Conditions: Contraception
Keywords: Birth Control Progestin Only Pill Estrogen Free Pill Norgestrel Oral Contraception Female Contraception Cervical Mucus Ovarian Activity
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 52
Healthy volunteers: yes

Brief summary:
Norgestrel 75 mcg is a progestin-only pill (POP), which is a kind of oral birth control pill.

To be effective in preventing pregnancy, this kind of birth control pill is supposed to be taken every day at the same time, without delaying the intake for more than 3 hours.

This study aims to find out if taking the pill 6 hours late or not taking it for one day will affect the way it works.

Detailed description:
This study is an exploratory, prospective, multi-center, randomized, cross-over study to assess the effect of norgestrel 75 mcg on cervical mucus and ovarian activity during reported perfect daily use, after a delayed intake of 6 hours and after a missed pill.

After a screening period up to one month, depending on the menstrual cycle of the subject, the subjects will take norgestrel 75 mcg for three 28-day treatment periods, every day at the same time except for one day in the middle of treatment period 2 and treatment period 3 where they will either take it 6 hours late or not take it.

In week 5 (1st visit of treatment period 2), they will be randomized to 2 sequences, either 6 hours delayed intake in treatment period 2 and missed pill in treatment period 3 or the opposite.

After the end of treatment period 3, a follow-up up to 12 days may be required to follow ovarian activities.

Subjects will have visits twice a week and sometimes more often to assess the effects of the pill on:

* cervical mucus properties by a cervical mucus sampling
* ovarian activity by a vaginal ultrasound (TVUS)
* reproductive hormones levels by a blood sample (Progesterone (P4), Estradiol (E2), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH))
* plasma drug level by a blood sample

Arms:
arm 1: Treatment period 2, Day 42 +/- 3 days: 6 hour delayed intake of Norgestrel 75 mcg Treatment period 3, Day 70 +/- 3 days: missed pill of Norgestrel 75 mcg arm 2: Treatment period 2, Day 42 +/- 3 days: missed pill of Norgestrel 75 mcg Treatment period 3, Day 70 +/- 3 days: 6 hour delayed intake of the pill of Norgestrel 75 mcg

Interventions: intervention 1: Norgestrel 0.075 mg
Intervention descriptions: intervention 1: Subjects will take norgestrel 75 mcg every day at the same time for three 28-day treatment periods, except for 1 specific day during treatment period 2 and treatment period 3

Protocol document:
Prot_000.pdf: 
Protocol 151042-002 
 
 
  
 
FINAL VERSION 1.0 – Date: 26-FEB-2018 
 
1/80 
 
CLINICAL STUDY PROTOCOL 
 
A prospective, multi-center, randomized, cross-over study to assess the effect 
of norgestrel 75 mcg on cervical mucus and ovarian activity during perfect 
use, after one delayed intake and after a missed pill  
 
NCT03585712 
 
 
Principal investigator 
 
 
Prof Alison Edelman                                           
Department of Obstetrics and Gynecology         
Oregon Health & Science University (OHSU)     
3181 SW Sam Jackson, UHN 50                        
Portland, Oregon, USA                                       
  
Preclinical and Pharmacokinetic Clinical 
Officer 
 
Agnès Hemon 
 
Sponsor 
 
HRA Pharma                                                       
75003 Paris, France                                           
15 rue Béranger 
                                                                           
  
Pharmacovigilance Manager 
 
 
Senior Medical Officer 
 
 
 
Outside of office hours 
 
 
This protocol is the confidential information of HRA Pharma and is intended solely for the guidance of the clinical 
investigation.  This protocol may not be disclosed to parties not associated with the clinical investigation or used 
for any purpose without the prior written consent of HRA Pharma. 
CONFIDENTIAL 
 


Protocol: 151042-002 
 
CONFIDENTIAL-PROPRIETARY INFORMATION 
 
Version 1.0 (FINAL) Date: 26-Feb-2018 
 
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SIGNATURE PAGE (signatures on file) 
 
Prof Alison Edelman, MD 
Overall Principal investigator 
Date 
Signature 
 
 
Agnès Hemon 
Preclinical and Pharmacokinetic Clinical 
Officer 
HRA Pharma 
Date 
Signature 
 
Senior Medical Officer  
HRA Pharma 
Date 
Signature 
 
Head of Clinical Operations 
HRA Pharma 
 
Date 
Signature 
 
Head of Pharmacovigilance, EU QPPV 
HRA Pharma 
Date 
Signature 
 
Statistician 
 
Date 
Signature 
 
Research & Development Director 
HRA Pharma 
 
Date 
Signature 
 
 
 


Protocol: 151042-002 
 
CONFIDENTIAL-PROPRIETARY INFORMATION 
 
Version 1.0 (FINAL) Date: 26-Feb-2018 
 
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PROTOCOL SYNOPSIS 
Title 
A prospective, multi-center, randomized, cross-over study to assess the effect of norgestrel 75 mcg on 
cervical mucus and ovarian activity during perfect use, after one delayed intake and after a missed pill. 
 
Investigator(s), Study site(s) 
2 clinical sites in the United States (US): Oregon Health & Science University, Portland, Oregon and 
University of California Davis Health, Sacramento, California  
 
Phase: IIa 
 
Indication 
Oral contraception 
 
Objectives: 
Primary objective 
• 
To determine the effect on cervical mucus score of a delayed intake of 6 hours or of a missed 
pill of norgestrel 75 mcg compared to the effect observed during reported perfect daily use  
 
Subordinate primary objective 
• 
To estimate the duration of the protective effect of cervical mucus after last pill intake of 
norgestrel 75 mcg during reported perfect use 
 
Secondary objectives 
• 
To evaluate and compare the percentage of subjects with a protective cervical mucus score 
during reported perfect daily use, during a treatment period with a delayed intake of 6 hours and 
during a treatment period with a missed pill of norgestrel 75 mcg.   
• 
To evaluate and compare the ovarian activity during reported perfect daily use, during a 
treatment period with a delayed intake of 6 hours and during a treatment period with a missed 
pill of norgestrel 75 mcg.  
• 
To assess if a combination of cervical mucus score and ovarian status can be considered as a 
measure of protection from conception during reported perfect daily use, during a treatment 
period with a delayed intake of 6 hours and during a treatment period with a missed pill of 
norgestrel 75 mcg. 
• 
To determine levonorgestrel pharmacokinetics after a single dose of norgestrel 75 mcg, at 
steady state, after a delayed intake of 6 hours and after a missed pill.  
• 
To assess the safety of norgestrel 75 mcg taken daily for 12 weeks. 
 
Study design 
This is an exploratory, prospective, multi-center, randomized, cross-over study to assess the effect of 
norgestrel 75 mcg on cervical mucus and ovarian activity during reported perfect daily use, after a 
delayed intake of 6 hours and after a missed pill.  
 
Study subject participation will be approximately 4.5 months long (up to one month for screening, three 
28-day treatment periods, up to 12 days of follow-up and up to 5 days for the end of study visit (EOS) 
after the last pill intake or follow-up visit) (see Figure 1 below).  
 


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Figure 1 Design of the study 
 
 
Screening period 
Screening period will start with the screening visit performed during the luteal phase of the menstrual 
cycle and end with the start of next menses. The following visit (enrollment visit) is intended to start 
within 5 days after onset of menses, but subjects will be allowed to delay this visit for up to one cycle if 
necessary. 
 
Treatment period 1:   
• 
Treatment: norgestrel 75 mcg  
o Treatment initiation within 5 days of start of menses (enrollment visit) 
o Continue at the same time daily throughout the study (except for specific days in 
treatment periods 2 and 3, see below)  
• 
Regular visits:  
o Scheduled twice a week (every 3-4 days) 
o Procedures 
 
Cervical mucus sampling, 
 
Transvaginal ultrasound (TVUS)*, 
 
Blood sampling for hormone levels (progesterone (P4), estradiol (E2), FSH, LH) 
• 
Extra visits: 
o To be initiated two days after a regular visit TVUS shows an ovarian follicle >15 mm in 
one dimension 
o To occur every other day for a maximum of 3 visits before a postovulatory image is 
obtained 
o Procedures 
 
Cervical mucus sampling, TVUS, and blood sampling for hormone levels (P4, 
E2, FSH, LH) 
 
Extra visits to be stopped when a post ovulatory image is obtained or if a 
postovulatory image is not obtained at the third extra visit 
• 
PK sampling (levonorgestrel): 
o Day 1 from before treatment to 24 h post treatment (4 samples per subject) 
o Study week 3, 1st visit (Steady State): from before treatment to 5-9 h post treatment (1-
2 samples per subject) 
 
Treatment period 2:  
• 
Starts on day 29 
• 
Randomization at first visit of treatment period 2, either in: 
o Arm A: delayed pill intake of 6 hours on day 42±3 of treatment period 2 followed by 
missed pill on day 70±3 of treatment period 3  
OR 
o Arm B: missed pill on day 42±3 of treatment period 2 followed by delayed pill intake of 6 
hours on day 70±3 of treatment period 3 
• 
Regular visits: same as in treatment period 1 except for delayed/missed pill period (DMP period, 
see below) 
• 
Extra visits: 
o Same as in treatment period 1  
 
* TVUS always to be performed after cervical mucus sampling 


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o Extra visits will be suspended during the DMP period and can start again afterwards if 
applicable 
• 
DMP period (Days 41 to 43 ±3) 
o 3 consecutive days 
o V2R-1 (Day 41±3):  
 
Study pill intake. The time of intake will be defined as T2R-1  
 
Cervical mucus sampling at T2R-1 + 8h 
 
PK sampling: at T2R-1 + 8h (1 sample per subject) 
 
TVUS 
 
Blood sampling for hormone levels (P4, E2, FSH, LH) 
o V2R (Day 42±3): 
 
Delayed pill intake of 6 hours (Arm A, intake at T2R-1 + 6h) or missed pill (Arm B) 
 
Cervical mucus sampling: at T2R-1 +3h (Arm A) or T2R-1 + 6h (Arm B)  
 
PK sampling: at T2R-1 +3h, T2R-1 + 5.5h, T2R-1 + 7.5h in Arm A (3 samples per 
subject) or T2R-1 + 6h in Arm B (1 sample per subject) 
o V2R+1 (Day 43±3): 
 
PK sampling: at T2R-1 - 30 min (1 sample per subject) 
 
Cervical mucus sampling: at T2R-1 - 30 min 
 
Study pill intake at T2R-1 
 
TVUS 
 
Blood sampling for hormone levels (P4, E2, FSH, LH) 
• 
Study week 5 
o 1st visit: PK sampling within 30 minutes of mucus sampling (1 sample per subject) 
 
Treatment period 3:  
• 
Starts on day 57 
• 
Regular visits: same as in treatment period 1 except for DMP period (see below) 
• 
Extra visits before Day 84:  
o Same as in period 1  
o Extra visits will be suspended during DMP period and can start again afterwards if 
applicable 
• 
Extra visits after Day 84 (follow-up visits) 
o Extra visits could continue after the last day of treatment intake (Day 84) until the criteria 
for stopping them are fulfilled 
o To occur every other day for a maximum of 6 visits (3 before and 3 after a postovulatory 
image is obtained) 
o Procedures – visits before a post-ovulatory image is obtained 
 
Cervical mucus sampling, TVUS, and blood sampling for hormone levels (P4, 
E2, FSH, LH) 
 
Extra visits to be stopped if a postovulatory image is not obtained at the third 
extra visit 
o Procedures – visits after a post-ovulatory image is obtained 
 
Cervical mucus sampling and blood sampling for hormone levels (P4) 
 
Extra visits to be stopped if P4 > 30 nmol/L at one visit or > 10 nmol/L at two 
consecutive visits or after 3 visits after a postovulatory image is obtained 
• 
DMP period 
o 3 consecutive days 
o V3R-1 (Day 69±3):  
 
Study pill intake. The time of intake will be defined as T3R-1 
 
Cervical mucus sampling: at T3R-1 + 8h 
 
PK sampling: at T3R-1 + 8h (1 sample per subject) 
 
TVUS 
 
Blood sampling for hormone levels (P4, E2, FSH, LH) 
o V3R (Day 70±3): 
 
Missed pill (Arm A) or delayed pill intake of 6 hours (Arm B, intake at T3R-1 + 6h)  
 
Cervical mucus sampling: at T2R-1 +3h (Arm B) or T2R-1 + 6h (Arm A) 


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 
PK sampling: at T3R-1 + 6h in Arm A (1 sample per subject) or T3R-1 +3h, T3R-1 + 
5.5h, T3R-1 + 7.5h in Arm B (3 samples per subject) 
o V3R+1 (Day 71±3): 
 
PK sampling: at T3R-1 - 30 min (1 sample per subject) 
 
Cervical mucus sampling: at T3R-1 - 30 min 
 
Study pill intake at T3R-1 
 
TVUS 
 
Blood sampling for hormone levels (P4, E2, FSH, LH) 
• 
Study week 9 
o 1st visit: PK sampling within 30 minutes of mucus sampling (1 sample per subject) 
 
End of study visit:  
The subjects will be scheduled for their EOS visit within 5 days of taking their last pill or their last extra 
visit (follow-up visit).  
 
See also Schedule of assessments for details. 
 
Population 
 
Inclusion criteria 
• 
Women in good overall health with no chronic medical conditions that result in periodic 
exacerbations that require significant medical care 
• 
Women between 18 and 35 years inclusive at the screening visit 
• 
BMI< 32 kg/m² 
• 
Regular menstrual cycles between 21 and 35 days when not using hormonal contraception. 
o Subjects postpartum or post-abortal must have one normal menstrual cycle (2 menses) 
prior to enrollment.  
o Subjects previously using IUD or taking hormonal contraception (or any other hormonal 
treatment, except an injectable treatment) need to have at least one menstrual cycle (2 
menses) without the treatment before screening.  
o Subject previously using an injectable (DMPA), must have had their last injection at least 
9 months before screening. 
• 
Women not at risk of pregnancy: not sexually active, or willing to protect all acts of intercourse 
with condoms, or have a sterile partner or have undergone previous tubal ligation (including 
validated Essure), or be in a same sex relationship. 
• 
Women able to give informed consent form to participate in the study and in the opinion of the 
investigator able to follow all study requirements, use the study medication and record the 
requested information appropriately  
• 
Intact uterus and both ovaries 
• 
At least one progesterone concentration > 3 ng/mL (>10 nmol/L) during the luteal phase of the 
screening period 
 
Exclusion criteria 
• 
Pregnant as confirmed by positive high-sensitivity urine pregnancy test at V11 (enrollment visit) 
• 
Trying to conceive or desire to conceive in the next 3 months 
• 
Currently breastfeeding, or within the last 2 months 
• 
Known Polycystic Ovarian Syndrome (PCOS) 
• 
Cancer (or past history of any carcinoma or sarcoma) 
• 
Known abnormal thyroid status, if in clinical judgment of the investigator it cannot be controlled 
during the study  
• 
Known hypersensitivity to the ingredients of the test active substances or its excipients 
• 
Current acute liver disease and/or benign liver tumors 
• 
Have vaginal or cervical infection including clinical evidence of bacterial vaginosis 
• 
Evidence of abnormal cervical lesion 
• 
History of excisional or ablative treatment procedure on cervix (ie. Loop Electrosurgical Excision 
Procedure (LEEP), Cryotherapy, Cold Knife Cone) 


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• 
Undiagnosed abnormal uterine bleeding 
• 
Prior malabsorptive-type bariatric surgery 
• 
Known or suspected alcoholism or illicit drug abuse 
• 
Use of any hormonal contraception or IUD other than the study medication during the study 
(including ulipristal acetate for emergency contraception in the past 5 days) 
• 
Use of any medications that can interfere with the metabolism of progestin-based contraceptives 
(e.g CYP3A4 enzymes inducers or inhibitors, etc) 
• 
Unstable diabetes mellitus   
• 
Current participation in any other trial of an investigational medicine or participation in the past 
two months (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for 
antibodies, whichever is the longer) before screening 
• 
Abnormalities in laboratory results or TVUS performed at screening visit recognized as clinically 
significant by the investigator 
• 
Conditions not suitable for frequent TVUS examinations, (e.g. virgo intacta) 
• 
In custody or submitted to an institution due to a judicial order 
• 
Relative or household member of the investigator's or sponsor's staff 
 
Sample size: This study will screen approximately 70 subjects to achieve at least 45 completed 
subjects.  
Study treatment and randomization 
The investigational product is norgestrel 75 mcg, supplied in blister package of 28 tablets. It will be 
taken orally at the same time everyday in a continuous regimen. 
 
The study medication will be provided only to subjects included in this study following the procedures 
set out in the protocol. In this study, all subjects will receive the study medication at the same dosing 
regimen. The randomization in this study will allocate subjects evenly to either: 
• 
Arm A (delayed pill in treatment period 2 and missed pill in treatment period 3) or, 
• 
Arm B (missed pill in treatment period 2 and delayed pill in treatment period 3). 
 
Randomization will occur during the 1st visit of treatment period 2.  
 
Pharmacodynamic parameters 
• 
Cervical mucus score between 0 and 12 
• 
Ovarian activity score between 0 and 7 and associated ovarian status* 
 
Pharmacokinetic parameters 
• 
Levonorgestrel PK populations parameters (CL and V) as well as derived parameters (C24h, Cmax 
and AUC) 
 
Safety parameters 
• 
Adverse events 
• 
Bleeding patterns 
• 
Laboratory parameters 
 
Statistical analysis 
• 
Significance of the mean change from baseline (V2R-1 or V3R-1) to post infringement 
assessments (V2R or V2R+1 and V3R or V3R+1) of cervical mucus score 
• 
Significance of the mean change from baseline to post delayed pill assessments of cervical 
mucus score. 
 
* The ovarian status are: 
OSq = quiescence defined as a OAS ≤ 3 
OSa = ovarian activity defined as a OAS = 4 or 5 
OSalp = ovulation with abnormal luteal phase defined as a OAS = 6 at only one visit  
OSnlp = ovulation with normal luteal phase defined as a OAS = 6 at two consecutive visits or OAS = 7 


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• 
Significance of the mean change from baseline to post missed pill assessments of cervical 
mucus score. 
• 
Significance of the difference between infringement type in the mean change from baseline. 
• 
Percentage of subjects with mucus score ≤ 4, 27h, 30h and 48h after the last treatment intake  
• 
Percentage of subjects with an absence of risk increase further to delayed intake. 
• 
Percentage of subjects with an absence of risk increase further to missed pill. 
• 
Percentage of subjects with a transient of risk increase further to delayed intake. 
• 
Percentage of subjects with a transient of risk increase further to missed pill. 
• 
Percentage of subjects with a prolonged risk increase further to delayed intake. 
• 
Percentage of subjects with a prolonged risk increase further to missed pill. 
• 
Percentage of subjects with no signals of loss of protection in treatment period 1 (no 
infringement (i.e. no delayed or missed pill) to intake schedule), in treatment period with a delay 
of 6 hours in pill intake and in treatment period with a missed pill.  
• 
Percentage of subjects with a cervical mucus score ≤ 4; between 5 and 8, and ≥ 9 during 
reported perfect daily use, during a treatment period with a delayed pill intake of 6 hours and 
during a treatment period with a missed pill of norgestrel 75 mcg. 
• 
Percentage of subjects with each ovarian status during reported perfect daily use, during a 
treatment period with a delayed pill intake of 6 hours and during a treatment period with a missed 
pill of norgestrel 75 mcg. 
• 
Percentage of subjects with each binary and ternary conception protection status (protected/not 
protected and minimum/medium/maximum). 
 
Adverse events (AEs) 
AEs will be coded using the MedDRA dictionary.  
Frequencies of subjects (occurrence rate) with treatment-emergent AEs, regardless of relationship to 
study treatment and sorted by system organ class and preferred term will be summarized.  
Frequencies of subjects with possible treatment-related AEs will also be displayed. Serious and non-
serious possibly-related AEs will be described on a case by case basis and the relationship with the 
treatment intake will be discussed.  
Frequency tables of AEs, displayed by intensity will also be provided. 
 
Study Duration and dates 
Subjects will be evaluated for a period of approximately 4.5 months (screening up to 1 month, treatment 
phase 3 months, extra follow-up and end of study visit up to 16 days).  
Besides the screening visit, a total of approximately 28 visits will be required for this study but 4-7 
additional visits per menstrual cycle may be required if an ovarian follicle of ≥ 15mm in one dimension 
is visualized on TVUS.   
 
Subject recruitment is expected to begin in Q2 2018 and is planned to continue through the beginning 
of Q1 2019. 


Protocol: 151042-002 
 
 
 
 
 
 
 
 
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Table 1 Schedule of assessments 
 
Study periods 
Screening 
visit 
Treatment phase 
Follow up(a) 
End of 
study visit 
Treatment period 
1 
Treatment period 2 
Treatment period 3 
Days 
- 
D1 to D28 
D29 to D56 
D57 to D84 
D85 to D96 
Between 
D85 and 
D100 
 
 
D1 to D28 
D29 to D40 ±3 
And D44±3 to 
D56 
D41±3 to D43±3 
D57 to D68 ±3 
And D72±3 to 
D84 
D69±3 to D71±3 
 
 
Visits
V0 
V11 to V1x 
V21 to V2x 
V31 to V3x 
V41 to V4x 
V4y 
 
 
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b)  
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b)  
Delayed/missed pill period 
Three consecutive days 
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b) 
Delayed/missed pill period 
Three consecutive days  
Visits every 
other day for a 
maximum of 
12 days if a 
growing follicle 
≥ 15 mm 
identified upon 
TVUS(c) 
 
 
 
 
V2R-1 
V2RA 
V2RB 
V2R+1 
 
V3R-1 
V3RA 
V3RB 
V3R+1 
 
 
Informed 
consent
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
X(d) 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical 
and 
gynecological 
history
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical & 
gynecological 
examination
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs(e) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pap smear(f) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
STI screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
High-sensitivity 
urine pregnancy 
test (β-HCG) 
 
X(g) 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispensation of 
study 
medication (h) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 


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Study periods 
Screening 
visit 
Treatment phase 
Follow up(a) 
End of 
study visit 
Treatment period 
1 
Treatment period 2 
Treatment period 3 
Days 
- 
D1 to D28 
D29 to D56 
D57 to D84 
D85 to D96 
Between 
D85 and 
D100 
 
 
D1 to D28 
D29 to D40 ±3 
And D44±3 to 
D56 
D41±3 to D43±3 
D57 to D68 ±3 
And D72±3 to 
D84 
D69±3 to D71±3 
 
 
Visits
V0 
V11 to V1x 
V21 to V2x 
V31 to V3x 
V41 to V4x 
V4y 
 
 
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b)  
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b)  
Delayed/missed pill period 
Three consecutive days 
Visits twice a week 
if follicle < 15 mm 
Visits every other 
day for a 
maximum of 6 
days if a growing 
follicle ≥ 15 mm 
identified upon 
TVUS(b) 
Delayed/missed pill period 
Three consecutive days  
Visits every 
other day for a 
maximum of 
12 days if a 
growing follicle 
≥ 15 mm 
identified upon 
TVUS(c) 
 
 
 
 
V2R-1 
V2RA 
V2RB 
V2R+1 
 
V3R-1 
V3RA 
V3RB 
V3R+1 
 
 
Study 
medication 
intake
 
X 
X 
X(i) 
X(j) 
 
X(k) 
X 
X(i) 
 
X(j) 
X(k) 
 
 
Diary completion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
TVUS
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X(l) 
 
Mucus analysis 
 
X(m) 
X 
X(n) 
X(o) 
X(p) 
X(q) 
X 
X(n) 
X(p) 
X(o) 
X(q) 
X 
 
PK samples
 
X(r)(s) 
X(t) 
X(u) 
X(v) 
X(w) 
X(x) 
X(t) 
X(u) 
X(w) 
X(v) 
X(x) 
 
 
P4
X  
X  
X  
X 
 
 
X 
X 
X 
 
 
X 
X 
 
E2, FSH, LH 
 
X  
X  
X 
 
 
X 
X 
X 
 
 
X 
X(y) 
 
Prior and 
concomitant 
treatments
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
and bleeding 
patterns
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes: 
 
(a) 
Only if follicle ≥ 15 mm is observed after Day 73 AND the criteria for stopping the extra-visits were not fulffilled by Day 84 
(b) 
Extra visits will be stopped before 6 days if there is no postovulatory image after 6 days 
(c) 
Extra visits will be stopped before 12 days if there is no postovulatory image after 6 days or if the P4 levels are > 30 nmol/L at 1 visit or > 10 nmol/L at 2 consecutive visits. 
(d) 
Randomisation at 1st visit of treatment period 2 
(e) 
Vital signs include heart rate, systolic and diastolic blood pressure after at least 2-minute rest and height and weight (at screening only). 
(f) 
Pap smear to be performed according to current US guideline if an abnormal cervical lesion is detected during the gynecological examination 
(g) 
At V11 only, before first pill intake  
(h) 
At V11, last visit of treatment period 1 and last visit of treatment period 2 
(i) 
Study pill intake will be at 9 am ± 1 hour and will be noted as T2/3R-1 (actual treatment time at Day 41 or Day 69) 
(j) 
Study pill intake at T2/3R-1+ 6h ± 15 min 
(k) 
Study pill intake at T2/3R-1 ± 30 min 


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(l) 
TVUS up to observation of postovulatory image 
(m) 
At V11, the mucus analysis will be performed before the 1st study medication intake 
(n) 
Mucus analysis to be performed at T2/3R-1 +8 h ± 30 min. 
(o) 
Mucus analysis to be performed at T2/3TR-1 +3h ± 15 min. 
(p) 
Mucus analysis to be performed at T2/3R-1 +6 h ± 15 min. 
(q) 
Mucus analysis to be performed within 30 min before study medication intake 
(r) 
Blood sampling for PK analysis at D1: subjects with even study number at predose, 2 h ± 15 min, 6 h ± 15 min and 12 h ± 30 min post-treatment and subjects with odd study number at 1 h ± 15 min, 4 h ± 
15 min , 8 h ± 30 min and 24 h ± 30 min post-treatment 
(s) 
Blood sampling for steady state during first visit in week 3: subjects with odd numbers at predose, and between 0.5 h and 2h (morning visit), and subject with even numbers between 5 h and 9 h post-
treatment (afternoon visit) 
(t) 
Blood sampling for compliance during 1st visit of weeks 5 and 9 within 30 min of cervical mucus sampling 
(u) 
Blood sampling for PK analysis at T2/3R-1 +8h ± 30 min 
(v) 
Blood sampling for PK analysis at T2/3R-1 +3h ± 15 min, T2/3R-1 + 5.5h ± 15min, T2/3R-1 + 7.5h ± 30min 
(w) 
Blood sampling for PK analysis at T2/3R-1 + 6h ±15min 
(x) 
Blood sampling for PK analysis at T2/3R-1 within 30 min before study medication intake 
(y) 
No E2, FSH and LH measurements during extra-visits after postovulatory image is observed 
 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse Event 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BSL 
Baseline 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and prevention 
CO2 
Carbon Dioxide 
COC 
Combined Oral Contraception 
CRO 
Contract Research Organization 
DMP 
Delayed/Missed Pill 
E2 
Estradiol 
e-CRF 
electronic Case Report Form 
EOS 
End-Of-Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FLS 
Follicle Like Structure 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IUD 
Intra-Uterine Device 
K2-EDTA 
Di Potassium-Ethylene Diamine Tetraacetic Acid 
LC-MS/MS 
Liquid Chromatography with double Mass Spectrometry 
LH 
Luteinizing Hormone 
LNG 
Levonorgestrel 
LUF 
Luteinized Unruptured Follicle 
NG 
Norgestrel 
OAS 
Ovarian Activity Score 


