Effect of Norgestrel 75 mcg on Cervical Mucus and Ovarian Activity During Perfect Use, After One Delayed Intake and After a Missed Pill

• Sponsor: HRA Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03585712
• Collaborator: Health Decisions (Other)
• Enrollment: 52
• Locations: 2
• Arms: 2
• Actual Duration (Months): 20.5
• Patients Per Site: 26
• Patients Per Site Per Month: 1.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Contraception	Drug: Norgestrel 0.075 mg	Phase 2

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Jul 24, 2018
• Actual Primary Completion Date: Apr 7, 2020
• Actual Study Completion Date: Apr 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: Arm A: Delayed then Missed Pill 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	Drug: Norgestrel 0.075 mg; 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; Other Names: Norgestrel 75 mcg
Other: Arm B: Missed then Delayed Pill 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	Drug: Norgestrel 0.075 mg; 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; Other Names: Norgestrel 75 mcg

Outcome Measures

Primary Outcome Measures

1. Effect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS) [Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days]

   Difference in Cervical Mucus Score between baseline (as Day 41 or Day 69) and delayed (Day 42 and Day 70) or missed pill (Day 43 or day 71) The Insler cervical mucus score (0-12) is the sum of 4 subscores: viscosity from 0 (thick, highly viscous) to 3 (watery,minimally viscous) ferning from 0 (no crystallization) to 3 (tertiary and quaternary stem ferning) spinnbarkeit from 0 (<1 cm) to 3 (>= 9 cm) rank for cells from 0 (>20 cells per High Power Field or >1000 cells per μL) to 3 (0 cell) A score <5 is considered as a protective score while a score >9 is considered as a non protective score

Secondary Outcome Measures

1. Duration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill [Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days]

   Subjects are classified according to the risk of losing cervical mucus protection after a 6h delayed or a missed pill, on the day of the infringement and on the day after A cervical mucus score (CMS) <5 is considered as a protective score Full protection: CMS stay <5 after both a delayed or a missed pill, on the day of infringement and on the day after. Absence of risk increase: CMS stay <5 on the day of infringement and on the day after. Transient risk increase: CMS increase >=5 on the day of infringement but go back to <5 on the day after. Prolonged risk increase: CMS increase >=5 on the day of infringement and stay >=5 on the day after.

2. Ovarian Status (OS) [From Day 1 to Day 84 (if no follow-up) or up to Day 90 (if follow-up)]

   Ovarian Status (OS) defined as: OSq = quiescence defined as an Ovarian Activity Score (OAS) =< 3 OSa = active defined as 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 defined as OAS = 6 at two consecutive visits or OAS = 7 Ovarian Activity Score between 1 and 7: 1= No ovarian activity 2= Potential activity 3= Non-active follicle like structure 4= Active follicle like structure 5= Postovulatory, low progesterone level 6= Postovulatory, intermediate progesterone level 7= Postovulatory, high progesterone level

3. Cervical Mucus Protection [From Day 1 to Day 84]

   Higher Cervical Mucus Score (CMS) in: Treatment Period 1 (Reported Perfect Use Period) Delayed pill period: Treatment Period 2 for Arm A and Treatment Period 3 for Arm B Missed pill period: Treatment Period 3 for Arm A and Treatment Period 2 for Arm B A score =< 4 is considered as a protective score and a score >= 9 is considered as a non protective score

4. Conception Protection Risk [Day 1 to Day 84 (up to Day 90 if follow-up)]

   Binary analysis of whether a subject is at risk of conception based only on their ovarian status (OS) and cervical mucus score (CMS) the days before ovulation: Are considered protected, subjects with OSq, OSa OR CMS =<4 Are considered at risk, subjects with OSalp or OSnlp AND CMS >=5

5. Conception Protection Level [Day 1 to Day 84 (up to Day 90 if follow-up)]

   Ternary analysis of the level of protection from conception of subjects, based only on the ovarian status (OS) and cervical mucus score (CMS) the days before ovulation: Minimum protection or unlikely to be protected: OSnlp and CMS ≥ 9 Medium protection or likely to be protected: OSnlp and CMS comprised between 5 and 8 or OSalp and CMS ≥ 5 Maximum protection or highly likely to be protected: OSq or OSa or a CMS ≤ 4

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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.

