After the study is completed at a given study site, the electronic data collection tool will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• 
If a study site receives a report of a new SAE from a participant or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the study site can report this 
information on a paper SAE form (see next section) or to the Medical Monitor/SAE coordinator. 
• 
Contacts for SAE reporting can be found in the study manual, Investigator Study File Binder, or equivalent. 
 
SAE Reporting to the Sponsor or Designee via Paper SAE Report Form 
• 
Email transmission of the SAE form should be done in case there are technical issues with the electronic data 
capture system and SAE cannot be reported within 24 hours of awareness per the ICH guidelines via electronic 
data capture. The SAE/Pregnancy paper forms should be emailed to the 
 safety project mailbox detailed 
in the form. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the SAE 
CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in study manual, Investigator Study File Binder, or equivalent. 
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Appendix 5 
Collection of Pregnancy Information  
Pregnancy Testing: 
Participants should only be included after a confirmed negative serum pregnancy test at Screening 
(V1) and a negative urine pregnancy test at treatment allocation (V2). In addition to the negative 
Visit 2 serum β-hCG test result, it is required to have a negative urine home pregnancy test result 
on the day of the intended first tablet intake, just prior to the actual first tablet intake. 
Additional urine pregnancy testing will be performed by participants at home at prior to starting 
each blister, whenever a pregnancy is suspected, and within 48 hours after the last tablet from the 
last blister. Results are to be recorded in the e-Diary. A positive urine pregnancy test must be 
reported to the site immediately and must be confirmed by a serum test within 24 hours. The 
earliest positive pregnancy test should be entered into the e-Diary and into the database (even if 
performed at home) after confirming the results. 
Note, serum pregnancy testing may be performed in a local laboratory to confirm the results of a 
positive urine pregnancy test. Otherwise, all serum pregnancy testing will be performed and 
assayed in the central laboratory (see Laboratory Manual for more information). 
Urine pregnancy testing is to be performed using the test kit provided by the Sponsor and in 
accordance with instructions provided in its package insert. 
Collection of Pregnancy Information  
Female Participants Who Become Pregnant 
The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate form 
and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. The 
participant will be followed to determine the outcome of the pregnancy. For pregnancies 
potentially exposed to NOMAC-E2, ie, pre-treatment pregnancies diagnosed after the onset of 
treatment and pregnancies with a conception date between first tablet intake and 7 days after the 
last active tablet intake, the Investigator will collect follow-up information on the participant and 
the neonate and the information will be forwarded to the Sponsor. Follow-up will be required until 
delivery/termination of pregnancy (unless the participant withdraws consent or assent, if 
applicable). Any information on termination of pregnancy will be collected, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
A first trimester ultrasound must be performed to determine the gestational age of the pregnancy. 
While pregnancy itself is the primary study efficacy endpoint, and is therefore not treated as an 
AE, any pregnancy complication will be reported as an AE or SAE, and pregnancy outcomes such 
as spontaneous abortion, missed abortion, benign or malignant hydatidiform mole, fetal death, 
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intrauterine death, ectopic pregnancy, and stillbirth must be reported as serious events (important 
medical events). 
Any female participant who becomes pregnant while participating in the study will discontinue 
study treatment and be withdrawn from the study. 
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Appendix 6 
Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment (Amendment 2) 
is located directly before the table of contents. 
Amendment 1 (01 December 2021) 
Overall Rationale for the Amendment: 
 
 
 
 
 
 
 
 
 
 
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Table 13 
Description of Changes in Amendment 1  
Section # and Name 
Description of Change 
Brief Rationale 
Title Page (Protocol Title)  
1.1 Synopsis (Protocol Title, 
Overall Design, Key 
Inclusion/Exclusion Criteria, 
Number of Participants, Statistical 
Methods) 
3.0 Objectives and Endpoints 
4.1 Overall Design 
4.2 Scientific Rationale for Study 
Design 
5.1 Inclusion Criteria 
9.2.1 Main Analysis 
Inclusion criteria #1, and 
corresponding protocol text, 
revised to specify lower age limit 
(14 years) for inclusion in study 
For alignment with the current 
Investigator’s Brochure, as per 
Central IRB request 
1.1 Synopsis (Overall Design) 
1.3 Table 3 Schedule of Activities 
2.3 Benefit/Risk Assessment 
4.1 Overall Design 
Appendix 3, Table 12 
Protocol-specified Safety 
Laboratory Assessment 
STI panel revised to include 
mandatory testing for gonorrhea 
and chlamydia at V1 and V6, and 
if abnormal discharge is present, 
trichomonas and bacterial 
vaginosis at V1, and as needed 
throughout the study 
To mitigate the possibility of 
participants contracting a sexually 
transmitted disease, as per Central 
IRB request 
1.1 Synopsis (Objectives and 
Endpoints, Overall Design) 
3.0 Table 4 Study Objectives and 
Endpoints 
4.1 Overall Design 
8.0 Table 7 Blood Volume 
8.6 Pharmacokinetics and 
Pharmacodynamics 
9.2.2 Pharmacokinetic Analysis 
9.3.6 Pharmacokinetic Analysis 
Population 
9.4.4.1 Pharmacokinetics 
Study design (including objectives, 
assessments, procedures, and 
statistical considerations) amended 
to include collection of sparse PK 
samples for development of a 
population PK model for NOMAC 
 