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OC 
Oral contraceptives 
OS (q, a, alp, nlp) Ovarian Status (quiescence, ovarian activity, ovulation with 
abnormal luteal phase, ovulation with normal luteal phase) 
P4 
Progesterone 
PCOS 
Polycystic Ovary Syndrome 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PHI 
Protected Health Information 
PK 
Pharmacokinetic(s) 
POP 
Progestin Only Pill 
PP 
Per-Protocol 
 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPC 
Summary of Product Characteristics 
STI 
Sexually Transmitted Infection 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2R-1/T3R-1 
Time of treatment intake on the day before delayed intake/missed 
pill per Randomization arm, in treatment period 2/3 
TVUS 
TransVaginal Ultrasound 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WoA 
Waiver of Authorization 
WHRU 
Women’s Health Research Unit 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ......................................................................................................... 3 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................. 12 
TABLE OF CONTENTS ........................................................................................................ 14 
1. 
INTRODUCTION AND BACKGROUND ........................................................................ 17 
2. 
RATIONALE, BENEFITS AND RISKS .......................................................................... 17 
3. 
OBJECTIVES ................................................................................................................. 18 
4. 
STUDY DESIGN ............................................................................................................. 19 
5. 
PRINCIPAL INVESTIGATOR & RESEARCH CENTERS .............................................. 20 
6. 
SUBJECT RECRUITMENT ............................................................................................ 20 
7. 
STUDY DURATION ........................................................................................................ 20 
8. 
SAMPLE SIZE/NUMBER OF SUBJECTS ..................................................................... 21 
9. 
SELECTION OF SUBJECTS ......................................................................................... 21 
9.1 
Inclusion criteria: ................................................................................................................................... 21 
9.2 
Exclusion criteria ................................................................................................................................... 22 
10. RANDOMIZATION ......................................................................................................... 22 
11. PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS ................................. 22 
11.1 
Prior and concomitant illnesses ........................................................................................................... 22 
11.2 
Prior and concomitant medications ..................................................................................................... 23 
11.3 
Prohibited medications ......................................................................................................................... 23 
11.4 
Surgical procedures .............................................................................................................................. 23 
12. STUDY MEDICATION .................................................................................................... 23 
12.1 
Details of Study medication .................................................................................................................. 23 
12.2 
Packaging and Labelling ....................................................................................................................... 23 
12.3 
Dosage schedule .................................................................................................................................... 24 
12.4 
Treatment dispensation ......................................................................................................................... 25 
12.5 
Investigational product accountability ................................................................................................ 25 
12.6 
Storage .................................................................................................................................................... 25 
12.7 
Disposal/return ....................................................................................................................................... 26 
12.8 
Compliance ............................................................................................................................................. 26 
13. LABORATORY TESTS AND EVALUATIONS ............................................................... 26 
13.1 
Physical and gynecological examination ............................................................................................ 26 
13.2 
Vital signs ............................................................................................................................................... 26 
13.3 
Laboratory parameters .......................................................................................................................... 26 
13.4 
Hormone testing ..................................................................................................................................... 27 
13.5 
Levonorgestrel concentrations ............................................................................................................ 27 
13.6 
Pap test and STI screening ................................................................................................................... 27 
13.7 
Transvaginal ultrasound (TVUS) .......................................................................................................... 27 
13.8 
Cervical mucus ....................................................................................................................................... 28 
13.9 
IMP intake and bleeding reporting (e-diary) ........................................................................................ 28 
14. STUDY VISITS ............................................................................................................... 28 
14.1 
Screening visit (V0, during luteal phase) ............................................................................................. 28 
14.2 
Treatment period 1 (V11 to V1x – Day 1 to Day 28) .............................................................................. 30 
14.2.1 
V11 Enrollment visit (V11 - Day 1, morning) ................................................................................ 30 
14.2.2 
Regular twice-weekly visits (V12 to V1x – Day 1 to 28) .............................................................. 31 
14.2.3 
Extra visits (V12 to V1x – Day 1 to 28) .......................................................................................... 31 
14.3 
Treatment period 2 (V21 to V2x – Day 29 to 56) ................................................................................... 32 
14.3.1 
Regular twice-weekly visits and extra visits (V21 to V2x – Day 29 to 40 ±3 days AND Day 44 ± 
3 days to Day 56) ............................................................................................................................................. 32 
14.3.2 
DMP period (V2R-1 to V2R+1 – Day 41 ± 3 days to Day 43 ± 3 days) ........................................... 32 
14.4 
Treatment period 3 (V31 to V3x – Day 57 to 84) ................................................................................... 33 
14.4.1 
Regular twice-weekly visits and extra visits (V31 to V3x – Day 57 to 68 ±3 days AND Day 72 ± 
3 days to Day 84) ............................................................................................................................................. 33 
14.4.2 
DMP period (V3R-1 to V3R+1 – Day 69 ± 3 days to Day 71 ± 3 days) ........................................... 33 


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14.4.3 
Follow-up visits (V12 to V1x – Day 84 to Day 96) ........................................................................ 33 
14.5 
End of study visit (EOS) (V4y – between Day 85 and Day 100) .......................................................... 34 
14.6 
Study flow summary .............................................................................................................................. 35 
15. ADVERSE EVENTS ....................................................................................................... 37 
15.1 
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY REPORTING ................................. 37 
15.1.1 
Definitions of Adverse Events (AE), Serious Adverse Events (SAE), severity and causality 
assessment ..................................................................................................................................................... 37 
15.1.2 
Adverse Events: Recording and Reporting ................................................................................ 38 
15.1.3 
Instructions to study participants ............................................................................................... 39 
15.1.4 
Study reporting for SAEs ............................................................................................................. 39 
15.1.5 
Follow up ........................................................................................................................................ 40 
15.1.6 
Event of special interest ............................................................................................................... 40 
15.1.7 
Notification of IRB of SAEs .......................................................................................................... 40 
15.2 
OBLIGATIONS OF THE SPONSOR REGARDING SAFETY REPORTING .......................................... 40 
15.3 
PREGNANCY DETERMINATION AND FOLLOW-UP ........................................................................... 41 
16. STUDY CONDUCT ......................................................................................................... 41 
16.1 
Deviation from the Protocol .................................................................................................................. 41 
16.2 
Amendments to the Protocol ................................................................................................................ 41 
16.3 
Subject Confidentiality .......................................................................................................................... 42 
16.4 
Discontinuing Subjects ......................................................................................................................... 42 
16.5 
Withdrawals from Study ........................................................................................................................ 43 
17. STUDY MONITORING AND DOCUMENTATION .......................................................... 43 
17.1 
Clinical Monitoring, Quality Control, and Quality Assurance ........................................................... 43 
17.2 
Administrative and Record Management and Retention of Data ...................................................... 44 
17.3 
Study Documentation ............................................................................................................................ 45 
17.4 
Electronic Data Capture System........................................................................................................... 45 
17.5 
Confidentiality and Reporting of Results ............................................................................................ 45 
18. DOCUMENTATION AND USE OF STUDY FINDINGS .................................................. 45 
18.1 
Documentation of study findings ......................................................................................................... 45 
18.2 
Use of study findings ............................................................................................................................. 46 
19. STATISTICAL AND ANALYTICAL METHODS ............................................................. 46 
19.1 
Populations ............................................................................................................................................. 46 
19.2 
Description of Subjects ......................................................................................................................... 47 
19.3 
Efficacy analysis .................................................................................................................................... 48 
19.3.1 Primary analysis ..................................................................................................................................... 48 
19.3.2 Subordinated objective ......................................................................................................................... 50 
19.3.3 Secondary analyses ............................................................................................................................... 51 
19.3.4 Other secondary analyses .................................................................................................................... 52 
19.3.5 Presentation of pharmacodynamic data .............................................................................................. 54 
19.4 
Safety analysis ....................................................................................................................................... 54 
19.4.1 
Incidence of Adverse Events ....................................................................................................... 55 
19.4.2 
Discontinuation Due to Adverse Events ..................................................................................... 55 
19.4.3 
Serious Adverse Events ............................................................................................................... 55 
19.4.4 
Deaths ............................................................................................................................................. 55 
20. ADJUDICATION COMMITTEE ...................................................................................... 55 
21. ETHICAL CONSIDERATIONS AND LEGAL ASPECTS ............................................... 55 
21.1 
Good Clinical Practice ........................................................................................................................... 55 
21.2 
Study without direct benefit to individual subjects ............................................................................ 56 
21.3 
Delegation of investigator responsibilities ......................................................................................... 56 
21.4 
Interactions with Institutional Review Boards .................................................................................... 56 
21.5 
Ongoing information for IRB ................................................................................................................. 56 
21.6 
Informed Consent .................................................................................................................................. 57 
21.7 
Conflicts of Interest ............................................................................................................................... 57 
21.8 
Confidentiality ........................................................................................................................................ 58 
21.9 
Premature closure of the study ............................................................................................................ 58 
21.10 Liability and insurance .......................................................................................................................... 58 
22. REFERENCES ............................................................................................................... 59 
APPENDICES........................................................................................................................ 61 
Appendix 1: List of Exclusionary Medications .................................................................................................. 62 
Appendix 2: Cervical mucus sampling and scoring .......................................................................................... 64 
Appendix 3: Determination of Ovarian Activity Score (OAS) and Ovarian Status (OS) ................................... 71 


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Appendix 4: Helsinki Declaration ...................................................................................................................... 72 
Appendix 5: Serious Adverse Event Report Form ............................................................................................ 77 
Appendix 6: Pregnancy Collection Form .......................................................................................................... 79 
 
 
LIST OF TABLES 
 
Table 1 Schedule of assessments ....................................................................................................................... 9 
Table 2 Main study flow (not including DMP period, see Table 3) ................................................................. 35 
Table 3 Study flow of DMP period ..................................................................................................................... 36 
Table 4 Conception protection based on OS and cervical mucus score ...................................................... 53 
Table 5 PK sampling schedule at Day 1 ........................................................................................................... 53 
Table 6 PK sampling schedule during the DMP period................................................................................... 54 
Table 7 Determination of Ovarian Status .......................................................................................................... 71 
 
LIST OF FIGURES 
 
Figure 1 Design of the study ................................................................................................................................ 4 
Figure 2 Design of the study .............................................................................................................................. 19 
Figure 3 Primary measures of mucus ............................................................................................................... 49 
Figure 4 Conception protection based on OS and cervical mucus score (binary analysis) ....................... 52 
 
 
 
 


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1. INTRODUCTION AND BACKGROUND 
 
Oral contraceptives (OCs) are the most widely used hormonal method of contraception in the United 
States (US). Combined estrogen-progestin OCs (COCs) are the most frequently-prescribed OCs in the 
US, while progestin-only pills (POPs) are less frequently prescribed. POPs are mainly prescribed to 
breastfeeding women or when the use of a COC is contra-indicated.  
 
POPs prevent conception by suppressing ovulation in approximately half of the cycles in users, 
thickening the cervical mucus to inhibit sperm penetration, lowering the midcycle LH and FSH peaks, 
slowing the movement of the ovum through the fallopian tubes, and altering the endometrium (McCann 
1994). 
 
Because of the lower dose of progestin in POPs compared to the dose in COCs, the reliance on 
mechanisms of action other than ovulation inhibition, and the potential importance of consistent daily 
pill taking, POPs are perceived to be not as effective as COCs. However, when used as directed, POPs 
seem to be as highly effective as a COC, with a perfect-use failure rate estimated at 0.3% and a typical 
use failure rate estimated at 9% (Trussell, 2011; Curtis, 2016). A recent Cochrane review concluded 
that no firm conclusion is possible concerning the comparative efficacy of POPs or whether such pills 
are as effective as COCs (Grimes A, 2013). 
 
 
Opill® (norgestrel (NG) 75 mcg) is a 2nd generation synthetic progestin-only oral contraceptive approved 
in the US in 1973, (under the proprietary name Ovrette®) at a daily dose of 75 mcg and first marketed 
in 1974 in the US. NG is a mixture of two enantiomers, only one of which levonorgestrel (LNG) being 
the active form. LNG have been marketed in the US and in Europe for more than 30 years in a wide 
variety of contraceptive products (including combined and progestin-only oral contraceptives, implant, 
vaginal ring, intrauterine system, and emergency contraceptives)..  
  
Approval for marketing in the US by the Food and Drug Administration (FDA) was based upon the 
results of eight clinical trials of continuous daily oral NG 75 mcg. The study sites represented all major 
US geographic regions and participants were 53% Caucasian and 47% African-American. There was 
a combined 2 575 women, of whom 2 173 completed at least one cycle of medication (28 days), and 
21 856  28-day cycles of exposure in women aged 15 to 49 years. Thirty-seven pregnancies were 
confirmed during the eight clinical investigations, resulting in an overall use effectiveness (Pearl Index) 
of 2.0 pregnancies per 100 women-years of use.  Eighteen pregnancies were confirmed to be a result 
of method failure and 19 pregnancies occurred among women who omitted 1 or more pills during the 
cycle in which the conception took place. The theoretical use effectiveness rate among women 
experiencing a method failure therefore has a Pearl Index of 0.98 per 100 women-years (N = 2 173; 21 
854 cycles; 1 821 women-years). 
 
As with other POPs, Opill® has only few contra-indications, the most relevant is having history of breast 
cancer. The World Health Organization (WHO) and the US Medical Eligibility Criteria for Contraceptive 
Use, 2016, list “current breast cancer” as the single condition that represents an unacceptable health 
risk (category 4) for a woman if she uses POPs. Only a few other conditions are listed for which the use 
of POPs is not usually recommended unless other, more appropriate, methods are not available. The 
main adverse reactions consist in the disturbance of the menstrual cycles, and other few and moderate 
hormonal reactions such as delayed follicular atresia or ovarian cysts. 
 
 
2. RATIONALE, BENEFITS AND RISKS 
 
NG, as with other POPs, is currently prescribed with the advice that it should be taken without 
interruption every day at the same time to achieve maximum contraceptive effectiveness. Any pill taken 
more than 3 hours late is considered a missed pill due to diminishing effects on cervical mucus (Han L 
2017). 


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It has also been emphasized that the effect of progestins on cervical mucus is the most immediate level 
of protection provided by POPs, but offering a full protection for less than 24 hours (McCann 1994). 
In fact, there are only very few studies assessing the PK of oral NG/LNG for use as POP and no data 
linking the PK to the pharmacodynamic (PD) action of POPs. In one study where five subjects were 
given a single dose of 30 mcg LNG (Weiner 1976), the mean plasma half-life was 13.7 hours with large 
variability between subjects (7.95 to 23.23 hours). Twenty four hours after drug intake, the plasma 
concentrations were 0.05 to 0.14 ng/mL. The plasma levels observed in 3 subjects taking 30 mcg LNG 
daily for 3 weeks were between 0.10 and 0.40 ng/mL when measured 12 hours after the oral 
administration each day during the 3-week treatment period. Brenner et al. (1977) found that serum 
levels of LNG were 0.2 to 0.5 ng/mL 24 hours after oral administration of 75 mcg NG.  
 
In addition, there are very few clinical data assessing the temporality of the effect of POPs on cervical 
mucus. In healthy women given 350 mcg of norgestrienone for 13 days, cervical mucus displayed 
changes in its macromolecular structure, i.e. an extreme degree of compactness, an appearance typical 
of the late luteal phase (Chretien et al. 1980). The cervical mucus remained extremely dense 24 hours 
after the last dose of norgestrienone but, 12 hours later, few samples exhibited meshes large enough 
to permit the easy passage of sperm cells and, 48 hours after the last dose mucus was considered as 
not protective. Lebech et al. (1970) found that sperm penetration of the cervical mucus was totally 
inhibited in 3 out of 4 subjects treated with 0.5 mg/day megestrol acetate but returned to normal 
38 hours after the ingestion of the last dose. However, interpretation of the results of these continuous 
low-dose progestogen contraceptive studies is hampered by the small sample sizes, the incomplete 
description of the methodology, and the absence of statistical analysis and it is not known whether such 
results can be extrapolated to NG 75 mcg.  
 
Regarding ovarian activity, it was shown that 75 mcg NG daily for 30 days inhibited or suppressed LH 
and FSH peaks and the rise of serum progesterone (P4) and urinary pregnanediol during the luteal 
phase, suggesting that even if there was follicular rupture, this was associated with luteal insufficiency 
(Moghissi and Marks, 1971). In another study where 29 subjects received 30 mcg LNG daily, an 
ovulation defined as follicular rupture associated with P4 level above 30 nmol/L was observed in 28% 
of all studied 57 cycles (Rice CF, 1999). However, there is no study analysing both ovarian activity and 
cervical mucus in women treated with NG and no data are available regarding the effect of delayed or 
missed pill on these parameters.  
 
In the light of limited PK and PD data on NG and POPs in general that supports the clinical guidance of 
taking it everyday at the same time within a three hour window, this exploratory study aims to determine 
the PD mechanisms underlying the contraceptive protection of NG 75 mcg. Primarily, the study will 
evaluate whether these PD mechanisms are impacted by a delayed intake or a missed pill. 
 
The main PD endpoints will be the cervical mucus assessed according to the WHO guidelines excluding 
the volume component as already described (Dunson et al, 1998; Petta et al, 1998) and the ovarian 
activity measured with a Ovarian Activity Score (OAS) (see Appendix 3).  
 
 
3. OBJECTIVES 
 
The primary objective of the study is to determine the effect of a delayed intake of 6 hours or of a missed 
pill on cervical mucus score compared to cervical mucus score during reported perfect daily use of 
norgestrel 75 mcg.  
 
The subordinate primary objective is to estimate the duration of the protective effect of cervical mucus 
after last pill intake of norgestrel 75 mcg during reported perfect use. 
The protective effect of cervical mucus is considered as present when the score is below or equal 4. 
 


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The secondary objectives are: 
• 
to evaluate and compare the percentage of subjects with a protective cervical mucus score 
during reported perfect daily use of norgestrel 75 mcg, during a treatment period with a delayed 
intake of 6 hours and during a treatment period with a missed pill of norgestrel 75 mcg.   
• 
To evaluate and compare the ovarian activity during reported perfect daily use, during a 
treatment period with a delayed intake of 6 hours and during a treatment period with a missed 
pill of norgestrel 75 mcg.  
• 
To assess if a combination of cervical mucus score and ovarian status can be considered as a 
measure of protection from conception during reported perfect daily use, during a treatment 
period with a delayed intake of 6 hours and during a treatment period with a missed pill of 
norgestrel 75 mcg.  
• 
To determine levonorgestrel pharmacokinetics after a single dose of norgestrel 75 mcg, at 
steady state, after a delayed intake and after a missed pill.  
• 
To assess the safety of norgestrel 75 mcg taken daily for 12 weeks. 
 
 
4. STUDY DESIGN 
 
This is an exploratory, prospective, multi-center, randomized, cross-over study to assess the effect of 
norgestrel 75 mcg on cervical mucus and ovarian activity during reported perfect daily use and after a 
delayed intake of 6 hours and after a missed pill.  
 
This study includes three 28-day treatment periods (approximately 3 months) with a screening period 
of up to 1 month to demonstrate ovulatory status prior to enrollment, a possible follow-up of 12 days to 
follow ovarian activity if a follicle ≥ 15 mm is observed at the end of period 3 and an end of study (EOS) 
visit within 5 days. Women of reproductive age (18-35 years old) who meet eligibility requirements will 
receive treatment for a total of three 28-day periods (84 days) but in treatment period 2 and 3, will have 
a 6-hour delay in pill intake or a missed pill (see Figure 2 below).  
 
Figure 2 Design of the study 
 
 
Besides the screening visit, a total of approximately 28 visits will be required for this study but up to 7 
additional visits per menstrual cycle (up to 3 in treatment periods 1 & 2, up to 7 in treatment period 3) 
may be required if an ovarian follicle of ≥ 15mm in one dimension is visualized on TVUS.   
 
The study is designed to evaluate cervical mucus attributes, ovarian activity and PK of LNG after daily 
treatment by norgestrel 75 mcg as well as the PK and PD changes that ensue with poor regimen 
adherence.  
 
In the first treatment period, treatment will be installed and cervical mucus attributes and ovarian activity 
in the first weeks of treatment will be observed. In addition, PK profile of LNG will be determined after 
a single dose (Day 1) and at steady state (on week 3). 
 
In the second and third periods of treatment, the difference on cervical mucus score and ovarian activity 
score between a perfect use (Day 41 ± 3 / Day 69 ± 3) and a 6-hour delayed intake (Arm A Day 42 ± 3 
and Arm B Day 70 ± 3) or a missed pill (Arm B Day 43 ± 3 and Arm A Day 71) will be assessed.  
 
 


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5. PRINCIPAL INVESTIGATOR & RESEARCH CENTERS 
 
Two investigational research centers located in the US will conduct the study. A complete list of 
investigators, sub-investigators, and coordinators will be maintained with trial documentation. 
 
Listed here are the investigational research centers conducting this study: 
• 
Alison Edelman, MD, MPH: Oregon Health & Science University, Portland, Oregon 
• 
Mitchell Creinin, MD: University of California Davis Health, Sacramento, California 
 
 
6. SUBJECT RECRUITMENT 
 
Participants will be recruited from two research centers in the US. Competitive recruitment will be 
planned between the two centers. Each center will enroll a minimum of 20 subjects but the total number 
of completers should reach at least 45 subjects.  
 
Subjects will be recruited from family planning clinics and other clinics serving reproductive-aged 
women for gynecologic care and reproductive health services (including the clinics’ database) as well 
as through IRB-approved research recruitment efforts (newsletters, in-services, tear-ads, radio ads, 
social network ads, online form etc). Referrals from previous / ongoing participants are accepted. This 
study will be listed on the website ClinicalTrials.gov (see section 21.1). Subjects will be selected for the 
study according to the inclusion and exclusion criteria detailed in section 9.  
 
Information collected before signature of the informed consent form (ICF), if used, will be stored in a 
locked office, with access limited to study staff. For subjects electing to enroll in the study, this 
information will become a part of their protected research record. For subjects choosing not to enroll, 
all protected health information (PHI) will be stored confidentially with the research study information in 
a locked cabinet and archived with other study-specific documents at the closure of the trial. 
Confidentiality of PHI will be maintained according to regulations and sites’ procedures.    
 
Women will be screened for eligibility and interest in study participation. If they meet the basic criteria 
and agree to participate, they will be required to provide informed written consent prior to beginning any 
study procedures. The protocol and patient information sheet/ ICF will be reviewed and approved by 
the IRB prior to initiation of the study. Information collected and created in order to conduct and oversee 
this research study may be stored according to regulation, sites’ procedures and with the agreement of 
the participant.  
 
 
7. STUDY DURATION 
 
The total duration of the study for each participant is expected to be approximately 4.5 months: up to 4 
weeks for screening to meet enrollment criteria, 12 weeks of treatment and a possible follow-up of 12 
days to follow ovarian activity if a follicle ≥ 15 mm is observed at the end of period 3 and an EOS visit 
within 5 days. 
 
Subject recruitment is expected to begin Q2 2018 and is planned to continue through the beginning of 
Q1 2019. However, if the enrollment rate declines, the enrollment period may be extended beyond this 
date. If this enrollment timeline is met, all subjects should finish active treatment by approximately the 
end of Q2 2019. Therefore, the total duration of the study will be approximately 15 months for each 
study site.  
 
Results of the study are expected to be available Q3 2019. 
 
 


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8. SAMPLE SIZE/NUMBER OF SUBJECTS 
 
Approximately 70 subjects will be screened to have at least 45 subjects who complete the study.  
 
The primary analysis is based on the score of cervical mucus as a quantitative variable because it is 
expected to be the most powerful analysis. However the justification of the sample size will not be based 
on the primary analysis because too much information is missing such as an order of magnitude of the 
variance covariance matrix of the change from time point of reference. This is the reason why the 
sample size calculation will be based on proportions of women with no loss of protection.   
 
A total sample size of 45 subjects should allow to detect a loss of protection that affect pertinently a 
substantial proportion of the population. Indeed if the difference between a cycle with a perfect use and 
a cycle with an infringement in the schedule is 14 % in the expected proportions of women with a loss 
of protection at any time and if the proportion of discordances between the 2 situations is 17% then the 
exact power is equal to 79.1%. If the expected difference in proportions is 15% with a rate of 
discordance of 18% then the exact power is 82.4% for an unconditional test. The expected difference 
in proportions need therefore to reach 14-15 % to get a sufficient power for detecting a significant 
difference. This difference in proportions is a substantial difference knowing that most of change in 
status (see discordance rate) are in the same direction i.e. from protection to loss of protection.      
 
 
9. SELECTION OF SUBJECTS 
 
9.1 Inclusion criteria:  
 
To enroll into the clinical trial, potential subjects must: 
• 
Be in good overall health with no chronic medical conditions that result in periodic exacerbations 
that require significant medical care. 
• 
Be women between 18 and 35 years inclusive at the screening visit. 
• 
Have a BMI< 32 kg/m². 
• 
Have regular menstrual cycles between 21 and 35 days when not using hormonal contraception. 
o Subjects postpartum or post-abortal must have one normal menstrual cycle (2 menses) 
prior to enrollment.  
o Subjects previously using IUD or taking hormonal contraception (or any other hormonal 
treatment, except an injectable treatment) need to have at least one menstrual cycle (2 
menses) without the treatment before screening.  
o Subject previously using an injectable (DMPA), must have had their last injection at least 
9 months before screening.  
• 
Not be at risk of pregnancy: not sexually active, or willing to protect all acts of intercourse with 
condoms, or have a sterile partner or have undergone previous tubal ligation (including validated 
Essure), or be in a same sex relationship. 
• 
Be able to give informed consent form to participate in the study and in the opinion of the 
investigator able to follow all study requirements, use the study product and record the 
requested information appropriately. 
• 
Have a negative pregnancy test at the enrollment visit. 
• 
Have an intact uterus and both ovaries. 
• 
Have at least one progesterone concentrations > 10 nmol/L (> 3 ng/mL) during the luteal phase 
of the screening period. 
 


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9.2 Exclusion criteria 
 
To enroll into the clinical trial, potential subjects must NOT: 
• 
Be pregnant as confirmed by positive high-sensitivity urine pregnancy test at V11 (enrollment 
visit) 
• 
Trying to conceive or desire to conceive in the next 3 months 
• 
Currently be breastfeeding, or within the last 2 months 
• 
Have known Polycystic Ovarian Syndrome (PCOS). 
• 
Have cancer (or past history of any carcinoma or sarcoma). 
• 
Have known abnormal thyroid status, if in clinical judgment of the investigator it cannot be 
controlled during the study. 
• 
Have known hypersensitivity to the ingredients of the test active substances or its excipients. 
• 
Have current acute liver disease and/or benign liver tumors.  
• 
Have vaginal or cervical infection including clinical evidence of bacterial vaginosis 
• 
Have evidence of abnormal cervical lesion 
• 
Have history of excisional or ablative treatment procedure on cervix (ie. Loop Electrosurgical 
Excision Procedure (LEEP), Cryotherapy, Cold Knife Cone) 
• 
Have undiagnosed abnormal uterine bleeding. 
• 
Have had prior malabsorptive-type bariatric surgery. 
• 
Have known or suspected alcoholism or drug abuse. 
• 
Use any hormonal contraception or IUD other than the study medication during the study.  
• 
Use of any medications that can interfere with the metabolism of progestin-based contraceptives 
(e.g CYP3A4 enzymes inducers or inhibitors, etc). 
• 
Have unstable diabetes mellitus. 
• 
Currently participate in any other trial of an investigational medicine or participation in the past 
two months (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for 
antibodies, whichever is the longer) before start of baseline period. 
• 
Have abnormalities in laboratory results or TVUS performed at screening visit recognized as 
clinically significant by the investigator 
• 
Present conditions not suitable for frequent TVUS examinations, (e.g. virgo intacta) 
• 
Be in custody or submitted to an institution due to a judicial order 
• 
Be a relative, family household member of the investigator’s or sponsor’s staff 
 
 
10.  RANDOMIZATION 
 
The study medication will be delivered only to subjects included in this study following the procedures 
set out in the protocol. In this study, all subjects will receive the study medication at the same dosing 
regimen. The randomization in this study will allocate subjects evenly to either: 
• 
Arm A (delayed pill in treatment period 2 and missed pill in treatment period 3) or, 
• 
Arm B (missed pill in treatment period 2 and delayed pill in treatment period 3). 
 
Randomization will occur during the 1st visit of period 2. 
 
 
11. PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
 
11.1 
Prior and concomitant illnesses 
 
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Conditions present prior to study entry (screening) that do not worsen in severity are considered medical 
or surgical history, not considered AEs. Conditions identified and treated at screening, i.e. laboratory 
abnormalities, urinary tract infections, gynecologic infections including Chlamydia, gonorrhea, candida, 
bacterial vaginosis are included in medical history and are not reported as AEs. 
 
11.2 
Prior and concomitant medications 
 
All concomitant medications, including any medication taken in the 2 weeks preceding entry into the 
study, will be recorded on the subject’s electronic case report forms (e-CRF), including the name of the 
drug, start and stop dates and reason for use from the time of informed consent signature through to 
the end of study visit.  
 
Other medications for the treatment of inter-current medical conditions should be permitted and 
recorded as detailed above unless they are part of the list of prohibited medications described in section 
11.3. 
 
11.3 
Prohibited medications 
 
The following medications are prohibited during the course of the study (refer to Appendix 1 for the 
complete list of excluded medicines): 
• 
Sex hormones or other forms of hormonal contraception are exclusionary, including emergency 
contraception. Subjects must be educated that use of levonorgestrel- or ulipristal acetate-based 
emergency contraception could impact the endpoints of the study. 
• 
Drugs that can interfere in the metabolism of hormonal contraceptives 
o CYP3A4 inducers (rifampin, barbiturates, carbamazepine, bosentan, felbamate, 
griseofulyin, oxcarbazepine, phenytoin, St. John’s Wort, topiramate, efavirenz, etc.)  
o CYP3A4 inhibitors (clarithromycin, conivaptan, grapefruit juice, indinavir, oral azole 
antifungals, etc.) 
• 
Drugs with significant evidence of fetal risks  
 
11.4 
Surgical procedures 
 
For subjects who need to undergo unplanned surgical procedures during the study, the reason for 
surgery must be documented as a serious adverse event (SAE) on the e-CRF (see Section 15. Adverse 
Events). The surgical procedure should be documented in the “comments” section of the adverse event 
(AE) form in the e-CRF.  
 