• Subjects postpartum or post-abortal must have one normal menstrual cycle (2 menses) prior to enrollment.

• Subjects previously using Intra-Uterine Device (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.

• 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 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)

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis	Sacramento	California	United States	95616
2	Oregon Health and Sciences University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• HRA Pharma
• Health Decisions

Investigators

• Principal Investigator: Alison Edelman, MD, Oregon Health and Sciences University
• Principal Investigator: Mitchell Creinin, MD, University of California, Davis

Study Documents (Full-Text)

• Study Protocol - Feb 26, 2018
• Statistical Analysis Plan - Sep 1, 2019

More Information

Additional Information:

• World Health Organization Laboratory Manual for the Examination and Processing of Human Semen. Fifth edition 2010

Publications

None provided.

• Responsible Party: HRA Pharma
• ClinicalTrials.gov Identifier: NCT03585712
• Other Study ID Numbers: 151042-002
• First Posted: Jul 13, 2018
• Last Update Posted: Jun 3, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by HRA Pharma: Birth Control; Progestin Only Pill; Estrogen Free Pill; Norgestrel; Oral Contraception; Female Contraception; Cervical Mucus; Ovarian Activity
• Additional relevant MeSH terms: Norgestrel

Study Results

Participant Flow

Pre-assignment Detail	Enrolled subjects were randomized at the first visit of week 5 (first week of treatment period 2) in Arm A or B. All subjects received the same treatment during the first four weeks of treatment

Arm/Group Title	Treatment Period 1: All Enrolled Subjects	Arm A: Delayed Then Missed Pill	Arm B: Missed Then Delayed Pill
Arm/Group Description	Subjects were enrolled in treatment period 1 without being assigned an arm (Arm A or Arm B) until week 5. Subjects took 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	Treatment period 2, visit Day 42+/- 3 days: 6 hour delayed intake of Norgestrel 75 mcg Treatment period 3, visit Day 70+/- 3 days: missed pill of Norgestrel 75 mcg Subjects took 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	Treatment period 2, visit Day 42+/- 3 days: missed pill of Norgestrel 75 mcg Treatment period 3, visit Day 70+/-3 days: 6 hour delayed intake of the pill of Norgestrel 75 mcg Subjects took 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
Period Title: Treatment Period 1
STARTED	52	0	0
COMPLETED	51	0	0
NOT COMPLETED	1	0	0
Period Title: Treatment Period 1
STARTED	0	26	25
COMPLETED	0	23	22
NOT COMPLETED	0	3	3

Baseline Characteristics

Arm/Group Title	All Enrolled Subjects
Arm/Group Description	All subjects enrolled in the study
Overall Participants	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.3 (4.47)
Sex: Female, Male (Count of Participants)
Female	52 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 13.5%
Not Hispanic or Latino	45 86.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 9.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 3.8%
White	38 73.1%
More than one race	2 3.8%
Unknown or Not Reported	5 9.6%
Region of Enrollment (Count of Participants)
United States	52 100%
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	23.96 (3.65)

Outcome Measures

1. Primary Outcome

Title	Effect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS)
Description	Difference in Cervical Mucus Score between baseline (as Day 41 or Day 69) and delayed (Day 42 and Day 70) or missed pill (Day 43 or day 71) The Insler cervical mucus score (0-12) is the sum of 4 subscores: viscosity from 0 (thick, highly viscous) to 3 (watery,minimally viscous) ferning from 0 (no crystallization) to 3 (tertiary and quaternary stem ferning) spinnbarkeit from 0 (<1 cm) to 3 (>= 9 cm) rank for cells from 0 (>20 cells per High Power Field or >1000 cells per μL) to 3 (0 cell) A score <5 is considered as a protective score while a score >9 is considered as a non protective score
Time Frame	Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days

Outcome Measure Data

Analysis Population Description

Full Analysis Set for Primary endpoint: Subjects who had cervical mucus score for either D41-D43 or D69-71

Arm/Group Title	Delayed Pill Intake	Missed Pill Intake
Arm/Group Description	All the subjects of Arm A during treatment period 2 and all the subjects of Arm B during treatment period 3 Norgestrel 0.075 mg: Subjects took norgestrel 75 mcg every day at the same time for three 28-day treatment periods, except for one specific day (Day 42 +/3 days) during treatment period 2 or treatment period 3 (Day 70 +/3 days) where they delayed their pill intake of 6 hours	All the subjects of Arm B during treatment period 2 and all the subjects of Arm A during treatment period 3 Norgestrel 0.075 mg: Subjects took norgestrel 75 mcg every day at the same time for three 28-day treatment periods, except for one specific day (Day 42 +/3 days) during treatment period 2 or treatment period 3 (Day 70 +/3 days) where they missed their pill
Measure Participants	46	47
Difference in CMs after a 3-hour late pill	1.0 (0.3)
Difference in CMs after a 6-hour late pill	0.7 (0.3)
Difference in CMs after a 24-hour late pill (missed pill)	0.1 (0.3)
Difference in CMS between 3h delay and next pill 18h later	0.3 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	Mixed model for repeated measures using as response delta to Day41, delta to Day42, delta to Day70 and delta to Day71. Covariates: period, intervention (missed pill or delayed pill), sequence of intervention (missed pill then delayed pill and vice versa), time and subject. Subject as random effect + time repeated effect within each combination subject* period
	Type of Statistical Test	Other
	Comments	Is the overall mean change from baseline different from zero? Or did the infringement of schedule regardless the type of infringement lead to a change in mucus score?
Statistical Test of Hypothesis	p-Value	0.26
	Comments	P value from model testing intercept (does infringement change mucus score?) P-value from a repeated measures mixed model with the period, intervention, sequence and time (visit) as covariates. P-values ≤0.050 are considered significant
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Duration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill
Description	Subjects are classified according to the risk of losing cervical mucus protection after a 6h delayed or a missed pill, on the day of the infringement and on the day after A cervical mucus score (CMS) <5 is considered as a protective score Full protection: CMS stay <5 after both a delayed or a missed pill, on the day of infringement and on the day after. Absence of risk increase: CMS stay <5 on the day of infringement and on the day after. Transient risk increase: CMS increase >=5 on the day of infringement but go back to <5 on the day after. Prolonged risk increase: CMS increase >=5 on the day of infringement and stay >=5 on the day after.
Time Frame	Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days

Outcome Measure Data

Analysis Population Description

Full Analysis Set for Primary endpoint: Subjects who had cervical mucus score for either D41-D43 or D69-71 and a CMS at Baseline =< 5

Arm/Group Title	Delayed Pill Intake	Missed Pill Intake
Arm/Group Description	All the subjects of Arm A during treatment period 2 and all the subjects of Arm B during treatment period 3 Norgestrel 0.075 mg: Subjects took norgestrel 75 mcg every day at the same time for three 28-day treatment periods, except for one specific day (Day 42 +/3 days) during treatment period 2 or treatment period 3 (Day 70 +/3 days) where they delayed their pill intake of 6 hours	All the subjects of Arm B during treatment period 2 and all the subjects of Arm A during treatment period 3 Norgestrel 0.075 mg: Subjects took norgestrel 75 mcg every day at the same time for three 28-day treatment periods, except for one specific day (Day 42 +/3 days) during treatment period 2 or treatment period 3 (Day 70 +/3 days) where they missed their pill
Measure Participants	44	41
Full Protection	30 57.7%	30 NaN
Absence of risk increase	38 73.1%	37 NaN
Transient risk increase	5 9.6%	4 NaN
Prolonged risk increase	1 1.9%	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	Absence of risk increase
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	p values > 0.050 (Not Statistically significant)
	Method	McNemar
	Comments	McNemar test comparing agreement in the missed and delayed periods

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	Transient risk increase
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.655
	Comments	p values > 0.050 (Not Statistically significant)
	Method	McNemar
	Comments	McNemar test comparing agreement in the missed and delayed periods

