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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02874248
Recruitment Status : Completed
First Posted : August 22, 2016
Last Update Posted : April 21, 2017
Sponsor:
Information provided by (Responsible Party):
Estetra

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).

Condition or disease Intervention/treatment Phase
Contraception Drug: 15 mg E4/3 mg DRSP Drug: 30 mg E4/6 mg DRSP Drug: 60 mg E4/12 mg DRSP Drug: Visually matching placebo Drug: 75 mg E4/15 mg DRSP Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
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 Start Date : May 2016
Actual Primary Completion Date : November 21, 2016
Actual Study Completion Date : November 21, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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
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
Other Name: 15 mg estetrol and 3 mg drospirenone

Placebo Comparator: 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
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

Active Comparator: 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
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
Other Name: 30 mg estetrol and 6 mg drospirenone

Experimental: 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
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

Active Comparator: 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
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
Other Name: 60 mg estetrol and 12 mg drospirenone

Placebo Comparator: 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
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

Active Comparator: 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
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

Placebo Comparator: 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
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




Primary Outcome Measures :
  1. Cmax: Maximum observed plasma concentration of E4 and DSRP [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  2. Tmax: time to attain maximum observed plasma concentration of E4 and DSRP [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  3. 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 [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  4. 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 [ Time Frame: On day 1 only ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  5. 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 [ Time Frame: On day 1 only ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  6. Kel: terminal elimination rate constant of E4 and DSRP [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  7. T1/2: terminal elimination half-life of E4 and DSRP, calculated as 0.693/kel [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  8. AUC0-tau: Area under the plasma concentration time curve over a dosing interval tau - of E4 and DSRP [ Time Frame: On day 28 only ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35

  9. Ra: Accumulation ratio for AUC [ Time Frame: On day 1 and day 28 (steady state) ]
    PK sampling on day 1, 2-3, 4-8, 16-25, 26-27, 28, 29, 30, 31-35


Secondary Outcome Measures :
  1. Number of adverse events and number of subjects with AEs as a measure of safety and tolerability [ Time Frame: From admission until follow-up visit (between day 37 and 41) ]
    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

  2. deltaQTcF as measured by Holter monitoring (continuous cardiac monitoring) [ Time Frame: Time matched on day -1 (for baseline measurements) and on day 28: 1 hour pre-dose until 24h post-dose ]
    To define the effect of E4 in combination with DRSP on QT interval corrected with Fridericia's formula (QTcF)

  3. ECG parameters [ Time Frame: 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) ]
    To define the effect of E4 in combination with DRSP on heart rate (HR), PR, and QRS



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02874248


Sponsors and Collaborators
Estetra
Investigators
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Principal Investigator: Jeroen van de Wetering, MD PRA Health Sciences
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Responsible Party: Estetra
ClinicalTrials.gov Identifier: NCT02874248    
Other Study ID Numbers: MIT-Es0001-C103
2016-000861-22 ( EudraCT Number )
First Posted: August 22, 2016    Key Record Dates
Last Update Posted: April 21, 2017
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Drospirenone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents