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

Contraception Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Parallel, Single Center Study to Investigate the Pharmacokinetics, Safety, Tolerability, and QT Concentration-effect Modelling of Estetrol in Combination With Drospirenone After Single and Multiple Dosing in Healthy Women

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02874248
• Other study ID #: MIT-Es0001-C103
• Secondary ID: 2016-000861-22
• Status: Completed
• Phase: Phase 1
• First received: August 9, 2016
• Last updated: April 20, 2017
• Start date: May 2016
• Est. completion date: November 21, 2016

Study information

• Verified date: August 2016
• Source: Estetra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: November 21, 2016
• Est. primary completion date: November 21, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Contraception

Intervention

Drug:
• 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
• 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
• 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
• 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
• 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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Estetra

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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
Primary	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
Primary	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)
Primary	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)
Primary	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
Primary	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	Number of adverse events and number of subjects with AEs as a measure of safety and tolerability	Any clinically significant observations in results of clinical laboratory tests, 12-lead ECGs, echocardiography, continuous cardiac monitoring (Holter monitoring), vital signs, or physical examinations will be recorded as AEs	From admission until follow-up visit (between day 37 and 41)
Secondary	deltaQTcF as measured by Holter monitoring (continuous cardiac monitoring)	To define the effect of E4 in combination with DRSP on QT interval corrected with Fridericia's formula (QTcF)	Time matched on day -1 (for baseline measurements) and on day 28: 1 hour pre-dose until 24h post-dose
Secondary	ECG parameters	To define the effect of E4 in combination with DRSP on heart rate (HR), PR, and QRS	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)