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	Prolonged risk increase
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.317
	Comments	p values > 0.050 (Not Statistically significant)
	Method	McNemar
	Comments	McNemar test comparing agreement in the missed and delayed periods

3. Secondary Outcome

Title	Ovarian Status (OS)
Description	Ovarian Status (OS) defined as: OSq = quiescence defined as an Ovarian Activity Score (OAS) =< 3 OSa = active defined as 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 defined as OAS = 6 at two consecutive visits or OAS = 7 Ovarian Activity Score between 1 and 7: 1= No ovarian activity 2= Potential activity 3= Non-active follicle like structure 4= Active follicle like structure 5= Postovulatory, low progesterone level 6= Postovulatory, intermediate progesterone level 7= Postovulatory, high progesterone level
Time Frame	From Day 1 to Day 84 (if no follow-up) or up to Day 90 (if follow-up)

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Ovarian Activity: Subjects with an Ovarian Status (OS) for either Treatment Period 2 or Treatment Period 3

Arm/Group Title	OS: Reported Perfect Use Period (Treatment Period 1)	OS: Delayed Pill Period	OS: Missed Pill Period
Arm/Group Description	Subjects in Treatment Period 1 who also had an Ovarian Status in either Treatment Period 2 or Treatment Period 3	Subjects with Ovarian Status, of: Arm A in Treatment Period 2 Arm B in Treatment Period 3	Subjects with Ovarian Status, of: Arm A in Treatment Period 3 Arm B in Treatment Period 2
Measure Participants	49	46	46
OSq	7 13.5%	10 NaN	7 NaN
OSa	25 48.1%	22 NaN	25 NaN
OSalp	5 9.6%	4 NaN	2 NaN
OSnlp	12 23.1%	10 NaN	12 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	A stratified McNemar test (stratification on the site, AGREE option in SAS) was 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 was used for the analyses.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Indicates significance at the 0.05 level (p-value ≤ 0.05)
	Method	McNemar
	Comments	P-value from an exact kappa test comparing agreement of ovarian status vs the reported perfect use period

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, OS: Missed Pill Period
	Comments	A stratified McNemar test (stratification on the site, AGREE option in SAS) was 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 was used for the analyses.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Indicates significance at the 0.05 level (p-value ≤ 0.05)
	Method	McNemar
	Comments	P-value from an exact kappa test comparing agreement of ovarian status vs the reported perfect use period.

4. Secondary Outcome

Title	Cervical Mucus Protection
Description	Higher Cervical Mucus Score (CMS) in: Treatment Period 1 (Reported Perfect Use Period) Delayed pill period: Treatment Period 2 for Arm A and Treatment Period 3 for Arm B Missed pill period: Treatment Period 3 for Arm A and Treatment Period 2 for Arm B A score =< 4 is considered as a protective score and a score >= 9 is considered as a non protective score
Time Frame	From Day 1 to Day 84

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Mucus Secondary: Subjects who had cervical mucus scores for at least 7 visits for either Treatment Period 2 or Treatment Period 3

Arm/Group Title	CMS: Reported Perfect Use Period (Treatment Period 1)	CMS: Delayed Pill Period	CMS: Missed Pill Period
Arm/Group Description	Subjects in Treatment Period 1 who had at least 7 cervical mucus scores in either Treatment Period 2 or Treatment Period 3	Subjects who had at least 7 cervical mucus scores in: Arm A: Treatment Period 2 Arm B: Treatment Period 3	Subjects who had at least 7 cervical mucus scores in: Arm A: Treatment Period 3 Arm B: Treatment Period 2
Measure Participants	49	47	47
CMS <=4	32 61.5%	27 NaN	28 NaN
CMS between 5 & 8 (inclusive)	17 32.7%	20 NaN	15 NaN
CMS >=9	0 0%	0 NaN	4 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, Missed Pill Intake
	Comments	Stratified McNemar test (stratification on the site, AGREE option in SAS) to compare the distribution of cervical mucus scores in the perfect use period to the delayed and missed pill periods (pairwise vs perfect use).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.127
	Comments
	Method	McNemar
	Comments	P-value from an exact kappa test comparing agreement of cervical mucus score classification vs the reported perfect use period

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Delayed Pill Intake, OS: Missed Pill Period
	Comments	Stratified McNemar test (stratification on the site, AGREE option in SAS) to compare the distribution of cervical mucus scores in the perfect use period to the delayed and missed pill periods (pairwise vs perfect use).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	* Indicates significance at the 0.05 level (p-value ≤ 0.05).
	Method	McNemar
	Comments	P-value from an exact kappa test comparing agreement of cervical mucus score classification vs the reported perfect use period.

