E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - United States/Canada Study

• 15 mg E4/3 mg DRSP (Drug), also known as 15 mg estetrol and 3 mg drospirenone: 15 mg estetrol and 3 mg drospirenone tablets administered once daily for 13 consecutive cycles following a 24/4-day regimen, i.e. one 15 mg E4/3 mg DRSP active tablet per day for 24 consecutive days followed by one placebo tablet per day for 4 consecutive days.

Primary outcomes

• The Number of On-treatment Pregnancies (With + 7-day Window) Per 100 Woman-years of Exposure (Pearl Index) in Subjects Aged 16 to 35 Years, Inclusive, at the Time of Screening [Up to 12 months (13 cycles with 1 cycle = 28 days)]: On-treatment pregnancies are pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 7 days after the last intake of investigational product (whether active or inactive tablet). The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment was calculated as: Pearl Index = (1300*number of on-treatment pregnancies)/number of women 28-day equivalent cycles of treatment. Only at-risk cycles were included in the denominator of the Pearl Index calculation, unless a conception occurred during a cycle. At-risk-cycle was defined as cycle in which no other methods of birth control (including condoms and emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.

Secondary outcomes

• The Number of On-treatment Pregnancies (With +7-day Window) as Assessed by the Method Failure Pearl Index in Subjects Aged 16 to 35 Years, Inclusive, at the Time of Screening [Up to 12 months (13 cycles with 1 cycle = 28 days)]: On-treatment pregnancies are pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 7 days after the last intake of investigational product (whether active or inactive tablet). The method failure Pearl Index, defined as the number of pregnancies as a result of method failure per 100 women-years of treatment, was calculated as follow: (1300*number of on-treatment pregnancies as a result of method failure)/number of women 28-day equivalent cycles of treatment. Pregnancies due to user failure were excluded from the numerator. User failure pregnancies were pregnancies that occurred when the subject did not take the investigational product correctly. At-risk-cycle was defined as cycle in which no other methods of birth control (including condoms and emergency contraception) were used by the subject and during which the subject confirmed that sexual intercourse had occurred.
• The Number of On-treatment Pregnancies (With + 7-day Window) Per 100 Woman-years of Exposure (Pearl Index) in the Overall Study Population (16-50 Years) [Up to 12 months (13 cycles with 1 cycle = 28 days)]: On-treatment pregnancies are pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 7 days after the last intake of investigational product (whether active or inactive tablet). The Pearl Index, defined as the number of pregnancies per 100 women-years of treatment was calculated as: Pearl Index = (1300*number of on-treatment pregnancies)/number of women 28-day equivalent cycles of treatment. Only at-risk cycles were included in the denominator of the Pearl Index calculation, unless a conception occurred during a cycle. At-risk-cycle was defined as cycle in which no other methods of birth control (including condoms and emergency contraception) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.
• The Number of On-treatment Pregnancies as Assessed by the Method Failure Pearl Index in the Overall Study Population (16-50 Years) [Up to 12 months (13 cycles with 1 cycle = 28 days)]: On-treatment pregnancies are pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 7 days after the last intake of investigational product (whether active or inactive tablet). The method failure Pearl Index, defined as the number of pregnancies as a result of method failure per 100 women-years of treatment, was calculated as follow: (1300*number of on-treatment pregnancies as a result of method failure)/number of women 28-day equivalent cycles of treatment. Pregnancies due to user failure were excluded from the numerator. User failure pregnancies were pregnancies that occurred when the subject did not take the investigational product correctly. At-risk-cycle was defined as cycle in which no other methods of birth control (including condoms and emergency contraception) were used by the subject and during which the subject confirmed that sexual intercourse had occurred.
• Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 35 Years [Up to 12 months (13 cycles with 1 cycle = 28 days)]: The life-table analysis evaluates the cumulative probability of pregnancy over 13 cycles. Cumulative Rate and 95% CI are from Kaplan-Meier estimation. Only on-treatment pregnancies are included. On-treatment pregnancy is a pregnancy with an estimated date of conception after the date of the first dose of study medication to 7 days after the last dose of study medication (regardless of whether the last dose is an active or inactive tablet) inclusive.
• Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 50 Years [Up to 12 months (13 cycles with 1 cycle = 28 days)]: The life-table analysis evaluates the cumulative probability of pregnancy over 13 cycles. Cumulative Rate and 95% confidence interval (CI) are from Kaplan-Meier estimation. Only on-treatment pregnancies are included. On-treatment pregnancy is a pregnancy with an estimated date of conception after the date of the first dose of study medication to 7 days after the last dose of study medication (regardless of whether the last dose is an active or inactive tablet) inclusive.
• Number of Subjects With Unscheduled Bleeding/Spotting Episodes [Up to 11 months (12 cycles with 1 cycle = 28 days)]: Unscheduled bleeding/spotting is defined as any bleeding/spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding.
• Number of Unscheduled Bleeding Days Per Cycle [Up to 11 months (12 cycles with 1 cycle = 28 days)]: Unscheduled bleeding is defined as any bleeding that occurs while taking active hormones that does not meet the criteria for scheduled bleeding and/or spotting.
• Number of Unscheduled Spotting Days Per Cycle [Up to 11 months (12 cycles with 1 cycle = 28 days)]: Unscheduled spotting is defined as any spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding and/or spotting.
