E4/DRSP Single and Multiple Dose PK and Early QT Study

NCT ID: NCT02874248

Last Updated: 2017-04-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

55 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-05-31

Study Completion Date

2016-11-21

Brief Summary

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This study is conducted to evaluate the effect of single and multiple therapeutic and supratherapeutic oral doses of E4/DRSP combinations on PK parameters, safety, tolerability and on cardiac repolarization, as detected by QT interval corrected with Fridericia's formula (QTcF).

Detailed Description

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This will be a randomized, double-blind, placebo-controlled, parallel, single center study in healthy female subjects. A total of 42 female subjects will be enrolled in 3 groups of 14 subjects each. A potential fourth group of 14 healthy female subjects may be added. In each group, subjects will be randomized in a 2.5 to 1 ratio between active (n=10) and placebo (n=4).

Subjects will receive a single dose on Day 1 and, after a washout of at least 14 days, multiple doses on 14 consecutive days from Days 15 to 28.

Group 1 and Group 2 may be dosed in parallel. After completion of Group 1 and Group 2, a Dose Escalation Report (DER), including PK data up to at least 24 hours post-last dose, will be prepared by the Principal Investigator (PI). Escalation to the planned dose level of 60 mg E4/12 mg DRSP will only proceed if the safety and tolerability of the dose levels of 15 mg E4/3 mg DRSP and 30 mg E4/6 mg DRSP up to 24 hours post-last dose, are acceptable to the PI and the Sponsor and, if deemed necessary by the Independent Ethics Committee (IEC) following their review of the protocol, after a statement of no objection of the DER from the IEC.

After completion of Group 3, a second DER, including PK data, will be prepared by the PI. If in Group 3 the expected exposure level of approximately 4 times the exposure of Group 1 is not achieved, and treatment in Group 3 is well tolerated, an additional group with 14 subjects may be enrolled, using a dose level that is estimated to result in at least 4 times the exposure after administration of the 15 mg E4/3 mg DRSP therapeutic dose.

Conditions

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Contraception

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Group 1: 15 mg E4/3 mg DRSP (n=10)

a single oral dose of 15 mg E4/3 mg DRSP (n=10) followed, after a washout of at least 14 days, by multiple oral doses of 15 mg E4/3 mg DRSP (n=10) once daily for 14 days

Group Type ACTIVE_COMPARATOR

15 mg E4/3 mg DRSP

Intervention Type DRUG

a single oral dose of 15 mg E4/3 mg DRSP (n=10) followed, after a washout of at least 14 days, by multiple oral doses of 15 mg E4/3 mg DRSP (n=10) once daily for 14 days

Group1: Placebo (n=4)

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group Type PLACEBO_COMPARATOR

Visually matching placebo

Intervention Type DRUG

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group 2: 30 mg E4/6 mg DRSP (n=10)

a single oral dose of 30 mg E4/6 mg DRSP, followed, after a washout of at least 14 days, by multiple oral doses of 30 mg E4/6 mg DRSP once daily for 14 days

Group Type ACTIVE_COMPARATOR

30 mg E4/6 mg DRSP

Intervention Type DRUG

a single oral dose of 30 mg E4/6 mg DRSP, followed, after a washout of at least 14 days, by multiple oral doses of 30 mg E4/6 mg DRSP once daily for 14 days

Group 2: Placebo (n=4)

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group Type EXPERIMENTAL

Visually matching placebo

Intervention Type DRUG

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group 3: 60 mg E4/12 mg DRSP (n=10)

a single oral dose of 60 mg E4/12 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 60 mg E4/12 mg DRSP once daily for 14 days

Group Type ACTIVE_COMPARATOR

60 mg E4/12 mg DRSP

Intervention Type DRUG

a single oral dose of 60 mg E4/12 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 60 mg E4/12 mg DRSP once daily for 14 days

Group 3: Placebo (n=4)

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group Type PLACEBO_COMPARATOR

Visually matching placebo

Intervention Type DRUG

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group 4: 75 mg E4/15 mg DRSP (n=9)

a single oral dose of 75 mg E4/15 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 75 mg E4/15 mg DRSP once daily for 14 days

Group Type ACTIVE_COMPARATOR

75 mg E4/15 mg DRSP

Intervention Type DRUG

a single oral dose of 75 mg E4/15 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 75 mg E4/15 mg DRSP once daily for 14 days

Group 4: Placebo (n=4)

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Group Type PLACEBO_COMPARATOR

Visually matching placebo

Intervention Type DRUG

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Interventions

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15 mg E4/3 mg DRSP

a single oral dose of 15 mg E4/3 mg DRSP (n=10) followed, after a washout of at least 14 days, by multiple oral doses of 15 mg E4/3 mg DRSP (n=10) once daily for 14 days

Intervention Type DRUG

30 mg E4/6 mg DRSP

a single oral dose of 30 mg E4/6 mg DRSP, followed, after a washout of at least 14 days, by multiple oral doses of 30 mg E4/6 mg DRSP once daily for 14 days

Intervention Type DRUG

60 mg E4/12 mg DRSP

a single oral dose of 60 mg E4/12 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 60 mg E4/12 mg DRSP once daily for 14 days

Intervention Type DRUG

Visually matching placebo

a single oral dose of a placebo which visually matches the active medication, followed, after a washout of at least 14 days, by multiple oral doses of matching placebo once daily for 14 days

Intervention Type DRUG

75 mg E4/15 mg DRSP

a single oral dose of 75 mg E4/15 mg DRSP, followed, after a washout of at least 14 days, by oral doses of 75 mg E4/15 mg DRSP once daily for 14 days

Intervention Type DRUG

Other Intervention Names

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15 mg estetrol and 3 mg drospirenone 30 mg estetrol and 6 mg drospirenone 60 mg estetrol and 12 mg drospirenone

Eligibility Criteria

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Inclusion Criteria

1. Gender : Healthy female subject
2. Age : 18-50 years, inclusive
3. Body mass index (BMI) : 18.0-35.0 kg/m2
4. At screening, female subjects must be non-pregnant and non-lactating, or of non-childbearing potential
5. Willing to use a double-barrier method of contraception from screening until 90 days after the follow up visit.
6. Willingness to abstain from alcohol and grapefruit (juice) from 48 hours prior to admission into the clinical research center up to follow-up.
7. Normal resting supine blood pressure and pulse showing no clinically relevant deviations as judged by the PI at screening.
8. Computerized (12-lead) ECG recording without signs of clinically relevant pathology at screening
9. Willing and able to sign the ICF.
10. Willing and able to comply with the study procedures

Exclusion Criteria

1. Postmenopausal status
2. History or presence of clinically relevant disease of any major system organ class (e.g., cardiovascular, pulmonary, renal, hepatic, gastrointestinal, reproductive, endocrinological, neurological, psychiatric or orthopedic disease) as judged by the PI
3. Condition of hyperkalemia resulting from renal insufficiency, hepatic dysfunction, adrenal insufficiency or medication intake
4. Previous participation in the current study
5. Use of:

* combined contraceptives (i.e., COC, Nuvaring®) within 28 days prior to the first dose administration until study completion
* progestogen-only contraceptive methods (e.g., minipill, implant, or hormonal intrauterine system) within 28 days prior to the first dose administration until study completion
* depot progestogen preparations or an injectable hormonal method of contraception (e.g., Depo-Provera®) within 6 months prior to the first dose until study completion
6. Use of:

* any prescription drugs or herbal supplements acting on CYP3A4 functions (e.g., St. John's Wort) within 28 days prior to the first study dose administration until study completion
* any over-the-counter medication or dietary supplements (vitamins included) within 14 days prior to the first study dose administration until study completion.
7. Use of any tobacco products within the last 3 months prior to the first admission
8. History of alcohol abuse or drug addiction (including soft drugs like cannabis products)
9. Positive drug screening
10. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) 1 and 2 antibodies
11. Participation in an investigational drug study within 60 days prior to the first drug administration in the current study
12. History of relevant drug and/or food allergies
13. Donation or loss of more than 100 mL of blood within 60 days prior to the first drug administration. Donation or loss of more than 1.0 L of blood in the 10 months prior to the first drug administration in the current study
14. Significant and/or acute illness within 5 days prior to the first drug administration that may impact safety assessments, as judged by the PI
15. History and/or family history of congenital long QT syndrome, unexplained syncope or other additional risks for Torsade de Pointes, or sudden death
16. History or presence of hormone-related malignancy treated or not, whatever the time of onset. History of malignancy of any other organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years prior to screening
17. History of migraine with aura
18. Any surgical or medical condition that could significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study
19. Contraindications for the use of contraceptive steroids
20. Sponsor employees or clinical site personnel directly affiliated with this study
Minimum Eligible Age

18 Years

Maximum Eligible Age

50 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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Estetra

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Jeroen van de Wetering, MD

Role: PRINCIPAL_INVESTIGATOR

PRA Health Sciences

Other Identifiers

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2016-000861-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MIT-Es0001-C103

Identifier Type: -

Identifier Source: org_study_id

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