5. Secondary Outcome

Title	Conception Protection Risk
Description	Binary analysis of whether a subject is at risk of conception based only on their ovarian status (OS) and cervical mucus score (CMS) the days before ovulation: Are considered protected, subjects with OSq, OSa OR CMS =<4 Are considered at risk, subjects with OSalp or OSnlp AND CMS >=5
Time Frame	Day 1 to Day 84 (up to Day 90 if follow-up)

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Conception: Subjects who had a OS + enough CMS to assess their Conception Protection Risk & Level in either Treatment Period 2 or Treatment Period 3

Arm/Group Title	CP/R&L: Reported Perfect Use Period (Treatment Period 1)	CP/R&L: Delayed Pill Period	CP/R&L: Missed Pill Period
Arm/Group Description	Subjects in Treatment Period 1 who had a OS + enough CMS to assess their Conception Protection Risk & Level in either Treatment Period 2 or Treatment Period 3	Subjects who had a OS + enough CMS to asses their Conception Protection Risk & Level in: Arm A: Treatment Period 2 Arm B: Treatment Period 3	Subjects who had a OS + enough CMS to assess their Conception Protection Risk & Level in: Arm A: Treatment Period 3 Arm B: Treatment Period 2
Measure Participants	49	46	46
Protected	46 88.5%	42 NaN	41 NaN
At risk	3 5.8%	4 NaN	5 NaN

6. Secondary Outcome

Title	Conception Protection Level
Description	Ternary analysis of the level of protection from conception of subjects, based only on the ovarian status (OS) and cervical mucus score (CMS) the days before ovulation: Minimum protection or unlikely to be protected: OSnlp and CMS ≥ 9 Medium protection or likely to be protected: OSnlp and CMS comprised between 5 and 8 or OSalp and CMS ≥ 5 Maximum protection or highly likely to be protected: OSq or OSa or a CMS ≤ 4
Time Frame	Day 1 to Day 84 (up to Day 90 if follow-up)

Outcome Measure Data

Analysis Population Description

Full Analysis Set - Conception: Subjects who had a OS + enough CMS to assess their Conception Protection Risk & Level in either Treatment Period 2 or Treatment Period 3

Arm/Group Title	CP/R&L: Reported Perfect Use Period (Treatment Period 1)	CP/R&L: Delayed Pill Period	CP/R&L: Missed Pill Period
Arm/Group Description	Subjects in Treatment Period 1 who had a OS + enough CMS to assess their Conception Protection Risk & Level in either Treatment Period 2 or Treatment Period 3	Subjects who had a OS + enough CMS to asses their Conception Protection Risk & Level in: Arm A: Treatment Period 2 Arm B: Treatment Period 3	Subjects who had a OS + enough CMS to assess their Conception Protection Risk & Level in: Arm A: Treatment Period 3 Arm B: Treatment Period 2
Measure Participants	49	46	46
Maximum/Highly Likely to be Protected	46 88.5%	42 NaN	41 NaN
Medium/Likely to be Protected	3 5.8%	4 NaN	3 NaN
Minimum/Unlikely to be Protected	0 0%	0 NaN	2 NaN