• Number of Subjects With Absence of Scheduled Bleeding and/or Spotting [Up to 11 months (12 cycles with 1 cycle = 28 days)]: Scheduled bleeding/spotting is defined as any bleeding/spotting that occurs during the hormone-free interval (i.e. Days 25 - 28) and continues through Days 1-3 of the subsequent active cycle.
• Number of Scheduled Bleeding and/or Spotting Days Per Cycle [Up to 11 months (12 cycles with 1 cycle = 28 days)]: Scheduled bleeding/spotting is defined as any bleeding/spotting that occurs during the hormone-free interval (i.e. Days 25 - 28) and continues through Days 1-3 of the subsequent active cycle.
• Number of Subjects With Bleeding and/or Spotting Episodes by Reference Period [Up to 12 months (13 cycles with 1 cycle = 28 days)]: Bleeding data were analysed by 91-day reference period. There were 4 RPs: Reference Period 1 = Day 1 to Day 91; Reference Period 2 = Day 92 to Day 182; Reference Period 3 = Day 183 to Day 273; and Reference Period 4 = Day 274 to Day 364.
• Mean Number of Bleeding and Spotting Days by Reference Period [up to 12 months (13 cycles)]: Bleeding data were analysed by 91-day reference period (RP). There were 4 RPs: Reference Period 1 = Day 1 to Day 91; Reference Period 2 = Day 92 to Day 182; Reference Period 3 = Day 183 to Day 273; and Reference Period 4 = Day 274 to Day 364.
• Number of Subjects With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability. [Up to 12 months (13 cycles with 1 cycle = 28 days)]: A treatment-emergent adverse event (TEAE) was defined as any AE not present prior to the initiation of the treatment or any event already present that worsened in either intensity or frequency following exposure to the treatment. Since the starting point for adverse event (AE) collection was the signing of the informed consent, not the start of the investigational product, the AEs recorded prior to first investigational product administration were designated as AEs while those that occurred or worsened after the initiation of the investigational product were designated as TEAEs.
• Number of Participants With Clinically Significant out-of Range Hematology Results [Up to 12 months (13 cycles with 1 cycle = 28 days)]
• Number of Participants With Clinically Significant out-of Range Serum Chemistry and Lipid Profile Results [Up to 12 months (13 cycles with 1 cycle = 28 days)]
• Number of Subjects With Clinically Abnormal Vital Signs [Up to 12 months (13 cycles with 1 cycle = 28 days)]: Vital signs included sitting systolic and diastolic blood pressures, and heart rate. All abnormal findings in vital signs that were considered by the Investigator to be clinically significant were recorded as adverse events.
• Number of Participants With Clinically Abnormal Physical Examination Results [Baseline and end of treatment (Cycle 13 with 1 cycle = 28 days)]: Physical examinations included an evaluation of body as a whole, skin, head, eyes, ears, nose, and throat, neck, cardiovascular, respiratory, musculoskeletal, neurologic, lymphatic/thyroid, abdomen. When reporting the results of the physical examination, the use of the "Abnormal" category was reserved for findings that were considered clinically significant, in the opinion of the Investigator; the "Normal" category included "Abnormal" results that were not clinically significant, as well as no findings.
• Number of Participants With Clinically Abnormal Gynecological Examination Results [Baseline and end of treatment (Cycle 13 with 1 cycle = 28 days)]: Gynecological examinations included breast examination (performed by palpation) and assessment of the adnexa, cervix, uterus, vagina, and external genitalia. When reporting the results, the use of the "Abnormal" category was reserved for findings that were considered clinically significant, in the opinion of the Investigator; the "Normal" category included "Abnormal" results that were not clinically significant, as well as no findings.
• Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Results at Baseline and End of Treatment - Percentage Maximum (Sum of First 14 Items) [Baseline and end of treatment (Cycle 13 with 1 cycle = 28 days)]: The Q-LES-Q-SF is a self-report measure designed to assess the degree of enjoyment and satisfaction in daily functioning. Participants were asked to rate 16 different items on a 5-point scale where score 1 = very poor and score 5 = very good. A raw total score is calculated by summing the first 14 items and ranges from 14 to 70. The raw total score is then transformed into a percentage maximum score using the following formula: (raw total score-minimum score)/(maximum possible raw score-minimum score). The minimum raw is 14 and maximum raw score is 70. Thus the formula for % maximum score can be written as (raw score -14)/56. A higher percentage maximum score indicates a higher life enjoyment and satisfaction.
• Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Results at Baseline and End of Treatment - Satisfaction With Medicine and Overall Life Satisfaction and Contentment Over the Past Week [Baseline and end of treatment (Cycle 13 with 1 cycle = 28 days)]: The Q-LES-Q-SF is a self-report measure designed to assess the degree of enjoyment and satisfaction in daily functioning. Participants were asked to rate 16 different items on a 5-point scale where score 1 = very poor and score 5 = very good. The last two items - item 15 rating "satisfaction with medicine" and item 16 rating "overall life satisfaction over the past week" are two global items that are scored individually. For both items, a higher score is associated with a better outcome.
• Change From Baseline to End of Treatment in the Score of the Menstrual Distress Questionnaire (MDQ) [Baseline and end of treatment (Cycle 13 with 1 cycle = 28 days)]: The MDQ is a standard method for measuring cyclical perimenstrual symptoms. The participants rated common symptoms and feelings associated with menstruation using the following scale: 0 (no experience of symptom), 1 (present, mild), 2 (present, moderate), 3 (present, strong),and 4 (present, severe) observed during pre-menstrual (4 days before menstruation), menstrual (most recent flow) and intermenstrual (remainder of the cycle) phases. Reported values are values at Cycle 13 minus values at Baseline. An overall positive change from baseline represents an increase in symptom or feeling severity.

