NCT02817841

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

Completed Phase 3 Results posted Last updated 10 February 2020

What this trial tests

Phase 3 trial testing 15 mg E4/3 mg DRSP in Contraception in 2,148 participants. Completed in 16 November 2018.

Timeline

30 August 2016

Primary endpoint
16 October 2018

16 November 2018

Quick facts

Lead sponsor	Estetra
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	prevention
Enrollment	2,148
Start date	30 August 2016
Primary completion	16 October 2018
Estimated completion	16 November 2018
Sites	2 locations across Canada, United States

Drugs / interventions tested

• 15 mg E4/3 mg DRSP — full drug profile →

Conditions studied

• Contraception — all drugs for Contraception →

Sponsor

Estetra — full company profile →

Who can join

Adults 16 to 50, female only, with Contraception. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 · 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

Group	Value	95% CI
15 mg E4/3 mg DRSP	2.65	1.73 – 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 · 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 p

Group	Value	95% CI
15 mg E4/3 mg DRSP	1.43	0.78 – 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 · 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

Group	Value	95% CI
15 mg E4/3 mg DRSP	2.52	1.68 – 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 · 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 p

Group	Value	95% CI
15 mg E4/3 mg DRSP	1.44	0.82 – 2.34

Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 35 Years Secondary · 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.

Group	Value	95% CI
15 mg E4/3 mg DRSP	2.06	1.40 – 3.04

Rate of Pregnancy (Life-table Analysis) in Participants Aged 16 to 50 Years Secondary · 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.

Group	Value	95% CI
15 mg E4/3 mg DRSP	2.00	1.38 – 2.91

Number of Subjects With Unscheduled Bleeding/Spotting Episodes Secondary · 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.

Cycle 1

Group	Value	95% CI
15 mg E4/3 mg DRSP	532

Cycle 2

Group	Value	95% CI
15 mg E4/3 mg DRSP	345

Cycle 3

Group	Value	95% CI
15 mg E4/3 mg DRSP	337

Cycle 4

Group	Value	95% CI
15 mg E4/3 mg DRSP	302

Cycle 5

Group	Value	95% CI
15 mg E4/3 mg DRSP	238

Cycle 6

Group	Value	95% CI
15 mg E4/3 mg DRSP	253

Cycle 7

Group	Value	95% CI
15 mg E4/3 mg DRSP	229

Cycle 8

Group	Value	95% CI
15 mg E4/3 mg DRSP	204

Number of Unscheduled Bleeding Days Per Cycle Secondary · 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.

Cycle 1

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.4	± 1.42

Cycle 2

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.3	± 1.08

Cycle 3

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.4	± 1.20

Cycle 4

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.3	± 1.00

Cycle 5

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.3	± 1.04

Cycle 6

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.3	± 1.04

Cycle 7

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.3	± 1.04

Cycle 8

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.2	± 0.94

Number of Unscheduled Spotting Days Per Cycle Secondary · 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.

Cycle 1

Group	Value	95% CI
15 mg E4/3 mg DRSP	1.0	± 2.21

Cycle 2

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.6	± 1.50

Cycle 3

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.6	± 1.40

Cycle 4

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.5	± 1.31

Cycle 5

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.5	± 1.26

Cycle 6

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.5	± 1.30

Cycle 7

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.5	± 1.31

Cycle 8

Group	Value	95% CI
15 mg E4/3 mg DRSP	0.4	± 1.18

Number of Subjects With Absence of Scheduled Bleeding and/or Spotting Secondary · 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.

Cycle 1

Group	Value	95% CI
15 mg E4/3 mg DRSP	230

Cycle 2

Group	Value	95% CI
15 mg E4/3 mg DRSP	254

Cycle 3

Group	Value	95% CI
15 mg E4/3 mg DRSP	274

Cycle 4

Group	Value	95% CI
15 mg E4/3 mg DRSP	233

Cycle 5

Group	Value	95% CI
15 mg E4/3 mg DRSP	209

Cycle 6

Group	Value	95% CI
15 mg E4/3 mg DRSP	225

Cycle 7

Group	Value	95% CI
15 mg E4/3 mg DRSP	191

Cycle 8

Group	Value	95% CI
15 mg E4/3 mg DRSP	183

Number of Scheduled Bleeding and/or Spotting Days Per Cycle Secondary · 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.

Cycle 1

Group	Value	95% CI
15 mg E4/3 mg DRSP	6.1	± 10.16

Cycle 2

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.7	± 4.01

Cycle 3

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.7	± 6.72

Cycle 4

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.8	± 6.50

Cycle 5

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.4	± 3.70

Cycle 6

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.4	± 3.39

Cycle 7

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.5	± 5.00

Cycle 8

Group	Value	95% CI
15 mg E4/3 mg DRSP	4.5	± 3.69

Number of Subjects With Bleeding and/or Spotting Episodes by Reference Period Secondary · 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.