 
12. STUDY MEDICATION 
 
12.1 
Details of Study medication 
 
The study medication is norgestrel 75 mcg, an oral contraceptive pill consisting of a synthetic progestin: 
Drug code: Opill® 
INN: norgestrel 
Dosage form and strength: 1 tablet containing 75 mcg norgestrel 
Packaging: blister containing 28 tablets 
Manufacturer: XXX  
 
12.2 
Packaging and Labelling 
 
All packaging and labeling of the study medication will be prepared in accordance with 21CFR, Section 
312.6 and GMP by XXX. Thus, packs labelled specifically for this study will be provided to the clinical 
sites. 


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The study drug will be provided in boxes containing one blister pack of 28 tablets (75 mcg per tablet) 
which correspond to 28 days of study medication (1 pill per day, single dose). Study subjects will be 
provided with 2 boxes at the start of treatment period 1 and 1 box at the end of treatment period 1 and 
end of treatment period 2.   
 
Blisters will be made of XXX sealed with an aluminium foil printed with the required information.  
The study treatment labels will be in local language (English). 
 
Information listed on the labels on the treatment boxes should comply with GCP and GMP requirements 
as well as local regulations. The labels will contain the following information: 
• 
Clinical Study Number  
• 
Site Number (space to record) 
• 
Subject Number (space to record) 
• 
Treatment period number (space to record)  
• 
Product Identification : Opill® (norgestrel) Oral Contraception 
• 
Administration Directions: Take 1 tablet by mouth every day at the same time. 
• 
Number of dosage units (e.g. tablets) and strength 
• 
Lot Number 
• 
Expiry Date 
• 
Name and address of Sponsor : HRA Pharma, 15 rue Beranger | 75003 Paris | France 
• 
Name, adress and phone number of PI: Dr Edelman; Oregon Health & Science University, 3181 
SW Sam Jackson, UHN 50, Portland, OR 97239, USA – Tel XXX or XXX  
• 
Storage conditions: between 20-25°C (68° to 77°F) (see USP controlled temperature) 
• 
FDA Caution Statement: CAUTION :New drug-- Limited by Federal (or United States) law to 
investigational use. 
• 
For Clinical Trial Use Only. 
• 
Keep Out of Reach of Children 
 
12.3 
Dosage schedule 
The first dose will be taken at 9:00 am ± 3 hours during V11 (enrollment visit) while the subject is present 
at the study site.  
At V11, she will also choose, with the site, her treatment time (T) starting on Day 2 for all the rest of the 
study (3 treatment periods).  
This treatment time should be: 
• 
same every day (± 1.5 hours) except the day of V2R and V3R (DMP period, see section 14.3.2. 
and 14.4.2) 
• 
between 6:00 am and 12:00 pm 
• 
within 3 hours of the 1st dose taken at V11 
On V2R-1 and V3R-1, the subject will come on site to take her daily pill at 9:00 am ± 1 hour (T2/3R-1) 
during the scheduled study visit. She will also come to site at V2/3R and V2/3R+1 to take/miss her pill 
according to the site’s instructions. 
NB: at time of summer and winter time change, specific schedule has to be followed: 
• 
If the day of time change is within 2 days before the first day of DMP period (V2R-1 or V3R-1), the 
subject will be asked to take her pill between 8:00 am and 10:00, for the two days before DMP 
period. 
• 
If the day of time change is on the 2nd or 3rd day of the DMP period, the subject will take on site 
her pill according to the site’s instructions, without taking account of the time change (i.e. at the 
“old” time).  
• 
If the day of time change is any other day, the subject will take her pill between 7:00 am and 
11:00 am on the day before and on the day of time change.  
 


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In case of missed study pills (with the exception to DMP periods): If one dose is missed, it should be 
taken as soon as it is remembered and at the latest at the time of the next dosing, thus allowing a 
subject to take two doses within 24 hours. The event will have to be reported to the study staff at the 
next visit. 
If more than one consecutive dose is missed, the subject should contact the site for dosing instructions. 
The subject will be advised to take only the most recently missed pill, at the latest at the time of the next 
dosing, and to leave the other missed pills in the blister.  
 
In any case, she will be reminded to use a non-hormonal back-up method of contraception (such as 
condoms or spermicides) for the next 48 hours. 
 
In case of diarrhea and/or vomiting: if a subject has diarrhea and/or vomiting within 4 hours after taking 
a pill, another pill should be taken as soon as possible on the same day and the event reported to the 
study staff at the next visit.  
 
In case of lost blister: if a subject loses a blister, she should call the site to be instructed either to use 
the extra blister she was provided with or to come back to the site for a new blister if necessary. 
 
12.4 
Treatment dispensation 
 
Prior to dispensing the study medication, the investigator or designee will record the site number and 
subject’s study identification number on the medication box label, and the subject’s study identification 
number on the blister. The investigator or designee will record the amount dispensed and date of 
dispensation in the investigational study medication accountability log. 
 
Subjects should be instructed to bring back both used and unused blister packs to the site at each visit 
so that remaining pill accountability can be performed. All unused, partially/fully used blister packs 
should be retained by the site at the end of each treatment period for study medication accountability. 
Each participant will be provided with a total of 4 medication boxes containing 1 blister of 28 tablets 
each, i.e. one for each of the 3 treatment periods and one for back-up. Two boxes will be provided at 
the start of treatment period 1 (one to be used in treatment period 1 and one to be used as back-up if 
necessary), one at the end of treatment period 1, and one at the end of treatment period 2. 
 
12.5 
Investigational product accountability  
Each study site is required to maintain study records of the disposition of study medication, including 
dates and quantities of distribution by subject ID number, and initials of the research center personnel 
distributing the study product. Study accountability logs will be provided for this purpose. 
Study medication will be shipped to each research center after the receipt and acceptance of all 
necessary regulatory documents. Upon receipt of study medication, an inventory of the study 
medication must be completed by the Investigator (or designee). All study medication dispensed and 
returned must be recorded as outlined above. All dosing records must be consistent with the study 
accountability logs. 
 
12.6 
Storage 
Study medication will be stored at the designated research sites in a dry place at the study site at room 
temperature (≥15⁰C [59⁰F] and ≤25⁰C [77⁰F]) under controlled and secured conditions, in a locked 
storage area away from sunlight to avoid temperature fluctuations. A temperature log for the 
investigational product storage area must be maintained for the duration of the study. 
 


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12.7 
Disposal/return 
 
At the end of the study, the monitor will complete a final accountability of all clinical supplies, including 
used and unused medication boxes. Once accountability is completed, remaining study product will be 
shipped back to the sponsor or its designee.  
 
12.8 
Compliance 
 
Subjects will be instructed to bring their study medication pack at each visit. Compliance will be 
assessed by monitoring of norgestrel pill packs during these visits as well as at the end of each 
treatment period and by information recorded by the e-diary.  
 
During the DMP periods, the 6-hour delayed intake will be directly observed by study staff and the 
missed pill will be removed from the blister by site staff and placed in a small container (clear bag, small 
box, etc) labeled with subject number, period, date of removal in order for the CRA to monitor the 
accountability.  
 
Subjects will report pill intake (yes/no) daily and the time through e-diary.   
 
Levonorgestrel plasma levels will be determined during the first visit of weeks 5 and 9 at the time of 
cervical mucus collection  without informing the subject of the exact date (see section 14.Study Visit for 
details). Letting the subject know that they will have a blood sample to check the levonorgestrel level, 
at some point in the study may encourage them to stay compliant. 
 
If a subject missed three or more consecutive pills in any treatment period or misses one pill in treatment 
period 2 or 3, the research center staff will discuss the matter with her and determine with the sponsor, 
case by case, whether she can continue moving forward in the study or if she has to be withdrawn from 
the study.  
 
 
13. LABORATORY TESTS AND EVALUATIONS 
 
13.1 
Physical and gynecological examination 
 
Physical and gynecological examinations (breast and pelvic examinations) will be performed at 
screening visit only. 
 
13.2 
Vital signs 
 
Vital signs will be measured at screening and end of study (EOS) visits. They include systolic and 
diastolic blood pressure and heart rate after at minimum 2-minute rest. Height and weight will be 
recorded at screening only. 
 
13.3 
Laboratory parameters 
 
Complete Blood Count (CBC) and a complete metabolic panel will be obtained at screening and then 
at the EOS visit. The testing will include: 
• 
CBC: red blood cell count, white blood cell count, platelet count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils (% & absolute), lymphocytes (% & absolute), monocytes (% & 
absolute), eosinophils (% & absolute), basophils (% & absolute) 
• 
Electrolytes: sodium, potassium, CO2 (carbon dioxide, bicarbonate), chloride, calcium 
• 
Metabolic panel: glucose, proteins, albumin, total protein 
• 
Renal function: blood urea nitrogen, creatinine 
• 
Hepatic function: alkaline phosphatase, alanine amino transferase, aspartate amino 
transferase, total bilirubin  
 


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Samples will be analyzed at the local certified laboratories at each study center.  
 
The investigator or medically qualified designee must review and sign all laboratory reports; a copy of 
the report must be kept with each subject’s chart. All out-of-range laboratory results must be assessed 
by the investigator or medically qualified designee for clinical significance. Any reports required from 
the screening assessment must be reviewed, signed and dated on or before the date/time of enrollment 
in order to properly document the determination of eligibility. 
 
13.4 
Hormone testing 
 
Hormone testing (P4, E2, FSH, LH) will be performed locally at each site.  
 
P4 will be tested at all visits up to EOS visit, with the exception of V2R and V3R during the DMP periods. 
 
E2, FSH and LH will be tested at all regular visits, extra visits and follow-up visits until a postovulatory 
image is observed, with the exception of V2R and V3R during the DMP periods. 
 
The samples will be destroyed after completion of CSR. 
 
Point of care urine high-sensitivity pregnancy testing will be performed at V11 (enrollment visit) before 
dispensation of study drug and at the EOS visit.  
 
13.5 
Levonorgestrel concentrations 
 
Blood sampling for levonorgestrel concentrations will be performed at the following visits: 
• 
V11 
• 
1st visit of week 3 
• 
1st visit of week 5 (V21) 
• 
V2R-1, V2R, V2R+1 
• 
1st visit of week 9 (V31) 
• 
V3R-1, V3R, V3R+1 
 
2K- EDTA tubes will be used for sampling. After separation of plasma, samples will be frozen at -80°C 
until shipment to the bioanalytical centre that will perform centralized analysis of the samples from both 
clinical sites. Levonorgestrel concentrations in plasma will be determined by a LC-MS/MS method. 
 
13.6 
Pap test and STI screening 
 
A Pap test will be performed at screening for subjects with an abnormal cervical lesion detected during 
the gynecological examination. Subjects with high-grade lesions prior to enrollment are to be excluded. 
 
Subjects will be screened for Chlamydia and gonorrhea by vaginal or cervical swab or urine test and 
results will be read on site in accordance with local standards. A wet mount should be obtained if 
vaginitis is suspected. Women who test positive should be treated for any infections and enrollment 
should be delayed until treatment has been completed.  
 
If a non-physiologic vaginal discharge is detected, diagnosis of bacterial vaginosis will be made using 
wet mount and potassium hydroxide (KOH) preparation. Treatment should be instituted and completed 
prior to enrolment in the study for those who were diagnosed at screening. For the subjects who develop 
bacterial vaginosis during the treatment, oral treatment will be instituted and the subjects will remain in 
the study. 
 
13.7 
Transvaginal ultrasound (TVUS) 
 
TVUS will be performed at screening, at all regular and extra visits until a postovulatory image is 
observed, with the exception of V2R and V3R during the DMP periods. 
 


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TVUS examinations will be performed by licensed and trained study personnel. Standard 
measurements will include documentation of the largest follicle’s maximum measurements in 3 
dimensions and average size if it is ≥10 mm, postovulatory image1 and TVUS abnormalities. A cross-
sectional picture of each ovary even if no follicles >10 mm are present will also be taken.  
 
To maintain a high level of consistency for these evaluations, it is recommended that an experienced 
sonographer perform the scans on each subject, and the number be limited to the smallest group 
needed by the site for successful completion of the protocol. 
 
All ultrasounds procedures should be performed using a vaginal transducer of at least 5 mHz. 
The ultrasound equipment must be capable of printing the images or saving them digitally for later 
printing. Printed images will be placed in the source documents. All images should be clearly labeled 
with a subject identifier and date the TVUS was performed. 
 
13.8 
Cervical mucus 
 
Cervical mucus will be sampled and analysed at all regular and extra visits, including all the visits during 
the DMP period. The cervical mucus collection will always be performed before TVUS. 
 
A gynecologic exam is completed to assess the cervical mucus score based on the modified Insler 
score (WHO manual 2010). Consistency (viscosity), ferning, spinnbarkeit and cellularity will be scored 
on a 4-point scale (0-3), see Appendix 2 for details. 
The protective effect of cervical mucus is considered as present when the score is below or equal 4. 
 
The cervical mucus will be collected by aspiration. The cervical mucus assessment will be made by a 
limited amound of trained clinic personnel in order to limit variability. A centralized training will be 
organized to maintain a high level of consistency for these evaluations. It is recommended that an 
experienced physician or specifically trained nurse (whoever is available on site at the time of subject 
visit) perform the exam on each subject, and the number of examiners be limited to the smallest group 
needed by the site for successful completion of the protocol. 
 
13.9 
IMP intake and bleeding reporting (e-diary) 
 
Every day, the subject will have to record the time of intake of study medication and the volume of 
bleedings if any in an e-diary: 
 
 
14. STUDY VISITS 
 
14.1 
Screening visit (V0, during luteal phase) 
 
The purpose of the screening evaluation is to obtain baseline history, physical exam, and laboratory 
evaluations to determine if the subject meets eligibility criteria. Prior to any screening procedure being 
performed, potential participants will receive information about the study, including potential risks, and 
patient information sheet / informed consent form, that they will sign.  
 
Screening will include the following procedures: 
• 
The risks, benefits, and alternative methods of contraception will be reviewed with each subject 
in a manner consistent with her education level. 
• 
Each woman must sign an IRB-approved informed consent form before any of the study-related 
procedures can be performed. The original signed informed consent form will be kept on file by 
 
1 postovulatory image is defined as:  
• 
abrupt disappearance of follicle like structure (FLS) or 
• 
reduction in size of the leading follicle > 4 mm at two consecutive visits or  
• 
haemorrhagic corpus luteum (FLS at least as large as the leading follicle) 


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the investigator with the subject’s records. A copy of the executed form will be given to the 
subject. 
• 
A unique subject identification number will be assigned by the site after the subject signs the 
informed consent form and prior to the initiation of screening assessments. 
• 
Demographic characteristics will be collected including date of birth, ethnicity, and race. 
• 
Previous medical, surgical and gynecological history will be collected, including history of acute 
and chronic medical and gynecological conditions, marijuana, illicit drug and alcohol use history, 
menstrual cycle history, current sexual activity, previous contraceptive use, pregnancy history 
and plans for future pregnancies. This includes recording the date of onset of last menstrual 
bleeding along with the date of last use of a method of contraception. 
• 
Vital signs (pulse, and blood pressure) will be obtained and recorded with the subject in a sitting 
position after at least 2 minutes’ rest. This method will be employed for all blood pressure 
measurements taken during the study.  
• 
Height and weight will be recorded. BMI will be calculated in kg/m².  
• 
General physical and gynecological examinations (breast and pelvic examinations) will be 
performed. 
• 
A TVUS will be performed to ensure the subject has an intact uterus and both ovaries and 
assess endometrial thickness, endometrial appearance, presence of follicles and TVUS 
abnormalities. 
• 
If indicated, a Pap test will be performed. 
• 
Chlamydia and gonorrhea tests. A wet mount should be obtained if vaginitis is suspected. 
• 
Wet mount and KOH preparation of vaginal fluid to confirm diagnosis bacterial vaginosis if there 
is presence of non-physiologic vaginal discharge. 
• 
Blood sampling for clinical chemistry and CBC tests for safety as well as P4 to check ovulatory 
status.  
• 
Women will be questioned regarding concomitant medications. Concomitant medications taken 
within the 2 weeks before screening and from time of consent will be reported, in addition to 
indications for the medications and reasons for discontinuing. 
• 
Subject eligibility will be assessed based on all inclusion/exclusion criteria. 
• 
Adverse events happening after signature of ICF will be recorded 
The results of the routine laboratory tests, Pap and STI test results (if indicated), and remaining eligibility 
criteria must be reviewed by the PI/medical designee before enrolling the subject. The 
investigator/medical designee must review laboratory reports, which should be filed with each subject’s 
chart. The PI/medical designee will consider an individual subject’s risks regarding use of a POP. The 
woman will be informed by telephone/email of her screening results and, if eligible, she will be instructed 
to notify the study site when her next menstrual bleeding occurs in order to schedule the next visit.  
If any laboratory results are abnormal, according to local lab standards and clinically significant per the 
investigator’s judgment, the subject will be informed and excluded from the study as well as referred to 
her primary health care provider. At the discretion of the investigator, abnormal laboratory assessments 
may be repeated before a final determination of exclusion is made. Subjects who have vaginitis, or 
those that screen positive for Chlamydia or gonorrhea, should be treated and can then be enrolled into 
the trial once proof of cure is obtained. It is advisable to have partners of women who screen positive 
for Chlamydia or gonorrhea treated as well.  
If a subject is on a moderate or strong CYP3A4 inhibitor at time of screening, and is not taking the 
CYP3A4 inhibitor on a chronic basis, the subject may be re-evaluated for enrollment 6 days after they 
complete their course of treatment. Stoppage of the inhibitor must be related to treatment completion 
and unrelated to the purpose of enrollment in this study. 
 
Laboratory assessments performed >60 days prior to enrollment should be repeated. Subjects who 
have delayed enrollment beyond 60 days since screening should be queried regarding any changes in 
their medical history and the investigator will determine if there is a need to repeat the physical exam, 
including the gynecologic exam (breast and pelvic examinations). Vital signs (BP and pulse) and 
weight/BMI should be verified in accordance with exclusion criteria.  
 


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If a subject has a P4 level below 10 nmol/L during the screening visit, she will have to come back for 
P4 level later in the menstrual cycle. If the second level is also below 10 nmol/L, she will not be able to 
enroll. 
 
Site staff should also reconfirm smoking history, drug and alcohol use, partner status, and ascertain if 
a subject is sexually active. CYP3A4 inducers are exclusionary. 
 
If a subject meets all eligibility criteria, she will be invited to move forward with study treatment at V11 
(enrollment). She will also be asked to fast overnight (8 hours) before V11 but water will be allowed. 
 
14.2 
Treatment period 1 (V11 to V1x – Day 1 to Day 28) 
 
After confirmation of ovulation via an elevated P4 of 3 ng/mL (10 nmol/L) or greater in the screening 
cycle and fulfillment of all inclusion and exclusion criteria, eligible subjects will attend the Enrollment 
Visit (Visit V11 = Day 1). Treatment will be initiated during V11 which should occur within 5 days after 
the onset of the next menses after the Screening Visit. The subjects are allowed to delay the enrollment 
for one cycle if necessary. 
 
All women will take norgestrel 75 mcg daily at the same time during treatment period 1 (28 days) as 
described in section 12.3.  
 
Women will undergo twice weekly visits with blood sampling, TVUS, and cervical mucus sampling as 
long as follicle < 15 mm on the TVUS. If an ovarian follicle ≥ 15 mm in one dimension is visualized on 
TVUS, visits will be performed every other day for a maximum of 6 visits (12 days), details are provided 
below. 
 
14.2.1 V11 Enrollment visit (V11 - Day 1, morning) 
 
The visit V11 will consist of: 
• 
Review of history and medications 
• 
Review of inclusion & exclusion criteria 
• 
High-sensitivity urine pregnancy test before 1st pill intake 
• 
Blood sampling for hormone levels (P4, E2, FSH and LH) 
• 
Blood sampling for pharmacokinetic analysis (4 samples/subject) 
o Half of subjects (subjects with even study number) will be sampled at predose, 2h ± 15 
min, 6h ± 15 min, 12h ± 30 min after treatment 
o Half of subjects (subjects with odd study number) will be sampled at 1h ± 15 min, 4h ± 
15 min, 8h ± 30 min, 24h ± 30 min after treatment. 
• 
Subjects will be asked to stay fasted until 4 hours after administration (water will be allowed) 
• 
Cervical mucus collection and analysis before treatment intake 
o Note: at all visits where both cervical mucus analysis and TVUS are performed, the 
cervical mucus collection will be performed before TVUS. 
• 
TVUS 
• 
Dispensation of two study medication boxes (one to be used as a back-up) and intake of the 
first norgestrel pill at the site at 9:00 am ± 3 hours 
• 
Determine with subject the intake time on day 2 and advise subject of intake time of norgestrel 
on a daily basis and importance of compliance 
• 
Provide instructions to the subject in case she vomits or has diarrhea within 4 hours of taking a 
pill, misses a pill or loses a pill (as per section 12.3 dosage schedule) 
• 
A mobile phone for the ediary will be lent if the subject doesn’t have one  
• 
E-diary instructions: remind the subjects to complete the diary on a daily basis with bleeding 
data and information relative to the intake of norgestrel (dates and times) 


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• 
Concomitant medications 
• 
Occurrence of AEs 
 
Subjects will be allowed to leave the site between the PK samples after the 2h/4h sampling. 
 
14.2.2 Regular twice-weekly visits (V12 to V1x – Day 1 to 28) 
 
If an ovarian follicle ≥15 mm in one dimension is visualized on ultrasound, visits frequency will be 
increased to a visit every other day (see 14.2.3). The investigator will also be allowed to add another 
extra visit, if it is needed to follow the follicle before or between the extra visits. 
 
Visits will always take place every 3 or 4 days, preferably during weekdays. 
 
They will consist of: 
• 
review of concomitant medications, occurrence of AEs 
• 
review of diary data  
• 
blood sampling to obtain hormone levels 
o P4 and E2 
o FSH and LH 
• 
blood sampling for measurement of levonorgestrel plasma concentration 
o during the first visit in week 3, for steady-state pharmacokinetic analysis (1-2 
samples/subject), at the following time points: 
 
Half the subjects (subjects with odd study number) at predose and between 30 
min and 2 h (morning visit before the administration) 
 
Half the subjects (subjects with even study number) between 5 h and 9 h post-
treatment (afternoon visit) 
• 
cervical mucus collection and analysis  
• 
TVUS 
• 
At the last visit in treatment period 1, a new study medication box will be dispensed for the 
subject to be used in treatment period 2 
 
If necessary, the investigator or study site staff member will contact the subject more frequently. E-mail, 
phone or text message communication may be used based on subject preference and study site 
assessment regarding this mode of communication with individual subjects.  
 
14.2.3 Extra visits (V12 to V1x – Day 1 to 28)  
 
If an ovarian follicle ≥ 15 mm in one dimension is visualized on TVUS, visits will be increased to one 
visit every other day for a maximum of 3 visits (6 days) before obtention of a postovulatory image1. 
 
The visits will consist of: 
• 
review of concomitant medications, occurrence of AEs 
• 
review of diary data  
• 
blood sampling to obtain hormone levels 
o P4 and E2  
o FSH and LH  
• 
cervical mucus collection and analysis 
• 
TVUS 
 
1 a postovulatory image is defined as:  
• 
abrupt disappearance of FLS or 
• 
reduction in size of the leading follicle > 4 mm at two consecutive visits or 
• 
haemorrhagic corpus luteum (FLS at least as large as the leading follicle before ovulation) 


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The extra visits will be stopped and the subject will go back to twice a week visits: 
• 
when a post-ovulatory image is obtained 
• 
if a postovulatory image is not obtained at the third extra visit 
 
14.3 
Treatment period 2 (V21 to V2x – Day 29 to 56) 
 
14.3.1 Regular twice-weekly visits and extra visits (V21 to V2x – Day 29 to 40 ±3 
days AND Day 44 ± 3 days to Day 56) 
 
Regular and extra visits will be performed according to the same schedule as described for treatment 
period 1 in section 14.2 and visits will consist of the same assessments as visits described in section 
14.2.2 and 14.2.3. 
 
The exceptions to the treatment period 1 will be: 
• 
1st visit (study week 5):  
o Collection of box/blister of treatment period 1 
o Randomisation of the subjects to either Arm A or Arm B 
o Blood sampling for measurement of LNG plasma concentration within 30 min of mucus 
sampling2 
• 
Delayed/missed pill (DMP) period (V2R-1 to V2R+1 - Day 41 ± 3 days to Day 43 ± 3 days) 
o DMP visits will take precedence over regular and extra visits (see details in section 
14.3.2 below) 
o After the DMP period, subjects will go back to regular twice a week visits or extra visits 
every other day (if a follicule ≥ 15 mm was observed before or during the DMP period) 
 
14.3.2 DMP period (V2R-1 to V2R+1 – Day 41 ± 3 days to Day 43 ± 3 days) 
 
On 3 consecutive days (Day 41 ± 3 days to Day 43 ± 3 days), the subjects will undergo 3 visits (V2R-1 
to V2R+1) to evaluate the effects of a delayed intake or a missed pill. 
 
On visit V2R-1 (Day 41 ± 3 days), the subjects will have to come to the site twice in the same day, first 
for the study medication intake and second for the cervical mucus collection and analysis, and PK blood 
sampling. 
 
The assessments will be the same for all subjects: 
• 
Blood sampling for hormone levels (P4, E2, FSH, LH) 
• 
Study medication intake on site at 9:00 am ±1 hour (actual time = treatment time V2R-1 (T2R-1)) 
• 
Blood sampling for PK at T2R-1 + 8 hours ± 30 min post-dose 
• 
Cervical mucus collection and analysis at T2R-1 + 8 hours ± 30 min post-dose 
• 
TVUS 
• 
Review of diary data 
• 
Review of concomitant treatments and occurrence of AEs 
 
On visit V2R (Day 42 ±3 days ), the subjects will either delay their pill intake by 6 hours (Arm A) or not 
take it (Arm B). They will not be requested to stay on site between the assessments.  
 
The assessments for subjects randomized to group A will consist of: 
• 
Cervical mucus collection and analysis at T2R-1 + 3 hours ± 15 min 
• 
Blood sampling for PK at T2R-1 + 3 hours ± 15 min, T2R-1 + 5.5 hours ± 15 min  
• 
Study medication intake on site at T2R-1 + 6 hours ±15 min on site 
 
2 The blood sampling will be done for all subjects at the 1st visit of week 5, but the subjects will only be told that 
a blood sampling will be performed at random visits. It should encourage them to stay compliant. 


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• 
Blood sampling for PK at T2R-1 + 7.5h ± 30 min 
• 
Review of diary data 
• 
Review of concomitant treatments and occurrence of AEs 
 
The assessments for subjects randomized to group B will consist of: 
• 
No study medication intake 
• 
Blood sampling for PK at T2R-1 + 6 hours ± 15 min 
• 
Cervical mucus collection and analysis to be performed at T2R-1 + 6 hours ± 15 min 
• 
Review of diary data 
• 
Review of concomitant treatments and occurrence of AEs 
 
The V2R+1 (Study Day 43 ± 3 days) visit will consist of the same assessments for all subjects: 
• 
Blood sampling for PK within 30 min before study medication intake 
• 
Cervical mucus collection and analysis to be performed within 30 min before study medication 
intake 
• 
TVUS 
• 
Study medication intake at T2R-1 ± 30 min 
• 
Blood sampling for hormone levels (P4, E2, FSH, LH)  
• 
Review of diary data 
• 
Review of concomitant treatments and occurrence of AEs 
 
14.4 
Treatment period 3 (V31 to V3x – Day 57 to 84)  
 
14.4.1 Regular twice-weekly visits and extra visits (V31 to V3x – Day 57 to 68 ±3 
days AND Day 72 ± 3 days to Day 84) 
 
Regular and extra visits will be performed according to the same schedule as described for treatment 
period 1 in section 14.2 and visits will consist of the same assessments as visits described in section 
14.2.2 and 14.2.3. 
 
The exceptions to the treatment period 1 will be: 
• 
1st visit (study week 9):  
o Collection of box/blister of treatment period 2 
o Blood sampling for measurement of LNG plasma concentration within 30 min of mucus 
sampling1 
• 
DMP period (V3R-1 to V3R+1 - Day 69 ± 3 days to Day 71 ± 3 days) 
o DMP visits will take precedence over regular and extra visits (see details in section 
14.3.2 below) 
o After the DMP, subjects will go back to regular twice a week visits or extra visits every 
other day (if a follicule ≥ 15 mm was observed before or during the DMP period) 
• 
Extra visits will continue/be initiated after Day 84 if needed (see 14.4.3) 
 
14.4.2 DMP period (V3R-1 to V3R+1 – Day 69 ± 3 days to Day 71 ± 3 days) 
 
The schedule of assessments will be the same as during treatment period 2, except that during visit 
V3R, subjects in Arm A will not take their pill and subjects in Arm B will delay their pill intake by 6 hours. 
 
