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Trial record 6 of 23 for:    estetrol

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

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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:
Collaborator:
PRA Health Sciences
Information provided by (Responsible Party):
Estetra

Study Type Interventional
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
Enrollment 1577
Recruitment Details  
Pre-assignment Details A total of 1,577 participants aged 18-50 years were enrolled. Of those, 1,553 started the study treatment. Twenty-four participants did not start the treatment for the following reasons: consent withdrawn (8), unspecified reason (5), protocol deviation (3), pregnancy (4), lost to follow-up (3), and adverse event not related to bleeding (1).
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Period Title: Overall Study
Started 1553
Completed 1218
Not Completed 335
Reason Not Completed
Lost to Follow-up             41
Adverse event not related to bleeding             104
Adverse event related to bleeding             53
Protocol Violation             11
Pregnancy             7
Pregnancy wish             15
Withdrawal by Subject             78
Other             26
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Baseline Participants 1,553
Hide Baseline Analysis Population Description
All participants aged 18 to 50 years who received at least one dose of 15 mg E4/3 mg DRSP
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1,553 participants
<=18 years
0
   0.0%
Between 18 and 65 years
1,553
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1,553 participants
27.1  (6.86)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1,553 participants
Female
1,553
 100.0%
Male
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1,553 participants
Hispanic or Latino
13
   0.8%
Not Hispanic or Latino
1540
  99.2%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1,553 participants
Belgium
87
   5.6%
Czechia
335
  21.6%
Finland
181
  11.7%
Germany
141
   9.1%
Hungary
190
  12.2%
Norway
108
   7.0%
Poland
221
  14.2%
Russia
280
  18.0%
Sweden
10
   0.6%
Body mass index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 1,553 participants
23.0  (3.469)
1.Primary Outcome
Title 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
Hide Description

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.

Time Frame Up to 12 months (13 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 35 years, inclusive, at screening with at least 1 cycle included in the denominator.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,313
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Pearl Index
0.47
(0.15 to 1.11)
2.Secondary Outcome
Title 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
Hide Description 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.
Time Frame Up to 12 months (13 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 35 years, inclusive, at screening with at least 1 cycle included in the denominator.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,313
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Method failure Pearl Index
0.29
(0.06 to 0.83)
3.Secondary Outcome
Title 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)
Hide Description

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.