Sex: Female, ages: 16 Years to 50 Years, accepts healthy volunteers

Inclusion Criteria:

* Heterosexually active female at risk for pregnancy and requesting contraception.
* Negative serum pregnancy test at subject screening.
* Willing to use the investigational product as the primary method of contraception for 13 consecutive cycles.
* Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, gynecological examination, clinical laboratory, and vital signs.
* Body mass index (BMI) below or equal to (≤) 35.0 kg/m2.
* Able to fulfill the requirements of the protocol and have indicated a willingness to participate in the study by providing written informed consent.
* Willing and able to complete the diaries and questionnaires.

Exclusion Criteria:

* Known hypersensitivity to any of the investigational product ingredients.
* Smoking if ≥ 35 years old, at screening.
* Any condition associated with decrease fertility.
* Dyslipoproteinemia requiring active treatment with antilipidemic agent.
* Diabetes mellitus with vascular involvement (nephropathy, retinopathy, neuropathy, other) or diabetes mellitus of more than 20-year duration.
* Arterial hypertension.
* Any condition associated with an increased risk of venous thromboembolism and/or arterial thromboembolism.
* Any condition associated with abnormal uterine/vaginal bleeding.
* Abnormal Pap test based on current international recommendations.
* Presence of an undiagnosed breast mass.
* Current symptomatic gallbladder disease.
* History of combined oral contraceptive (COC) related cholestasis.
* Presence or history of severe hepatic disease.
* Presence or history of pancreatitis if associated with hypertriglyceridemia.
* Porphyria.
* Presence or history of hepatocellular adenoma or malignant liver tumors.
* Renal impairment.
* Hyperkaliemia or presence of conditions that predispose to hyperkaliemia.
* Presence or history of hormone-related malignancy.
* History of non-hormone-related malignancy within 5 years before screening. Subjects with a non-melanoma skin cancer are allowed in the study.
* History of alcohol or drug abuse (including laxatives) within 12 months prior to screening.
* Use of drugs potentially triggering interactions with COCs.
* Any condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product.
* Uncontrolled thyroid disorders.
* Participation in another investigational drug clinical study within 1 month (30 days) or have received an investigational drug within the last 3 months (90 days) prior to study entry. Subjects who participated in an oral contraceptive clinical study, using FDA/European (EU) approved active ingredients, may be enrolled 2 months (60 days) after completing the preceding study.
* Sponsor, Contract Research Organization (CRO) or Investigator's site personnel directly affiliated with this study.
* Is judged by the Investigator to be unsuitable for any reason.