 
 
 
1.1 Synopsis (Overall Design) 
1.3 Table 3 Schedule of Activities 
4.1 Overall Design 
8.2.1.1.1 Home Urine Pregnancy 
Test 
 
Study procedures for urine home 
pregnancy tests revised to include 
the following: 
• Urine home pregnancy test must 
be performed within 48 hours 
after the last tablet from the last 
blister of study drug has been 
taken 
• If a positive urine home 
pregnancy result is obtained, a 
confirmatory serum β-hCG must 
be performed within 24 hours 
Clarification to ensure participants 
are not pregnant at the time they 
completed the last blister of study 
drug 
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Section # and Name 
Description of Change 
Brief Rationale 
(can be completed by local 
laboratory, if required) 
• Negative urine home pregnancy 
tests to be documented in the 
e-Diary 
1.1 Synopsis (Overall Design) 
1.3 Table 3 Schedule of Activities 
4.1 Overall Design 
8.2.3.1 Participant e-Diary 
8.2.3.1.3 Monitoring e-Diary 
Compliance 
9.2.1 Main Analysis 
9.4.2.1.1 Definitions 
9.4.2.2 Primary Contraceptive 
Efficacy Endpoint(s) 
9.4.2.3 Secondary Contraceptive 
Efficacy Endpoint(s) 
Overall design text revised to 
specify that participants must 
engage in heterosexual vaginal 
intercourse at least once per month 
with a partner who is not known to 
be subfertile or infertile 
All references to “vaginal 
intercourse” or “sexual 
intercourse” throughout document 
revised to “heterosexual vaginal 
intercourse”  
Clarification 
1.1 Synopsis (Objectives and 
Endpoints, Overall Design) 
3.0 Table 4 Study Objectives and 
Endpoints 
4.1 Overall Design 
9.4.2.3 Secondary Contraceptive 
Efficacy Endpoints(s) 
Description of endpoints associated 
with the secondary objective 
assessing contraceptive efficacy of 
NOMAC-E2 COC by BMI 
subgroup was revised (text updated 
to state “efficacy endpoints” and 
“potential” removed from 
description of PI evaluation) 
Clarification 
1.1 Synopsis (Objectives and 
Endpoints, Bleeding Profile) 
3.0 Table 4 Study Objectives and 
Endpoints 
9.4.2.5.1 Cycle Control Analysis 
Bleeding definitions for Cycle 
Control Analysis revised to replace 
“amenorrhea” with “no scheduled 
or unscheduled bleeding-spotting 
at all”. Corresponding secondary 
bleeding endpoint updated 
accordingly.  
Clarification of terminology to 
reflect different definitions for 
“amenorrhea” used in the Cycle 
Control Analysis compared with the 
Reference Period Analysis 
1.1 Synopsis (Objectives and 
Endpoints) 
3.0 Objectives and Endpoints 
Reference Period length changed 
from “90 days” to “91 days” 
Clarification to align with 
information presented in other 
protocol sections 
1.1 Synopsis (Overall Design) 
4.1 Overall Design 
Text describing Screening Visit 
and V1 assessments revised to 
specify that pregnancy will be 
evaluated as part of blood sampling 
To align with Schedule of Activities 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Overall Design) 
4.1 Overall Design 
8.2.3.1 Participant e-Diary 
8.2.3.1.1 Daily e-Diary Questions 
8.2.3.1.2 Monthly e-Diary 
Questions (before Starting a New 
Blister) 
Procedures for e-Diary use revised 
to include the following: 
• Clarified duration of monitoring 
for estimating e-Diary 
compliance prior to treatment 
allocation (revised to “at least 
7 days”) 
• Statement added to specify that 
only participants provided with 
a device are expected to return it 
on completion of the required 
e-Diary entries  
• Description of data to be 
collected in the e-Diary revised 
to specify information to be 
collected on a daily basis versus 
a monthly basis 
• Every day from V2 onwards, 
participants should record their 
intake of study drug during the 
past 24 hours 
• Menstrual cup use to be 
recorded in daily e-Diary entries 
• Daily e-Diary questions to be 
completed every day until V7 
• Monthly e-Diary questions to be 
completed before starting a new 
blister 
• Timeframe (4 days) for 
completion of monthly e-Diary 
questions added 
To clarify expectations of device 
ownership and return of devices 
provided, as well as procedures for 
e-Diary data collection 
1.1 Synopsis (Objectives and 
Endpoints, Statistical Methods) 
3.0 Table 4 Objectives and 
Endpoints 
9.2.1 Main Analysis 
9.4.2.1.1 Definitions 
Calculation of Pearl Index revised 
to specify that it is calculated from 
total exposure expressed in 28-day 
cycles “at-risk” for conception  
Clarification 
1.2 Figure 1 Study Schema 
Figure revised to include visit 
windows in days 
Clarification 
5.1 Inclusion Criteria 
Inclusion criteria #3 revised to 
specify that withdrawal method is 
considered a form of contraception 
To clarify forms of contraception 
which should not be used by 
participant 
5.2 Exclusion Criteria 
New exclusion criteria added (#20) 
excluding participants with a 
history or presence of meningioma 
To reflect new information released 
by the Periodic Risk Assessment 
Committee of the European 
Medicines Agency, and upon 
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Section # and Name 
Description of Change 
Brief Rationale 
recommendation by Organon’s Risk 
Management Safety Team and 
endorsement by Organon’s Safety 
Review Committee 
5.2 Exclusion Criteria 
Exclusion criteria #26 revised to 
exclude individuals with history or 
current evidence of a circumstance 
that affects their well-being 
Clarification, as per Central IRB 
request 
5.4 Screen Failures 
Description of AE and SAE 
reporting for screen failures 
revised to clarify that events are 
defined as “pre-treatment” 
To align with clarifications to the 
definition of AEs and SAEs in 
Section 8.4.1 
6.2 Preparation/ Handling/ Storage/ 
Accountability 
Text added to refer to the 
Pharmacy Manual for reporting of 
quality issues with blister 
Clarification 
6.4.1 Timing of the First Dose 
Text added to note that participants 
using a non-hormone medicated 
intrauterine device should have the 
device removed prior to starting 
study drug 
To clarify the timing of removing 
non-hormone medicated intrauterine 
devices in relation to starting study 
drug 
6.6.1 Prohibited Medications 
Text revised to state that 
contraceptive use can begin the day 
after the last tablet intake of study 
drug from the last blister (last 
cycle) 
 