Reference Period 1

Group	Value	95% CI
15 mg E4/3 mg DRSP - RP1	1,249

Reference Period 2

Group	Value	95% CI
15 mg E4/3 mg DRSP - RP1	1,098

Reference Period 3

Group	Value	95% CI
15 mg E4/3 mg DRSP - RP1	982

Reference Period 4

Group	Value	95% CI
15 mg E4/3 mg DRSP - RP1	914

Adverse events — posted to ClinicalTrials.gov

Time frame: From screening to end of treatment (13 months). Reporting threshold: 1%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

15 mg E4/3 mg DRSP

Serious: 25/1864 (1%)

Deaths: 1/1864

Serious adverse events (21 terms)

Reaction	System	15 mg E4/3 mg DRSP
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	—
Ectopic pregnancy	Pregnancy, puerperium and perinatal conditions	—
Depression	Psychiatric disorders	—
Affective disorder	Psychiatric disorders	—
Bipolar I disorder	Psychiatric disorders	—
Psychotic disorder	Psychiatric disorders	—
Suicidal ideation	Psychiatric disorders	—
Gastroenteritis	Infections and infestations	—
Appendicitis	Infections and infestations	—
Bacterial pyelonephritis	Infections and infestations	—
Campylobacter gastroenteritis	Infections and infestations	—
Infection parasitic	Infections and infestations	—
Cholecystitis	Hepatobiliary disorders	—
Hepatic haematoma	Hepatobiliary disorders	—
Accidental overdose	Injury, poisoning and procedural complications	—
Rib fracture	Injury, poisoning and procedural complications	—
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—
Thyroid neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—
Pancreatitis acute	Gastrointestinal disorders	—
Drug hypersensitivity	Immune system disorders	—
Pneumomediastinum	Respiratory, thoracic and mediastinal disorders	—

Other adverse events (36 terms — click to expand)

Reaction	System	15 mg E4/3 mg DRSP
Headache	Nervous system disorders	—
Metrorrhagia	Reproductive system and breast disorders	—
Nausea	Gastrointestinal disorders	—
Dysmenorrhoea	Reproductive system and breast disorders	—
Urinary tract infection	Infections and infestations	—
Acne	Skin and subcutaneous tissue disorders	—
Upper respiratory tract infection	Infections and infestations	—
Weight increased	Investigations	—
Viral upper respiratory tract infection	Infections and infestations	—
Breast tenderness	Reproductive system and breast disorders	—
Bacterial vaginosis	Infections and infestations	—
Anxiety	Psychiatric disorders	—
Fatigue	General disorders	—
Vaginal haemorrhage	Reproductive system and breast disorders	—
Menorrhagia	Reproductive system and breast disorders	—
Abdominal pain	Gastrointestinal disorders	—
Mood swings	Psychiatric disorders	—
Depression	Psychiatric disorders	—
Sinusitis	Infections and infestations	—
Vomiting	Gastrointestinal disorders	—
Back pain	Musculoskeletal and connective tissue disorders	—
Breast pain	Reproductive system and breast disorders	—
Libido decreased	Psychiatric disorders	—
Fungal infection	Infections and infestations	—
Influenza	Infections and infestations	—
Vulvovaginal mycotic infection	Infections and infestations	—
Diarrhoea	Gastrointestinal disorders	—
Insomnia	Psychiatric disorders	—
Dizziness	Nervous system disorders	—
Vaginal discharge	Reproductive system and breast disorders	—
Abdominal distension	Gastrointestinal disorders	—
Mood altered	Psychiatric disorders	—
Pharyngitis streptococcal	Infections and infestations	—
Abdominal pain lower	Gastrointestinal disorders	—
Irritability	Psychiatric disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—

Most-reported serious reactions: Abortion spontaneous, Ectopic pregnancy, Depression, Affective disorder, Bipolar I disorder, Psychotic disorder, Suicidal ideation, Gastroenteritis.

Data from ClinicalTrials.gov NCT02817841 adverse events section.

Sponsor's own description

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 16 to 50 years.

Publications & conference data

4 peer-reviewed publications reference this trial (live from Europe PMC):

1. Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.
   Gérard C, Foidart JM. · · 2023 · cited 17× · PMID 37133685 · DOI 10.1007/s40268-023-00419-5
2. Bleeding Patterns of Oral Contraceptives with a Cyclic Dosing Regimen: An Overview.
   Archer DF, Mansour D, Foidart JM. · · 2022 · cited 11× · PMID 35956249 · DOI 10.3390/jcm11154634
3. Combined Oral Contraceptive Adherence and Pregnancy Rates.
   Creinin MD, Jensen JT, Chen MJ, Black A, et al · · 2023 · cited 6× · PMID 37023457 · DOI 10.1097/aog.0000000000005155
4. Abstracts of the 16th European Congress of Paediatric and Adolescent Gynaecology ^†.
   Christopoulos P, Christopoulos P, Vatopoulou A, Michala L, et al · · 2024 · PMID 39768498 · DOI 10.3390/jcm13247574