Time Frame Up to 12 months (13 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with at least 1 cycle included in the denominator.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,510
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Pearl Index
0.41
(0.13 to 0.96)
4.Secondary Outcome
Title The Number of On-Treatment Pregnancies as Assessed by the Method Failure Pearl Index in the Overall Study Population (18-50 Years)
Hide Description 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.
Time Frame Up to 12 months (13 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with at least 1 cycle included in the denominator.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,510
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Method Failure Pearl Index
0.25
(0.05 to 0.72)
5.Secondary Outcome
Title Number of Subjects With Unscheduled Bleeding/Spotting
Hide Description Unscheduled bleeding/spotting is defined as any bleeding/spotting that occurs while taking active hormones that does not meet the criteria for scheduled bleeding.
Time Frame Up to 11 months (12 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, with evaluable cycle data for the bleeding analysis.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
Cycle 1 Number Analyzed 1,507 participants
354
  23.5%
Cycle 2 Number Analyzed 1,465 participants
282
  19.2%
Cycle 3 Number Analyzed 1,436 participants
250
  17.4%
Cycle 4 Number Analyzed 1,409 participants
249
  17.7%
Cycle 5 Number Analyzed 1,361 participants
238
  17.5%
Cycle 6 Number Analyzed 1,331 participants
207
  15.6%
Cycle 7 Number Analyzed 1,287 participants
170
  13.2%
Cycle 8 Number Analyzed 1,277 participants
202
  15.8%
Cycle 9 Number Analyzed 1,245 participants
182
  14.6%
Cycle 10 Number Analyzed 1,236 participants
168
  13.6%
Cycle 11 Number Analyzed 1,209 participants
155
  12.8%
Cycle 12 Number Analyzed 1,183 participants
154
  13.0%
6.Secondary Outcome
Title Number of Unscheduled Bleeding Days Per Cycle
Hide Description 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.
Time Frame Up to 11 months (12 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, with evaluable cycle data for the bleeding analysis.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Mean (Standard Deviation)
Unit of Measure: Days
Cycle 1 Number Analyzed 1,507 participants
0.2  (0.89)
Cycle 2 Number Analyzed 1,465 participants
0.1  (0.66)
Cycle 3 Number Analyzed 1,436 participants
0.1  (0.67)
Cycle 4 Number Analyzed 1,409 participants
0.2  (0.79)
Cycle 5 Number Analyzed 1,361 participants
0.1  (0.70)
Cycle 6 Number Analyzed 1,331 participants
0.1  (0.80)
Cycle 7 Number Analyzed 1,287 participants
0.1  (0.68)
Cycle 8 Number Analyzed 1,277 participants
0.1  (0.72)
Cycle 9 Number Analyzed 1,245 participants
0.1  (0.70)
Cycle 10 Number Analyzed 1,236 participants
0.1  (0.61)
Cycle 11 Number Analyzed 1,209 participants
0.1  (0.72)
Cycle 12 Number Analyzed 1,183 participants
0.1  (0.68)
7.Secondary Outcome
Title Number of Unscheduled Spotting Days Per Cycle
Hide Description 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.
Time Frame Up to 11 months (12 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, with evaluable cycle data for the bleeding analysis.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Mean (Standard Deviation)
Unit of Measure: Days
Cycle 1 Number Analyzed 1,507 participants
0.8  (1.99)
Cycle 2 Number Analyzed 1,465 participants
0.5  (1.50)
Cycle 3 Number Analyzed 1,436 participants
0.5  (1.46)
Cycle 4 Number Analyzed 1,409 participants
0.5  (1.55)
Cycle 5 Number Analyzed 1,361 participants
0.5  (1.35)
Cycle 6 Number Analyzed 1,331 participants
0.4  (1.24)
Cycle 7 Number Analyzed 1,287 participants
0.4  (1.17)
Cycle 8 Number Analyzed 1,277 participants
0.4  (1.19)
Cycle 9 Number Analyzed 1,245 participants
0.4  (0.13)
Cycle 10 Number Analyzed 1,236 participants
0.4  (1.25)
Cycle 11 Number Analyzed 1,209 participants
0.3  (1.18)
Cycle 12 Number Analyzed 1,183 participants
0.4  (1.23)
8.Secondary Outcome
Title Number of Subjects With Absence of Scheduled Bleeding and/or Spotting
Hide Description 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.
Time Frame Up to 11 months (12 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, with evaluable cycle data for the bleeding analysis.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
Cycle 1 Number Analyzed 1,507 participants
84
   5.6%
Cycle 2 Number Analyzed 1,465 participants
90
   6.1%
Cycle 3 Number Analyzed 1,436 participants
105
   7.3%
Cycle 4 Number Analyzed 1,409 participants
83
   5.9%
Cycle 5 Number Analyzed 1,361 participants
91
   6.7%
Cycle 6 Number Analyzed 1,331 participants
91
   6.8%
Cycle 7 Number Analyzed 1,287 participants
90
   7.0%
Cycle 8 Number Analyzed 1,277 participants
103
   8.1%
Cycle 9 Number Analyzed 1,245 participants
92
   7.4%
Cycle 10 Number Analyzed 1,236 participants
89
   7.2%
Cycle 11 Number Analyzed 1,209 participants
80
   6.6%
Cycle 12 Number Analyzed 1,183 participants
94
   7.9%
9.Secondary Outcome
Title Number of Scheduled Bleeding and/or Spotting Days Per Cycle
Hide Description 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.
Time Frame Up to 11 months (12 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, with evaluable cycle data for the bleeding analysis.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Mean (Standard Deviation)
Unit of Measure: Days
Cycle 1 Number Analyzed 1,507 participants
6.1  (4.95)
Cycle 2 Number Analyzed 1,465 participants
5.3  (3.62)
Cycle 3 Number Analyzed 1,436 participants
5.2  (3.99)
Cycle 4 Number Analyzed 1,409 participants
5.0  (3.14)
Cycle 5 Number Analyzed 1,361 participants
4.9  (3.43)
Cycle 6 Number Analyzed 1,331 participants
4.9  (3.34)
Cycle 7 Number Analyzed 1,287 participants
4.7  (2.80)
Cycle 8 Number Analyzed 1,277 participants
4.8  (3.85)
Cycle 9 Number Analyzed 1,245 participants
4.7  (2.87)
Cycle 10 Number Analyzed 1,236 participants
4.6  (2.69)
Cycle 11 Number Analyzed 1,209 participants
4.7  (3.16)
Cycle 12 Number Analyzed 1,183 participants
4.6  (2.97)
10.Secondary Outcome
Title Number of Subjects With Abnormal Vital Signs
Hide Description Vital signs included sitting systolic and diastolic blood pressures, and heart rate.
Time Frame From screening to end of treatment (12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, who received at least one dose of investigational product.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
15
   1.0%
11.Secondary Outcome
Title Number of Subjects With Abnormal Laboratory Assessment Results
Hide Description Laboratory assessment included blood hematology, biochemistry, and lipids
Time Frame From screening to end of treatment (12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, who received at least one dose of investigational product.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
55
   3.5%
12.Secondary Outcome
Title Number of Subjects With Abnormal Physical Examination Results
Hide Description

