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

Study Overview
=================
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.

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

Conditions
-----------------
Contraception

Intervention / Treatment
-----------------
* Drug: 15 mg E4/3 mg DRSP


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 15 mg E4/3 mg DRSP<br>15 mg E4/3 mg DRSP tablet | Drug: 15 mg E4/3 mg DRSP<br>* 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.<br>* Other names: 15 mg estetrol and 3 mg drospirenone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Up to 12 months (13 cycles with 1 cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Up to 12 months (13 cycles with 1 cycle = 28 days) | 
| 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) | 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. | 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 (18-50 Years) | 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. | Up to 12 months (13 cycles with 1 cycle = 28 days) | 
| Number of Subjects With Unscheduled Bleeding/Spotting | Unscheduled bleeding/spotting is defined as any bleeding/spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding. | Up to 11 months (12 cycles with 1 cycle = 28 days) | 
| Number of Unscheduled Bleeding Days Per Cycle | 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. | Up to 11 months (12 cycles with 1 cycle = 28 days) | 
| Number of Unscheduled Spotting Days Per Cycle | 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. | Up to 11 months (12 cycles with 1 cycle = 28 days) | 
| Number of Subjects With Absence of 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. | Up to 11 months (12 cycles with 1 cycle = 28 days) | 
| Number of Scheduled Bleeding and/or Spotting Days Per Cycle | 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. | Up to 11 months (12 cycles with 1 cycle = 28 days) | 
| Number of Subjects With Abnormal Vital Signs | Vital signs included sitting systolic and diastolic blood pressures, and heart rate. | From screening to end of treatment (12 months) | 
| Number of Subjects With Abnormal Laboratory Assessment Results | Laboratory assessment included blood hematology, biochemistry, and lipids | From screening to end of treatment (12 months) | 
| Number of Subjects With Abnormal Physical Examination Results | 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. | From screening to end of treatment (12 months) | 
| Number of Subjects With Abnormal Gynecological Examination Results | 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. | From screening to end of treatment (12 months) | 
| Endometrial Biopsy Histology at Screening and End of Treatment | 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. | Baseline and end of treatment (up to 13 cycles with 1 cycle = 28 days) | 
| 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) | 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. | Baseline and Cycle 13 (1 cycle = 28 days) | 
| 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 | 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. | Baseline and Cycle 13 (1 cycle = 28 days) | 
| Change From Baseline to End of Treatment in the Score of the Menstrual Distress Questionnaire (MDQ) | 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. | Baseline and Cycle 13 (1 cycle = 28 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Estetrol