Clinical trial NCT02874248: E4/DRSP Single and Multiple Dose PK and Early QT Study
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Contraception
Lead sponsor: Estetra
Sponsor class: INDUSTRY
First posted: 2016-08-22
Enrollment: 55
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cmax: Maximum observed plasma concentration of E4 and DSRP
timeFrame: On day 1 and day 28 (steady state)
measure: Tmax: time to attain maximum observed plasma concentration of E4 and DSRP
timeFrame: On day 1 and day 28 (steady state)
measure: 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
timeFrame: On day 1 and day 28 (steady state)
measure: 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
timeFrame: On day 1 only
measure: 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
timeFrame: On day 1 only
measure: Kel: terminal elimination rate constant of E4 and DSRP
timeFrame: On day 1 and day 28 (steady state)
measure: T1/2: terminal elimination half-life of E4 and DSRP, calculated as 0.693/kel
timeFrame: On day 1 and day 28 (steady state)
measure: AUC0-tau: Area under the plasma concentration time curve over a dosing interval tau - of E4 and DSRP
timeFrame: On day 28 only
measure: Ra: Accumulation ratio for AUC
timeFrame: On day 1 and day 28 (steady state)
Secondary outcomes:
measure: Number of adverse events and number of subjects with AEs as a measure of safety and tolerability
timeFrame: From admission until follow-up visit (between day 37 and 41)
measure: deltaQTcF as measured by Holter monitoring (continuous cardiac monitoring)
timeFrame: Time matched on day -1 (for baseline measurements) and on day 28: 1 hour pre-dose until 24h post-dose
measure: ECG parameters
timeFrame: 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)
Other outcomes:
Locations:
Study officials:
affiliation: PRA Health Sciences
name: Jeroen van de Wetering, MD
role: PRINCIPAL_INVESTIGATOR
References: