CompletedNCT03585712Updated Jun 3, 2021Results posted

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

A Phase 2 interventional study of Norgestrel 0.075 mg in Contraception, sponsored by HRA Pharma. Completed at 2 sites in United States. Open to female participants aged 18 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-06-03.

Sponsored by HRA Pharma · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 52
Allocation: Randomized
Ages: 18 Years to 35 Years
Sex: Female

Study 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.

Read the 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

Conditions studied

Contraception

Keywords

Birth Control
Progestin Only Pill
Estrogen Free Pill
Norgestrel
Oral Contraception
Female Contraception
Cervical Mucus
Ovarian Activity

In context

Lead sponsor

HRA Pharma is the lead sponsor of 14 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 35 Years
Sexes eligible: 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

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

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: None (open label)
Enrollment: 52 participants (actual)

Study arms

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
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

Interventions

DrugNorgestrel 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
Also known as: Norgestrel 75 mcg

What researchers measure

Primary outcomes

Effect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS)
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

Secondary outcomes

Duration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill
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
Ovarian Status (OS)
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)
Cervical Mucus Protection
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
Conception Protection Risk
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)
Conception Protection Level
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)

Results

Posted Jun 3, 2021

Participant flow

Treatment Period 1

Participant flow — Treatment Period 1
Milestone	Treatment Period 1: All Enrolled Subjects	Arm A: Delayed Then Missed Pill	Arm B: Missed Then Delayed Pill
Started	52	0	0
Completed	51	0	0
Not completed	1	0	0
Withdrew: Protocol violation	1	0	0

Treatment Periods 2 and 3

Participant flow — Treatment Periods 2 and 3
Milestone	Arm A: Delayed Then Missed Pill	Arm B: Missed Then Delayed Pill
Started	26	25
Completed	23	22
Not completed	3	3
Withdrew: Protocol violation	1	1
Withdrew: Withdrawal by subject	2	0
Withdrew: Physician decision	0	2

Outcome measures

PrimaryEffect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS)

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
Reported as:: Least squares mean · changes in scores on a scale

Effect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS)
changes in scores on a scale	Delayed Pill Intake	Missed Pill Intake
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

Delayed Pill Intake vs Missed Pill Intake · Mixed Models Analysis · p = 0.26 (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)

SecondaryDuration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill

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
Reported as:: Count of participants · Participants

Duration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill
Participants	Delayed Pill Intake	Missed Pill Intake
Full Protection	30	30
Absence of risk increase	38	37
Transient risk increase	5	4
Prolonged risk increase	1	0

Statistical analysis

Delayed Pill Intake vs Missed Pill Intake · McNemar · p = >0.999 (p values \> 0.050 (Not Statistically significant))McNemar test comparing agreement in the missed and delayed periods
Delayed Pill Intake vs Missed Pill Intake · McNemar · p = 0.655 (p values \> 0.050 (Not Statistically significant))McNemar test comparing agreement in the missed and delayed periods
Delayed Pill Intake vs Missed Pill Intake · McNemar · p = 0.317 (p values \> 0.050 (Not Statistically significant))McNemar test comparing agreement in the missed and delayed periods

SecondaryOvarian Status (OS)

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)
Reported as:: Count of participants · Participants

Ovarian Status (OS)
Participants	OS: Reported Perfect Use Period (Treatment Period 1)	OS: Delayed Pill Period	OS: Missed Pill Period
OSq	7	10	7
OSa	25	22	25
OSalp	5	4	2
OSnlp	12	10	12

Statistical analysis

OS: Reported Perfect Use Period (Treatment Period 1) vs OS: Delayed Pill Period · McNemar · p = <0.001 (Indicates significance at the 0.05 level (p-value ≤ 0.05))P-value from an exact kappa test comparing agreement of ovarian status vs the reported perfect use period
OS: Reported Perfect Use Period (Treatment Period 1) vs OS: Missed Pill Period · McNemar · p = <0.001 (Indicates significance at the 0.05 level (p-value ≤ 0.05))P-value from an exact kappa test comparing agreement of ovarian status vs the reported perfect use period.

SecondaryCervical Mucus Protection

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
Reported as:: Count of participants · Participants

Cervical Mucus Protection
Participants	CMS: Reported Perfect Use Period (Treatment Period 1)	CMS: Delayed Pill Period	CMS: Missed Pill Period
CMS <=4	32	27	28
CMS between 5 & 8 (inclusive)	17	20	15
CMS >=9	0	0	4

Statistical analysis

CMS: Reported Perfect Use Period (Treatment Period 1) vs CMS: Delayed Pill Period · McNemar · p = 0.127P-value from an exact kappa test comparing agreement of cervical mucus score classification vs the reported perfect use period
CMS: Reported Perfect Use Period (Treatment Period 1) vs CMS: Missed Pill Period · McNemar · p = 0.018 (\* Indicates significance at the 0.05 level (p-value ≤ 0.05).)P-value from an exact kappa test comparing agreement of cervical mucus score classification vs the reported perfect use period.