Participant flow

Outcome results

• The Number of On-treatment Pregnancies (With + 7-day Window) Per 100 Woman-years of Exposure (Pearl Index) in Subjects Aged 16 to 35 Years, Inclusive, at the Time of Screening (Primary), Number, Pearl Index: 15 mg E4/3 mg DRSP 2.65 (1.73 to 3.88)
• The Number of On-treatment Pregnancies (With +7-day Window) as Assessed by the Method Failure Pearl Index in Subjects Aged 16 to 35 Years, Inclusive, at the Time of Screening (Secondary), Number, Method failure Pearl Index: 15 mg E4/3 mg DRSP 1.43 (0.78 to 2.39)
• The Number of On-treatment Pregnancies (With + 7-day Window) Per 100 Woman-years of Exposure (Pearl Index) in the Overall Study Population (16-50 Years) (Secondary), Number, Pearl Index: 15 mg E4/3 mg DRSP 2.52 (1.68 to 3.64)
• The Number of On-treatment Pregnancies as Assessed by the Method Failure Pearl Index in the Overall Study Population (16-50 Years) (Secondary), Number, Method failure Pearl Index: 15 mg E4/3 mg DRSP 1.44 (0.82 to 2.34)
• Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 35 Years (Secondary), Number, percentage of participants: 15 mg E4/3 mg DRSP 2.06 (1.40 to 3.04)
• Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 50 Years (Secondary), Number, percentage of participants: 15 mg E4/3 mg DRSP 2.00 (1.38 to 2.91)
• Number of Subjects With Unscheduled Bleeding/Spotting Episodes (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 532
• Number of Unscheduled Bleeding Days Per Cycle (Secondary), Mean, Days: 15 mg E4/3 mg DRSP 0.4 +/- 1.42
• Number of Unscheduled Spotting Days Per Cycle (Secondary), Mean, Days: 15 mg E4/3 mg DRSP 1.0 +/- 2.21
• Number of Subjects With Absence of Scheduled Bleeding and/or Spotting (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 230
• Number of Scheduled Bleeding and/or Spotting Days Per Cycle (Secondary), Mean, Days: 15 mg E4/3 mg DRSP 6.1 +/- 10.16
• Number of Subjects With Bleeding and/or Spotting Episodes by Reference Period (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP - RP1 1,249
• Mean Number of Bleeding and Spotting Days by Reference Period (Secondary), Mean, Days: 15 mg E4/3 mg DRSP 3.6 +/- 1.23
• Number of Subjects With Treatment-emergent Adverse Events as a Measure of Safety and Tolerability. (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 1,002
• Number of Participants With Clinically Significant out-of Range Hematology Results (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 8
• Number of Participants With Clinically Significant out-of Range Serum Chemistry and Lipid Profile Results (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 21
• Number of Subjects With Clinically Abnormal Vital Signs (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 10
• Number of Participants With Clinically Abnormal Physical Examination Results (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 1,862
• Number of Participants With Clinically Abnormal Gynecological Examination Results (Secondary), Count of participants, Participants: 15 mg E4/3 mg DRSP 1,857
• Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) Results at Baseline and End of Treatment - Percentage Maximum (Sum of First 14 Items) (Secondary), Mean, Percentage maximum score on a scale: 15 mg E4/3 mg DRSP 75.8 +/- 13.58
• 2 more outcome measures not shown.

Adverse events

Time frame: From screening to end of treatment (13 months)

Serious adverse events by term

Other adverse events by term

• Results publication: Creinin MD, Jensen JT, Chen MJ, Black A, Costescu D, Foidart JM. Combined Oral Contraceptive Adherence and Pregnancy Rates. Obstet Gynecol. 2023 May 1;141(5):989-994. doi: 10.1097/AOG.0000000000005155. Epub 2023 Apr 5. PMID 37023457

• Statistical Analysis Plan (PDF, 2018-12-11)
• Study Protocol (PDF, 2017-07-10)

• Estetra, Study director, Estetra