14.4.3 Follow-up visits (V12 to V1x – Day 84 to Day 96)  
 
If an ovarian follicle ≥ 15 mm in one dimension is visualized on TVUS between Day 72 and Day 84, 
extra visits may be continued/initiated after the end of treatment (Day 84). In that case, visits will be 
 
1 The blood sampling will be done for all subjects at the 1st visit of week 9, but the subjects will only be told that 
a blood sampling will be performed at random visits. It should encorage them to stay compliant.  


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scheduled every other day for a maximum of 6 visits (12 days), 3 before obtention of a postovulatory 
image1 and 3 after. 
 
Before a postovulatory image is obtained, the visits will consist of: 
• 
review of concomitant medications, occurrence of AEs 
• 
review of diary data  
• 
blood sampling to obtain hormone levels 
o P4 and E2  
o FSH and LH  
• 
cervical mucus collection and analysis 
• 
TVUS 
 
The extra visits will be stopped if: 
• 
a postovulatory image is not obtained at the third extra visit 
 
After a postovulatory image is observed, the visits will consist of: 
• 
review of concomitant medications, occurrence of AEs 
• 
review of diary data  
• 
blood sampling to obtain hormone levels 
o P4  
• 
cervical mucus collection and analysis 
 
The extra visits will be stopped if: 
• 
P4 levels rise above 30 nmol/L at one visit or 10 nmol/L for two consecutive visits, or 
• 
after 3 additional extra visits  
 
14.5 
End of study visit (EOS) (V4y – between Day 85 and Day 100) 
 
Subjects will be scheduled for their EOS either: 
• 
within 5 days of taking their last dose (at the latest on day 84 of treatment) if no follow-up visits 
are required. 
• 
within 5 days of their last follow-up visit if extra visits were initiated/continued after Day 84  
 
The visit will consist of: 
• 
Vital signs 
• 
Blood sampling for clinical chemistry and CBC tests, for safety 
• 
High-sensitivity pregnancy urine test 
• 
Review of diary data and collection of mobile phone lent at screening visit, if applicable 
• 
Review of concomitant treatments and occurrence of AEs 
• 
Subjects will bring back medication boxe(s) including used/unused blister pack(s) 
.
 
1 a postovulatory image is defined as:  
• 
abrupt disappearance of FLS or 
• 
reduction in size of the leading follicle > 4 mm at two consecutive visits or 
• 
haemorrhagic corpus luteum (FLS at least as large as the leading follicle before ovulation) 


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14.6 
Study flow summary 
 
Table 2 Main study flow (not including DMP period, see Table 3) 
Study periods 
Screening 
visit 
Treatment phase 
Follow up of treatment period 3 (2) 
 
End of 
study visit  
Treatment period 1(1) 
Treatment period 2 
Treatment period 3 
Visits 
V0 
V11 to V1x 
V21 to V2x 
V31 to V3x 
V41 to V4x 
V4y 
Days 
- 
1 to 28 
29 to 56 
57 to 84 
85 to 96 
85 to 100 
Norgestrel intake 
- 
Daily pill intake at the same time between 6:00 am and 12:00 pm  
- 
- 
Visit 
frequency
 
if follicle < 
15 mm 
Within a 
maximum of 
60 days 
before start 
of treatment 
phase 
 
Regular visits - Twice a week  
Not applicable 
X 
if follicle > 
15 mm 
identified 
upon 
TVUS 
Extra visits - Every other day 
For a maximum of 3 visits (6 days) before postovulatory image 
Extra visits - Every other day 
For a maximum of 6 visits (12 days): 
• 
maximum of 3 visits before 
postovulatory image 
• 
maximum of 3 visits after 
postovulatory image 
 
TVUS 
X 
At each visit 
At each visit before postovulatory 
image 
- 
Mucus analysis 
- 
At each visit 
At each visit 
- 
Hormone levels 
P4 
P4, FHS, LH, E2 at each visit 
P4, at each visit 
FHS, LH, E2 at each visit before 
postovulatory image 
- 
PK blood sampling 
- 
Day 1 (3) 
1st visit week 3 (4)  
1st visit week 5 
1st visit week 9 
 
- 
1 Study pill is to be started within 5 days after last menstrual period.  
2 Extra visits will be initiated /continue after Day 84 if needed3  
3 Half of subjects at predose, 2h, 6h, 12h and half of subjects at 1h, 4h, 8h, 24h  
4 Half of subjects at predose and between 0.5h and 2h and half of subjects between 5h and 9h 
 
 
 


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Table 3 Study flow of DMP period 
Study periods 
Treatment Period 2 
DMP 
 
Visits V2R-1 V2R and V2R+1 should occur on 3 consecutive days. 
Treatment Period 3 
DMP 
 
Visits V3R-1 V3R and V3R+1 should occur on 3 consecutive days. 
Visits 
V2R-1 
V2R 
V2R+1 
V3R-1 
V3R 
V3R+1 
Days 
41 ± 3 
42 ± 3 
43 ± 3 
69 ± 3 
70 ± 3 
71 ± 3 
Norgestrel 
intake as per 
study arm 
Arm A 
Pill intake at 9 am ± 1 
h (T2R-1) 
Pill intake at T2R = 
T2R-1 + 6 h ± 15min 
Pill intake at T2R+1 = 
T2R-1 ± 30 min 
Pill intake at 9 am ± 
1 h (T3R-1) 
No pill intake 
Pill intake at T3R+1 = 
T3R-1 ± 30 min 
Arm B 
No pill intake 
Pill intake at T3R = 
T3R-1 + 6 h ± 15min 
TVUS 
Arm A 
Yes 
No 
Yes 
Yes 
No 
Yes 
Arm B 
Mucus 
analysis 
Arm A 
T2R-1 +8 h ± 30 min 
T2R-1 + 3 h ± 15 min 
Within 30 min before 
T2R+1 
T3R +8 h ± 30 min 
T3R + 6 h ± 15 min 
Within 30 min 
before T3R+1 
Arm B 
T2R-1 + 6 h ± 15 min 
T3R-1 + 3 h ± 15 min 
Hormone 
Levels 
Arm A 
Yes 
No 
Yes 
Yes 
No 
Yes 
Arm B 
PK blood 
sampling 
Arm A 
T2R-1 +8 h ± 30 min 
T2R-1 + 3 h ± 15 min 
T2R-1 + 5.5h ± 15 min 
T2R-1 + 7.5h ± 30 min 
Within 30 min before 
T2R+1 
T3R-1 +8 h ± 30 min 
T3R-1 + 6 h ± 15 min 
Within 30 min 
before T3R+1 
Arm B 
T2R-1 + 6 h ± 15 min 
T3R-1 + 3 h ± 15 min 
T3R-1 + 5.5h ± 15 min 
T3R-1 + 7.5h ± 30 min 
 


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15. ADVERSE EVENTS 
 
15.1 
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY REPORTING   
 
15.1.1 Definitions of Adverse Events (AE), Serious Adverse Events (SAE), severity 
and causality assessment 
 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject administered 
a medicinal product and which does not necessarily have a causal relationship with this treatment. 
 
An adverse reaction is defined as “all untoward and unintended responses to an investigational 
medicinal product related to any dose administered”. The definition also covers medication errors and 
uses outside what is foreseen in the protocol, including misuse and abuse of the product. The definition 
implies a reasonable possibility of a causal relationship between the event and the IMP. This means 
that there are facts (evidence) or arguments to suggest a causal relationship. 
 
The reference document used to assess the expectedness is US Product Information of the study 
treatment. A copy of the document will be provided to the investigators before study start. 
 
An event is considered a Serious Adverse Event (SAE), if in the view of either the investigator or 
sponsor, it meets the criteria as outlined in 21 CFR 312.32 (a) as per the following:  
Any adverse drug experience occurring at any dose that results in any of the following outcomes:  
• 
death,  
• 
a life threatening adverse drug experience,  
NOTE: The “life-threatening” criterion in the definition of “seriousness” refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it was more severe. 
• 
inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization 
is for:  
1. routine medical treatment or monitoring or surgery in relation with the indication 
studied in the protocol and not associated with any deterioration  
2. planned treatment for a pre-existing condition that is unrelated to the indication 
of the current study and has not worsened since the start of study medication (in 
that case, this pre-existing condition should be mentioned in the e-CRF as 
patient’s history or concomitant disease) 
3. Emergency consultation without any medical admission 
• 
a persistent or significant disability/incapacity, 
• 
or a congenital anomaly/birth defect, 
• 
is medically important 
Medical and scientific judgement should be exercised in deciding whether the case should be 
considered serious in other situations, such as important medical events that may not result in death, 
be immediately life-threatening or require hospitalization but, may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization or development of drug dependency or drug abuse.”  
 
Severity 
The Investigator is responsible for assessing the severity of each AE using the following definitions for 
severity criteria: 
• 
Mild – events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate – events result in a low level of inconvenience or concern with the therapeutic 
measures.  Moderate events may cause some interference with functioning. 


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• 
Severe – events interrupt a subject’s usual daily activity and may require systemic drug therapy 
or other treatment.  Severe events are usually incapacitating. 
 
Relationship to Investigational Product 
The Investigator is responsible for assessing the relationship between the AE and the investigational 
product. The Investigator must determine whether there is a reasonable possibility that the 
investigational product caused or contributed to an AE. The relationship assessment, based on clinical 
judgment, often relies on the following: 
• 
A temporal relationship between the event and administration of investigational product; 
• 
A plausible biological mechanism for the investigational product to cause the AE; 
• 
Another possible etiology of the AE; or 
• 
Previous report of similar AEs associated with the investigational product or other agents 
in the same class. 
 
The terms used to assess the relationship of an event to the investigational product are: 
Causality Assessment 
Criteria for Assessment (note that re-challenge does not 
apply in this study) 
Certainly Related 
The experience occurs immediately following investigational 
product administration, related pharmacologically (not related to 
underlying condition/concurrent disease or other drugs or 
chemicals) 
Possibly Related 
The experience follows a reasonable temporal sequence from 
the time of drug administration and/or follows a known response 
pattern to the investigational product but could have been 
produced by other factors such as the participant’s clinical state, 
therapeutic intervention or concomitant therapy. 
Unlikely Related 
Improbable temporal relationship. The experience was most 
probably produced by other factors such as the participant’s 
clinical state, therapeutic intervention or concomitant therapy and 
does not follow a known response pattern to the investigational 
product. 
Not Related 
There is not a reasonable possibility that the AE is related to the 
investigational product; when an AE is assessed as not related to 
the investigational product, an alternative etiology, diagnosis or 
explanation for the AE should be provided. If new information 
becomes available, the relationship of any AE should be 
reviewed again and updated as required. 
 
15.1.2 Adverse Events: Recording and Reporting 
All AEs will be managed and reported in compliance with all applicable regulations and reported in the 
eCRF and in the clinical study report (CSR). 
At every visit, study staff will ask each subject how she has felt since her last visit as well as directly 
and indirectly ask if she has experienced any AEs. A review of the subject’s diary should be completed 
during the visit with the subject to identify any possible AEs reported through the diary.  
The reporting period for AEs, regardless of seriousness or relationship to the study drug, is the period 
immediately following the subject signing the informed consent through the EOS. However if an AE/SAE 
is reported after the last visit and considered as related to the IMP, the sponsor has to be informed. 


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All AEs must be recorded in the subject’s e-CRFs and must include the following information (when 
applicable):  
• 
Specific condition or event.  
o Whenever possible, diagnosis or syndrome should be reported instead of symptoms.  
o Laboratory, vital signs or ECG parameters should be recorded as AE only if they are 
medically relevant (e.g.: symptomatic, leading to study drug discontinuation, requiring 
medical treatment). 
o Indication of whether the condition was preexisting prior to study entry or not and if yes, 
whether it has worsened in severity or frequency in which case it is reported as an AE. 
Conditions present prior to study entry (screening) that do not worsen in severity are 
considered medical history, not considered AEs. (Refer to Section 11.2 Prior and 
Concomitant Illnesses and Treatments).  
• 
Date of occurrence.  
• 
Date of resolution. If the event has not resolved by the end of the study-reporting period, it will be 
documented as still present on the case report form.  
• 
Severity (AEs that change in intensity are recorded at the intensity level that is the most severe 
reported by the subject over consecutive days. If the intensity category changes over a non-
consecutive period of time, then these changes should be recorded separately with distinct onset 
dates). 
• 
Relationship to study medication as evaluated by the investigator (causality assessment). 
• 
AE outcome (recovered, ongoing, etc.) 
• 
Seriousness 
 
The investigator should also specify actions taken with respect to the study drug(s), corrective treatment 
given, additional investigations performed, outcome and his/her opinion as to whether there is a 
reasonable possibility that the AE was caused by the study drug(s). 
 
15.1.3 Instructions to study participants 
 
Participants will be provided with instructions for contacting the study site to report any untoward 
medical occurrences they may experience, except for possible life-threatening events, for which they 
will be instructed to seek immediate emergency care. Participants will be able to seek evaluation at the 
study site, where feasible and medically appropriate. With permission of the participant, and whenever 
possible, records from all non-study medical providers related to untoward medical occurrences will be 
obtained for review. Participants who have ongoing SAEs or related AEs at their last study visit will be 
followed until resolution or stabilization, or referred for additional care. If a SAE occurs after the last 
visit, the participant will be asked to report it to investigator, so it can be reported to the sponsor (see 
section 15.1.2). 
 
15.1.4 Study reporting for SAEs 
The reporting period for SAEs is the period immediately following the informed consent signature until 
the EOS. In case a SAE is brought to the attention of the investigator at any time after the end of the 
clinical trial and is considered by him to be caused by the study drug with a reasonable possibility, the 
SAE will be reported to the Sponsor’s Pharmacovigilance Department. 
SAEs must be followed until resolution, even if this extends beyond the study-reporting period. 
Resolution of a SAE is defined as the return to baseline status or stabilization of the condition with the 
expectation that it will remain chronic.  
In case of SAE, the investigator must immediately: 
• 
Enter within 24 hours the information related to the SAE in the appropriate screen of the e-CRF. 
• 
Attach the photocopies of all examinations carried out with the dates on which they were 
performed as well as the laboratory normal ranges 


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• 
All further documentation should be sent by Fax or email to the Sponsor’s Pharmacovigilance 
Department within 1 working day of knowledge or upon request from the Sponsor 
Pharmacovigilance Department. 
Fax:  
E-mail:  
 
Any additional SAE supporting documentation should be transmitted to Sponsor’s Pharmacovigilance 
Department whenever possible (with subject identification information redacted) to verify the medical 
diagnosis. This includes hospital discharge summaries, lab report, death certificates/autopsy reports 
(where applicable), surgical procedure summaries, histology reports, and imaging reports.  
 
As the IND holder, HRA is responsible for the appropriate recording, review and compliance with 
regulatory reporting requirements of SAEs to the FDA in accordance with 21 CFR 312.50.  
 
15.1.5 Follow up 
 
The investigator should take all appropriate measures to ensure the safety of the patient and should 
follow the outcome of the AE/SAE until return to normal or consolidation of the patient’s condition. 
Any new information should be sent by Fax or email to the Sponsor’s Pharmacovigilance Department 
within 1 working day of knowledge: 
Fax: + 
E-mail:  
 
15.1.6 Event of special interest 
 
Pregnancy: 
In case of pregnancy, the study drug will be discontinued and the investigator must immediately: 
Fill in the Pregnancy Collection Form (see Appendix 6) and send it by fax or email within 1 working 
day to HRA Pharma’s Pharmacovigilance Department: 
Fax:  
E-mail:  
All cases of pregnancy will be recorded in the e-CRF. 
The investigator should take all appropriate measures to follow the pregnancy until its final outcome 
(abortion, delivery or other).The Pharmacovigilance Department will contact the investigator in order to 
collect needed information on the pregnancy.  
 
15.1.7 Notification of IRB of SAEs 
 
All expedited SAEs that occur at each site must be directly reported to the IRB by the Investigator within 
10 business days of the investigator’s knowledge of the event. However, the death of a subject must 
be reported within 24 hours of discovery. The investigator should report non-expedited SAEs/AEs for 
their own site per their IRBs reporting guidelines.  
 
The final adjudication of an SAE will be conducted by HRA and the final form will be sent to the principal 
investigator for submission to the IRB for applicable events. Investigators must also submit applicable 
safety information provided by HRA to their IRB.  
 
15.2 
OBLIGATIONS OF THE SPONSOR REGARDING SAFETY REPORTING   
 
During the course of the study, the sponsor will report in an expedited manner all Suspected 
Unexpected Serious Adverse Reactions (SUSARs) to the Health authorities as appropriate. The 
sponsor should also inform investigators of SUSARs. 
 


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No specific DSMB will be set up for this trial. However, in case of pertaining safety issues emerging 
during the study, the independent, autonomous Data and Safety Monitoring Board (DSMB) established 
by the WHRU, Portland, Oregon may be used. 
 
15.3 
PREGNANCY DETERMINATION AND FOLLOW-UP 
 
Subjects are not supposed to be at risk for pregnancy (see inclusion criteria) but If a subject becomes 
pregnant during the study, the investigator must inform HRA of the pregnancy within 24 hours of such 
determination, the subject must be discontinued from the trial, and all procedures scheduled for the 
EOS Visit should be performed. Additional pregnancy data will be submitted as it becomes available. 
The estimated date of ovulation will be made by the investigator based upon results of the following 
pregnancy determination criteria, listed in order from most accurate to least accurate:  
1. TVUS. 
2. Estimate based on pelvic and/or abdominal examination or pregnancy outcome. 
3. Daily diary information (e.g., last menstrual period). 
4. Quantitative β-hCG determination. 
5. Investigator estimation in the absence of above criteria. 
 
Subjects who become pregnant during the study will be informed of pregnancy options and referred for 
appropriate care.  
All pregnancies will be monitored until outcome (i.e. 9 months follow-up or until outcome information is 
obtained). Information will also be collected on any maternal or fetal complications. Congenital 
anomalies or birth defects will be classified as SAEs. Pregnancy outcome data will be collected for 
analysis. Reports of pregnancy outcome and examinations during the pregnancy will be requested from 
the attending physician/outside clinic, if applicable. Pregnancy outcome data will include the rates of 
spontaneous abortion, stillbirth, live preterm, and full-term births. 
If a subject has a spontaneous abortion or ectopic pregnancy this will be considered as a SAE. In 
addition, congenital malformations and anomalies will be recorded as SAEs and summarized.  
If a subject continues with her pregnancy through childbirth, every effort will be made to maintain contact 
with her so that health of the baby can be evaluated at six and twelve months. Any outstanding data at 
the end of the study that is collected will be submitted to the FDA as a Safety Update to the NDA 
submission. A clinical summary of the prenatal and postnatal events will be reported separately from 
the case report form in narrative format in the clinical summary report.  
 
 
16. STUDY CONDUCT 
 
16.1 
Deviation from the Protocol 
 
The Investigator should not deviate from the protocol without prior notification and approval of HRA with 
the exception of minor visit window deviations. In the event that the investigator or the subject deviates 
from the protocol without a protocol waiver, notification should be provided to HRA as soon as possible 
detailing the circumstances of the protocol violation. Certain protocol violations may require the subject 
to be terminated early from the study. It is the responsibility of the research centers to report all protocol 
waivers and protocol violations to their IRB according to IRB policy.  
 
16.2 
Amendments to the Protocol 
 
Neither the investigator nor the sponsor will alter this study protocol without obtaining the written 
agreement of the other.  
 
Any change of the clinical trial must be written and filed as an amendment to this protocol. The 
Investigator(s) must submit the protocol amendment for review by their IRB and shall obtain the 
approval of their IRB before it is implemented. 
 


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In cases of emergency, when the protocol change or deviation is to eliminate or reduce an immediate 
hazard or risk to human subjects, the amendment may be implemented before review or approval by 
their IRB. In such cases, the investigator shall notify their IRB of the change or deviation in writing within 
10 working days after implementation. Any protocol-related issues that pose an immediate or significant 
hazard to subjects must be reported to HRA immediately. If the protocol amendment is an administrative 
change, it will be sent to their IRB for information (updating of file). 
All modifications of the clinical trial will be written and filed with FDA as an amendment to this protocol, 
maintaining original section identification. Such modifications will be made jointly by HRA, and all the 
Investigators with the approval of all the IRBs. 
 
16.3 
Subject Confidentiality 
Subject names will not be supplied to the sponsor. Only the subject number and subject initials will be 
recorded in the e-CRF, and if the subject name appears on any other document, it must be obliterated 
before a copy of the document is supplied to the sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The subjects will be told that representatives of 
the sponsor, IRB, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in the strictest 
confidence and in accordance with local data protection laws. 
Subject confidentiality will be maintained by the use of coded subject ID numbers. Clinical information 
will not be released without the written permission of the participant, except as necessary for monitoring 
by the FDA, HRA.  
The investigator will maintain a personal subject identification list (subject ID numbers with the 
corresponding subject names) to enable records to be identified.  
 
16.4 
Discontinuing Subjects 
 
A subject will be considered to have completed the clinical trial after she has completed the three 28-
day treatment periods and completes the EOS Visit and after the final set of data has been collected 
and entered in the e-CRF.  
 
Subjects may be discontinued prematurely for any of the following reasons: 
• 
Emergence of AE or SAE that, in the judgment of the investigator, should result in premature 
discontinuation. 
• 
Inter-current illness that, in the judgment of the investigator, should result in premature 
discontinuation. 
• 
Major protocol violation as per investigator’s judgment and after sponsor’s approval. 
• 
Use of prohibited medications, including any outlined in the Inclusion/Exclusion criteria  
• 
Suspected drug interaction. 
• 
Pathologically changed laboratory values. 
• 
Knowledge of new risks necessitating new benefit/risk evaluation. 
• 
Non-compliance (see section 12.8) 
• 
Missing multiple visits  
• 
Emergence of any of the exclusions listed above. 
 
Subjects must be discontinued for any of the following reasons: 
• 
Withdrawing their consent (e.g., due to personal reasons, experiencing AE).  
• 
Subject lost to follow up 
• 
Trial closed-out. 
• 
Confirmed Pregnancy. 
• 
Gonorrhea or Chlamydia or a pelvic-inflammatory disease diagnosis during the course of the study, 
except for the diagnosis being made on the initial screening test, at which time the Investigator 
chooses to suspend the subject’s enrollment until proof of cure is obtained. 
• 
Suspected unexpected serious adverse reaction to study medication  
• 
Serious intercurrent problems requiring admission to the critical care unit or surgery   


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Subjects have the right to withdraw from the study at any stage and for any reason. 
 
The reason for premature discontinuation will be recorded on the End of Trial form. If withdrawal from the 
study is due to an AE, this information will also be recorded on the Adverse Event form. 
All subjects who terminate early from the trial will undergo EOS visit procedures regardless of the 
reason for discontinuation with the exception of those subjects who have lost contact with the research 
center. A subject cannot be considered lost to follow-up until the subject misses a visit and the research 
center performs and documents at least three (3) attempts to contact her. Documentation must include 
a letter sent return receipt requested to the subject instructing her to call the research center. Every 
effort must be made to follow-up with subjects who terminate with product-related adverse experiences, 
in order to determine the final outcome of AEs.  
 
16.5 
Withdrawals from Study 
 
All efforts should be made to contact the woman when she decides to discontinue so that appropriate 
discontinuation data can be obtained. Such contact will not be used to dissuade any subject who wishes 
to terminate the study.  
 
As far as possible, all examinations scheduled for the EOS visit must be performed on all subjects who 
receive study medication but do not complete the study according to protocol. 
 
The procedures outlined for the EOS visit should be performed, whenever it occurs. Additionally, all 
study medication will be collected. The reasons for discontinuation will be recorded in the End of Trial 
CRF.  
 
At a minimum, all subjects who discontinue study medication, including those who refuse to return for 
a final visit, will be contacted for safety evaluations during the 30 days following the last dose of study 
medication. Subjects who discontinue study medication should be considered withdrawn from the study 
after the final visit assessments are performed or when it is clear that the subject will not return for these 
assessments 
 
 
17. STUDY MONITORING AND DOCUMENTATION 
 
17.1 
Clinical Monitoring, Quality Control, and Quality Assurance 
 
Monitoring and auditing procedures developed by the sponsor will be followed, in order to comply with 
GCP guidelines. On-site checking of the CRFs for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 
 
The Principal Investigator and sub-investigators will allow representatives from HRA and subcontractors 
direct access to all CRFs, source documents, and corresponding portions of the medical records for 
each participant at mutually convenient times for periodic review before, during, and after the study has 
been completed.  The monitoring visits provide HRA Pharma and subcontractors with the opportunity 
to: 
• 
Initiate the research center. 
• 
Evaluate the progress of the study. 
• 
Verify the accuracy and completeness of the e-CRFs. 
• 
Ensure that all protocol requirements, applicable FDA regulations, and investigators’ obligations 
are being fulfilled. 
• 
Resolve any inconsistencies in the study records. 
• 
Close out the trial at the research center.  
 


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In addition to routine monitoring, HRA or its designee may, at its discretion, perform site audits. The 
purpose of such audits will be to evaluate site trial conduct and compliance with the protocol, SOPs, 
GCP, and the applicable regulatory requirements. If an audit is performed, a site must provide the 
auditors with direct access to all relevant records and documentation related to the study. 
 
Regulatory authorities, the Institutional Review Board may also request access to all source documents, 
CRFs, and other study documentation for on-site inspection.  
 
17.2 
Administrative and Record Management and Retention of Data 
All investigative site records (source documents and other subject records) will be kept in a secure and 
hazard free storage area. Access will be restricted to study personnel authorized to handle research 
documents. All records will be retained 15 years after the study completion.  
HRA should be notified before destruction of any site records or transfer of oversight of the records 
should there be PI change at a site. 
All Essential Documents as defined in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial) contained in the Trial Master File and the Investigator’s 
File must be retained after the completion or termination of the study by the investigator and the sponsor 
for at least 15 years after the study completion. 
However, because of international regulatory requirements, the sponsor may request retention for a 
longer period of time. The investigator must therefore obtain approval in writing from the sponsor prior 
to destruction of any records. 
Throughout the study, e-CRFs and data clarification forms will be transmitted from the clinical site(s) to 
the sponsor or its designee and the information will be stored in an electronic database.. The final e-
CRFs will be copied onto a CD-rom and sent to the site for archiving.  
Data entered by subjects in e-diaries throughout the trial will be transferred at study end to the Contract 
Research Organization (CRO) in charge of data management..  
In order to assure the accuracy of data collected into the e-CRF, it is mandatory that the sponsor (or 
designees), as well as representatives of regulatory agencies, have access to original source 
documents (e.g., patient records, patient charts, laboratory reports). During the review of these 
documents, the anonymity of the patient will be respected with strict adherence to professional 
standards of confidentiality. 
Normally, investigator’s records will be held in the investigator's archives. If the investigator is unable 
to meet this obligation, he or she must ask the sponsor for permission to make alternative 
arrangements.  Details of these arrangements should be documented. 
Key documents to be retained are summarized below: 
Investigator 
Sponsor 
• 
Signed informed consent documents 
for all subjects 
Signed original 
NA 
• 
Subject 
identification 
code 
list, 
screening log (if applicable), and 
enrollment log 
X 
NA 
• 
Record 
of 
all 
communications 
between the investigator and the IRB 
Signed original 
Copy 
• 
Composition of the IRB  
X 
X 


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• 
Record 
of 
all 
communications 
between the investigator and sponsor 
(or CRO) 
X 
X 
• 
List of sub-investigators and other 
appropriately qualified persons to 
whom the investigator has delegated 
significant 
trial-related 
duties, 
together with their roles in the study 
and their signatures 
Copy 
Signed original 
• 
e-CRFs 
and 
documentation 
of 
corrections for all subjects 
Copy 
Copy 
• 
Drug accountability records 
X 
X 
• 
Record of any body fluids or tissue 
samples retained 
X 
X 
• 
All other source documents (subject 
records, hospital records, laboratory 
records, etc.) 
X 
NA 
 
17.3 
Study Documentation 
HRA monitoring subcontractor is responsible for assuring that the essential documents maintained in 
the investigator site files at the research centers are accurate and complete. Essential documents in 
the investigator site files / trial master file will be maintained according to written SOPs. 
 
17.4 
Electronic Data Capture System 
All requested information should be entered in the Electronic Data Capture (EDC) system. Prior to the 
start of the clinical trial, the investigator will complete an authorized signature sheet showing the 
signatures and handwritten initials of all individuals who are authorized to maintain study records and 
submit data using the EDC system.  
 
17.5 
Confidentiality and Reporting of Results 
Subject names will not be entered into the EDC system; instead, unique subject identifiers will be 
assigned. Medical records will be kept at the research center and will be available to study staff and, 
HRA, site IRBs, or the FDA only. Any publications or presentations that result from this study will 
maintain participant confidentiality. All data will only be used for the purpose for which it has been 
approved. Data collected during this study and any analyses of that data will not be used in any way 
other than those ways already approved without further approval from HRA. 
 
 
18. DOCUMENTATION AND USE OF STUDY FINDINGS 
 
18.1 
Documentation of study findings 
 
An e-CRF will be used for each subject. 
 