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.

Time Frame From screening to end of treatment (12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, who received at least one dose of investigational product with baseline and end of treatment (EOT) results.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
Body as a whole - Baseline Number Analyzed 1,553 participants
Normal
1548
  99.7%
Abnormal
5
   0.3%
Not done
0
   0.0%
Body as a whole - EOT Number Analyzed 1,498 participants
Normal
1493
  99.7%
Abnormal
5
   0.3%
Not done
0
   0.0%
Skin - Baseline Number Analyzed 1,553 participants
Normal
1537
  99.0%
Abnormal
16
   1.0%
Not done
0
   0.0%
Skin - EOT Number Analyzed 1,498 participants
Normal
1,476
  98.5%
Abnormal
22
   1.5%
Not done
0
   0.0%
Head, Eyes, Ears, Nose and Throat - Baseline Number Analyzed 1,553 participants
Normal
1,543
  99.4%
Abnormal
10
   0.6%
Not done
0
   0.0%
Head, Eyes, Ears, Nose and Throat - EOT Number Analyzed 1,498 participants
Normal
1,492
  99.6%
Abnormal
3
   0.2%
Not done
3
   0.2%
Neck - Baseline Number Analyzed 1,553 participants
Normal
1,552
  99.9%
Abnormal
1
   0.1%
Not done
0
   0.0%
Neck - EOT Number Analyzed 1,498 participants
Normal
1,495
  99.8%
Abnormal
1
   0.1%
Not done
2
   0.1%
Cardiovascular - Baseline Number Analyzed 1,553 participants
Normal
1,553
 100.0%
Abnormal
0
   0.0%
Not done
0
   0.0%
Cardiovascular - EOT Number Analyzed 1,498 participants
Normal
1,496
  99.9%
Abnormal
1
   0.1%
Not done
1
   0.1%
Respiratory - Baseline Number Analyzed 1,553 participants
Normal
1,551
  99.9%
Abnormal
2
   0.1%
Not done
0
   0.0%
Respiratory - EOT Number Analyzed 1,498 participants
Normal
1,496
  99.9%
Abnormal
1
   0.1%
Not done
1
   0.1%
Musculoskeletal - Baseline Number Analyzed 1,553 participants
Normal
1,553
 100.0%
Abnormal
0
   0.0%
Not done
0
   0.0%
Musculoskeletal - EOT Number Analyzed 1,498 participants
Normal
1,495
  99.8%
Abnormal
1
   0.1%
Not done
2
   0.1%
Neurologic - Baseline Number Analyzed 1,553 participants
Normal
1,553
 100.0%
Abnormal
0
   0.0%
Not done
0
   0.0%
Neurologic - EOT Number Analyzed 1,498 participants
Normal
1,494
  99.7%
Abnormal
2
   0.1%
Not done
2
   0.1%
Lymphatic/Thyroid - Baseline Number Analyzed 1,553 participants
Normal
1,549
  99.7%
Abnormal
2
   0.1%
Not done
2
   0.1%
Lymphatic/Thyroid - EOT Number Analyzed 1,498 participants
Normal
1,494
  99.7%
Abnormal
1
   0.1%
Not done
3
   0.2%
Abdomen - Baseline Number Analyzed 1,553 participants
Normal
1,553
 100.0%
Abnormal
0
   0.0%
Not done
0
   0.0%
Abdomen - EOT Number Analyzed 1,498 participants
Normal
1,496
  99.9%
Abnormal
1
   0.1%
Not done
1
   0.1%
13.Secondary Outcome
Title Number of Subjects With Abnormal Gynecological Examination Results
Hide Description