Table 6 updated to list 
Contraceptive Vaginal Ring, 
Contraceptive Patch (last allowable 
use clarified as Cycle 1 Day 1), 
and oral contraceptives (other than 
study drug) as prohibited 
medications, supplements, and 
other substances 
To clarify the timing for initiation of 
contraception after completion of 
participation in the study 
7.2 Discontinuation of Study 
Treatment 
The criteria for discontinuing a 
participant from study drug due to 
the participant not being at risk for 
pregnancy revised to specify 
participant must be persistently not 
a risk of pregnancy 
For alignment with compliance 
guidance in Section 8.2.3.3 
8.2.1 Assessment of On-treatment 
Pregnancy 
9.4.2.1.1 Definitions 
Definitions of on-treatment 
pregnancy and post-treatment 
pregnancy revised to specify 
timing relates to last intake of 
“active” study drug 
For clarity of assessment of 
on-treatment pregnancy 
8.2.1.1 Pregnancy Testing 
8.2.1.2 Pregnancy 
Text updated to specify that a urine 
pregnancy test performed either at 
home or during a study visit can be 
used for a rapid result if pregnancy 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
is suspected (result should be 
confirmed by serum β-hCG within 
24 hours). 
 
Text updated to specify that 
participants with a confirmed 
pregnancy during the study will be 
discontinued from study drug and 
from the study  
8.2.1.2 Pregnancy 
Follow-up and outcomes 
procedures clarified 
Clarification 
8.2.2 Vaginal Bleeding Event 
8.2.3.1 Participant e-Diary 
9.4.2.5 Vaginal Bleeding 
Endpoint(s) 
Procedures for recording sanitary 
product use and definition for “no 
bleeding” clarified 
Clarification 
8.2.3.2 Study Treatment 
Compliance 
Section restructured and 
procedures for measuring 
compliance clarified 
(accountability-specific 
information moved to Section 6.2) 
To clarify procedures for assessing 
treatment compliance 
8.3.4 Clinical Safety Laboratory 
Assessment 
Definition of clinically significant 
abnormal laboratory findings 
removed 
Statement is part of standard 
template text and is not applicable to 
the study 
8.4.1 Time Period and Frequency 
for Collecting AE and SAE 
Information 
Definition of AEs and SAEs 
revised 
 