All protocol-required information collected during the study must be entered by the investigator, or 
designated representative, in the e-CRF. Details of e-CRF completion and correction will be explained 
to the investigator. If the investigator authorizes other persons to make entries in the e-CRF, the names, 
positions, signatures, and initials of these persons must be supplied to the sponsor. 
 


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The investigator, or designated representative, should complete the e-CRF as soon as possible after 
information is collected, preferably on the same day that a study subject is seen for an examination, 
treatment, or any other study procedure. Any outstanding entries must be completed immediately after 
the final examination. An explanation should be given for all missing data. 
 
A source data location list will be prepared and updated during the study. This list will be filed in both 
the trial master file and the investigator study file. This list should also include identification of any data 
to be recorded directly on the e-CRFs and to be considered to be source data. 
 
The completed e-CRF must be reviewed and approved by the investigator named in the study protocol 
or by a designated sub-investigator. 
 
The data management CRO will provide the sponsor and the investigator with paper renditions of the 
e-CRF (for example, in pdf format) and / or a CD-ROM of the e-CRF at study end. 
 
18.2 
Use of study findings 
 
All information concerning the product as well as any matter concerning the operation of HRA Pharma, 
such as clinical indications for the drug, its formula, methods of manufacture and other scientific data 
relating to it, that have been provided by HRA Pharma and are unpublished, are confidential and must 
remain the sole property of HRA Pharma. The investigator will agree to use the information only for the 
purposes of carrying out this study and for no other purpose unless prior written permission from HRA 
Pharma is obtained. 
 
By signing the Investigator’s declaration, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for medical 
and pharmaceutical professionals. If necessary, the authorities will be notified of the investigator’s 
name, address, qualifications, and extent of involvement. 
 
The sponsor will prepare a final report on the study and will communicate a summary of key findings to 
all investigators. 
Only the principal investigator will be required to sign a statement that he or she has read the report 
and confirms that, to the best of his or her knowledge, it accurately describes the conduct and results 
of the study. 
 
Only after the study has been completed can the findings of the study be published in a scientific journal 
or presented at a scientific meeting. For any publication manuscript prepared by HRA Pharma, HRA 
Pharma reserves the right to select the investigators who will be authors and review the manuscript. 
HRA Pharma will allow the selected investigators 30 days for full review of the manuscript before 
publication. It is generally preferable that the results of the multicenter study be published together. 
Before submitting the results of the study for publication or presentation, the investigator will allow HRA 
Pharma 30 days in which to review and comment on the manuscript.  
 
 
19. STATISTICAL AND ANALYTICAL METHODS 
 
19.1 
Populations 
 
Four populations of interest will be analyzed.  


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• 
The Intent-To-Treat (ITT) population consists of all subjects who were randomized; 
• 
The Full Analysis Set (FAS) or population of evaluable women is dependent on the question 
of interest. 
o  It is composed of all randomized and treated women with cervical mucus 
information (mucus score) at the second or third treatment periods for the questions 
related to mucus and the effect of unperfect use of norgestrel. 
o It is all randomized and treated women with ovarian activity information (OAS: 
ovarian activity score) at the second or third treatment periods for questions related 
to ovarian activity. 
o It is all women with complete information on mucus and ovarian activity for questions 
related to overall conception protection. 
Cycles with a very early ovulation (within 10 days before the DMP period) at period 2 or 3 may 
be removed from the set of evaluable cycles in a sensitivity analysis or included as failure 
depending upon the question of interest because the effect of intake infringement cannot be 
assessed in these cycles. The exclusion of cycles from a given analysis, the exclusion of a 
woman from the FAS and the status of non evaluable cycles will be decided in a blind manner 
by an independent adjudication committee.  
• 
The per-protocol (PP) population is composed of subjects from the FAS without major 
protocol violation/deviation and with complete cervical mucus and ovarian activity data at the 
three periods. Relevant protocol violation/deviation will be defined during the data review but 
will include at least compliance issues and early ovulation;  
• 
The Safety population that consists of all subjects who took at least one dose of study 
medication (Opill® 75 mcg). 
 
The ITT population will be used to describe the population and to get information on the level of 
compliance in a clinical trial (treatment period 1) that is expected to be better than in the real life. 
 
The FAS or evaluable population will be used in the ‘primary’ analysis for assessing the effect of delayed 
or missed pill on mucus permeability to spermatozoids and on secondary pharmacodynamic analyses.  
 
The PP population will be used for assessing the pharmacodynamic effect without missing data and 
possibly biased data due to protocol violations/deviations. This will be the "cleanest" results for 
assessing the effect of infringement and the PD effect at the expense of completeness of the set of 
randomized women and representativeness of the treated population. 
 
The Safety set will mainly be used for safety purposes. 
 
19.2 
Description of Subjects 
 
The number of subjects, who were screen failures, enrolled, treated, withdrawn and who completed the 
clinical trial will be tabulated. This will be presented in a chart called patient disposition. 
 
Baseline demographics and characteristics will be summarized for all subjects per population. The 
characteristic of the ITT, FAS, PP and safety populations at entry in the study will be provided through 
descriptive statistics (mean, standard deviation, minimum, median, maximum and number of 
observations and missing cases) for quantitative variables and frequencies and percentages for 
categorical variables. 
 


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19.3 
Efficacy analysis 
 
19.3.1 Primary analysis 
 
The primary working hypothesis states that an infringement in the schedule of intake of norgestrel 
75 mcg has a negative impact on the level of conception protection of women.  
 
The primary objectives of the study is to verify whether a delayed intake of 6 hours or a missed pill of 
norgestrel 75 mcg has an effect on cervical mucus protection and more specifically tends to increase 
the cervical mucus score compared to reported perfect use of norgestrel 75 mcg just before 
infringement. 
 
The primary population of subjects is the FAS. It is composed of all randomized and treated women 
with cervical mucus information (mucus score) at the second or third treatment period. Subjects with a 
very early ovulation will be discarded from the set of evaluable cycles in the primary analysis. 
 
The primary treatment periods of interest are the second and third treatment periods.  
 
The primary assessment criterion of interest is the cervical mucus score during the treatment periods 
2 and 3. 
 
The symbols used in the statistical section are: 
• 
T is the time of treatment (pill) 
• 
TMS is the time of mucus scoring 
• 
TMS score is the value of mucus score at the time of mucus scoring  
• 
A or B concerns arm A or B respectively 
• 
R denotes the day of pill intake infringement in period 2 and period 3  
• 
R-1 denotes the day before infringement in periods 2 and 3  
• 
R+1 denotes the day after infringement in periods 2 and 3  
• 
V1, V2 and V3 or 1, 2 and 3 denote visits during the first, second and third periods respectively. 
• 
T2R-1 and T3R-1 are times of pill intake at V2R-1 and V3R-1 respectively. 
 
The primary time points of interest are: 
  
• 
Time of mucus scoring (TMS) the day before infringement (delayed pill or missed pill) in 
period 2 and period 3 (baseline):  
o TMS2R-1 = T2R-1+ 8 h ± 30 min at V2R-1 and  
o TMS3R-1 = T3R-1 + 8 h ± 30 min at V3R-1.  
 
• 
Time of mucus scoring the day of infringement in period 2 or 3: 
o Subjects belonging to arm A 
 
TMS2A,R = T2R-1 +3 h ± 15 min at V2R and  
 
TMS3A,R = T3R-1 + 6 h ± 15 min at V3R  
o Subjects belonging to arm B   
 
TMS2B,R  = T2R-1 + 6 h ± 15 min at V2R 
 
TMS3B,R = T3R-1 +3 h ± 15 min at V3R  
 
• 
Time of mucus scoring the day after infringement (both arms):   
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 and   
o TMS3R+1 = T3R-1 - 30 min at V3R+1.  
 
N.B.: The time of pill intake the day after infringement should be the same as the day before 
infringement (expected around 9 am).  
 
The primary baseline time points are: 


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• 
TMS2R-1 = T2R-1+ 8 h ± 30 min at V2R-1 and  
• 
TMS3R-1 = T3R-1 + 8 h ± 30 min at V3R-1  
 
Around 8 hours after pill intake the day before infringement. 
 
The primary response time points are:  
 
• 
Arm A: 
o TMS2A,R = T2R-1 + 3 h ± 15 min at V2R  
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 
o TMS3A,R = T3R-1 +6 h ± 15 min at V3R  
o TMS3R+1 = T3R-1 - 30 min (before pill intake) at V3R+1   
• 
Arm B 
o TMS2B,R = T2R-1 +6 h ± 15 min at V2R  
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 
o TMS3B,R = T3R-1 + 3h ± 15 min at V3R 
o TMS3R+1 =T3R-1 - 30 min (before pill intake) at V3R+1. 
 
The primary measures of mucus are taken at the time presented in the following figure: 
 
Figure 3 Primary measures of mucus 
V2R-1 
V2R 
V2R+1 
 
V3R-1 
V3R 
V3R+1 
VISITS 
TMS2A,R
TMS3B,R
DELAYED PILL




TMS2R-1
TMS2R+1

TMS3R-1
TMS3R+1




 
TMS2B,R 
 
 
 
TMS3A,R 
 
MISSED PILL 
PERIOD 2
PERIOD 3
PERIOD
 
The primary outcomes/endpoints are the changes from baseline (BSL):  
• 
Delta from BSL to V2R = Mucus score at V2R − score at V2R-1 (period 2): change from baseline 
to 3 or 6 hour after infringement  
• 
Delta from BSL to V2R+1 = Mucus score at V2R+1 − score at V2R-1 (period 2): Change from 
baseline to just before pill intake the day after infringement 
• 
Delta from BSL to V3R =  Mucus score at V3R − score at V3R-1 (period 3) change from baseline 
to 3 or 6 hour after infringement  
• 
Delta from BSL to V3R+1 = Score at V3r+1 − score at V3r-1 (period 3) Change from baseline to 
just before pill intake the day after infringement 
 
The primary model of interest is a mixed model for repeated measures using as response delta to V2R, 
delta to V2R+1, delta to V3R and delta to V3r+1. The covariates will be the period (or period effect), the 
intervention (type of infringement: missed pill or delayed pill), the sequence of intervention (missed pill 
then delayed pill and vice versa), the time and the subject. Time, period intervention type, and sequence 
will be considered as categorical variables. The subject as random effect (RANDOM statement of the 
MIXED procedure). This will permit to take into account the fact that measures from each period are 
derived from the same subjects. A time repeated effect (REPEATED statement of the MIXED 
procedure) within each combination subject* period (SUBJECT = subject* period as option of the 
REPEATED statement). This will permit to take into account the fact that for each subject, at each 
period several measures are performed over time. The proper struture of the variance covariance matrix 
will be retained using the best fit among unstructured matrix (UN) compound symetry (CS) and 
autoregressive structure (AR1).    
 
The primary test of interest will be the significance of the overall mean (intercept). This will answer 
the question: is the overall mean change from baseline different from zero? Or does the infringement 


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of schedule regardless the type of infringement lead to a change in mucus score?  
 
The contrasts or estimates of interest are 
• 
the effect of infringement type: does the effect of missed pill differ from the effect of 6 hours 
delay? If the answer is yes then a signal of effect is detected. 
• 
The effect of time: does the response on the day of infringement differ from the response on 
the day after infringement? If the answer is yes then a signal of effect of infringement is 
detected. 
 
The SAP may present other models (secondary models) to answer other questions of interest or to 
get a more parsimonious model. For example if the sequence of intervention effect is not significant a 
model without this covariate can be planned in the SAP. 
  
19.3.2 Subordinated objective 
 
The subordinate primary objective is to estimate the duration of the protective effect of cervical mucus 
after last pill intake of norgestrel 75 mcg during reported perfect use (at the day before the infringement). 
 
The possible increase in mucus score may have no detectable effect on conception risk depending on 
the level of score because it increased but remained below a threshold of good protection.  
 
The mucus score has a value ranging from zero (not propicious for spermatozoïds progression: 
maximal protection) to 12 (propicious for spermatozoïds progresion: minimal protection). The primary 
cut-off for full cervical mucus protection is a cervical mucus score of 4. There is therefore a good 
conception protection by cervical mucus if the cervical mucus score is ≤ 4. 
 
The responses of interest are: 
 
1. The full protection by cervical mucus regardless of the use of norgestrel 75 mcg if the score 
was and remained at 4 or below at V2R-1, V2R, V2R+1, V3R-1, V3R and V3R+1. The full protection 
by the mucus lasted for 2 x 3 days. The proportion of patients meeting this criterion is pFP. 
2. The absence of risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement and remained at 4 or less the day of infringement and the day after the delayed 
pill intake. The protection by the mucus lasted at least up to the day after infringement. The 
proportion of patients fulfilling this criterion is pdelay.   
3. The absence of risk increase further to missed pill: The score was ≤ 4 the day before 
infringement and remained at 4 or less the day of infringement and the day after missed pill. 
The protection by the mucus lasted at least up to the day after infringement.The proportion of 
patients fulfilling this criterion is pmissed.     
4. The absence of risk increase due to infringement regardless of the type: The score was ≤ 4 the 
day before infringement and remained at 4 or less the day of infringement and the day after 
infringement. The protection by the mucus lasted at least up to the day after infringement. The 
proportion of patients fulfilling this criterion is pbreach.   
5. The transient risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement but came back to 4 or less the day after the 
delayed pill intake. The protection by the mucus was interrupted the day of infringement. The 
proportion of patients fulfilling this criterion is pdelay,trasient risk.   
6. The transient risk increase further to missed pill: The score was ≤ 4 the day before infringement, 
exceeded 4 the day of infringement but came back to 4 or less the day after the delayed pill 
intake, The protection by the mucus was interrupted the day of infringement. The proportion of 
patients fulfilling this criterion is pmissed,transient risk.   
7. The prolonged risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement and the day after the delayed pill intake. The 
protection by the mucus was interrupted the day of infringement and at least up to the day after. 
The proportion of patients fulfilling this criterion is pdelay, prolonged risk, .   


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8. The prolonged risk increase further to missed pill: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement and the day after the missed pill. The 
protection by the mucus was interrupted the day of infringement and at least up to the day after. 
The proportion of patients fulfilling this criterion is pmissed, prolonged risk, .   
9. Other definitions can be added in the SAP to get a detailed picture of the effect of infringement 
and its duration. 
 
Comparison between the missed pill and the delayed pill can easily be performed and tested through a 
stratified McNemar test (stratification on the site, CMH option in SAS). The SAS glimmix procedure for 
repeated measures was not retained for decision making test because convergence issues in fitting the 
model are too frequent. The first null hypothesis is H0: Proportion of protected women at baseline (R-1) 
is equal to the proportion of protected women after schedule infringement and more specifically at Day 
R (27 hours and 30 hours post treatment). The second null hypothesis is the equality of proportions at 
baseline (R-1) and at Day R+1 (48 hours post treatment). 
 
19.3.3 Secondary analyses 
 
Cervical mucus protection in each type of treatment period 
 
The aim of this secondary objective is to assess the level of cervical mucus protection during reported 
perfect use, during a treatment period with a delayed pill intake of 6 hours and during a treatment period 
with a missed pill of norgestrel 75 mcg. 
 
The time frames are: 
• 
reported perfect use: all the visits of the period 1 before a postovulatory image is obtained 
• 
delayed pill intake: all the visits of the period 2 for Arm A and all the visits of period 3 for Arm B 
before a postovulatory image is obtained 
• 
missed pill: all the visits of the period 2 for Arm B and all the visits of period 3 for Arm A before 
a postovulatory image is obtained. 
 
The assessment criterion is the cervical mucus score. The cut off is a cervical mucus score of 4. There 
is conception protection by cervical mucus if the cervical mucus score is ≤ 4. 
 
The endpoints are: 
• 
The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in reported 
perfect use period 
• 
The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in delayed 
pill intake periods 
• 
The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in missed 
pill periods 
• 
The percentage of subjects with cervical mucus score ≤ 4 in all periods  
 
Other analyses based on other endpoint of interest can be in the SAP. 
 
Ovarian Activity in each type of treatment period 
 
The aim of this secondary objective is to describe the distribution of the ovarian status among the 
subjects, during reported perfect use, during a treatment period with a delayed pill intake of 6 hours and 
during a treatment period with a missed pill of norgestrel 75 mcg. 
 
The time frames are: 
• 
reported perfect use: all the visits of the period 1  
• 
delayed pill intake: all the visits of the period 2 for Arm A and all the visits of period 3 for Arm B  


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• 
missed pill: all the visits of the period 2 for Arm B and all the visits of period 3 for Arm A 
 
The assessment criterion is the OS as defined in Appendix 31. 
The OS are ranked depending on the risk of conception: OSnlp > OSalp > OSa > OSq. 
For each treatment period the most risky OS will be considered. 
 
The endpoints are: 
• 
The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in reported perfect use 
period 
• 
The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in delayed pill intake periods 
• 
The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in missed pill periods 
• 
The percentage of subjects with OSnlp in all periods 
 
19.3.4 Other secondary analyses 
 
Protection from conception based on cervical mucus score and OS (binary and ternary 
analyses)) 
 
Based on cervical mucus score and OS only, the aim of these exploratory analyses are to assess if a 
combination of cervical mucus score and ovarian status can be considered as a measure of protection 
from conception or not and the level of protection, during reported perfect use of norgestrel 75 mcg and 
after a delayed intake/missed pill. 
 
For both analyses, the assessment criteria will be the OS and the highest cervical mucus score during 
the 3 visits before a postovulatory image is obtained including the visit when the postovulatory image 
is obtained2. 
For the OS, the risk of conception is ranked depending on the OS: OSnlp > OSalp > OSa > OSq and for 
each treatment period the most risky OS will be considered.  
 
Binary analysis 
 
The aims of this analysis is to determine whether a subject is protected on not, according to the 
algorithm presented in Figure 4 
 
Figure 4 Conception protection based on OS and cervical mucus score (binary analysis) 
 
 
The endpoints will be, for each treatment period, the distribution of subjects:  
 
1 The ovarian status are: 
OSq = quiescence defined as a OAS ≤ 3 
OSa = ovarian activity defined as a OAS = 4 or 5 
OSalp = ovulation with abnormal luteal phase defined as a OAS = 6 at only one visit 
OSnlp = ovulation with normal luteal phase as a OAS = 6 at two consecutive visits or OAS = 7 
2 The number of visits considered for the evaluation of the mucus score may be modified by the adjudication 
committee (see section 20). 


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• 
considered as protected: OSq or OSa OR cervical mucus score ≤4 
• 
considered as at risk of conception: OSalp or OSnlp AND cervical mucus score ≥ 5  
 
Ternary analysis 
 
The aims of this analysis is to determine the level of protection for a subject, according to Table 4 
presented below. 
 
Table 4 Conception protection based on OS and cervical mucus score 
 
 
Ovarian Status 
 
 
OSq 
OSa 
OSalp 
OSnlp 
Highest
Mucus 
score 
0-4 
maximum 
maximum 
maximum
maximum
5-8
maximum
maximum
medium
medium
9-12
maximum
maximum
medium
minimum
 
The endpoints will be, for each treatment period, the distribution of subjects with:  
• 
Minimum protection or unlikely to be protected: OSnlp and cervical mucus score ≥ 9 
• 
Medium protection or likely to be protected: OSnlp and cervical mucus score comprised between 
5 and 8 or OSalp and cervical mucus score ≥ 5 
• 
Maximum protection or highly likely to be protected: OSq or OSa or a cervical mucus score ≤ 4 
 
Pharmacokinetics of LNG and PK/PD analysis 
 
The PK profile of LNG after administration of norgestrel 75 mcg will be assessed at different times 
during the study. 
 
The PK profile of LNG will first be assessed at Day 1 after the first administration of norgestrel 75 mcg 
in fasted conditions. 
 
All the subjects will be sampled at different time points after administration as presented in the table 
below: 
 
Table 5 PK sampling schedule at Day 1 
 
Sampling times 
 
predose
1h
2h
4h
6h
8h
12h
24h
Odd # 
 
X 
 
X 
 
X 
 
X 
Even #
X 
 
X 
 
X 
 
X 
 
 
 
During the first visit of the 3rd week of treatment, the pharmacokinetics of LNG at steady state will be 
assessed. 
All the subjects will be sampled at different times points. If the visit is in the morning, they will be sampled 
predose and between 0.5h and 2h post administration. If the visit is in the afternoon, they will be 
sampled between 5h and 9h post administration. 
The plasma concentration(s) for each subject will be reported with the nominal time of sampling. 
 
 
The pharmacokinetics of LNG will also be assessed during the DMP period. The sampling schedule 
will depend on the arm the subjects had been randomized in (see Table 6 below). 
 
 
 
 


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Table 6 PK sampling schedule during the DMP period 
 
DMP 2 
DMP 3 
 
V2R-1 
V2R 
V2R+1 
V3R-1 
V3R 
V3R+1 
 
T2R-1 
+ 8h 
T2R-1 
+ 3h 
T2R-1 
+ 5.5h 
T2R-1 
+ 6h 
T2R-1 
+ 7.5h
T2R-1 
- 0.5h 
T3R-1 
+ 8h 
T3R-1 
+ 3h 
T3R-1 
+ 5.5h 
T3R-1 
+ 6h 
T3R-1 
+ 7.5h 
T3R-1 
- 0.5h 
Arm A 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
Arm B 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
The mean plasma concentration for each time point will be calculated:  
• 
V2/3R-1: C2/3R-1,8h (Arm A + Arm B) 
• 
V2/3R: C2R-1,27h (Arm A), C3R-1,27h (Arm B), C2R-1,29.5h (Arm A), C3R-1,29.5h (Arm B), C2R-1,30h (Arm 
B), C3R-1,30h (Arm A), C2R,1.5h (Arm A), C3R,1.5h (Arm B) 
• 
V2/3R+1: C2/3R+1,-0.5h (Arm A + Arm B) 
 
 
The concentration of LNG will also be determined in all subjects during the 1st visit of study week 5 
(V21) and 9 (V31). The sample will be drawn within 30 minutes of the mucus analysis. 
The concentrations will be reported as C21 and C31. 
 
 
A population pharmacokinetic model will  be developed using a dedicated software for nonlinear mixel 
model. The model will be developed using a sparse sampling scheme. This model will be used to 
estimate population PK parameters such as clearance and volume of distribution as well as derived PK 
parameters (C24h, Cmax and AUC). Complete details of all PK analyses and methods will be provided in 
a separate analysis plan finalized before the database lock (DBL). 
 
A PK/PD analysis, describing the relationships between pharmacokinetic and pharmacodynamic data 
will be performed; details will be provided in a separate analysis plan finalized before database lock. 
 
19.3.5 Presentation of pharmacodynamic data 
 
PD effect will be evaluated by cervical mucus analysis and ovarian activity during the three treatment 
periods. 
• 
Cervical mucus score: the time course of the mucus score will be presented for each period 
graphically along with summary statistics. 
• 
TVU largest follicle diameter measurement: The time course of the diameter will be presented 
graphically along with summary statistics. The time series will be truncated after a postovulatory 
image has been obtained  
• 
P4, E2, FSH and LH measurement. The time course of each parameter will be presented for 
each period graphically along with summary statistics. 
 
19.4 
Safety analysis 
 
Safety data will be collected by querying subjects about AEs and vaginal bleeding patterns and by 
performing safety laboratory parameters at screening and the EOS visit. Subjects will report bleeding 
data and drug intake using a e-diary every day.  
Evaluation of the bleeding patterns will be based on the subjects responses in the e-diary and validated 
during clinic visits. Vaginal bleeding in between expected menstrual periods will be categorised as 
breakthrough bleeding and spotting based on the bleeding intensity recorded in the e-diary. 
Amenorrhea or absence of bleeding for two menstrual cycles or more than 60 days in subjects who 
took the medication as prescribed will also be noted.   
 
Safety will be evaluated by incidence of premature discontinuation and AEs. Summaries will be 
provided for all AEs reported, and separately for AEs leading to study discontinuation. Serious Adverse 
Events (SAEs) will be listed separately and described by narrative. 
 


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19.4.1 Incidence of Adverse Events 
 
The number (percentage) of subjects with at least one AE will be presented in a frequency table. 
Summaries will also be presented by relationship to study medication (“relationship” is defined as not 
related, unlikely related, possibly, or definitely related to study medication) and intensity of AE). 
 
19.4.2 Discontinuation Due to Adverse Events 
 
Subjects who are discontinued due to one or more AEs will be listed, and specific information about the 
AEs leading to discontinuation will become part of the final clinical study report. 
 
19.4.3 Serious Adverse Events 
 
Subjects with SAEs will be listed and the following variables included: SAE description (as reported by 
investigator), MedDRA “lowest level” term, MedDRA “preferred” term, MedDRA system-organ class 
(based on the “included” term), start and stop dates relative to the admission, maximum intensity, 
relationship to the investigational product (according to the investigator), action taken, and outcome. 
Subject SAE narratives will be part of the final clinical study report. 
 
19.4.4 Deaths 
 
Subjects who died during the study will be listed and the following variables will be included: main 
reason(s) for death (as reported by the investigator), diagnosis of the SAE contributing to the death, 
date of death relative to the first day of product use, and relationship to study drug according to the 
Investigator. Subject SAE narratives, including information regarding the death, will be part of the final 
clinical study report. 
         
 
20. ADJUDICATION COMMITTEE 
 
An adjudication committee will be implemented for the study. Experts in the cervical mucus assessment 
and ovarian activity who are not affiliated with either of the study sites will comprise the committee. The 
committee will gather at study end, after the data review meeting. 
Its responsibilities will be to review data regarding IMP intake and TVU, hormonal and mucus 
measurements, to make decisions for each subject on compliance (for the analysis of the data), and 
reach agreement on ovarian activity score, ovarian status and cervical mucus score. They will also 
define the set of evaluable cycles. The adjudication committee will work in a blinded manner (see 
section 19.1). 
A separate charter will be drawn to provide the details. 
 
 
21. ETHICAL CONSIDERATIONS AND LEGAL ASPECTS 
 
21.1 
Good Clinical Practice 
 
The study will be conducted in accordance with legal and regulatory requirements including FDA’s 
applicable Code of Federal Regulations, as well as the general principles set forth in the International 
Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International 
Organizations of Medical Sciences 2002), Guidelines for GCP (ICH 1996 incl rev6), and the Declaration 
of Helsinki (World Medical Association 2013). 
In addition, the study will be conducted in accordance with the protocol, the International Conference 
on Harmonization (ICH) guideline on GCP, and applicable local regulatory requirements and laws. 
 


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This study will be listed on the website ClinicalTrials.gov by HRA Pharma, before the first subject is 
enrolled. 
 
21.2 
Study without direct benefit to individual subjects  
No direct benefit to individual subjects is expected from this study. Because participation is on a 
voluntary basis, subjects will be remunerated for their time spent in the study and travel expenses at 
the end of the study and on a prorated basis in the event of early discontinuation. Details of 
remuneration will be listed in the participant’s information sheet approved by the IRB. 
 
21.3 
Delegation of investigator responsibilities 
The investigator should ensure that all persons assisting with the trial are adequately informed about 
the protocol, any amendments to the protocol, the study medication, and their trial-related duties and 
functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified persons to 
whom he or she has delegated significant trial-related duties. 
 
21.4 
Interactions with Institutional Review Boards 
This protocol and any protocol amendments, together with the required documents will be submitted by 
the sponsor to the responsible IRB according to the applicable requirements at the site. The study will 
commence at each participating site only after their IRB has granted full approval. 
Investigators/institutions will permit trial related monitoring, audits, IRB review and regulatory 
inspection(s) providing direct access to source data/documents. 
Study medication can only be supplied to the investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the sponsor. This documentation must also 
include a list of the members of the IRB and their occupation and qualifications. If the IRB will not 
disclose the names of the committee members, it should be asked to issue a statement confirming that 
the composition of the committee is in accordance with GCP. Formal approval by the IRB should 
preferably mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed. It must mention the date on which the decision was made and must 
be officially signed by a committee member. 
 
Before the first subject is enrolled in the study, all ethical and legal requirements must be met. 
 
The IRB and, if applicable, the authorities must be informed of all subsequent protocol amendments, in 
accordance with local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be revised. 
 
The investigator must keep a record of all communication with the IRB and, if applicable, between a 
coordinating investigator and the IRB. This also applies to any communication between the investigator 
(or coordinating investigator, if applicable) and the authorities. 
 
21.5 
Ongoing information for IRB 
 
The site will notify the sponsor at the time of IRB submission. 
If required by legislation or the independent IRB, the sponsor must verify that the following is submitted 
to the IRB: 
• 
Information on serious or unexpected AEs as soon as possible 
• 
Periodic reports on the progress of the study 
 


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21.6 
Informed Consent 
 
Under informed consent, the subject shall understand that she is authorizing access to medical records 
as required for monitors, auditors, IRBs and regulatory authorities. Subjects that agree to participate in 
the study must sign the informed consent form (ICF) prior to study-specific procedures. The ICF will be 
HIPAA compliant. 
 
