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| Name | Class |
|---|---|
| Premier Research | OTHER |
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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A: Delayed then Missed Pill | Other | 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 B: Missed then Delayed Pill | Other | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Norgestrel 0.075 mg | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
A score <5 is considered as a protective score while a score >9 is considered as a non protective score | Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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
|
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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.
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:
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| Name | Affiliation | Role |
|---|---|---|
| Alison Edelman, MD | Oregon Health and Sciences University | Principal Investigator |
| Mitchell Creinin, MD | University of California, Davis | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Davis | Sacramento | California | 95616 | United States | ||
| Oregon Health and Sciences University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33970869 | Derived | 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. |
| Label | URL |
|---|---|
| World Health Organization Laboratory Manual for the Examination and Processing of Human Semen. Fifth edition 2010 | View source |
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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
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Period 1: All Enrolled Subjects | 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 |
| FG001 | Arm A: Delayed Then Missed Pill | 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 |
| FG002 | Arm B: Missed Then Delayed Pill | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 |
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| ||||||||||||||||||
| Treatment Periods 2 and 3 |
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All subjects enrolled in the study
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| ID | Title | Description |
|---|---|---|
| BG000 | All Enrolled Subjects | All subjects enrolled in the study |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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:
A score <5 is considered as a protective score while a score >9 is considered as a non protective score | Full Analysis Set for Primary endpoint: Subjects who had cervical mucus score for either D41-D43 or D69-71 | Posted | Least Squares Mean | Standard Error | changes in scores on a scale | Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days |
|
From Day 1 to Day 84
Systematic Assesment:
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Enrolled Subjects | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaphylactic Reaction | Immune system disorders | MedDRA 21.0 | Systematic Assessment | Anaphylaxis Reaction with difficulty breathing. Severe. Recovered/Resolved Not Related to study medication |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Metrorrhagia | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Agnes Hemon | HRA Pharma | 0140337092 | a.hemon@hra-pharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 26, 2018 | Apr 6, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 1, 2019 | Apr 6, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009644 | Norgestrel |
| ID | Term |
|---|---|
| D009652 | Norpregnenes |
| D009650 | Norpregnanes |
| D009654 | Norsteroids |
| D013256 | Steroids |
| D000072473 |
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|
| 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:
Ovarian Activity Score between 1 and 7:
| 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:
A score =< 4 is considered as a protective score and a score >= 9 is considered as a non protective score | 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 | 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:
| Day 1 to Day 84 (up to Day 90 if follow-up) |
| Portland |
| Oregon |
| 97239 |
| United States |
| NOT COMPLETED |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m² |
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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 |
| OG001 | Missed Pill Intake | 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 |
|
|
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| Secondary | 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 Analysis Set for Primary endpoint: Subjects who had cervical mucus score for either D41-D43 or D69-71 and a CMS at Baseline =< 5 | Posted | Count of Participants | Participants | Day 41 +/- 3 day to Day 43 +/3 days and Day 69 +/- 3 days to Day 71 +/-3 days |
|
|
|
|
| Secondary | Ovarian Status (OS) | Ovarian Status (OS) defined as:
Ovarian Activity Score between 1 and 7:
| Full Analysis Set - Ovarian Activity: Subjects with an Ovarian Status (OS) for either Treatment Period 2 or Treatment Period 3 | Posted | Count of Participants | Participants | From Day 1 to Day 84 (if no follow-up) or up to Day 90 (if follow-up) |
|
|
|
|
| Secondary | Cervical Mucus Protection | Higher Cervical Mucus Score (CMS) in:
A score =< 4 is considered as a protective score and a score >= 9 is considered as a non protective score | 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 | Posted | Count of Participants | Participants | From Day 1 to Day 84 |
|
|
|
|
| Secondary | 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 | 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 | Posted | Count of Participants | Participants | Day 1 to Day 84 (up to Day 90 if follow-up) |
|
|
|
| Secondary | 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:
| 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 | Posted | Count of Participants | Participants | Day 1 to Day 84 (up to Day 90 if follow-up) |
|
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| 0 |
| 52 |
| 1 |
| 52 |
| 50 |
| 52 |
| EG001 | Perfect Use Period | 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. | 0 | 52 | 0 | 52 | 42 | 52 |
| EG002 | Delayed Pill Intake | 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. | 0 | 50 | 1 | 50 | 29 | 50 |
| EG003 | Missed Pill Intake | 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. | 0 | 48 | 0 | 48 | 33 | 48 |
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| Upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
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| Acne | Skin and subcutaneous tissue disorders | MedDRA 21.0 | Systematic Assessment |
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| Breast tenderness | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Dysmenorrhea | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 21.0 | Systematic Assessment |
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| Menorrhagia | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Vulvovaginal discomfort | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
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| Muscle spams | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
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| Pelvic pain | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
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| Uterine spasm | Reproductive system and breast disorders | MedDRA 21.0 | Systematic Assessment |
|
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| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| Transient risk increase |
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| Prolonged risk increase |
|
Transient risk increase
| McNemar |
McNemar test comparing agreement in the missed and delayed periods |
| 0.655 |
p values > 0.050 (Not Statistically significant) |
| Other |
| Prolonged risk increase | McNemar | McNemar test comparing agreement in the missed and delayed periods | 0.317 | p values > 0.050 (Not Statistically significant) | Other |
| OSalp |
|
| OSnlp |
|
| 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. | McNemar | P-value from an exact kappa test comparing agreement of ovarian status vs the reported perfect use period. | <0.001 | Indicates significance at the 0.05 level (p-value ≤ 0.05) | Other |
| CMS >=9 |
|
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). |
| McNemar |
P-value from an exact kappa test comparing agreement of cervical mucus score classification vs the reported perfect use period. |
| 0.018 |
* Indicates significance at the 0.05 level (p-value ≤ 0.05). |
| Other |
| Minimum/Unlikely to be Protected |
|