SecondaryConception Protection Risk

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)
Reported as:: Count of participants · Participants

Conception Protection Risk
Participants	CP/R&L: Reported Perfect Use Period (Treatment Period 1)	CP/R&L: Delayed Pill Period	CP/R&L: Missed Pill Period
Protected	46	42	41
At risk	3	4	5

SecondaryConception Protection Level

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)
Reported as:: Count of participants · Participants

Conception Protection Level
Participants	CP/R&L: Reported Perfect Use Period (Treatment Period 1)	CP/R&L: Delayed Pill Period	CP/R&L: Missed Pill Period
Maximum/Highly Likely to be Protected	46	42	41
Medium/Likely to be Protected	3	4	3
Minimum/Unlikely to be Protected	0	0	2

Adverse events

Collected over From Day 1 to Day 84. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
All Enrolled Subjects	0/52 (0%)	1/52 (1.9%)	50/52 (96.2%)
Perfect Use Period	0/52 (0%)	0/52 (0%)	42/52 (80.8%)
Delayed Pill Intake	0/50 (0%)	1/50 (2%)	29/50 (58%)
Missed Pill Intake	0/48 (0%)	0/48 (0%)	33/48 (68.8%)

Most frequent serious events

Most frequent serious events
Event	All Enrolled Subjects	Perfect Use Period	Delayed Pill Intake	Missed Pill Intake
Anaphylactic ReactionImmune system disorders	1/52	0/52	1/50	0/48

Most frequent other events

Showing 10 of 15

Most frequent other events
Event	All Enrolled Subjects	Perfect Use Period	Delayed Pill Intake	Missed Pill Intake
MetrorrhagiaReproductive system and breast disorders	41/52	23/52	13/50	15/48
Upper respiratory tract infectionRespiratory, thoracic and mediastinal disorders	16/52	6/52	7/50	6/48
AcneSkin and subcutaneous tissue disorders	11/52	9/52	0/50	2/48
Breast tendernessReproductive system and breast disorders	6/52	5/52	1/50	0/48
DysmenorrheaReproductive system and breast disorders	5/52	1/52	2/50	2/48
FatigueGeneral disorders	5/52	4/52	1/50	0/48
MenorrhagiaReproductive system and breast disorders	5/52	1/52	2/50	2/48
Vulvovaginal discomfortReproductive system and breast disorders	5/52	0/52	2/50	3/48
HeadacheNervous system disorders	4/52	3/52	1/50	0/48
NauseaGastrointestinal disorders	4/52	2/52	1/50	1/48

Baseline characteristics

All subjects enrolled in the study

Age, Continuous
Age, Continuous(years)	All Enrolled Subjects
Mean	28.3 ± 4.47

Sex: Female, Male
Sex: Female, Male(Participants)	All Enrolled Subjects
Female	52
Male	0

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	All Enrolled Subjects
Hispanic or Latino	7
Not Hispanic or Latino	45
Unknown or Not Reported	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	All Enrolled Subjects
American Indian or Alaska Native	0
Asian	5
Native Hawaiian or Other Pacific Islander	0
Black or African American	2
White	38
More than one race	2
Unknown or Not Reported	5

Region of Enrollment
Region of Enrollment(Participants)	All Enrolled Subjects
United States	52

Body Mass Index (BMI)
Body Mass Index (BMI)(kg/m²)	All Enrolled Subjects
Mean	23.96 ± 3.65

Study locations

2 sites

University of California Davis
Sacramento, California 95616, United States
Oregon Health and Sciences University
Portland, Oregon 97239, United States

References and documents

Publications

Edelman A, Hemon A, Creinin M, Borensztein P, Scherrer B, Glasier A. Assessing the Pregnancy Protective Impact of Scheduled Nonadherence to a Novel Progestin-Only Pill: Protocol for a Prospective, Multicenter, Randomized, Crossover Study. JMIR Res Protoc. 2021 Jun 8;10(6):e29208. doi: 10.2196/29208. PubMed 33970869 ↗

Study documents

Study protocol · Feb 26, 2018
Statistical analysis plan · Sep 1, 2019

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jun 3, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03585712
Lead sponsor: HRA Pharma
Collaborators: Health Decisions
Responsible party: Sponsor
First posted: Jul 13, 2018
Start date: Jul 24, 2018
Primary completion: Apr 7, 2020
Completion: Apr 7, 2020
Results posted: Jun 3, 2021
Last update: Jun 3, 2021

Study contacts

Alison Edelman, MD

principal investigator · Oregon Health and Sciences University

Mitchell Creinin, MD

principal investigator · University of California, Davis

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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

Study summary

Conditions studied

Keywords

In context

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Related links

Study documents

Individual participant data

Updates

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies from this sponsor

Inclusion criteria

Exclusion criteria