Clinical Trials Register

Summary
EudraCT Number:	2015-003150-40
Sponsor's Protocol Code Number:	MIT-Es0001-C301
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-02-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2015-003150-40

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to investigate the efficacy and safety of a new combination oral contraceptive tablet. All participants will receive the same combination oral contraceptive.

A.3.2

Name or abbreviated title of the trial where available

E4 FREEDOM

A.4.1

Sponsor's protocol code number

MIT-Es0001-C301

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Estetra SPRL
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Estetra SPRL
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Estetra SPRL
B.5.2	Functional name of contact point	Sophie Ledant
B.5.3	Address:
B.5.3.1	Street Address	Rue Saint Georges 5-7
B.5.3.2	Town/ city	Liège
B.5.3.3	Post code	4000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+324349 28 22
B.5.5	Fax number	+324349 28 21
B.5.6	E-mail	Clinical.Trials@mithra.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Estelle
D.3.2	Product code	15 mg estetrol (E4) / 3 mg drospirenone (DRSP)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Estetrol
D.3.9.1	CAS number	15183-37-6
D.3.9.2	Current sponsor code	E4
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Drospirenone
D.3.9.1	CAS number	67392-87-4
D.3.9.2	Current sponsor code	DRSP
D.3.9.3	Other descriptive name	DROSPIRENONE
D.3.9.4	EV Substance Code	SUB06413MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Contraception

E.1.1.1

Medical condition in easily understood language

Contraception

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10030970
E.1.2	Term	Oral contraception
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index in subjects aged 18 to 35 years inclusive at the time of
screening.

E.2.2

Secondary objectives of the trial

Efficacy:
1. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the method failure Pearl Index and life-table analysis in subjects aged 18 to 35 years inclusive at the time of screening.
2. To evaluate the contraceptive efficacy of 15 mg E4/3 mg DRSP using the Pearl Index, the method failure Pearl Index and life-table analysis in the overall study population.

Other:
3. To evaluate cycle control and bleeding pattern associated with 15 mg E4/3 mg DRSP.
4. To evaluate general safety of 15 mg E4/3 mg DRSP.
5. To evaluate the impact of 15 mg E4/4 mg DRSP on physical,
psychological and social functioning and well being.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Endometrial Safety Sub-study

167 Subjects

Objective:
To evaluate the endometrial safety using histological assessment of
endometrial biopsy samples in a subset of subjects aged 18 to 50 years, inclusive at the time of screening.

Endpoint:
Change in endometrial histology from baseline to end of treatment in
subjects having been treated for at least 10 complete cycles.

E.3

Principal inclusion criteria

1. Heterosexually active female at risk for pregnancy and requesting
contraception.
2. Negative serum pregnancy test at subject enrollment.
3. Aged 18 to 50 years (inclusive) at the time of signing the informed
consent (IC).
4. Willing to use the investigational product as the primary method of
contraception for 13 consecutive cycles.
5. Good physical and mental health on the basis of medical, surgical and gynecological history, physical examination, gynecological examination, clinical laboratory, and vital signs.
6. Body mass index (BMI) below or equal to (≤) 35.0 kg/m2.
7. Able to fulfill the requirements of the protocol and have indicated a willingness to participate in the study by providing written IC.
8. Willing and able to complete he diaries and questionnaires.
For the endometrial safety sub-study:
9. Subset of subjects from the main study willing to participate in the
endometrial safety sub-study by giving their consent for the endometrial safety sub-study.
10. Endometrial biopsy taken at screening that reveals no abnormal
results, i.e. presence of hyperplasia (simple or complex, with or without atypia) or presence of carcinoma.