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.

Time Frame From screening to end of treatment (12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening, who received at least one dose of investigational product with baseline and end of treatment (EOT) gynecological results.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553
Measure Type: Count of Participants
Unit of Measure: Participants
Breast - Baseline Number Analyzed 1,553 participants
Normal
1,545
  99.5%
Abnormal
8
   0.5%
Not done
0
   0.0%
Breast - EOT Number Analyzed 1,499 participants
Normal
1,485
  99.1%
Abnormal
13
   0.9%
Not done
1
   0.1%
Adnexa - Baseline Number Analyzed 1,553 participants
Normal
1,549
  99.7%
Abnormal
4
   0.3%
Not done
0
   0.0%
Adnexa - EOT Number Analyzed 1,499 participants
Normal
1,496
  99.8%
Abnormal
2
   0.1%
Not done
1
   0.1%
Cervix - Baseline Number Analyzed 1,553 participants
Normal
1,532
  98.6%
Abnormal
21
   1.4%
Not done
0
   0.0%
Cervix - EOT Number Analyzed 1,499 participants
Normal
1,485
  99.1%
Abnormal
13
   0.9%
Not done
1
   0.1%
Uterus - Baseline Number Analyzed 1,553 participants
Normal
1,542
  99.3%
Abnormal
11
   0.7%
Not done
0
   0.0%
Uterus - EOT Number Analyzed 1,499 participants
Normal
1,492
  99.5%
Abnormal
6
   0.4%
Not done
1
   0.1%
Vagina - Baseline Number Analyzed 1,553 participants
Normal
1,545
  99.5%
Abnormal
8
   0.5%
Not done
0
   0.0%
Vagina - EOT Number Analyzed 1,499 participants
Normal
1,489
  99.3%
Abnormal
8
   0.5%
Not done
2
   0.1%
External genitalia - Baseline Number Analyzed 1,553 participants
Normal
1,552
  99.9%
Abnormal
1
   0.1%
Not done
0
   0.0%
External genitalia - EOT Number Analyzed 1,499 participants
Normal
1,497
  99.9%
Abnormal
1
   0.1%
Not done
1
   0.1%
14.Secondary Outcome
Title Endometrial Biopsy Histology at Screening and End of Treatment
Hide Description 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.
Time Frame Baseline and end of treatment (up to 13 cycles with 1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with an evaluable endometrial biopsies both at screening and end of treatment.
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 108
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline No tissue
0
   0.0%
Tissue insufficient for diagnosis
1
   0.9%
Benign histology:Atrophic
2
   1.9%
Benign histology: Inactive
7
   6.5%
Benign histology:Proliferative
76
  70.4%
Secretory
22
  20.4%
Menstrual type
0
   0.0%
Simple hyperplasia without atypia
0
   0.0%
Complex hyperplasia without atypia
0
   0.0%
Pre-malignant/Malignant histology
0
   0.0%
End of Treatment No tissue
0
   0.0%
Tissue insufficient for diagnosis
9
   8.3%
Benign histology:Atrophic
11
  10.2%
Benign histology: Inactive
61
  56.5%
Benign histology:Proliferative
22
  20.4%
Secretory
5
   4.6%
Menstrual type
0
   0.0%
Simple hyperplasia without atypia
0
   0.0%
Complex hyperplasia without atypia
0
   0.0%
Pre-malignant/Malignant histology
0
   0.0%
15.Secondary Outcome
Title 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)
Hide Description

