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

• ClinicalTrials.gov Identifier: NCT02817828
• Recruitment Status: Completed
• First Posted: June 29, 2016
• Results First Posted: October 4, 2019
• Last Update Posted: October 4, 2019
• Sponsor: Estetra
• Collaborator: PRA Health Sciences
• Information provided by (Responsible Party): Estetra

Tracking Information

• First Submitted Date: June 27, 2016
• First Posted Date: June 29, 2016
• Results First Submitted Date: April 26, 2019
• Results First Posted Date: October 4, 2019
• Last Update Posted Date: October 4, 2019
• Study Start Date: June 2016
• Actual Primary Completion Date: April 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 13, 2019)

The Number of On-treatment Pregnancies (With + 2-day Window) Per 100 Woman-years of Exposure (Pearl Index) in Subjects Aged 18 to 35 Years, Inclusive, at the Time of Screening [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]

On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 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. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.

Original Primary Outcome Measures (submitted: June 27, 2016)

The number of on-treatment pregnancies (with + 2-day window) per 100 woman-years of exposure (Pearl Index) in subjects aged 18 to 35 years, inclusive, at the time of screening. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]

On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 days after the last intake of investigational product (whether active or inactive tablet).

Current Secondary Outcome Measures (submitted: September 13, 2019)

• The Number of On-treatment Pregnancies (With 2-day Window) as Assessed by the Method Failure Pearl Index in Subjects Aged 18 to 35 Years, Inclusive, at the Time of Screening [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 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. The method failure Pearl Index includes only those pregnancies that were classified as method failure and not the pregnancies due to user failure, i.e. incorrect intake of the contraceptive method. Only at-risk cycles were included in the denominator of the Pearl Index calculation. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms) 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 (With + 2-day Window) Per 100 Woman-years of Exposure (Pearl Index) in the Overall Study Population (18-50 Years) [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 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. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms) 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 (18-50 Years) [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  On-treatment pregnancies are defined as pregnancies with an estimated date of conception within the in-treatment period i.e. Day 1 to 2 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. The method failure Pearl Index includes only those pregnancies that were classified as method failure and not the pregnancies due to user failure, i.e. incorrect intake of the contraceptive method. Only at-risk cycles were included in the denominator of the Pearl Index calculation. At-risk-cycles were defined as cycles in which no other methods of birth control (including condoms) were used by the subject as confirmed in the subject diary and during which the subject confirmed that sexual intercourse had occurred.
• Number of Subjects With Unscheduled Bleeding/Spotting [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 11 months (12 cycles with 1 cycle = 28 days) ]
  Scheduled bleeding and /or spotting is defined as any bleeding and/or 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 Abnormal Vital Signs [ Time Frame: From screening to end of treatment (12 months) ]
  Vital signs included sitting systolic and diastolic blood pressures, and heart rate.
• Number of Subjects With Abnormal Laboratory Assessment Results [ Time Frame: From screening to end of treatment (12 months) ]
  Laboratory assessment included blood hematology, biochemistry, and lipids
• Number of Subjects With Abnormal Physical Examination Results [ Time Frame: From screening to end of treatment (12 months) ]
  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 Subjects With Abnormal Gynecological Examination Results [ Time Frame: From screening to end of treatment (12 months) ]
  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.
• Endometrial Biopsy Histology at Screening and End of Treatment [ Time Frame: Baseline and end of treatment (up to 13 cycles with 1 cycle = 28 days) ]
  Endometrial biopsies was obtained from a subset of subjects included in the endometrial safety substudy at the screening visit and at the end of treatment visit if the subject has completed at least 10 cycles.
• 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) [ Time Frame: Baseline and Cycle 13 (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 with a higher scores indicating higher life enjoyment and satisfaction. 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). In addition, the last two items (15 and 16) are two global items that are scored individually. These items rate "satisfaction with medicine" and "overall life satisfaction over the past week".
• 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 Over the Past Week [ Time Frame: Baseline and Cycle 13 (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 with a higher scores indicating higher life enjoyment and satisfaction. 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). In addition, the last two items (15 and 16) are two global items that are scored individually. These items rate "satisfaction with medicine" and "overall life satisfaction over the past week".
• Change From Baseline to End of Treatment in the Score of the Menstrual Distress Questionnaire (MDQ) [ Time Frame: Baseline and Cycle 13 (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.

Original Secondary Outcome Measures (submitted: June 27, 2016)

• The number of on-treatment pregnancies as assessed by the method failure Pearl Index in subjects aged 18 to 35 years, inclusive, at the time of screening. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  The method failure Pearl Index is calculated using the same method used for the Pearl Index, but includes only those pregnancies that were classified as method failure and not the pregnancies due to user failure, i.e. incorrect intake of the contraceptive method.
• The number of on-treatment pregnancies (with + 2-day window) per 100 woman-years of exposure (Pearl Index) in the overall study population (18-50 years). [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
• The number of on-treatment pregnancies as assessed by the method failure Pearl Index in the overall study population. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
• Number of subjects with scheduled bleeding/spotting. [ Time Frame: Up to 12 months (13 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 unscheduled bleeding/spotting. [ Time Frame: Up to 12 months (13 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 subjects with absence of any bleeding/spotting. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
• Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
• Change in endometrial histology from baseline to end of treatment in subjects having been treated for at least 10 complete cycles. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  Endometrial biopsies will be obtained from a subset of 100 subjects included in the endometrial safety Substudy at the Screening Visit and at Visit 7a if the subject has completed at least 10 cycles.
• Change from baseline to end of treatment in the different items of well-established questionnaires. [ Time Frame: Up to 12 months (13 cycles with 1 cycle = 28 days) ]
  Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and The Menstrual Distress Questionnaire will be used for the quality of life analysis.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - EU/Russia Study
• Official Title: A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and Safety of a Combined Oral Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone
• Brief Summary: The objectives of this study are to evaluate the contraceptive efficacy, vaginal bleeding pattern (cycle control), and the general safety and acceptability of the 15 mg estetrol (E4)/3 mg drospirenone (DRSP) combination in healthy women aged 18 to 50 years.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Contraception

Intervention

Drug: 15 mg E4/3 mg DRSP

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.

Other Name: 15 mg estetrol and 3 mg drospirenone

Study Arms

Experimental: 15 mg E4/3 mg DRSP

15 mg E4/3 mg DRSP tablet

Intervention: Drug: 15 mg E4/3 mg DRSP

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 9, 2017): 1577
• Original Estimated Enrollment (submitted: June 27, 2016): 1550
• Actual Study Completion Date: April 26, 2018
• Actual Primary Completion Date: April 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Heterosexually active female at risk for pregnancy and requesting contraception.
• Negative serum pregnancy test at subject enrollment.
• 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 (IC).
• 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 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.
• Use of drugs potentially triggering interactions with COCs.
• History of alcohol or drug abuse (including laxatives) within 12 months prior to screening.
• 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/EU approved active ingredients, may be enrolled 2 months (60 days) after completing the preceding study.
• Sponsor, CRO or Investigator's site personnel directly affiliated with this study.
• Is judged by the Investigator to be unsuitable for any reason.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium

Administrative Information

• NCT Number: NCT02817828
• Other Study ID Numbers: MIT-Es0001-C301
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Estetra
• Original Responsible Party: Same as current
• Current Study Sponsor: Estetra
• Original Study Sponsor: Same as current
• Collaborators: PRA Health Sciences

Investigators

• Study Director: Estetra; Estetra

• PRS Account: Estetra
• Verification Date: September 2019