It is the investigator's responsibility to assure that each subject is provided an explanation of the details 
contained in the informed consent statement and other locally required documents prior to the individual 
signing the ICF certifying voluntary participation in the trial and prior to study participation.  
The document must be in a language understandable to the subject and must specify who informed the 
subject. Where required by local law, the person who informs the subject must be a physician. If not 
required by local law, another appropriately trained and qualified healthcare professional, other than a 
physician, is acceptable. 
 
After reading the informed consent document, the subject must give consent in writing. The subject's 
consent must be confirmed at the time of consent by the personally dated signature of the subject and 
by the personally dated signature of the person conducting the informed consent discussions.  
 
The subjects will be informed of their right to privacy and the fact that personal information will be treated 
as strictly confidential and will not be publicly available in accordance with HIPAA regulations. They will 
also be informed that HRA Pharma and the FDA have the right to inspect and possibly photocopy their 
medical records to verify the accuracy and completeness of the clinical trial results.  
 
Prior to study participation, all study candidates will: 
• 
Be informed of the nature and purpose of the study. 
• 
Be given an explanation of the procedures to be followed in the study. 
• 
Be given a description of any attendant discomforts and risks reasonably to be expected from 
the study, as well as from the study product. 
• 
Be given an opportunity to ask any questions concerning the study. 
• 
Be instructed that consent to participate in the study may be withdrawn at any time; and that the 
participant may discontinue participation in the study without prejudice. 
• 
Be given a copy of an ICF. 
• 
Be given the opportunity to decide to consent or not to consent to the study without coercion. 
• 
Be informed of alternative contraceptive methods available. 
• 
Be given information for whom to contact if there are questions about the research, participant 
rights, or to report research-related injury.  
 
21.7 
Conflicts of Interest 
 
Investigators will be affiliated with their study sites and report any conflicts of interest in accordance 
with their employer. They will receive support for this clinical study but will not profit from results, either 
positive or negative, with regard to the product being evaluated. HRA, the study sponsor, could profit 
from the successful development of this product. 
 


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21.8 
Confidentiality 
 
The information on individual subjects arising from this study is to be considered confidential and 
transmitted to the sponsor only in a form that will not permit identification of the individual. The 
information obtained from the subjects that can be identified with the subject will remain confidential 
within the research team. Regulatory and sponsoring agencies may request access to the study records 
and related medical records of each participating subject; the subject’s identity will remain confidential 
to the extent permitted by the applicable laws and regulations. The results of the research will be 
released to public agencies including regulatory agencies, clinical investigators, and research 
organizations without reference to items identifiable to a particular subject. The results will be published 
such that the identity of the subjects will not be disclosed and cannot be ascertained. National and 
international agencies and sponsoring agencies may request access to the medical records of each 
participating subject, and if requested, the subject’s identity will remain confidential. All records will be 
kept in a secure storage area with limited access. 
 
21.9 
Premature closure of the study  
 
The sponsor may decide to close this study at any time. As far as possible, this should occur after 
consultation with the investigator. The IRB must be informed. 
Should the study be closed prematurely, all study materials (study medication, lab equipment, etc.) 
must be returned to the sponsor, as if the study had been completed. 
 
21.10 Liability and insurance 
The sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal liability 
for injuries caused to participating persons and arising out of this research performed strictly in 
accordance with the study protocol as well as with applicable law and professional standards. 


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22. REFERENCES 
 
Brenner PF, Mishell DR Jr, Stanczyk FZ, Goebelsmann U. Serum levels of d-norgestrel, luteinizing 
hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion 
of combination oral contraceptives containing dl-norgestrel. 
Am J Obstet Gynecol. 1977 Sep 15;129(2):133-40. 
 
Cox HJ. The Pre-Coital Use of Mini-Dosage Progestagens. Journal of Reproduction and Fertility 
Supplement 6 (1968): 167–72. 
 
Curtis KM, Jatlaoui TC, Tepper NK, Zapata LB, Horton LG, Jamieson DJ, Whiteman MK. U.S. Selected 
Practice Recommendations for Contraceptive Use, 2016. 
CDC Recommendations and Reports. 2016 July 29, 65(4);1–66 
https://www.cdc.gov/mmwr/volumes/65/rr/rr6504a1.htm?s_cid=rr6504a1_w 
 
Dunson TR, Blumenthal PD, Alvarez F, Brache V, Cochon L, Dalberth B, Glover L, Remsburg R, Vu K, 
Katz D. Timing of onset of contraceptive effectiveness in Norplant implant users. Part I. Changes in cervical 
mucus. 
Fertility And Sterility. 1998 Feb 69(2): 258-266 
 
Grimes DA, Lopez LM, O'Brien PA, Raymond EG. Progestin-only pills for contraception. 
Cochrane Database Syst Rev. 2013 Nov 13;(11):CD007541.  
 
Han L, Taub R, Jensen JT. Cervical mucus and contraception: what we know and what we don't. 
Contraception. 2017 Aug 8. [Epub ahead of print] Review. 
 
Lebech PE, Svendsen PA, Ostergaard E. The effects of small doses of megestrol acetate on the cervical 
mucus. 
Int J Fertil. 1970 Apr-Jun;15(2):65-76. 
 
McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. 
Contraception. 1994 Dec;50(6 Suppl 1):S1-195. Review. 
 
Moghissi, K. S., & Marks, C.. Effects of microdose norgestrel on endogenous gonadotropic and steroid 
hormones, cervical mucus properties, vaginal cytology, and endometrium.  
Fertility and sterility. 1971 22(7):424-434. 
 
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a 
standardized method of Gram stain interpretation. 
J Clin Microbiol 1991;29:297–301 
 
Petta CA, Faundes A, Dunson TR, Ramos M, DeLucio M, Faundes D, Luis Bahamondes L. Timing of onset 
of contraceptive effectiveness in Depo-Provera users: Part I. Changes in cervical mucus. 
Fertility And Sterility. 1998 Feb 69(2): 252-257 
 
Rice CF, Killick SR, Dieben T, Coelingh Bennink H. A comparison of the inhibition of ovulation achieved 
by desogestrel 75 micrograms and levonorgestrel 30 micrograms daily.  
Hum Reprod. 1999 Apr;14(4):982-5. 
 
Trussell J. Contraceptive failure in the United States. 
Contraception. 2011 May;83(5):397-404.  
 


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Weiner E, Victor A, Johansson ED. Plasma levels of d-norgestrel after oral administration. 
Contraception. 1976 Nov;14(5):563-70.  
 
 


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APPENDICES 


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Appendix 1: List of Exclusionary Medications 
 
 
Interfere with the metabolism of hormone contraceptives:
Isotretinoin 
Modafinil  
barbiturates 
Oxcarbazepine 
Primidone 
Griseofulvin 
Topiramate 
Primidone 
Phenylbutazone 
anticonvulsants 
Ritonavir 
 
Certain antibiotics can interfere with metabolism of hormone contraceptives:  
      Please request an approval from HRA for specific antibiotics 
Liver enzyme inducers:  
Carbamazepine 
Rifampin 
Lansoprazole 
Rifabutin 
phenobarbital 
Herbal preparations containing St. John's 
Wort (hypericum perforatum) 
Phenytoin 
Efavirenz 
Bosentan 
 
 
FDA List of CYP3A4 Inhibitors
STRONG: 
Boceprevir 
Clarithromycin 
Conivaptan 
Grapefruit juice 
Indinavir  
Itraconazole 
Ketoconazole 
Lopinavir/Ritonavir 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Voriconazole 
 
MODERATE: 
Amprenavir 
Aprepitant 
Atazanavir 
Ciprofloxacin 
Darunavir/Ritonavir 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Grapefruit juice 
Imatinib 
Verapamil 
 
Drugs with significant evidence of fetal risks should not be allowed in our study.  
 
The following list includes some of the common drugs that contraindicate study participation.  Please 
note that this list is NOT exhaustive; drugs not on the list should be researched by the study center 
staff. 
  
• 
Clarithromycin (Biaxin) 
• 
Most anticonvulsant drugs including: divalproex sodium (Depakote), primidone (Mysoline), 
carbamazepine 
(Tegretol, 
Carbatrol), 
gabapentin 
(Neurontin), 
phenytoin 
(Dilantin), 
benzodiazepines (see below), etc. 
• 
Benzodiazepines, including: diazepam (Valium), alprazolam (Xanax), clonazepam (Klonopin), 
clorazepate (Tranxene), temazepam (Restoril), triazolam (Halcion), etc. 


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• 
Warfarin (Coumadin) 
• 
Lithium 
• 
Isotretinoin (Accutane) 
• 
Ribavirin 
• 
Measles, mumps, varicella, and rubella vaccination (within 3 months after vaccination) 
• 
High dose vitamin A (topical Retin-A is OK) 
• 
Thalidomide 
• 
Diethylstilbestrol (DES) 
• 
Misoprostol (Cytotec) 
• 
Lipid-lowering statin drugs, including: atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin 
(Zocar), Pravastatin (Provachol), etc. 
• 
Azathioprine (Imuran) 
• 
ACE inhibitors including benazepril (Lotensin), captopril (Capoten), Enalapril, Fosinopril 
(Monopril), Lisinopril (Zestril; Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril 
(Accupril), Ramipril (Altace), and Trandolapril (Mavik) 
• 
Paroxetine (Paxil) 
• 
Tetracyclines (Emtet, Panmycin, Sumycin, Tetra 250) 
• 
All chemotherapeutic agents. 
 
 
 
 


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Appendix 2: Cervical mucus sampling and scoring 
 
Cervical mucus will be sampled and assessed according to the methodology described in the WHO 
Laboratory Manual for the Examination and Processing of Human Semen. Fifth edition 2010 and 
provided in the next pages. 
 
Volume will not be assessed. 
 
Viscosity is scored as follows: 
0 = thick, highly viscous, premenstrual mucus 
1 = mucus of intermediate viscosity 
2 = mildly viscous mucus 
3 = watery, minimally viscous, mid-cycle (preovulatory) mucus 
 
Ferning is scored as follows: 
0 = no crystallization 
1 = atypical fern formation 
2 = primary and secondary stem ferning 
3 = tertiary and quaternary stem ferning 
 
Spinnbarkeit is scored as follows: 
0 = <1 cm 
1 = 1–4 cm 
2 = 5–8 cm 
3 = 9 cm or more 
 
The rank scores for cells are: 
0 = >20 cells per HPF or >1000 cells per µL 
1 = 11–20 cells per HPF or 501–1000 cells per µL 
2 = 1–10 cells per HPF or 1–500 cells per µL 
3 = 0 cells 
 
 
 


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Appendix 3: Determination of Ovarian Activity Score (OAS) and Ovarian Status (OS) 
 
Table 7 Determination of Ovarian Status 
Ovarian 
Activity 
Score
Activity 
Size FLS / 
sonographic 
image
Estradiol 
(nmol/L) 
Progesterone 
(nmol/L) 
Ovarian 
Status1 
1 
No activity 
≤ 10 mm 
Independent of 
E2 level 
≤ 5 
OSq 
2 
Potential activity 
> 10 and ≤ 13 mm 
Independent of 
E2 level 
≤ 5 
OSq 
3 
Non-active follicle 
like structure (FLS) 
> 13 mm 
≤0.12 
≤ 5 
OSq 
4 
Active follicle like 
structure (FLS) 
> 13 mm 
>0.12 
≤ 5 
OSa 
5 
Postovulatory, low P 
level 
Postovulatory 
image2 
>0.12 
≤ 10 
OSa 
6 
Postovulatory, 
intermediate P level 
Postovulatory 
image3 
> 0.12 
> 10 and ≤ 30 
Only 1 P > 10 
and ≤ 30 
→ OSalp 
2 consecutive 
P > 10 and ≤ 
30 
→ OSnlp 
7 
Postovulatory, high P 
level 
Postovulatory 
image3 
> 0.12 
> 30 
OSnlp 
1 The ovarian status are: 
• 
OSq = quiescence defined as a OAS ≤ 3 
• 
OSa = ovarian activity defined as a OAS = 4 or 5  
• 
OSalp = ovulation with abnormal luteal phase defined as OAS = 6 at only one visit  
• 
OSnlp = ovulation with normal luteal phase as a OAS = 6 at two consecutive visits or OAS = 7 
2~27.24 pg/mL 
3 A postovulatory image will be defined as follows: 
• 
Image observed after abrupt disappearance of FLS OR 
• 
Image observed after reduction in size of the leading follicle > 4 mm at two consecutive visits OR  
• 
Haemorrhagic and cystic corpus luteum (FLS at least as large as the leading follicle before 
ovulation) 
 
 
 
 


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Appendix 4: Helsinki Declaration 
 
Ethical Principles for Medical Research Involving Human Subjects Adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
PREAMBLE 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt these 
principles. 
GENERAL PRINCIPLES 
3. The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient 
will be my first consideration," and the International Code of Medical Ethics declares that, "A physician 
shall act in the patient's best interest when providing medical care." 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights.  
 
8. While the primary purpose of medical research is to generate knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 


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or other health care professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and standards. 
No national or international ethical, legal or regulatory requirement should reduce or eliminate any of 
the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other health 
care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value 
and if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
RISKS, BURDENS AND BENEFITS 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study. 
VULNERABLE GROUPS AND INDIVIDUALS 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs and priorities of this group and the research cannot b carried out in a non-vulnerable group. In 


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addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
21. Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for 
research must be respected. 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol.  
The protocol should contain a statement of the ethical considerations involved and should indicate how 
the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
RESEARCH ETHICS COMMITTEES 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any SAEs. No amendment to the protocol 
may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the study’s findings 
and conclusions.  
PRIVACY AND CONFIDENTIALITY 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
INFORMED CONSENT 
25. Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific information needs of 
individual potential subjects as well as to the methods used to deliver the information.  
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject's freely-given informed consent, 


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preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent should be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has 
been approved by a research ethics committee. Consent to remain in the research must be obtained 
as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study or the patient's decision to withdraw from the study 
must never adversely affect with the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impractical to obtain for such research. In such situations the research may be done only 
after consideration and approval of a research ethics committee. 
USE OF PLACEBO 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best current proven intervention(s), except in the following circumstances: 
• 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
Or 
• 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention  


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• 
And the patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm as result 
of not receiving the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
POST-TRIAL PROVISIONS 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent process. 
RESEARCH REGISTRATION AND PUBLICATION AND DISSEMINATION OF RESULTS 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 


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Appendix 5: Serious Adverse Event Report Form 
 
 


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Appendix 6: Pregnancy Collection Form 


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SAP_001.pdf: 
HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
 
 
 
Protocol 151042-002 
NCT03585712 
 
A prospective, multi-center, randomized, cross-over study to assess the effect 
of norgestrel 75 mcg on cervical mucus and ovarian activity during perfect 
use, after one delayed intake and after a missed pill 
 
 
Statistical Analysis Plan 
Final 01 Sep 2019 
 
 
 
 
 
 
 
 
Prepared for: 
 
HRA Pharma 
200 avenue de Paris 
92320 Châtillon, France 
 
 
 
 
 
Prepared by: 
 
Health Decisions 
2510 Meridian Parkway 
Durham, NC 27713 
 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 1 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
 
RESPONSIBILITY 
NAME AND COMPANY SIGNATURE 
DATE 
(DDMMMYYYY) 
Vice President of 
Biostatistics and 
Programming 
 
Health Decisions 
 
 
Senior Project 
Manager 
 
Health Decisions 
 
 
Pharmacokinetic 
Clinical Officer 
Agnès Hemon 
HRA Pharma 
 
 
Head of Clinical 
Operations 
 
HRA Pharma 
 
 
Statistician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 2 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN APPROVAL ......................................................................... 1 
LIST OF ABBREVIATIONS ...................................................................................................... 4 
1.0 
INTRODUCTION ............................................................................................................ 5 
2.0 
PROTOCOL SUMMARY ................................................................................................ 5 
2.1 
Background ................................................................................................................. 5 
2.2 
Objectives ................................................................................................................... 5 
2.3 
Design ......................................................................................................................... 6 
2.4 
Study Endpoints .......................................................................................................... 7 
2.4.1 
Primary Endpoint .................................................................................................. 7 
2.4.2 
Secondary Endpoints ........................................................................................... 7 
2.5 
Sample Size Consideration ....................................................................................... 10 
3.0 
STATISTICAL METHODS ............................................................................................ 10 
3.1 
Statistical Handling Policy and Analysis Conventions ............................................... 10 
3.2 
Subject Disposition .................................................................................................... 11 
3.3 
Protocol Deviations ................................................................................................... 12 
3.4 
Analysis Populations ................................................................................................. 12 
3.5 
Subject Demographics and Pre-Treatment Characteristics ....................................... 13 
3.5.1 
Demographics .................................................................................................... 13 
3.5.2 
Contraceptive History ......................................................................................... 13 
3.5.3 
Gynecological History ........................................................................................ 13 
3.5.4 
Pregnancy History .............................................................................................. 14 
3.5.5 
Substance Use History ....................................................................................... 14 
3.5.6 
Physical Examination ......................................................................................... 14 
3.5.7 
Gynecological Examination ................................................................................ 14 
3.5.8 
Gynecological Assessments .............................................................................. 15 
3.5.9 
Medical History ................................................................................................... 15 
3.5.10 
Pre-Treatment Signs and Symptoms ................................................................. 15 
3.5.11 
Prior and Concomitant Medications ................................................................... 15 
3.5.12 
Screening Transvaginal Ultrasound ................................................................... 16 
3.6 
Treatment Compliance .............................................................................................. 16 
3.7 
Efficacy Analysis ....................................................................................................... 16 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
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3.7.1 
Primary Efficacy Analysis ................................................................................... 16 
3.7.2 
Secondary Efficacy Analyses ............................................................................. 21 
3.7.2.1 Cervical mucus protection in each type of treatment period ........................... 21 
3.7.2.2 Ovarian activity in each type of treatment period ............................................ 22 
3.7.2.3 Protection from conception based on cervical mucus score and OS (binary and 
ternary analyses) .......................................................................................................... 23 
3.7.2.4 Cervical Mucus ............................................................................................... 24 
3.7.2.5 Transvaginal Ultrasound and Hormones ........................................................ 24 
3.8 
Pharmacokinetics ...................................................................................................... 25 
3.9 
Safety Analysis .......................................................................................................... 26 
3.9.1 
Treatment Exposure ........................................................................................... 26 
3.9.2 
Adverse Events .................................................................................................. 26 
3.9.3 
Hematology and Chemistry ................................................................................ 27 
3.9.4 
Vital Signs .......................................................................................................... 27 
3.9.5 
Vaginal Bleeding and Spotting ........................................................................... 27 
3.9.6 
Listing of Pregnancies ........................................................................................ 27 
4.0 
REFERENCES ............................................................................................................. 28 
5.0 
APPENDICES............................................................................................................... 29 
5.1 
Schedule of Assessments ......................................................................................... 30 
5.2 
Adjudication Committee ............................................................................................ 33 
5.3 
Cervical mucus sampling and scoring ....................................................................... 34 
5.4 
Determination of Ovarian Activity Score (OAS) and Ovarian Status (OS) ................. 35 
5.5 
Table of Contents for Data Displays .......................................................................... 36 
 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 4 
LIST OF ABBREVIATIONS 
 
 
Abbreviation  
 
 
Definition 
AE  
 
 
 
 
Adverse Event 
BMI   
 
 
 
Body Mass Index 
BSL 
 
 
 
 
Baseline 
COC   
 
 
 
Combined Oral Contraception 
CRO   
 
 
 
Contract Research Organization 
DMP   
 
 
 
Delayed/Missed Pill 
E2  
 
 
 
 
Estradiol 
e-CRF 
 
 
 
electronic Case Report Form 
EOS   
 
 
 
End-Of-Study 
FAS   
 
 
 
Full Analysis Set 
FASM  
 
 
 
Full Analysis Set – Cervical Mucus 
FASO  
 
 
 
Full Analysis Set – Ovarian Activity 
FASC  
 
 
 
Full Analysis Set – Overall Conception Protection 
FSH   
 
 
 
Follicle-Stimulating Hormone 
ICH   
 
 
 
International Conference on Harmonization 
IMP   
 
 
 
Investigational Medicinal Product 
ITT  
 
 
 
 
Intent-To-Treat 
LC-MS/MS   
 
 
Liquid Chromatography with double Mass Spectrometry 
LH  
 
 
 
 
Luteinizing Hormone 
LNG   
 
 
 
Levonorgestrel 
NG  
 
 
 
 
Norgestrel 
OAS   
 
 
 
Ovarian Activity Score 
OC  
 
 
 
 
Oral contraceptives 
OS (q, a, alp, nlp)   
 
Ovarian Status (quiescence, ovarian activity, ovulation with 
abnormal luteal phase, ovulation with normal luteal phase) 
P4  
 
 
 
 
Progesterone 
PD  
 
 
 
 
Pharmacodynamics 
PK  
 
 
 
 
Pharmacokinetic(s) 
POP   
 
 
 
Progestin Only Pill 
PP  
 
 
 
 
Per-Protocol 
SAF  
 
 
 
Safety 
SAE   
 
 
 
Serious Adverse Event 
SAP   
 
 
 
Statistical Analysis Plan 
T2R-1/T3R-1  
Time of treatment intake on the day before delayed 
intake/missed pill per randomization arm, in treatment period 
2/3 
TMS 
Time of Mucus Scoring 
TVUS  
 
 
 
TransVaginal Ultrasound 
WHO   
 
 
 
World Health Organization 
 
 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
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Page 5 
 
1.0 
INTRODUCTION 
 
This statistical analysis plan (SAP) was developed after review of the 151042-002 study protocol 
version 1.0 26FEB2018 and case report forms (e-CRFs) version 2.0 06JUN2018, but before any 
analysis of the data had begun.  Detailed information is given to aid in the production of the 
statistical output and the statistical section of the Final Study Report.  This document gives a 
summary of the protocol and describes the populations that will be analyzed.  All subject 
characteristics and efficacy and safety parameters that will be evaluated, along with the specific 
statistical methods, are described. 
 
2.0 
PROTOCOL SUMMARY 
 
2.1 
Background 
 
Oral contraceptives (OCs) are the most widely used hormonal method of contraception in the 
United States (US).  Combined estrogen-progestin OCs (COCs) are the most frequently-
prescribed OCs in the US, while progestin-only pills (POPs) are less frequently prescribed. POPs 
are mainly prescribed to breastfeeding women or when the use of a COC is contra-indicated. 
 
Opill® (norgestrel (NG) 75 mcg) is a 2nd generation synthetic progestin-only oral contraceptive  
in the US in 1973 (under the proprietary name Ovrette®) at a daily dose of 75 mcg and first 
marketed in 1974 in the US. NG is a mixture of two enantiomers, only one of which, 
levonorgestrel (LNG), being the active form. LNG have been marketed in the US and in Europe 
for more than 30 years in a wide variety of contraceptive products (including combined and 
progestin-only oral contraceptives, implant, vaginal ring, intrauterine system and emergency 
contraceptives). 
 
There are only very few studies assessing the PK of oral NG/LNG for use as POP and no data 
linking the PK to the pharmacodynamic (PD) action of POPs.  In the light of limited PK and PD 
data on NG and POPs in general that supports the clinical guidance of taking it every day at the 
same time within a three hour window, this exploratory study aims to determine the PD 
mechanisms underlying the contraceptive protection of NG 75 mcg.  Primarily, the study will 
evaluate whether these PD mechanisms are impacted by a delayed intake or a missed pill. 
 
2.2 
Objectives 
 
The primary objectives of the study are: 
 
• to determine the effect of a delayed intake of 6 hours or of a missed pill on cervical mucus 
score compared to cervical mucus score during reported perfect daily use1 of norgestrel 75 
mcg 
• to estimate the duration of the protective effect of cervical mucus after last pill intake of 
norgestrel 75 mcg during reported perfect use1 (The protective effect of cervical mucus is 
considered as present when the score is below or equal 4.) 
 
 
1 defined as the day before the delayed intake or the missed pill 


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The secondary objectives of the study are: 
 
• to evaluate and compare the percentage of subjects with a protective cervical mucus score 
during reported perfect daily use of norgestrel 75 mcg2, during a treatment period with a 
delayed intake of 6 hours and during a treatment period with a missed pill of norgestrel 75 
mcg. 
 
• to evaluate and compare the ovarian activity during reported perfect daily use2, during a 
treatment period with a delayed intake of 6 hours and during a treatment period with a missed 
pill of norgestrel 75 mcg. 
 
• 
to assess if a combination of cervical mucus score and ovarian status can be considered as 
a measure of protection from conception during reported perfect daily use2, during a 
treatment period with a delayed intake of 6 hours and during a treatment period with a missed 
pill of norgestrel 75 mcg. 
 
• to determine levonorgestrel pharmacokinetics after a single dose of norgestrel 75 mcg, at 
steady state, after a delayed intake and after a missed pill. 
 
• to assess the safety of norgestrel 75 mcg taken daily for 12 weeks. 
 
2.3 
Design 
 
This is an exploratory, prospective, multi-center, randomized, cross-over study to assess the 
effect of norgestrel 75 mcg on cervical mucus and ovarian activity during reported perfect daily 
use and after a delayed intake of 6 hours and after a missed pill. 
 
Women of reproductive age (18-35 years old inclusive) who meet eligibility requirements will be 
recruited for this study. This study has a screening period of up to 1 month to demonstrate 
ovulatory status prior to enrollment followed by three 28-day treatment periods (approximately 3 
months) and a possible follow-up of 12 days if ovarian activity shows a follicle ≥ 15 mm is 
observed at the end of period 3 and an end of study (EOS) visit within 5 days. During the 
treatment period 2 the subjects will be randomized into two arms: Arm A will have a delayed pill 
intake of 6 hours on D42 (± 3 days) and Arm B will have a missed pill (24-hour delayed pill intake 
on D42 (± 3 days). In the next treatment period, these subjects will cross-over meaning Arm A 
will have a missed pill (24-hour delayed pill intake) on D70 (± 3 days) and Arm B will have a 
delayed pill intake of 6 hours on D70 (± 3 days) (see Figure 1 below). 
 
Figure 1: Design of the Study 
 
 
 
2 defined as treatment period 1 


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2.4 
Study Endpoints 
 
2.4.1 
Primary Endpoint 
 
The primary outcomes/endpoints are the changes from baseline (BSL), where baseline is the 
day before the infringement. Abbreviations for visits are defined in section 3.7.1. 
 
• Delta from BSL to V2R (Day 42±3) = Mucus score at V2R - score at V2R-1 (Day 41±3): change 
from baseline to 3 (delayed pill period) or 6 hour (missed pill period) after infringement 
 
• Delta from BSL to V2R+1 (Day 43±3) = Mucus score at V2R+1 - score at V2R-1 (Day 41±3): 
Change from baseline to just before pill intake the day after infringement 
 
• Delta from BSL to V3R (Day 70±3) = Mucus score at V3R - score at V3R-1 (Day 69±3): Change 
from baseline to 3 (delayed pill period) or 6 hour (missed pill period) after infringement 
 
• Delta from BSL to V3R+1 (Day 71±3) = Score at V3R+1 - score at V3R-1 (Day 69±3): Change 
from baseline to just before pill intake the day after infringement 
 
The subordinate primary endpoint is the proportions of subjects with “protective effect of cervical 
mucus” the missed pill period and the delayed pill period for the following categories3: 
 
• Full protection by cervical mucus regardless of the use of norgestrel 75 mcg 
• Absence of risk increase further to delayed intake 
• Absence of risk increase further to missed pill 
• Absence of risk increase due to infringement regardless of the type 
• Transient risk increase further to delayed intake 
• Transient risk increase further to missed pill 
• Prolonged risk increase further to delayed intake 
• Prolonged risk increase further to missed pill 
 
2.4.2 
Secondary Endpoints 
 
Cervical Mucus 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8 (inclusive), and 
≥ 9 in reported perfect use period 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8 (inclusive), and 
≥ 9 in delayed pill intake periods 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8 (inclusive), and 
≥ 9 in missed pill periods 
• The percentage of subjects with cervical mucus score ≤ 4 in all periods 
 
The perfect use period is all visits in period 1 of the study. The worst (meaning highest) cervical 
mucus score in the period will be used for the analyses. 
 
 
 
3 see section 3.7.1 for definitions of each risk category  


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Ovarian Activity 
• The percentage of subjects with OSq, OSa, OSalp and OSnlp in reported perfect use period 
• The percentage of subjects with OSq, OSa, OSalp and OSnlp in delayed pill intake periods 
• The percentage of subjects with OSq, OSa, OSalp and OSnlp in missed pill periods 
• The percentage of subjects with OSnlp in all periods 
 
The perfect use period is all visits in period 1 of the study.  The worst (meaning most risk of 
ovulation) ovarian activity category in the period will be used for the analyses. 
 
