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

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

• Norgestrel 0.075 mg (Drug), also known as Norgestrel 75 mcg: 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

Primary outcomes

• 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 outcomes

• 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.
• 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
• 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
• 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
• 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

Sex: Female, ages: 18 Years to 35 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• Effect of Delayed Intake or Missed Pill on Cervical Mucus Score (CMS) (Primary), Least squares mean, changes in scores on a scale: Delayed Pill Intake 1.0 +/- 0.3; Missed Pill Intake (p 0.26)
• Duration of Protective Effect of Cervical Mucus After a 6h Delayed or a Missed Pill (Secondary), Count of participants, Participants: Delayed Pill Intake 30; Missed Pill Intake 30 (p >0.999)
• Ovarian Status (OS) (Secondary), Count of participants, Participants: OS: Reported Perfect Use Period (Treatment Period 1) 7; OS: Delayed Pill Period 10; OS: Missed Pill Period 7 (p <0.001)
• Cervical Mucus Protection (Secondary), Count of participants, Participants: CMS: Reported Perfect Use Period (Treatment Period 1) 32; CMS: Delayed Pill Period 27; CMS: Missed Pill Period 28 (p 0.127)
• Conception Protection Risk (Secondary), Count of participants, Participants: CP/R&L: Reported Perfect Use Period (Treatment Period 1) 46; CP/R&L: Delayed Pill Period 42; CP/R&L: Missed Pill Period 41
• Conception Protection Level (Secondary), Count of participants, Participants: CP/R&L: Reported Perfect Use Period (Treatment Period 1) 46; CP/R&L: Delayed Pill Period 42; CP/R&L: Missed Pill Period 41

Adverse events

Time frame: From Day 1 to Day 84

Serious adverse events by term

Other adverse events by term

• Results publication: 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. PMID 33970869

• Study Protocol (PDF, 2018-02-26)
• Statistical Analysis Plan (PDF, 2019-09-01)

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