Table 8 revised to clarify 
procedures for reporting events, to 
change “cancer” event type to 
“tumor” event type, and to remove 
overdose events 
To clarify the distinction between 
events reported after provision of 
consent but before treatment 
initiation and events reported after 
treatment initiation, and to clarify the 
procedures for event reporting 
8.4.1, Table 8 Reporting Time 
Periods and Time Frames for 
Adverse Events and Other 
Reportable Safety Events 
8.4.5 Events of Clinical Interest 
Appendix 4 Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting 
Description of events of clinical 
interest revised to remove overdose 
events and procedures for 
regulatory reporting of overdose 
events 
Adverse event definitions revised 
to state that while overdose events 
will not be considered as an 
AE/SAE, overdose will be reported 
on the AE form  
To align with FDA guidance which 
indicates that overdose without an 
associated AE or (suspected 
unexpected) SAE does not require 
regulatory reporting within 24 hours 
8.9 Changes to Study Procedures 
Due to COVID-19 Pandemic 
Statement regarding rescreening 
revised to remove “or run-in 
period” 
Statement is part of standard 
template text and is not applicable to 
the study 
9.4.2.6 Reference Period Analysis 
Bleeding definitions revised; 
bleeding episode revised to 
“Bleeding-only episode” and 
definition added for spotting-only 
Clarification of bleeding definitions 
for Reference Period Analysis 
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Section # and Name 
Description of Change 
Brief Rationale 
episodes 
9.4.3 Safety Analysis 
Definitions of on-treatment period 
and on-treatment AEs revised to 
specify period includes the day of 
last “active” study drug intake 
Clarification 
Appendix 2 Regulatory, Ethical, 
and Study Oversight 
Considerations 
Personnel responsible for 
providing financial information 
revised to include “any personnel 
listed on a Form FDA 1572” 
Clarification 
Appendix 3, Table 12 
Protocol-required Safety 
Laboratory Assessments 
Assessment of “highly sensitive 
serum β-hCG” replaced with 
“serum β-hCG” 
Clarification for consistency with 
revised pregnancy procedures in 
study 
Appendix 4 Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-up, 
and Reporting 
Definition of AE and procedures 
for assessment of causality and for 
reporting SAEs via paper CRF 
updated 
To reflect an update to the ICH-GCP 
guidelines for definition of an AE, 
and to accurately reflect the 
procedures to be undertaken in this 
study 
Appendix 5 Collection of 
Pregnancy Information 
Section revised for alignment with 
revised pregnancy procedures in 
study 
Appendix contains standard template 
text and was revised for consistency 
with the study design and procedures 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore have not been 
summarized 
Abbreviations: AE=adverse event; β-hCG=β-human chorionic gonadotropin; BMI=body mass index; 
COC=combined oral contraceptive; COVID-19=Coronavirus Disease 2019; E-diary = electronic diary; 
FDA=Food and Drug Administration; GCP=Good Clinical Practice; ICH= International Council for 
Harmonisation; IRB= Institutional Review Board; NOMAC-E2=nomegestrol acetate + 17β-estradiol; PI=Pearl 
Index; PK=pharmacokinetic/s; SAE=serious adverse event; STI=sexually transmitted infections; V=visit. 
 
 
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Appendix 7 
Signature of Investigator  
PROTOCOL TITLE: A Phase 3, Open-label, Multi-center, Single-arm Study to Assess 
Contraceptive Efficacy and Safety of the Nomegestrol Acetate + 17β-estradiol Combined Oral 
Contraceptive (OG-8175A) in Premenopausal Females Aged 14 to 35 Years (Inclusive) 
PROTOCOL NO: 
OG-8175A-023 
VERSION:  
 
Amendment 2 
This protocol is a confidential communication of Organon LLC. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with Good Clinical Practices and the applicable laws and regulations. Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will be 
published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to Organon LLC. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
____________________________ Date: ________________ 
Printed Name:  
 
___________________________ 
Investigator Title: 
 
___________________________ 
 
Name/Address of Center: 
 
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 
 
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FILE NAME:
OG-8175A-023 Protocol Amendment 2
ELECTRONIC SIGNATURES
Signed By:
Meaning of Signature
Server Date (dd-MMM-yyyy HH:mm 'GMT'Z)
Proxy Responsible Medical Officer
25-Oct-2022 13:28:43 GMT+0000
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