Clinical Trials/NCT04819906

NCT04819906

Completed

Phase 1

A Randomized, Placebo- and Active-controlled 4-way Crossover Study in Healthy Subjects to Evaluate the Effect of E4 on the QTc Interval

Estetra1 site in 1 country32 target enrollmentMarch 9, 2021

ConditionsProlonged QTc Interval

InterventionsEstetrol 20 mg Placebo Estetrol 100 mg Moxifloxacin 400 mg

DrugsEstetrol 20 mg Estetrol 100 mg Placebo Moxifloxacin 400 mg

Overview

Phase: Phase 1
Intervention: Estetrol 20 mg
Conditions: Prolonged QTc Interval
Sponsor: Estetra
Enrollment: 32
Locations: 1
Primary Endpoint: Effect of E4 20 mg and E4 100 mg on QTc interval: placebo-corrected change from baseline QTcF (ΔΔQTcF)
Status: Completed
Last Updated: 2 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this study is:

to evaluate if E4 has any effect on how the heart beats when a single dose is given at two different dose levels;
to determine the ability to detect small changes in how the heart beats using a positive control: moxifloxacin, a quinolone antibiotic approved by the FDA as a positive control in thorough QT (TQT) studies;
to assess the safety and tolerability of a single dose of E4 administered at two different dose levels;
to measure the amount of study drug in the blood stream and how long it takes for the body to eliminate it (Pharmacokinetics) after administration.

Detailed Description

This is a Phase 1, multicenter, randomized, placebo- and active-controlled, partially double-blinded, single-dose, 4-way crossover study in healthy postmenopausal female participants to evaluate the effect of E4 on the QTc interval. All participants will receive all 4 study treatments (E4 therapeutic dose \[20 mg\]; E4 supratherapeutic dose \[100 mg\]; placebo; moxifloxacin \[400 mg\]) in a randomized sequence. E4 and placebo administration will be blinded while moxifloxacin will be provided in an open-label fashion. Participants will report to the clinical research unit (CRU) for the eligibility screening within 28 days prior to the first study drug administration. Participants will sign the study specific informed consent form (ICF) prior to any study specific screening procedures being performed. In each study period, the participants will be confined in the CRU from the day before dosing (Day -1) until all safety assessments have been completed on Day 2, for a total of 2 days per period. Each study period will be separated by a 14 day (±2 days) washout. Cardiodynamic assessment using continuous 12-lead ECG (Holters) recordings will be performed on Day 1 of each treatment period starting approximately 1 hour before dosing and ending approximately 25 hours after dosing. ECGs will be extracted serially pre- and postdose and at predefined time points. Blood draws for PK will be performed in all periods after each ECG extraction. All participants (including participants who terminate the study prematurely) will receive a follow-up call 7 (±2) days after the last administration of study treatment to determine if any adverse events (AEs) have occurred since the last study visit.

Registry

clinicaltrials.gov

Start Date

March 9, 2021

End Date

July 14, 2021

Last Updated

2 years ago

Study Type

Interventional

Study Design

Crossover

Sex

Female

Investigators

Sponsor

Estetra

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Healthy, postmenopausal women, 40 years to 65 years of age, inclusive, at screening.
•Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dose of study drug.
•Minimum weight of 52 kg and body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening.
•Healthy status defined by the absence of evidence of any clinically significant, in the opinion of the Investigator, active or chronic disease following a detailed medical and surgical history, a complete physical examination including gynecological examination, vital signs, a 12-lead electrocardiogram (ECG), hematology, blood chemistry, serology, and urinalysis clinical laboratory tests.
•Postmenopausal status will be defined as any of the following:
•For non-hysterectomized participants:
•at least 12 months of spontaneous amenorrhea; or
•at least 6 months of spontaneous amenorrhea with serum FSH \>40 mIU/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20); or
•at least 6 weeks postsurgical bilateral oophorectomy.
•For hysterectomized participants:

Exclusion Criteria

•History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Principal Investigator.
•History of any illness that, in the opinion of the Principal Investigator, might confound the results of the study or pose an additional risk to the participant by their participation in the study.
•History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
•History or presence of hypersensitivity or idiosyncratic reaction to E4, moxifloxacin, related compounds, or inactive ingredients.
•History of significant multiple and/or severe allergies (e.g., latex allergy, band aids, adhesive dressing, or medical tape), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs.
•Positive urine drug or alcohol results at screening or check-in.
•Positive results at screening for human immunodeficiency virus (HIV), syphilis, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
•Unable to refrain from or anticipates the use of:
•any drug, including prescription and nonprescription medications (including antacids), herbal remedies, or vitamin supplements (especially those containing magnesium, aluminum, iron, or zinc; exception: vitamin C may be allowed) beginning 14 days before the first dose of study drug and throughout the study; or
•any drugs known to be significant inhibitors or inducers of cytochrome P450 (CYP) enzymes and/or P-glycoprotein (P-gp), including St. John's wort, for 28 days before the first dose of study drug and throughout the study. Appropriate sources will be consulted by the Principal Investigator or designee to confirm lack of pharmacokinetic (PK) or pharmacodynamic interaction with the study drug.