Conception Protection 
The endpoints will be, for each treatment period, the distribution of subjects: 
• considered as protected: OSq or OSa or cervical mucus score ≤4 
• considered as at risk of conception: OSalp or OSnlp and cervical mucus score ≥ 5 
• minimum protection or unlikely to be protected: OSnlp and cervical mucus score ≥ 9 
• medium protection or likely to be protected: OSnlp and cervical mucus score comprised 
between 5 and 8 (inclusive) or OSalp and cervical mucus score ≥ 5 
• maximum protection or highly likely to be protected: OSq or OSa or a cervical mucus score 
≤ 4 
 
Pharmacokinetics 
• 
PK parameters including C24h, Cmax and AUC 
 
Safety 
• incidence of adverse events 
• bleeding patterns by cycle 
 
A summary of the efficacy objectives and endpoints for the study is below: 
 
Efficacy 
Objective 
Efficacy Endpoint 
Statistical 
Test 
Table 
Number 
Effect on cervical 
mucus score  
Mucus score at V2R - score at V2R-1 (Day 
41±3): change from baseline to 3 (delayed 
pill period) or 6 hour (missed pill period) 
after infringement 
Repeated 
measures 
mixed model 
14.2.1 
Mucus score at V2R+1 - score at V2R-1 (Day 
41±3): Change from baseline to just before 
pill intake the day after infringement 
Repeated 
measures 
mixed model 
14.2.1 
Mucus score at V3R - score at V3R-1 (Day 
69±3): Change from baseline to 3 (delayed 
pill period) or 6 hour (missed pill period) 
after infringement 
Repeated 
measures 
mixed model 
14.2.1 
Score at V3R+1 - score at V3R-1 (Day 69±3): 
Change from baseline to just before pill 
intake the day after infringement 
Repeated 
measures 
mixed model 
14.2.1 
Duration of the 
protective effect 
of cervical mucus  
Full protection by cervical mucus regardless 
of the use of norgestrel 75 mcg 
McNemar 
14.2.3 
Absence of risk increase further to delayed 
intake 
McNemar 
14.2.3 


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Efficacy 
Objective 
Efficacy Endpoint 
Statistical 
Test 
Table 
Number 
Absence of risk increase further to missed pill McNemar 
14.2.3 
Absence of risk increase due to infringement 
regardless of the type 
McNemar 
14.2.3 
Transient risk increase further to delayed 
intake 
McNemar 
14.2.3 
Transient risk increase further to missed pill 
McNemar 
14.2.3 
Prolonged risk increase further to delayed 
intake 
McNemar 
14.2.3 
Prolonged risk increase further to missed pill McNemar 
14.2.3 
Percentage of 
subjects with a 
protective cervical 
mucus score  
The percentage of subjects with cervical 
mucus score ≤ 4, between 5 and 8 
(inclusive), and ≥ 9 in reported perfect use 
period 
McNemar 
14.2.6 
The percentage of subjects with cervical 
mucus score ≤ 4, between 5 and 8 
(inclusive), and ≥ 9 in delayed pill intake 
periods 
McNemar 
14.2.6 
The percentage of subjects with cervical 
mucus score ≤ 4, between 5 and 8 
(inclusive), and ≥ 9 in missed pill periods 
McNemar 
14.2.6 
The percentage of subjects with cervical 
mucus score ≤ 4 in all periods 
McNemar 
14.2.6 
Ovarian activity  
The percentage of subjects with OSq, OSa, 
OSalp and OSnlp in reported perfect use 
period 
 
McNemar 
14.2.9 
The percentage of subjects with OSq, OSa, 
OSalp and OSnlp in delayed pill intake periods 
McNemar 
14.2.9 
The percentage of subjects with OSq, OSa, 
OSalp and OSnlp in missed pill periods 
McNemar 
14.2.9 
The percentage of subjects with OSnlp in all 
periods 
McNemar 
14.2.9 
Combination of 
cervical mucus 
score and ovarian 
status  
Percentage of subjects in each period 
considered as protected: OSq or OSa or 
cervical mucus score ≤4 
None 
14.2.10 
Percentage of subjects in each period 
considered as at risk of conception: OSalp or 
OSnlp and cervical mucus score ≥ 5 
None 
14.2.10 
Percentage of subjects in each period with 
minimum protection or unlikely to be 
protected: OSnlp and cervical mucus score ≥ 
9 
None 
14.2.10 
Percentage of subjects in each period  with 
medium protection or likely to be protected: 
OSnlp and cervical mucus score comprised 
None 
14.2.10 


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Efficacy 
Objective 
Efficacy Endpoint 
Statistical 
Test 
Table 
Number 
between 5 and 8 (inclusive) or OSalp and 
cervical mucus score ≥ 5 
Percentage of subjects in each period with 
maximum protection or highly likely to be 
protected: OSq or OSa or a cervical mucus 
score ≤ 4 
None 
14.2.10 
 
 
2.5 
Sample Size Consideration 
 
Approximately 70 subjects will be screened to have at least 45 subjects who complete the study. 
 
The primary analysis is based on the score of cervical mucus as a quantitative variable because 
it is expected to be the most powerful analysis based on the consistent mechanism of action of 
norgestrel on cervical mucus.  However the justification of the sample size will not be based on 
the primary analysis as there is no basis provided by published data on this parameter, such as 
order of magnitude of the variance covariance matrix of the change from time point of reference.  
This is the reason why the sample size calculation will be based on proportions of women with 
no loss of protection. 
 
A total sample size of 45 subjects who complete the study should allow to detect a loss of 
protection that would demonstrate a pertinent effect on a substantial proportion of the population.  
Indeed if the difference between a cycle (or day) with a perfect use and a cycle (or day) with an 
infringement in the schedule is 14 % in the expected proportions of women with a loss of 
protection at any time and if the proportion of discordances between the 2 situations is 17% then 
the exact power is equal to 79.1%.  If the expected difference in proportions is 15% with a rate 
of discordance of 18% then the exact power is 82.4% for an unconditional test.  The expected 
difference in proportions need, therefore, to reach 14-15 % to get a sufficient power for detecting 
a significant difference.  This difference in proportions is a substantial difference knowing that 
most of change in status are in the same direction i.e. from protection to loss of protection. 
 
3.0 
STATISTICAL METHODS 
 
3.1 
Statistical Handling Policy and Analysis Conventions 
 
This section details general policies to be used for the statistical analyses.  Departures from 
these general policies may be given in the specific detailed sections of this SAP.  When this 
situation occurs, the rules set forth in the specific section take precedence over the general 
policies.  The following policies will be applied to all data presentations and analyses. 
 
• All statistical tests will use a significance level of  = 0.05.  Two-tailed tests will be performed 
for all analyses that use statistical testing. 
 
• All p-values will be rounded to 3 decimal places.  All p-values that round to 0.000 will be 
presented as ‘<0.001’ and p-values that round to 1.000 will be presented as ‘>0.999’.  Any 


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p-value  0.05 will be considered statistically significant and will be marked with one asterisk 
(e.g., 0.025*). 
 
• Summary statistics will consist of the number and percentage of responses in each category 
for discrete variables, and the mean, median, standard deviation (SD), minimum, and 
maximum for continuous variables. 
 
• All mean values will be formatted to one more decimal place than the measured value.  
Standard deviation values will be formatted to two more decimal places than the measured 
value.  Median values will be formatted to same decimal place as the measured values when 
that is possible without losing accuracy; otherwise, they will be formatted to one more decimal 
place than the measured values. 
 
• All percentages will be rounded to one decimal place.  The number and percentage of 
responses will be presented in the form XX (XX.X), where the percentage is in the 
parentheses.  The denominator for percentage calculations will be the number of non-missing 
observations. 
 
• All listings will be sorted for presentation in order of site number, subject number, and date 
of procedure or event. 
 
• All analysis and summary tables will have the population sample size (n and % (% will not 
be shown in the column header if the table also presents means)) for each treatment group 
in the column heading. 
 
• Calculating change from baseline to a visit will be done as follows: Change = Visit – Baseline. 
 
• Baseline is defined as the last data point before the day of infringement (i.e. V2R-1 or V3R-1). 
 
• Version 9.4 of SAS or higher will be the statistical software package used to produce all 
summaries, listings, statistical analyses, and graphs. 
 
3.2 
Subject Disposition 
 
Subject disposition will be summarized for the All Enrolled population (see Section 3.4 for 
Analysis Population definitions).  The following data will be presented: 
 
• The number and percentage of subjects who completed or discontinued prematurely from 
the study by each treatment phase (reported perfect use, delayed pill intake and missed pill) 
will be presented.  The number and percentage of subjects who discontinued for each reason 
will also be summarized. 
 
• A listing of subjects that discontinued prematurely from the study.  The listing will include site 
number, subject number, age, number of days on drug, and reason for discontinuation.  The 
number of days on drug will be calculated using the reported dosing days based on diary 
data. 
 
• The number and percentage of subjects at each scheduled visit for all subjects. 


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The End of Trial (DS) CRF will be used to determine who discontinued prematurely from the 
study. 
 
3.3 
Protocol Deviations 
 
The number and percentage of subjects with each protocol violation and the total will be 
tabulated for all subjects for the Intent-to-Treat population. 
 
3.4 
Analysis Populations 
 
All Enrolled – This population includes all successfully screened subjects enrolled in the study. 
AE will be primarily used for baseline and demographics tables including disposition. 
 
Safety (SAF) – This population consists of all subjects who took at least one dose of study 
medication. 
 
The Safety (SAF) set will be used for safety purposes including adverse events, intermenstrual 
bleedings and labs data, but also to describe the population and to summarize and describe the 
level of compliance based on daily intake. 
 
Intent-to-Treat (ITT) – This population consists of all subjects who were randomized. ITT will be 
the primary population used for sensitivity analyses. 
 
The ITT population will be used  in the primary sensitivity analysis for assessing the effect of 
delayed or missed pill on cervical mucus scores and on secondary pharmacodynamic analyses.  
 
Full Analysis Set – This population consists of all evaluable subjects. These are subjects who 
have complete (including mitigated) data on cervical mucus and ovarian activity for the 
adjudication committee to assess evaluability of a cycle. They will be classified into 3 analysis 
populations depending on the question of interest. There are 3 full analysis sets defined: Cervical 
Mucus, Ovarian Activity and Conception Protection. Full analysis set requires at least one 
evaluable treatment cycle. 
 
• Full Analysis Set – Cervical Mucus (FASM) – This population is composed of all randomized 
and treated subjects with cervical mucus information (mucus score) at the second or third 
treatment periods for the questions related to mucus on the effect of unperfect use (delayed 
and missed intake) of norgestrel. 
 
• 
Full Analysis Set – Ovarian Activity (FASO) – This population consists of all randomized and 
treated subjects with ovarian activity information (OAS: ovarian activity score) at the second 
or third treatment periods for questions related to ovarian activity. 
 
• Full Analysis Set – Conception Protection (FASC) – This population consists of all 
randomized and treated subjects with information on mucus and ovarian activity for questions 
related to overall conception protection. 
 
Cycles with a very early ovulation (within 10 days before the DMP period) at period 2 or 3 may 
be removed from the set of evaluable cycles in a sensitivity analysis or included as failure 


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depending upon the question of interest because the effect of intake infringement cannot be 
assessed in these cycles.  The assessment of evaluable cycles, the exclusion of cycles from a 
given analysis and the exclusion of a subject from the FASM/FASO/FASC will be decided in a 
blinded manner by an independent adjudication committee. 
 
The FASM, FASO and FASC (or evaluable populations) will be used in the primary analysis for 
assessing the effect of delayed or missed pill on cervical mucus scores and on secondary 
pharmacodynamic analyses. 
 
Per-protocol (PP) – This population consists of all subjects from the FASM/FASO/FASC without 
major protocol violation/deviation and with complete cervical mucus and ovarian activity data for 
all the three treatment periods.  Relevant protocol violation/deviation will be defined during the 
data review. This will include pill intake compliance issues and early ovulation. 
 
The PP population will be used for assessing the efficacy and PK results without missing data 
and possibly biased data due to protocol violations/deviations.  This will be the "cleanest" results 
for assessing the effect of infringement and the PD effect at the expense of completeness of the 
set of randomized women and representativeness of the treated population. 
 
The number of subjects in each population will be summarized for all subjects. 
 
3.5 
Subject Demographics and Pre-Treatment Characteristics 
 
Subject demographics will be summarized for the All Enrolled and Full Analysis Set – Cervical 
Mucus populations.  Pre-treatment characteristics will be summarized for the All Enrolled 
population. The demographics and pre-treatment characteristics will be summarized for all 
subjects. 
 
3.5.1 
Demographics 
 
The summary of demographics will include age, race, ethnicity, weight and height at screening 
and BMI.  The summary will be done for the All Enrolled and FAS Cervical Mucus populations 
and will include: 
 
• The number and percentage of subjects within each category of race and ethnicity.    
 
• The sample size, mean, median, SD, minimum, and maximum values for age, weight, height 
and BMI.  Age will be calculated (with the INTCK function) using the Screening Visit Date 
and the Date of Birth.   
 
3.5.2 
Contraceptive History 
 
The number and percentage of subjects reporting contraceptive history for each contraceptive 
method will be summarized.  For those subjects not at risk of pregnancy, the reasons why not 
at risk will also be summarized. 
 
3.5.3 
Gynecological History 
 


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The summary of gynecological history will include average cycle length, usual flow duration, 
heaviest volume of flow, history of irregular periods, yeast infection history and bacterial 
vaginosis history.  The summary will include: 
 
• The number and percentage of subjects within each category of heaviest volume of flow, 
history of irregular periods, yeast infection history and bacterial vaginosis history.  
 
• The sample size, mean, median, SD, minimum, and maximum values for average cycle 
length and usual flow duration. 
 
3.5.4 
Pregnancy History 
 
The summary of pregnancy history will summarize the following endpoints: 
 
• The number and percentage of subjects within each category of complications during 
pregnancy, complications with baby, any pregnancy planned within the next 4 months and 
breastfeeding history and current status.  
 
• The sample size, mean, median, SD, minimum, and maximum values for number of times 
pregnant and number of live births. 
 
3.5.5 
Substance Use History 
 
The summary of substance use will summarize the number and percentage of subjects for the 
following categories: 
 
• Alcohol use 
• Marijuana use 
• Illicit drug use 
 
The sample size, mean, median, SD, minimum, and maximum values quantify use of these 
substances will also be presented. 
 
3.5.6 
Physical Examination 
 
Physical examinations will be performed at screening.  Each body system will be categorized as 
normal or abnormal.  The number and percentage of subjects in each category will be given for 
each body system.   
 
3.5.7 
Gynecological Examination 
 
Gynecological examinations will be performed at screening.  Each body system will be 
categorized as normal or abnormal.  The number and percentage of subjects in each category 
will be given for each body system.   
 


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3.5.8 
Gynecological Assessments 
 
The summary of gynecological assessments will summarize the number and percentage of 
subjects for the following categories: 
 
• Chlamydia test type 
• Chlamydia test results 
• Chlamydia treated (positive test results only) 
• Gonorrhea test type 
• Gonorrhea test results 
• Gonorrhea treated (positive test results only) 
• Vaginitis test results 
• Vaginosis test results 
• Vaginosis treated (positive test results only) 
• PAP smear required? 
• PAP smear results 
 
3.5.9 
Medical History 
 
The number and percentage of subjects reporting a medical history for each body system will 
be summarized. 
 
3.5.10 
Pre-Treatment Signs and Symptoms 
 
Pre-treatment signs and symptoms will be coded using MedDRA 21.0.  The number and 
percentage of subjects reporting each pre-treatment sign and symptom will be summarized by 
system organ class and preferred term for the Safety population.  The number and percentage 
of subjects reporting any pre-treatment signs and symptoms will also be reported. 
 
If a subject reports the same pre-treatment sign or symptom more than once, then that subject 
is only counted once for the summary of that pre-treatment sign or symptom, using the most 
severe intensity. 
 
3.5.11 
Prior and Concomitant Medications 
 
Summaries for prior and concomitant medications will be done for the Safety population.  Each 
summary below will be done for all subjects: 
 
• Prior Medications – Prior medications are considered to be any medication that was stopped 
prior to the date of the first dose of study drug. 
 
• Concomitant Medications – Concomitant medications are considered to be any medication 
that was taken on or after the date of the first dose of study drug. 
 
All medications recorded on the CRF will be coded to the therapeutic drug classes and generic 
drug names using the World Health Organization (WHO) Drug classifications.  The WHO Drug 
dictionary version used for this study will be March 2018. 
 


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Each summary will give the number and percentage of subjects who took medications that were 
coded to each generic drug name and therapeutic drug class, as well as the number and 
percentage of subjects that took any medication at all. If the start of end date of the medication 
is a partial date (or completely unknown) then the medication will be classified as a concomitant 
medication unless the partial end date is clearly before the first dose of study drug. 
 
3.5.12 
Screening Transvaginal Ultrasound 
 
The endometrial stripe thickness and endometrium appearance at the screening transvaginal 
ultrasounds will be summarized for all subjects using the Safety population. 
 
3.6 
Treatment Compliance 
 
Compliance will be summarized for the Safety and FASM populations. 
 
Compliance =  100 * (total # pills indicated as taken on diary entries) / (date last pill taken – date 
first pill taken +1 – number of planned missed doses). The compliance calculation will be different 
for each treatment group, as based on treatment schedule. The reported perfect use period 
(treatment period 1) and the delayed pill period have 0 planned missed doses while the missed 
pill period has 1 planned miss dose. 
 
The following information will be presented for each treatment group for compliance: 
 
Summary statistics (sample size, mean, median, SD, minimum, and maximum) for treatment 
compliance 
 
The number and percentage of subjects in each of the following categories of compliance: <75%, 
75% - <85%, 85% - <95%, 95% - <100%, and 100%.  
 
Compliance will also be summarized for the Safety population for treatment periods 1 and 2 
combined as well as for all treatment periods combined. 
 
3.7 
Efficacy Analysis 
 
All efficacy analyses will be done for the appropriate FAS, PP and ITT populations unless 
otherwise specified. 
 
3.7.1 
 Primary Efficacy Analysis 
 
The primary working hypothesis states that an infringement in the schedule of intake of 
norgestrel 75 mcg has a negative impact on the level of conception protection of women. 
 
The primary objectives of the study is to verify whether a delayed intake of 6 hours or a missed 
pill of norgestrel 75 mcg has an effect on cervical mucus protection and more specifically tends 
to increase the cervical mucus score compared to reported perfect use of norgestrel 75 mcg just 
before infringement. 
 
The primary population of subjects is the FASM. It is composed of all randomized and treated 
women with cervical mucus information (mucus score) at the second or third treatment period. 


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A sensitivity analysis using the ITT population will be done to compare to the primary analysis 
on the FASM population.  Additionally, the analysis will be performed for the PP population. 
 
The primary treatment periods of interest are the second and third treatment periods. 
 
The primary assessment criterion of interest is the cervical mucus score during the treatment 
periods 2 and 3. 
 
The symbols used in the statistical section are: 
 
• T is the time of treatment (pill intake) 
• TMS is the time of mucus evaluation/scoring 
• TMS score is the value of mucus score at the time of mucus evaluation 
• A or B concerns arm A or B respectively 
• R denotes the day of pill intake infringement in period 2 and period 3 
• R-1 denotes the day before infringement in periods 2 and 3 
• R+1 denotes the day after infringement in periods 2 and 3 
• V1, V2 and V3 or 1, 2 and 3 denote visits during the first, second and third treatment periods 
respectively. 
• T2R-1 and T3R-1 are times of pill intake at V2R-1 and V3R-1 respectively. 
 
The primary time points of interest are: 
 
• Time of mucus scoring (TMS) the day before infringement (delayed pill or missed pill) in 
period 2 and period 3 (baseline): 
o TMS2R-1 = T2R-1+ 8 h ± 30 min at V2R-1 and 
o TMS3R-1 = T3R-1 + 8 h ± 30 min at V3R-1. 
 
• Time of mucus scoring the day of infringement in period 2 or 3: 
o Subjects belonging to arm A 
▪ TMS2A,R = T2R-1 +3 h ± 15 min at V2R and 
▪ TMS3A,R = T3R-1 + 6 h ± 15 min at V3R 
o Subjects belonging to arm B 
▪ TMS2B,R = T2R-1 + 6 h ± 15 min at V2R 
▪ TMS3B,R = T3R-1 +3 h ± 15 min at V3R 
 
• Time of mucus scoring the day after infringement (both arms): 
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 and 
o TMS3R+1 = T3R-1 - 30 min at V3R+1. 
 
The time of pill intake the day after infringement should be the same as the day before 
infringement (expected around 9 am). 
 
The primary baseline time points are: 
 
• TMS2R-1 = T2R-1+ 8 h ± 30 min at V2R-1 and 
• TMS3R-1 = T3R-1 + 8 h ± 30 min at V3R-1 
 


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Around 8 hours after pill intake the day before infringement. 
 
The primary response time points are: 
 
• Arm A: 
o TMS2A,R = T2R-1 + 3 h ± 15 min at V2R 
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 
o TMS3A,R = T3R-1 +6 h ± 15 min at V3R 
o TMS3R+1 = T3R-1 - 30 min (before pill intake) at V3R+1 
 
• Arm B 
o TMS2B,R = T2R-1 +6 h ± 15 min at V2R 
o TMS2R+1 = T2R-1 - 30 min (before pill intake) at V2R+1 
o TMS3B,R = T3R-1 + 3h ± 15 min at V3R 
o TMS3R+1 =T3R-1 - 30 min (before pill intake) at V3R+1. 
 
The primary measures of mucus are taken at the time presented in the following figure: 
 
 
 
The primary outcomes/endpoints are the changes from baseline (BSL): 
 
• Delta from BSL to V2R = Mucus score at V2R - score at V2R-1 (period 2): change from baseline 
to 3 or 6 hour after infringement 
• Delta from BSL to V2R+1 = Mucus score at V2R+1 - score at V2R-1 (period 2): Change from 
baseline to just before pill intake the day after infringement 
• Delta from BSL to V3R = Mucus score at V3R - score at V3R-1 (period 3) change from baseline 
to 3 or 6 hour after infringement 
• Delta from BSL to V3R+1 = Score at V3R+1 - score at V3R-1 (period 3) Change from baseline to 
just before pill intake the day after infringement 
 
The primary model of interest is a mixed model for repeated measures using as response delta 
to V2R, delta to V2R+1, delta to V3R and delta to V3R+1. The covariates will be the period (or period 
effect), the intervention (type of infringement: missed pill or delayed pill), the sequence of 
intervention (missed pill then delayed pill and vice versa), the time (visit) and the subject. Time, 
period intervention type, and sequence will be considered as categorical variables. The subject 
as random effect (RANDOM statement of the MIXED procedure). This will permit to take into 
account the fact that measures from each period are derived from the same subjects. A time 
repeated effect (REPEATED statement of the MIXED procedure) within each combination 
subject* period (SUBJECT = subject* period as option of the 


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REPEATED statement). This will permit to take into account the fact that for each subject, at 
each period several measures are performed over time. The proper structure of the variance 
covariance matrix will be retained using the best fit among unstructured matrix (UN) compound 
symmetry (CS) and autoregressive structure (AR1). 
 
The primary test of interest will be the significance of the overall mean (intercept). This will 
answer the question: is the overall mean change from baseline different from zero? Or does the 
infringement of schedule regardless the type of infringement lead to a change in mucus score? 
 
The contrasts or estimates of interest are 
 
• The effect of infringement type: does the effect of missed pill differ from the effect of 6 hours 
delay? If the answer is yes, then a signal of effect is detected. 
• The effect of time: does the response on the day of infringement differ from the response on 
the day after infringement? If the answer is yes, then a signal of effect of infringement is 
detected. 
 
The primary cut-off for full cervical mucus protection is a cervical mucus score of 4. There is, 
therefore, a good conception protection by cervical mucus if the cervical mucus score is ≤ 4.  If 
the cervical mucus was too thick to be collected (and thus a cervical mucus score could not be 
obtained) the analyses using the FASM, ITT and PP populations will use the following 
approach: 
 
Baseline Mucus Score 
Post-Baseline Mucus Score 
Mucus Score Used in Analysis 
0-4 
Too thick to collect 
Score equal to baseline 
>4 
Too thick to collect 
Post-baseline score =4 
Too thick to collect 
Any observed mucus score 
Baseline score =0 
Too thick to collect 
Too thick to collect 
Change from baseline = 0 
 
A sensitivity analysis using the FASM population will also be done and if the cervical mucus was 
too thick to be collected (and thus a cervical mucus score could not be obtained) the mucus 
score will be assigned using multiple imputation. 
 
The SAS code for the 2 primary contrasts of interest are: 
 
PROC MIXED DATA=MUCUS; 
CLASS VISIT PERIOD INTERVENTION SEQUENCE; 
MODEL MUCUS_CHG = PERIOD INTERVENTION VISIT SEQUENCE / S; 
RANDOM SUBJ_ID; 
REPEATED  / SUBJECT=SUBJ_ID*PERIOD; 
ESTIMATE ‘EFFECT OF INFRINGEMENT’ INTERVENTION 1 -1 ; 
ESTIMATE ‘EFFECT OF TIME’ VISIT 1 -1 1 -1; 
RUN; 
 
Subordinated Primary Objective 
 


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The subordinate primary objective is to estimate the duration of the protective effect of cervical 
mucus after last pill intake of norgestrel 75 mcg during reported perfect use (at the day before 
the infringement). 
 
The possible increase in mucus score may have no detectable effect on conception risk 
depending on the level of score because it increased but remained below a threshold of good 
protection.  
 
The mucus score has a value ranging from zero (not propicious for spermatozoïds progression: 
maximal protection) to 12 (propicious for spermatozoïds progression: minimal protection). The 
primary cut-off for full cervical mucus protection is a cervical mucus score of 4. There is, 
therefore, a good conception protection by cervical mucus if the cervical mucus score is ≤ 4.  If 
the cervical mucus was too thick to be collected (and thus a cervical mucus score could not be 
obtained) the subordinate primary objective analysis will consider the sample to have good 
contraception protection and have a cervical mucus score ≤ 4.  Otherwise if the cervical mucus 
score is missing the subject will not be included in the analysis for the missing endpoint. 
 
The responses of interest are: 
 
1. The full protection by cervical mucus regardless of the use of norgestrel 75 mcg if the score 
was and remained at 4 or below at V2R-1, V2R, V2R+1, V3R-1, V3R and V3R+1. The full protection 
by the mucus lasted for 2 x 3 days. The proportion of patients meeting this criterion is pFP. 
 
2. The absence of risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement and remained at 4 or less the day of infringement and the day after the delayed pill 
intake. The protection by the mucus lasted at least up to the day after infringement. The 
proportion of patients fulfilling this criterion is pdelay. 
 
3. The absence of risk increase further to missed pill: The score was ≤ 4 the day before 
infringement and remained at 4 or less the day of infringement and the day after missed pill. The 
protection by the mucus lasted at least up to the day after infringement. The proportion of 
patients fulfilling this criterion is pmissed. 
 
4. The absence of risk increase due to infringement regardless of the type: The score was ≤ 4 
the day before infringement and remained at 4 or less the day of infringement and the day after 
infringement. The protection by the mucus lasted at least up to the day after infringement. The 
proportion of patients fulfilling this criterion is pbreach. 
 
5. The transient risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement but came back to 4 or less the day after the 
delayed pill intake. The protection by the mucus was interrupted the day of infringement. The 
proportion of patients fulfilling this criterion is pdelay,transient risk. 
 
6. The transient risk increase further to missed pill: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement but came back to 4 or less the day after the 
delayed pill intake, The protection by the mucus was interrupted the day of infringement. The 
proportion of patients fulfilling this criterion is pmissed,transient risk. 
 


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7. The prolonged risk increase further to delayed intake: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement and the day after the delayed pill intake. The 
protection by the mucus was interrupted the day of infringement and at least up to the day after. 
The proportion of patients fulfilling this criterion is pdelay, prolonged risk. 
 
8. The prolonged risk increase further to missed pill: The score was ≤ 4 the day before 
infringement, exceeded 4 the day of infringement and the day after the missed pill. The protection 
by the mucus was interrupted the day of infringement and at least up to the day after. The 
proportion of patients fulfilling this criterion is pmissed, prolonged risk. 
 
Comparison between the missed pill and the delayed pill can easily be performed and tested 
through a stratified McNemar test (stratification on the site, CMH option in SAS). The SAS 
glimmix procedure for repeated measures was not retained for decision making test because 
convergence issues in fitting the model are too frequent. The first null hypothesis is H0: 
Proportion of protected women at baseline (R-1) is equal to the proportion of protected women 
after schedule infringement and more specifically at Day R (27 hours and 30 hours post 
treatment). The second null hypothesis (which is only performed for the missed pill arm) is the 
equality of proportions at baseline (R-1) and at Day R+1 (48 hours post treatment). 
 
3.7.2 
Secondary Efficacy Analyses 
 
3.7.2.1 
Cervical mucus protection in each type of treatment period 
 
The aim of this secondary objective is to assess the level of cervical mucus protection during 
reported perfect use, during a treatment period with a delayed pill intake of 6 hours and during 
a treatment period with a missed pill of norgestrel 75 mcg. The FASM population will be used 
for the analysis and a sensitivity analysis will be done using ITT and PP. 
 