Adverse Events

Time Frame	From Day 1 to Day 84
Adverse Event Reporting Description	Systematic Assesment: Adverse Events collected at each visit Hematology, Chemistry, Vital Signs collected at End of Study visit Vaginal Bleedings recorded daily by subjects in a diary
Arm/Group Title	All Enrolled Subjects		Perfect Use Period		Delayed Pill Intake		Missed Pill Intake
Arm/Group Description	All subjects enrolled in the study. The adverse events were reported for all the subjects enrolled in the study for the entire length of the study. The subjects were randomized in their respective arm in week 5. Subjects in Arm A had a 6 hour delayed pill at Day 42 +/- 3 days and a missed pill at Day 70+/- 3 days while subjects in Arm B had a missed pill at Day 70+/- 3 days and a 6 hour delayed pill at Day 42 +/- 3 days. It was considered that the difference in investigational medication intake between the arms would not have an impact on adverse event's frequency, so the adverse events were reported for all subjects enrolled, whatever the arm they were assigned to, and for the entire length of the study.		All the subjects having starting treatment period 1. Affected participants by an adverse event during this treatment period are reported out of the total of subjects having started the treatment period 1.		Subjects having started a delayed pill period, meaning treatment period 2 for subjects randomized in week 5 in Arm A, and treatment period 3 for subjects in Arm B Affected participants by an adverse event during this treatment period are reported out of the total of subjects having started this treatment period.		Subjects having started a missed pill period, meaning treatment period 3 for subjects randomized in week 5 in Arm A, and treatment period 2 for subjects in Arm B Affected participants by an adverse event during this treatment period are reported out of the total of subjects having started this treatment period.
All Cause Mortality
	All Enrolled Subjects		Perfect Use Period		Delayed Pill Intake		Missed Pill Intake
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/52 (0%)		0/50 (0%)		0/48 (0%)
Serious Adverse Events
	All Enrolled Subjects		Perfect Use Period		Delayed Pill Intake		Missed Pill Intake
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/52 (1.9%)		0/52 (0%)		1/50 (2%)		0/48 (0%)
Immune system disorders
Anaphylactic Reaction	1/52 (1.9%)	1	0/52 (0%)	0	1/50 (2%)	1	0/48 (0%)	0
Other (Not Including Serious) Adverse Events
	All Enrolled Subjects		Perfect Use Period		Delayed Pill Intake		Missed Pill Intake
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/52 (96.2%)		42/52 (80.8%)		29/50 (58%)		33/48 (68.8%)
Gastrointestinal disorders
Nausea	4/52 (7.7%)		2/52 (3.8%)		1/50 (2%)		1/48 (2.1%)
General disorders
Fatigue	5/52 (9.6%)		4/52 (7.7%)		1/50 (2%)		0/48 (0%)
Musculoskeletal and connective tissue disorders
Muscle spams	3/52 (5.8%)		2/52 (3.8%)		1/50 (2%)		1/48 (2.1%)
Myalgia	3/52 (5.8%)		2/52 (3.8%)		0/50 (0%)		1/48 (2.1%)
Nervous system disorders
Headache	4/52 (7.7%)		3/52 (5.8%)		1/50 (2%)		0/48 (0%)
Dizziness	3/52 (5.8%)		1/52 (1.9%)		1/50 (2%)		1/48 (2.1%)
Reproductive system and breast disorders
Metrorrhagia	41/52 (78.8%)		23/52 (44.2%)		13/50 (26%)		15/48 (31.3%)
Breast tenderness	6/52 (11.5%)		5/52 (9.6%)		1/50 (2%)		0/48 (0%)
Dysmenorrhea	5/52 (9.6%)		1/52 (1.9%)		2/50 (4%)		2/48 (4.2%)
Menorrhagia	5/52 (9.6%)		1/52 (1.9%)		2/50 (4%)		2/48 (4.2%)
Vulvovaginal discomfort	5/52 (9.6%)		0/52 (0%)		2/50 (4%)		3/48 (6.3%)
Pelvic pain	3/52 (5.8%)		2/52 (3.8%)		1/50 (2%)		0/48 (0%)
Uterine spasm	3/52 (5.8%)		1/52 (1.9%)		0/50 (0%)		2/48 (4.2%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	16/52 (30.8%)		6/52 (11.5%)		7/50 (14%)		6/48 (12.5%)
Skin and subcutaneous tissue disorders
Acne	11/52 (21.2%)		9/52 (17.3%)		0/50 (0%)		2/48 (4.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.