E.4

Principal exclusion criteria

1. For subjects who are not using hormonal contraception at screening, a menstrual cycle length shorter than 21 days or longer than 35 days
2. Clinically relevant abnormal laboratory result at screening in the
opinion of the investigator with an understanding of the central
laboratory normal range
3. Known hypersensitivity to any of the investigational product
ingredients
4. Currently pregnant or with the intention to become pregnant during the course of the study
5. Currently breastfeeding or before two spontaneous menstruations
have occurred after cessation of breastfeeding prior to start of trial
medication
6. Less than 6 weeks since last delivery/2nd trimester of abortion and
before spontaneous menstruation has occurred following a delivery or 2nd trimester of abortion
7. Smoking if ≥ 35 years old, at screening
8. Dyslipoproteinemia requiring active treatment with antilipidemic
agent
9. Diabetes mellitus with vascular involvement or diabetes mellitus of
more than 20 years duration
10. Any arterial hypertension (controlled and uncontrolled) defined by blood pressure values
11. Personal history of deep vein thrombosis or pulmonary embolism
12. Current prolonged immobilization or major surgery with prolonged immobilization planned in the next 12 months
13. Known inherited or acquired hypercoagulopathies or thrombogenic mutations
14. Current treatment with anticoagulants
15. Presence or history of atrial thromboembolism
16. Complicated valvular heart disease
17. History of pregnancy related cardiomyopathy or moderately or
severely impaired cardiac function
18. Systemic lupus erythematosus
19. Presence or history of migraine with aura at any age or migraine
without aura if >35 years old
20. Within the past 6 months, has had undiagnosed (unexplained)
abnormal vaginal bleeding or any abnormal bleeding that is expected to recur during the trial
21. In case of Chlamydial or Gonococcal infection at screening, when no treatment initiated at subject enrollment
22. Abnormal Pap test (written documentation of prior test at screening exam) based on provided criteria
23. Presence of an undiagnosed breast mass
24. Current symptomatic gallbladder disease
25. History of COC related cholestasis
26. Presence or history of severe hepatic disease as long as liver
function values have not returned to normal
27. Presence or history of pancreatitis if associated with
hypertriglyceridemia
28. Porphyria
29. Presence or history of hepatocellular adenoma or malignant liver
tumors
30. Renal impairment
31. Hyperkaliemia or presence of conditions that predispose to
hyperkaliemia such as renal impairment, hepatic impairment, adrenal
insufficiency and women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration
32. History of organ transplantation within 5 years before screening or chronic disease potentially necessitating organ transplantation during the anticipated course of the study
33. Presence or history of hormone-related malignancy
34. History of non-hormone-related malignancy within 5 years before screening. Subjects with a non-melanoma skin cancer are allowed in the study
35. Current regular use or regular use within 1 month prior to subject
enrollment of drugs potentially triggering interactions with COCs
36. Use of an injectable hormonal method of contraception within 10 months prior to screening of an injection with a 3-month duration,
within 6 months prior to screening of an injection with a 2-month
duration, within 3 months prior to screening of an injection with a 1-
month duration
37. History of alcohol or drug abuse (including laxatives) within 12
months prior to screening
38. Any prior procedure, disease or condition that could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the investigational product
39. Uncontrolled thyroid disorders
40. Participation in another investigational drug clinical study within 1
month or have received an investigational drug within the last 3 months prior to study entry. Subjects who participated in an oral contraceptive study, using FDA/EU approved active ingredients, may be enrolled 2 months after completing the preceding study
41. Sponsor, the Contract Research Organization (CRO) or Investigator's site personnel directly affiliated with this study
42. Is judged by the Investigator to be unsuitable for any reason
For the endometrial safety sub-study:
43. Use of hormone-releasing intra-uterine system immediately prior to the study treatment
44. Acute genital infection as diagnosed at the discretion of the
Investigator

E.5 End points

E.5.1

Primary end point(s)

The number of on-treatment pregnancies as assessed by the Pearl Index in subjects aged 18 to 35 years, inclusive at the time of screening.

E.5.1.1

Timepoint(s) of evaluation of this end point

From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet)

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
1. The number of on-treatment pregnancies as assessed by the method failure Pearl Index and the cumulative pregnancy rate in subjects aged 18 to 35 years, inclusive at time of screening
2. The number of on-treatment pregnancies as assessed by the Pearl
Index, the method failure Pearl Index and the cumulative pregnancy rate in the overall study population.

Other secondary endpoints:
3. Cycle control and bleeding pattern evaluated based on vaginal
bleeding information as recorded daily by the subjects in the diaries.
4. Safety data in the overall study population obtained from routine
laboratory parameters, vital signs and physical, gynecological and breast examinations and by number, frequency, type and intensity of adverse events (AEs) and serious adverse events (SAEs).
5. Change from baseline to end of treatment in the different items of
well-established questionnaires.

E.5.2.1

Timepoint(s) of evaluation of this end point

From day 1 of treatment until 2 days after the last intake of investigational product (whether active or inactive tablet)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Czech Republic

Finland

Germany

Hungary

Norway

Poland

Russian Federation

Sweden

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1550

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

179

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1350

F.4.2.2

In the whole clinical trial

1550

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No further treatment/supervision for patients who successfully finish.

Women who discontinue to pursue pregnancy will be followed. They will be contacted every 6-8 weeks for a max. of 1 year. The date of the 1st spontaneous menstruation will be recorded. When pregnancy is
reported or a new contraceptive method started, the date will be recorded and contact will stop.

Patients who have an on-treatment pregnancy identified during the course of the study will be monitored to completion.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-26

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