The time frames are: 
 
• reported perfect use: all the visits of the period 1 
• delayed pill intake: all the visits of the period 2 for Arm A and all the visits of period 3 for Arm 
B.  
• missed pill: all the visits of the period 2 for Arm B and all the visits of period 3 for Arm A. 
 
The assessment criterion is the cervical mucus score. The cut off is a cervical mucus score of 
4. There is conception protection by cervical mucus if the cervical mucus score is ≤ 4. 
 
The endpoints are: 
 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in 
reported perfect use period 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in 
delayed pill intake periods 
• The percentage of subjects with cervical mucus score ≤ 4, between 5 and 8, and ≥ 9 in 
missed pill periods 
• The percentage of subjects with cervical mucus score ≤ 4 in all periods 
 


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If the cervical mucus was too thick to be collected (and thus a cervical mucus score could not 
be obtained) the analysis will consider the sample to have good contraception protection and 
have a cervical mucus score ≤ 4.  Otherwise if the cervical mucus score is missing the subject 
will not be included in the analysis.  A period must have at least 7 cervical mucus assessment 
to be included in the summaries.  A stratified McNemar test (stratification on the site, CMH option 
in SAS) will be used to compare the distribution of cervical mucus scores in the perfect use 
period to the delayed and missed pill periods (pairwise vs perfect use). 
 
The worst (meaning highest) cervical mucus score in the period will be used for the analyses. 
  
3.7.2.2 
Ovarian activity in each type of treatment period 
 
The aim of this secondary objective is to describe the distribution of the ovarian status among 
the subjects, during reported perfect use, during a treatment period with a delayed pill intake of 
6 hours and during a treatment period with a missed pill of norgestrel 75 mcg. The adjucation 
committee will evaluate whether cycles should be excluded from analyses (including period 1 
cycles if low compliance of taking study drug). The details for the review process will be defined 
in a separate document prepared for the adjudication process. The FASO population will be 
used for the analysis and a sensitivity analysis will be done using ITT and PP. 
 
The time frames are: 
 
• reported perfect use period: all the visits of the period 1 
• delayed pill intake period: all the visits of the period 2 for Arm A and all the visits of period 3 
for Arm B 
• missed pill period: all the visits of the period 2 for Arm B and all the visits of period 3 for Arm 
A 
 
The assessment criterion is the OS as defined in Appendix 5.4. 
 
The OS are ranked depending on the risk of conception: OSnlp > OSalp > OSa > OSq. The OS 
classification will be determined by the adjudication committee. 
 
For each treatment period the most risky OS will be considered. 
 
The endpoints are: 
 
• The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in reported perfect use period 
• The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in delayed pill intake periods 
• The percentage of subjects with OSq, OSa, OSa/OSalp and OSnlp in missed pill periods 
• The percentage of subjects with OSnlp in all periods 
 
A stratified McNemar test (stratification on the site, CMH option in SAS) will be used to compare 
the distribution of ovarian activity classification in the perfect use period to the delayed and 
missed pill periods (pairwise vs perfect use). The worst (meaning most risk of ovulation) ovarian 
activity category in the period will be used for the analyses. 
 


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3.7.2.3 
Protection from conception based on cervical mucus score and OS (binary and 
ternary analyses) 
 
Based on cervical mucus score and OS only, the aim of these exploratory analyses are to assess 
if a combination of cervical mucus score and ovarian status can be considered as a measure of 
protection from conception or not and the level of protection, during reported perfect use of 
norgestrel 75 mcg and after a delayed intake/missed pill. The FASC population will be used for 
the analysis and a sensitivity analysis will be done using ITT and PP. 
 
For both analyses, the assessment criteria will be the OS and the highest cervical mucus score 
during the 3 visits before a postovulatory image is obtained including the visit when the 
postovulatory image is obtained. 
 
For the OS, the risk of conception is ranked depending on the OS: OSnlp > OSalp > OSa > OSq 
and for each treatment period the most risky OS will be considered. 
 
Binary analysis 
The aims of this analysis is to determine whether a subject is protected on not, according to the 
algorithm presented below: 
 
Conception protection based on OS and cervical mucus score (binary analysis) 
 
The endpoints will be, for each treatment period, the distribution of subjects: 
• considered as protected: OSq or OSa OR cervical mucus score ≤4 
• considered as at risk of conception: OSalp or OSnlp AND cervical mucus score ≥ 5 
 
Ternary Analysis 
The aim of this analysis is to determine the level of protection for a subject, according to the 
table below. 
 
Conception protection based on OS and cervical mucus score 
 
 
 
Ovarian Status 
 
 
OSq 
OSa 
OSalp 
OSnlp 
Highest
Mucus 
score 
0-4 
maximum 
maximum 
maximum maximum 
5-8 
maximum 
maximum 
medium 
medium 
9-12 
maximum 
maximum 
medium 
minimum 
 
The classification of OS (and thus conception protection level also) will be determined by the 
adjudication committee.  


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The endpoints will be, for each treatment period, the distribution of subjects with: 
 
• Minimum protection or unlikely to be protected: OSnlp and cervical mucus score ≥ 9 
• Medium protection or likely to be protected: OSnlp and cervical mucus score comprised 
between 5 and 8 or OSalp and cervical mucus score ≥ 5 
• Maximum protection or highly likely to be protected: OSq or OSa or a cervical mucus score ≤ 
4 
 
3.7.2.4 
Cervical Mucus 
 
Details on cervical mucus score calculations are in Section 5.3. The following information will be 
summarized for all subjects in the Safety population using descriptive statistics. 
 
• Was cervical mucus too thick to be collected? 
• Was cervical mucus collected prior to TVUS? 
• Viscosity score 
• Ferning score 
• Spinnbarkeit score 
• Cellularity score 
• Total cervical mucus score 
 
A plot of the total cervical mucus score by visit will be done for the Safety population. 
 
3.7.2.5 
Transvaginal Ultrasound and Hormones 
 
Transvaginal ultrasound (TVUS) examinations will be summarized at all assessed visits for the 
Safety population. The following endpoints will be summarized for the screening visit, each of 
the 3 treatment periods, delayed pill period and missed pill period: 
 
• Was postovulatory image seen? 
• Right Ovary 
o Presence of follicles 
• Left Ovary 
o Presence of follicles 
• Any abnormalities found? 
 
For each of the 3 treatment periods subjects will be counted as having the outcome (e.g, had a 
postovulatory image seen) if the outcome happens at least once during the treatment period.  
Summaries will also be done by infringement type. 
 
TVUS largest follicle diameter measurement: The time course of the diameter will be presented 
graphically along with P4 and E2 (see below) at each visit.  
 
Hormones 
 
Profile graphs for each subject will be prepared for P4 and E2 and will include largest follicle 
diameter (largest diameter for each day) also. 


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3.8 
Pharmacokinetics  
 
The PK profile of LNG after administration of norgestrel 75 mcg will be assessed at different 
times during the study. 
 
The PK profile of LNG will first be assessed at Day 1 after the first administration of norgestrel 
75 mcg in fasted conditions. 
 
All the subjects will be sampled at different time points after administration as presented in the 
table below: 
 
PK Sampling Schedule at Day 1 
 
Sampling times 
 
predose 
1h 
2h 
4h 
6h 8h 
12h 
24h 
Odd # 
 
X 
 
X 
 
X 
 
X 
Even # 
X 
 
X 
 
X 
 
X 
 
 
During the first visit of the 3rd week of treatment, all the subjects will be sampled at different 
times points. If the visit is in the morning, they will be sampled predose and between 0.5h and 
2h post administration. If the visit is in the afternoon, they will be sampled between 5h and 9h 
post administration. The plasma concentration(s) for each subject will be reported with the 
nominal time of sampling. 
 
During the DMP period, the sampling schedule will depend on the arm the subjects had been 
randomized in (see table below). 
 
PK Sampling Schedule during the DMP Period 
 
DMP 2 
DMP 3 
 
V2R-1 
V2R 
V2R+1 
V3R-1 
V3R 
V3R+1 
 
T2R-1 
+ 8h 
T2R-1 
+ 3h 
T2R-1 
+ 5.5h 
T2R-1 
+ 6h 
T2R-1 
+ 7.5h 
T2R-1 
- 0.5h 
T3R-1 
+ 8h 
T3R-1 
+ 3h 
T3R-1 
+ 5.5h 
T3R-1 
+ 6h 
T3R-1 
+ 7.5h 
T3R-1 
- 0.5h 
Arm A 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
Arm B 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
The mean plasma concentration for each time point will be calculated: 
• V2/3R-1: C2/3R-1,8h (Arm A + Arm B) 
• V2/3R: C2R-1,27h (Arm A), C3R-1,27h (Arm B), C2R-1,29.5h (Arm A), C3R-1,29.5h (Arm B), C2R-1,30h 
(Arm B), C3R-1,30h (Arm A), C2R,1.5h (Arm A), C3R,1.5h (Arm B) 
• V2/3R+1: C2/3R+1,-0.5h (Arm A + Arm B) 
 
The concentration of LNG will also be determined in all subjects during the 1st visit of study 
week 5 (V21) and 9 (V31). The sample will be drawn within 30 minutes of the mucus analysis. 
The concentrations will be reported as C21 and C31. 
 
LNG concentrations at each timepoint will be summarized in a table presenting summary 
statistics (sample size, mean, median, SD, minimum, and maximum) for all treatment periods 
for the PP population. A figure will be created to display the mean concentrations at each 
timepoint for all treatment periods. 
 


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3.9 
Safety Analysis 
 
All safety analyses will be done for the Safety population.  
 
All laboratory data will be presented in the conventional United States (US) units, as reported by 
the central laboratory, including normal ranges, and if an abnormal result triggers an AE reporting 
or not.   
 
Final evaluation is defined to be the last evaluation performed after the first dose of study drug 
was taken.   
 
3.9.1 
Treatment Exposure 
 
Treatment exposure will be calculated using the following formula:  
 
Exposure = Last Date of Dosing – First Date of Dosing + 1.  
 
The number of days of treatment exposure will be summarized using descriptive statistics.  
 
3.9.2 
Adverse Events 
 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.  Incidence of adverse events will be summarized for each treatment group 
by system organ class and preferred term.  The number and percentage of subjects with each 
system organ class and preferred term will be presented for all subjects. Tables to summarize 
the incidence rates will be created for each of the following groups: 
 
• Adverse events 
 
• Serious adverse events 
 
• Adverse events leading to premature discontinuation 
 
• Adverse events by intensity 
 
• Adverse events by relationship to study drug 
 
• Adverse events presented in descending order of frequency by preferred term (no system 
organ class shown) 
 
If a subject reports the same adverse event more than once, then that subject is only counted 
once for the summary of that adverse event, using the most severe intensity.  The only exception 
to this will be for the summary by relationship to study drug.  For that summary, if a subject 
reports the same adverse event more than once, then that subject is only counted once for the 
summary of that adverse event, using the most severe relationship to study drug. The same 
principle will be applied at the body system level summary. 
 


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If relationship to study drug are unknown then the adverse event will be summarized in the 
highest category of relationship to study drug. However every effort should be made to assess 
the relationship to the study drug before the data review.  If intensity is unknown for any AEs the 
summary table will present the unknown category. If the start date of the adverse event is a 
partial date (or completely unknown) then the adverse event will be included in the summary 
tables (i.e. assumed to be treatment-emergent) unless the partial start date is clearly before the 
first dose of study drug. 
 
Adverse events that led to premature discontinuation from the study will be listed.  Serious 
adverse events will also be listed.  These listings will contain details about the adverse event 
such as intensity, seriousness (only for AE leading to discontinuation) and relationship to study 
drug.  Other supportive data, such as the subject’s age, BMI, last menstrual period (for 
pregnancy reports) will be given. 
 
All adverse events will be coded with MedDRA 21.0 and subsequent versions. 
 
3.9.3 
Hematology and Chemistry 
 
Hematology and chemistry mean changes from screening to the end of study visit will be 
summarized.  The summary will present data for the screening visit and the mean change from 
screening to the end of study visit.  The sample size, mean, SD, median, minimum, and 
maximum values for each treatment will be presented for each parameter. 
  
A summary of shifts from screening to the end of study visit will be given for each parameter.  
The normal range for each parameter will be used to create categories of low, normal, or high.  
Any result that is higher (lower) than the upper (lower) limit of normal will be categorized as high 
(low) and any result within the lower and upper limits of normal will be categorized as normal. 
 
Hematology and chemistry data will be located in separate tables. 
 
3.9.4 
Vital Signs  
 
Vital signs and weight mean changes from screening to the end of study visit will be summarized.  
Vital sign measurements will include systolic blood pressure, diastolic blood pressure and sitting 
heart rate.  The summary will present data for the screening visit and the mean change from 
screening to the end of study visit.  For each visit, the sample size, mean, SD, median, minimum, 
and maximum values will be presented for each parameter. 
 
3.9.5 
Vaginal Bleeding and Spotting 
 
Vaginal bleeding and spotting will be recorded daily by subjects in the diary. The total number 
of bleeding or spotting days for each subject at each treatment period will be summarized. 
Menstrual bleeding, intermenstrual bleeding and spotting will be summarized separately.  No 
imputation of missing data will be performed.  The number of days with diary data recorded in 
each treatment period will be summarized. 
 
3.9.6 
Listing of Pregnancies 
 


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A listing of any pregnancies that occur will be created and will include the last menstrual period 
date as well as details the estimated date of conception and the methods used to estimate the 
date of conception.  The listing will also indicate which treatment period the estimated date of 
conception occurred. 
 
4.0 
REFERENCES 
 
HRA Pharma Protocol 151042-002: A prospective, multi-center, randomized, cross-over study 
to assess the effect of norgestrel 75 mcg on cervical mucus and ovarian activity during perfect 
use, after one delayed intake and after a missed pill, version 1.0 26FEB2018. 


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5.0 
APPENDICES 


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5.1 
Schedule of Assessments 
 
 
 
 
 


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(a) 
Only if follicle ≥ 15 mm is observed after Day 73 AND the criteria for stopping the extra-visits were not fulfilled by Day 84 
(b) 
Extra visits will be stopped before 6 days if there is no postovulatory image after 6 days 
(c) 
Extra visits will be stopped before 12 days if there is no postovulatory image after 6 days or if the P4 levels are > 30 nmol/L at 1 visit or > 10 nmol/L at 2 consecutive visits. 
(d) 
Randomization at 1st visit of treatment period 2 
(e) 
Vital signs include heart rate, systolic and diastolic blood pressure after at least 2-minute rest and height and weight (at screening only). 
(f) 
Pap smear to be performed according to current US guideline if an abnormal cervical lesion is detected during the gynecological examination 
(g) 
At V11 only, before first pill intake  
(h) 
At V11, last visit of treatment period 1 and last visit of treatment period 2 
(i) 
Study pill intake will be at 9 am ± 1 hour and will be noted as T2/3R-1 (actual treatment time at Day 41 or Day 69) 
(j) 
Study pill intake at T2/3R-1+ 6h ± 15 min 
(k) 
Study pill intake at T2/3R-1 ± 30 min 
(l) 
TVUS up to observation of postovulatory image 
(m) 
At V11, the mucus analysis will be performed before the 1st study medication intake 
(n) 
Mucus analysis to be performed at T2/3R-1 +8 h ± 30 min. 
(o) 
Mucus analysis to be performed at T2/3TR-1 +3h ± 15 min. 
(p) 
Mucus analysis to be performed at T2/3R-1 +6 h ± 15 min. 
(q) 
Mucus analysis to be performed within 30 min before study medication intake 
(r) 
Blood sampling for PK analysis at D1: subjects with even study number at predose, 2 h ± 15 min, 6 h ± 15 min and 12 h ± 30 min post-treatment and subjects with odd study number at 1 h 
± 15 min, 4 h ± 15 min , 8 h ± 30 min and 24 h ± 30 min post-treatment 


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(s) 
Blood sampling for steady state during first visit in week 3: subjects with odd numbers at predose, and between 0.5 h and 2h (morning visit), and subject with even numbers between 5 h and 
9 h post-treatment (afternoon visit) 
(t) 
Blood sampling for compliance during 1st visit of weeks 5 and 9 within 30 min of cervical mucus sampling 
(u) 
Blood sampling for PK analysis at T2/3R-1 +8h ± 30 min 
(v) 
Blood sampling for PK analysis at T2/3R-1 +3h ± 15 min, T2/3R-1 + 5.5h ± 15min, T2/3R-1 + 7.5h ± 30min 
(w) 
Blood sampling for PK analysis at T2/3R-1 + 6h ±15min 
(x) 
Blood sampling for PK analysis at T2/3R-1 within 30 min before study medication intake 
(y) 
No E2, FSH and LH measurements during extra-visits after postovulatory image is observed 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.2 
Adjudication Committee 
 
An adjudication committee will be convened for this study. Experts in the cervical mucus 
assessment and ovarian activity who are not affiliated with either of the study sites will comprise 
the committee. The committee will gather at study end before the database lock to review the 
data.  
 
Its responsibilities will be to review data regarding IMP intake in relation to TVU results, hormonal 
levels and mucus scores. They will define the set of evaluable treatment cycles. They will make 
decisions for each subject and reach agreement on cervical mucus score and ovarian activity 
score/ovarian status.  
 
A separate charter will be created to provide the details on this committee. 
 
 
 


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5.3 
Cervical mucus sampling and scoring 
 
General information on cervical mucus sampling and scoring is given below. See Appendix 5 in 
protocol for additional details. 
 
Cervical mucus will be sampled and assessed according to the methodology described in the 
WHO Laboratory Manual for the Examination and Processing of Human Semen, Fifth edition 
2010. 
 
Volume will not be assessed. 
 
Viscosity is scored as follows: 
0 = thick, highly viscous, premenstrual mucus 
1 = mucus of intermediate viscosity 
2 = mildly viscous mucus 
3 = watery, minimally viscous, mid-cycle (preovulatory) mucus 
 
Ferning is scored as follows: 
0 = no crystallization 
1 = atypical fern formation 
2 = primary and secondary stem ferning 
3 = tertiary and quaternary stem ferning 
 
Spinnbarkeit is scored as follows: 
0 = <1 cm 
1 = 1–4 cm 
2 = 5–8 cm 
3 = 9 cm or more 
 
The rank scores for cells are: 
0 = >20 cells per HPF or >1000 cells per μL 
1 = 11–20 cells per HPF or 501–1000 cells per μL 
2 = 1–10 cells per HPF or 1–500 cells per μL 
3 = 0 cells 
 
 
 


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5.4 
Determination of Ovarian Activity Score (OAS) and Ovarian Status (OS) 
 
 
Ovarian 
Activity 
Score 
Activity 
Size 
FLS 
/ 
sonographic image 
Estradiol 
(nmol/L) 
Progesterone 
(nmol/L) 
Ovarian 
Status1 
1 
No activity 
≤ 10 mm 
Independent 
of 
E2 level 
≤ 5 
OSq 
2 
Potential activity 
> 10 and ≤ 13 mm 
Independent 
of 
E2 level 
≤ 5 
OSq 
3 
Non-active follicle like 
structure (FLS) 
> 13 mm 
≤0.12 
≤ 5 
OSq 
4 
Active 
follicle 
like 
structure (FLS) 
> 13 mm 
>0.12 
≤ 5 
OSa 
5 
Postovulatory, 
low 
P 
level 
Postovulatory image2 
>0.12 
≤ 10 
OSa 
6 
Postovulatory, 
intermediate P level 
Postovulatory image3 
> 0.12 
> 10 and ≤ 30 
Only 1 P > 10 
and ≤ 30 
→ OSalp 
2 consecutive P 
> 10 and ≤ 30 
→ OSnlp 
7 
Postovulatory, high P 
level 
Postovulatory image3 
> 0.12 
> 30 
OSnlp 
1 The ovarian status are: 
• 
OSq = quiescence defined as a OAS ≤ 3 
• 
OSa = ovarian activity defined as a OAS = 4 or 5  
• 
OSalp = ovulation with abnormal luteal phase defined as OAS = 6 at only one visit  
• 
OSnlp = ovulation with normal luteal phase as a OAS = 6 at two consecutive visits or OAS = 7 
2~27.24 pg/mL 
3 A postovulatory image will be defined as follows: 
• 
Image observed after abrupt disappearance of FLS OR 
• 
Image observed after reduction in size of the leading follicle > 4 mm at two consecutive visits OR  
• 
Haemorrhagic and cystic corpus luteum (FLS at least as large as the leading follicle before ovulation) 
 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
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5.5 
Table of Contents for Data Displays 
 
Table or Graph 
Number 
Table or Graph Title 
Population 
14.1.1 
Summary of Study Disposition 
All Enrolled 
 
 
 
14.1.2 
Listing of Subjects that Discontinued Prematurely 
All Enrolled 
 
 
 
14.1.3 
Number of Subjects at Key Visits 
All Enrolled 
 
 
 
14.1.4 
Summary of Protocol Deviations 
All Enrolled 
 
 
 
14.1.5 
Summary of Analysis Populations 
All Enrolled 
 
 
 
14.1.6 
Summary of Demographics 
All Enrolled 
 
 
 
14.1.7 
Summary of Demographics 
FASM 
 
 
 
14.1.8 
Summary of Contraceptive History 
All Enrolled 
 
 
 
14.1.9 
Summary of Gynecological History 
All Enrolled 
 
 
 
14.1.10 
Summary of Pregnancy History 
All Enrolled 
 
 
 
14.1.11 
Summary of Substance Use History 
All Enrolled 
 
 
 
14.1.12 
Summary of Physical Examination 
All Enrolled 
 
 
 
14.1.13 
Summary of Gynecological Examination 
All Enrolled 
 
 
 
14.1.14 
Summary of Gynecological Assessments 
All Enrolled 
 
 
 
14.1.15 
Summary of Medical History  
All Enrolled 
 
 
 
14.1.16 
Summary of Pre-Treatment Signs and Symptoms  
Safety 
 
 
 
14.1.17 
Incidence of Prior Medication Use 
Safety 
 
 
 
14.1.18 
Incidence of Concomitant Medication Use 
Safety 
 
 
 
14.1.19 
Summary 
of 
Screening 
Transvaginal 
Ultrasound 
Examination 
Safety 
 
 
 
14.1.20 
Summary of Treatment Compliance 
Safety 
 
 
 
14.1.21 
Summary of Treatment Compliance 
FASM 
 
 
 
14.2.1 
Analysis of Effect of Delayed Intake or Missed Pill on 
Cervical Mucus Score 
FASM 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 37 
Table or Graph 
Number 
Table or Graph Title 
Population 
 
 
 
14.2.2 
Sensitivity Analysis of Effect of Delayed Intake or Missed 
Pill on Cervical Mucus Score 
ITT 
 
 
 
14.2.3 
Analysis of Effect of Delayed Intake or Missed Pill on 
Cervical Mucus Score 
PP 
 
 
 
14.2.4 
Sensitivity Analysis of Effect of Delayed Intake or Missed 
Pill on Cervical Mucus Score Using Multiple Imputation 
FASM 
 
 
 
14.2.5 
Analysis of Protective Effect of Cervical Mucus 
FASM 
 
 
 
14.2.6 
Analysis of Protective Effect of Cervical Mucus 
PP 
 
 
 
14.2.7 
Analysis of Protective Effect of Cervical Mucus 
ITT 
 
 
 
14.2.8 
Summary of Cervical Mucus Protection 
FASM 
 
 
 
14.2.9 
Summary of Cervical Mucus Protection 
PP 
 
 
 
14.2.10 
Summary of Cervical Mucus Protection 
ITT 
 
 
 
14.2.11 
Summary of Cervical Mucus Examination 
Safety 
 
 
 
14.2.12 
Plot of Total Cervical Mucus Score Across Visits 
Safety 
 
 
 
14.2.13 
Summary of Ovarian Activity 
FASO 
 
 
 
14.2.14 
Summary of Ovarian Activity 
PP 
 
 
 
14.2.15 
Summary of Ovarian Activity 
ITT 
 
 
 
14.2.16 
Summary of Transvaginal Ultrasound Examination 
Safety 
 
 
 
14.2.17 
Subject Profile Graphs for Largest Follicle, P4 and E2 
Safety 
 
 
 
14.2.18 
Summary of Conception Protection 
FASC 
 
 
 
14.2.19 
Summary of Conception Protection 
PP 
 
 
 
14.2.20 
Summary of Conception Protection 
ITT 
 
 
 
14.2.21 
Summary of PK Concentrations of LNG 
Per-Protocol 
 
 
 
14.2.22 
Plot of PK LNG Concentrations over Time for All Periods 
Per-Protocol 
 
 
 
14.3.1.1 
Incidence of Adverse Events 
Safety 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 38 
Table or Graph 
Number 
Table or Graph Title 
Population 
 
 
 
14.3.1.2 
Incidence of Serious Adverse Events 
Safety 
 
 
 
14.3.1.3 
Incidence of Adverse Events Leading to Discontinuation 
Safety 
 
 
 
14.3.1.4 
Incidence of Adverse Events by Intensity 
Safety 
 
 
 
14.3.1.5 
Incidence of Adverse Events by Relationship to Study 
Drug 
Safety 
 
 
 
14.3.1.6 
Incidence of Adverse Events Presented in Descending 
Frequency of Preferred Term 
Safety 
 
 
 
14.3.2.1 
Listing of Subjects with Serious Adverse Events 
Safety 
 
 
 
14.3.2.2 
Listing of Subjects with Adverse Events that Led to 
Premature Discontinuation 
Safety 
 
 
 
14.3.5.1 
Summary of Treatment Exposure 
Safety 
 
 
 
14.3.5.2 
Summary of Mean Change from Screening to End of 
Study Visit for Hematology Parameters  
Safety 
 
 
 
14.3.5.3 
Summary  of Mean Change from Screening to End of 
Study Visit for Chemistry Parameters  
Safety 
 
 
 
14.3.5.4 
Summary of Shifts from Screening to End of Study Visit 
for Hematology Parameters 
Safety 
 
 
 
14.3.5.5 
Summary of Shifts from Screening to End of Study Visit 
for Chemistry Parameters 
Safety 
 
 
 
14.3.5.6 
Summary of Change from Screening to End of Study Visit 
for Vital Signs  
Safety 
 
 
 
14.3.5.7 
Number of Days for Subjects with Bleeding and Spotting 
by Treatment Period 
Safety 
 
 
 
 
Listing Number 
Listing Title 
Population 
16.2.1.1 
Analysis Populations 
All Enrolled 
 
 
 
16.2.1.2 
Subject Disposition 
All Enrolled 
 
 
 
16.2.1.3 
Inclusion and Exclusion Criteria 
All Enrolled 
 
 
 
16.2.2 
Protocol Deviations  
All Enrolled 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 39 
Listing Number 
Listing Title 
Population 
 
 
 
16.2.3 
Patients Excluded from the Analysis Populations 
All Enrolled 
 
 
 
16.2.4.1 
Demographics 
All Enrolled 
 
 
 
16.2.4.2 
Contraceptive History  
All Enrolled 
 
 
 
16.2.4.3 
Gynecological History 
All Enrolled 
 
 
 
16.2.4.4 
Pregnancy History 
All Enrolled 
 
 
 
16.2.4.5 
Substance Use History 
All Enrolled 
 
 
 
16.2.4.6 
Gynecological Assessments 
All Enrolled 
 
 
 
16.2.4.7 
Medical History 
All Enrolled 
 
 
 
16.2.4.8 
Pre-Treatment Signs and Symptoms 
All Enrolled 
 
 
 
16.2.4.9 
Prior and Concomitant Medications  
All Enrolled 
 
 
 
16.2.5.1 
Study Drug Administration  
All Enrolled 
 
 
 
16.2.5.2 
IMP Intake  
All Enrolled 
 
 
 
16.2.5.3 
PK Concentrations of LNG 
All Enrolled 
 
 
 
16.2.6.1 
Cervical Mucus 
All Enrolled 
 
 
 
16.2.6.2 
Transvaginal Ultrasound 
All Enrolled 
 
 
 
16.2.6.3 
Hormones 
All Enrolled 
 
 
 
16.2.6.4 
Ovarian Status 
All Enrolled 
 
 
 
16.2.7.1 
Adverse Events 
All Enrolled 
 
 
 
16.2.8.1 
Hematology 
All Enrolled 
 
 
 
16.2.8.2 
Chemistry 
All Enrolled 
 
 
 
16.2.9.1 
Vital Signs and Weight 
All Enrolled 
 
 
 
16.2.9.2 
Physical Exam 
All Enrolled 
 
 
 
16.2.9.3 
Gynecological Exam 
All Enrolled 
 
 
 
16.2.9.4 
Pregnancy Test 
All Enrolled 


HRA Pharma                                                          CONFIDENTIAL                                                       151042-002 
TEM BM-001.06 (Eff. 06JUN2018)                       Statistical Analysis Plan, v1.0 
Page 40 
Listing Number 
Listing Title 
Population 
 
 
 
16.2.9.5 
Pregnancy Notification 
All Enrolled 
 
 
 
16.2.9.6 
Bleeding Diary 
All Enrolled