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".

Time Frame Baseline and Cycle 13 (1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with baseline and end of treatment Q-LES-Q-SF results.
Arm/Group Title 15 mg E4/3 mg DRSP - Baseline Results 15 mg E4/3 mg DRSP - End of Treatment Results
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,379 1,406
Mean (Standard Deviation)
Unit of Measure: Percentage maximum score on a scale
73.4  (12.77) 73.8  (12.82)
16.Secondary Outcome
Title 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
Hide Description

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".

Time Frame Baseline and Cycle 13 (1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with baseline and end of treatment Q-LES-Q-SF results.
Arm/Group Title 15 mg E4/3 mg DRSP - Baseline Results 15 mg E4/3 mg DRSP - End of Treatment Results
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,379 1,406
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Satisfaction with medicine 4.0  (0.78) 4.0  (0.77)
Overall life statisfaction over the past week 4.0  (0.68) 4.0  (0.70)
17.Secondary Outcome
Title Change From Baseline to End of Treatment in the Score of the Menstrual Distress Questionnaire (MDQ)
Hide Description

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.

Time Frame Baseline and Cycle 13 (1 cycle = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants aged 18 to 50 years, inclusive, at screening with both baseline and end of treatment MDQ results.
Arm/Group Title 15 mg E4/3 mg DRSP Tablet - Menstrual Phase 15 mg E4/3 mg DRSP Tablet - Premenstrual Phase 15 mg E4/3 mg DRSP Tablet - Intermenstrual Phase
Hide Arm/Group Description:

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

Overall Number of Participants Analyzed 1,553 1,553 1,553
Mean (Standard Deviation)
Unit of Measure: units on a scale
Pain Number Analyzed 1,392 participants 1,393 participants 1,396 participants
-0.4  (3.6) -0.1  (2.96) -0.1  (2.67)
Water retention Number Analyzed 1,392 participants 1,394 participants 1,395 participants
-0.1  (2.61) -0.1  (2.57) 0.0  (2.09)
Autonomic reactions Number Analyzed 1,392 participants 1,393 participants 1,396 participants
-0.1  (1.42) -0.0  (1.30) -0.0  (1.22)
Negative affect Number Analyzed 1,392 participants 1,393 participants 1,395 participants
-0.4  (4.90) -0.3  (4.70) -0.1  (3.93)
Impaired concentration Number Analyzed 1,392 participants 1,393 participants 1,395 participants
0.0  (2.67) -0.0  (2.55) 0.0  (2.23)
Behaviour change Number Analyzed 1,392 participants 1,394 participants 1,395 participants
-0.1  (2.86) -0.1  (2.55) -0.0  (1.99)
Arousal Number Analyzed 1,392 participants 1,393 participants 1,395 participants
-0.3  (3.46) -0.3  (3.62) -0.3  (3.91)
Control Number Analyzed 1,392 participants 1,393 participants 1,396 participants
0.0  (1.52) 0.0  (1.57) 0.0  (1.63)
Time Frame From screening to end of treatment (13 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 15 mg E4/3 mg DRSP
Hide Arm/Group Description

15 mg E4/3 mg DRSP tablet

15 mg E4/3 mg DRSP: 15 mg estetrol and 3 mg drospirenone tablets administered orally 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.

