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

NCT02874248 | Completed Phase 1

• 2 other identifiers: MIT-Es0001-C1032016-000861-22
• Study Type: interventional
• Target: 55
• Locations: 0 countries
• Sites: N/A

Brief Summary

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).

Conditions

Contraception

Outcome Measures

Primary Outcomes (9)

• Cmax: Maximum observed plasma concentration of E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

• Tmax: time to attain maximum observed plasma concentration of E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

• AUC0-t: Area under the plasma concentration-time curve up to time t, where t is the last point with concentrations above the lower limit of quantitation (LLOQ) - for E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

• AUC0-24: area under the plasma concentration-time curve up to time 24 hours (where 24 hours is the dosing interval) using linear-log trapezoidal rule - for E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 only

• AUC0-inf: Area under the plasma concentration-time curve from time 0 to infinity calculated as: AUC0-inf = AUC0-t + Clast/kel, where Clast is the last measurable plasma concentration

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 only

• Kel: terminal elimination rate constant of E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

• T1/2: terminal elimination half-life of E4 and DSRP, calculated as 0.693/kel

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

• AUC0-tau: Area under the plasma concentration time curve over a dosing interval tau - of E4 and DSRP

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 28 only

• Ra: Accumulation ratio for AUC

  PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  On day 1 and day 28 (steady state)

Secondary Outcomes (3)

• Number of adverse events and number of subjects with AEs as a measure of safety and tolerability

  From admission until follow-up visit (between day 37 and 41)

• deltaQTcF as measured by Holter monitoring (continuous cardiac monitoring)

  Time matched on day -1 (for baseline measurements) and on day 28: 1 hour pre-dose until 24h post-dose

• ECG parameters

  Once during screening period; on day -2, 2, 15, 28, 29; once between day 2-3 and once between day 37 and 41 (follow-up)

Study Arms (8)

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

ACTIVE COMPARATOR

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

Drug: 15 mg E4/3 mg DRSP

Group1: Placebo (n=4)

PLACEBO COMPARATOR

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

Drug: Visually matching placebo

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

ACTIVE COMPARATOR

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

Drug: 30 mg E4/6 mg DRSP

Group 2: Placebo (n=4)

EXPERIMENTAL

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

Drug: Visually matching placebo

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

ACTIVE COMPARATOR

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

Drug: 60 mg E4/12 mg DRSP

Group 3: Placebo (n=4)

PLACEBO COMPARATOR

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

Drug: Visually matching placebo

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

ACTIVE COMPARATOR

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

Drug: 75 mg E4/15 mg DRSP

Group 4: Placebo (n=4)

PLACEBO COMPARATOR

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

Drug: Visually matching placebo

Interventions

15 mg E4/3 mg DRSP 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

Also known as: 15 mg estetrol and 3 mg drospirenone

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

30 mg E4/6 mg DRSP 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

Also known as: 30 mg estetrol and 6 mg drospirenone

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

60 mg E4/12 mg DRSP 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

Also known as: 60 mg estetrol and 12 mg drospirenone

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

Visually matching placebo 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: Placebo (n=4); Group 3: Placebo (n=4); Group 4: Placebo (n=4); Group1: Placebo (n=4)

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

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Postmenopausal status
• 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
• Condition of hyperkalemia resulting from renal insufficiency, hepatic dysfunction, adrenal insufficiency or medication intake
• Previous participation in the current study
• 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
• 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.
• Use of any tobacco products within the last 3 months prior to the first admission
• History of alcohol abuse or drug addiction (including soft drugs like cannabis products)
• Positive drug screening
• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies or human immunodeficiency virus (HIV) 1 and 2 antibodies

Sponsors & Collaborators

• Estetra: lead

MeSH Terms

Interventions

Estetrol; drospirenone

Intervention Hierarchy (Ancestors)

Estriol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Jeroen van de Wetering, MD

  PRA Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2016
• First Posted: August 22, 2016
• Study Start: May 1, 2016
• Primary Completion: November 21, 2016
• Study Completion: November 21, 2016
• Last Updated: April 21, 2017

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will not share