Trial Outcomes & Findings for E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - United States/Canada Study (NCT NCT02817841)

A total of 2,148 participants aged 16-50 years were enrolled. Of those, 1,864 participants started the investigational product. Two hundred and eighty-four participants did not start the investigational product for the following reasons: lost to follow-up (166), withdrew consent (31), and other reasons (87).

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

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.

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.

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.

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 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.

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.

Unscheduled bleeding/spotting is defined as any bleeding/spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.