All-Cause Mortality
15 mg E4/3 mg DRSP
Affected / at Risk (%)
Total   0/1,553    
Hide Serious Adverse Events
15 mg E4/3 mg DRSP
Affected / at Risk (%) # Events
Total   13/1,553    
Ear and labyrinth disorders   
Vertigo * 1  1/1553 (0.06%)  1
Gastrointestinal disorders   
Abdominal pain * 1  1/1553 (0.06%)  1
Colitis * 1  1/1553 (0.06%)  1
General disorders   
Pyrexia * 1  1/1553 (0.06%)  1
Infections and infestations   
Appendicitis * 1  2/1553 (0.13%)  2
Abscess limb * 1  1/1553 (0.06%)  1
Injury, poisoning and procedural complications   
Spinal column injury * 1  1/1553 (0.06%)  1
Concussion * 1  1/1553 (0.06%)  1
Upper limb fracture * 1  1/1553 (0.06%)  1
Nervous system disorders   
Migraine without aura * 1  1/1553 (0.06%)  1
Pregnancy, puerperium and perinatal conditions   
Abortion spontaneous * 1  1/1553 (0.06%)  1
Reproductive system and breast disorders   
Haemorrhagic ovarian cyst * 1  1/1553 (0.06%)  1
Vascular disorders   
Venous thrombosis * 1  1/1553 (0.06%)  1
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
15 mg E4/3 mg DRSP
Affected / at Risk (%) # Events
Total   784/1,553    
Gastrointestinal disorders   
Abdominal pain * 1  36/1553 (2.32%)  48
Diarrhoea * 1  25/1553 (1.61%)  45
Vomiting * 1  27/1553 (1.74%)  49
Nausea * 1  20/1553 (1.29%)  25
Infections and infestations   
Tonsilitis * 1  29/1553 (1.87%)  31
Vaginal infection * 1  29/1553 (1.87%)  33
Influenza * 1  28/1553 (1.80%)  30
Urinary tract infection * 1  30/1553 (1.93%)  35
Vulvovaginal mycotic infection * 1  17/1553 (1.09%)  22
Bronchitis * 1  15/1553 (0.97%)  16
Sinusitis * 1  17/1553 (1.09%)  19
Respiratory tract infection * 1  18/1553 (1.16%)  19
Cystitis * 1  24/1553 (1.55%)  29
Vulvovaginal candidiasis * 1  20/1553 (1.29%)  23
Investigations   
Weight increased  1  36/1553 (2.32%)  36
Low density lipoprotein increased  1  18/1553 (1.16%)  19
Musculoskeletal and connective tissue disorders   
Back pain * 1  19/1553 (1.22%)  20
Nervous system disorders   
Dizziness * 1  19/1553 (1.22%)  24
Headache * 1  120/1553 (7.73%)  171
Mood altered * 1  19/1553 (1.22%)  19
Libido decreased * 1  38/1553 (2.45%)  43
Irritability * 1  18/1553 (1.16%)  18
Mood swings * 1  18/1553 (1.16%)  18
Reproductive system and breast disorders   
Vaginal haemorrhage * 1  74/1553 (4.76%)  151
Dysmenorrhoea * 1  47/1553 (3.03%)  74
Metrorrhagia * 1  85/1553 (5.47%)  156
Breast pain * 1  42/1553 (2.70%)  51
Vaginal discharge * 1  16/1553 (1.03%)  19
Respiratory, thoracic and mediastinal disorders   
Oropharyngeal pain * 1  15/1553 (0.97%)  16
Skin and subcutaneous tissue disorders   
Acne * 1  65/1553 (4.19%)  69
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Mithra Pharmaceuticals SA Pharma Department
Organization: Estetra SPRL
Phone: +3243492822
EMail: clinical.trials@mithra.com
Layout table for additonal information
Responsible Party: Estetra
ClinicalTrials.gov Identifier: NCT02817828    
Other Study ID Numbers: MIT-Es0001-C301
First Submitted: June 27, 2016
First Posted: June 29, 2016
Results First Submitted: April 26, 2019
Results First Posted: October 4, 2019
Last Update Posted: October 4, 2019