Arms & Interventions

T-ST-P-M

Treatment T: Therapeutic E4 dose (20 mg): one E4 20 mg tablet plus four E4 placebo tablets Treatment ST: Supratherapeutic E4 dose (100 mg): five E4 20 mg tablets Treatment P: Placebo: five E4 placebo tablets Treatment M: Moxifloxacin: 1 moxifloxacin 400 mg tablet

Intervention: Estetrol 20 mg

T-ST-P-M

Intervention: Placebo

T-ST-P-M

Intervention: Estetrol 100 mg

T-ST-P-M

Intervention: Moxifloxacin 400 mg

ST-M-T-P

Intervention: Estetrol 20 mg

ST-M-T-P

Intervention: Estetrol 100 mg

ST-M-T-P

Intervention: Placebo

ST-M-T-P

Intervention: Moxifloxacin 400 mg

P-T-M-ST

Intervention: Estetrol 20 mg

P-T-M-ST

Intervention: Estetrol 100 mg

P-T-M-ST

Intervention: Placebo

P-T-M-ST

Intervention: Moxifloxacin 400 mg

M-P-ST-T

Intervention: Estetrol 20 mg

M-P-ST-T

Intervention: Moxifloxacin 400 mg

M-P-ST-T

Intervention: Estetrol 100 mg

M-P-ST-T

Intervention: Placebo

ST-P-T-M

Intervention: Estetrol 20 mg

ST-P-T-M

Intervention: Estetrol 100 mg

ST-P-T-M

Intervention: Placebo

ST-P-T-M

Intervention: Moxifloxacin 400 mg

P-M-ST-T

Intervention: Estetrol 20 mg

P-M-ST-T

Intervention: Estetrol 100 mg

P-M-ST-T

Intervention: Placebo

P-M-ST-T

Intervention: Moxifloxacin 400 mg

T-ST-M-P

Intervention: Estetrol 20 mg

T-ST-M-P

Intervention: Estetrol 100 mg

T-ST-M-P

Intervention: Placebo

T-ST-M-P

Intervention: Moxifloxacin 400 mg

M-T-P-ST

Intervention: Estetrol 20 mg

M-T-P-ST

Intervention: Estetrol 100 mg

M-T-P-ST

Intervention: Placebo

M-T-P-ST

Intervention: Moxifloxacin 400 mg

P-T-ST-M

Intervention: Estetrol 20 mg

P-T-ST-M

Intervention: Estetrol 100 mg

P-T-ST-M

Intervention: Placebo

P-T-ST-M

Intervention: Moxifloxacin 400 mg

T-M-P-ST

Intervention: Estetrol 20 mg

T-M-P-ST

Intervention: Estetrol 100 mg

T-M-P-ST

Intervention: Placebo

T-M-P-ST

Intervention: Moxifloxacin 400 mg

ST-P-M-T

Intervention: Estetrol 20 mg

ST-P-M-T

Intervention: Estetrol 100 mg

ST-P-M-T

Intervention: Placebo

ST-P-M-T

Intervention: Moxifloxacin 400 mg

M-ST-T-P

Intervention: Estetrol 20 mg

M-ST-T-P

Intervention: Estetrol 100 mg

M-ST-T-P

Intervention: Placebo

M-ST-T-P

Intervention: Moxifloxacin 400 mg

Outcomes

Primary Outcomes

Effect of E4 20 mg and E4 100 mg on QTc interval: placebo-corrected change from baseline QTcF (ΔΔQTcF)

Time Frame: from 45 minutes pre-dose to 24 hours post-dose

Continuous 12-lead ECG (Holters) recordings will be performed. Baseline will be the average of the derived ECG intervals from the 3 predose ECG time points (-45, -30, and -15 minutes).

Secondary Outcomes

Effect of E4 20 mg and E4 100 mg on heart rate (HR): change-from-baseline heart rate (∆HR)(from 45 minutes pre-dose to 24 hours post-dose)
Effect of E4 20 mg and E4 100 mg on heart rate (HR): placebo-corrected change-from-baseline heart rate (∆∆HR)(from 45 minutes pre-dose to 24 hours post-dose)
Time to attain maximum observed plasma concentration (tmax) for E4(from 1 hour pre-dose to 24 hours post-dose)
Effect of E4 20 mg and E4 100 mg on PR interval: change-from-baseline PR interval (∆PR)(from 45 minutes pre-dose to 24 hours post-dose)
Effect of E4 20 mg and E4 100 mg on PR interval: placebo-corrected change-from-baseline PR interval (∆∆PR)(from 45 minutes pre-dose to 24 hours post-dose)
Maximum observed plasma concentration (Cmax) for E4(from 1 hour pre-dose to 24 hours post-dose)
Effect of E4 20 mg and E4 100 mg on QRS duration: change-from-baseline QRS duration (∆QRS)(from 45 minutes pre-dose to 24 hours post-dose)
Effect of E4 20 mg and E4 100 mg on QRS duration: placebo-corrected change-from-baseline QRS duration (∆∆QRS)(from 45 minutes pre-dose to 24 hours post-dose)
Sensitivity Assay: effect of moxifloxacin 400 mg on QTc interval: placebo-corrected change from baseline QTcF (ΔΔQTcF)(from 45 minutes pre-dose to 24 hours post-dose)
Frequency of Adverse events (AEs), Treatment-emergent adverse events (TEAEs), and Serious adverse events (SAEs)(from Day -1 of Period 1 up to end of study (i.e. 7 (±2) days after the last dose of study drug))
Area under the plasma concentration-time curve up to 24 hours (AUC0-24) for E4(from 1 hour pre-dose to 24 hours post-dose)