Prolonged QTc Interval
Conditions
Keywords
Estetrol, Moxifloxacin
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.
Interventions
DRUGEstetrol 20 mg
One estetrol monohydrate (E4) 20 mg tablet plus four matching placebo tablets orally once
DRUGEstetrol 100 mg
Five estetrol monohydrate (E4) 20 mg tablets orally once
DRUGPlacebo
Five placebo tablets orally once
DRUGMoxifloxacin 400 mg
One moxifloxacin 400 mg tablet orally once (open-label)
Sponsors
Estetra
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy, postmenopausal women, 40 years to 65 years of age, inclusive, at screening. 2. Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dose of study drug. 3. Minimum weight of 52 kg and body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 4. 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. 5. Postmenopausal status will be defined as any of the following: 1. 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. 2. For hysterectomized participants: * serum FSH \>40 mIU/mL (values obtained after washout of estrogen/progestin containing drug, see
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of E4 20 mg and E4 100 mg on QTc interval: placebo-corrected change from baseline QTcF (ΔΔQTcF) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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). |
| 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 | 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). |
| 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 | 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). |
| 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 | 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). |
| 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 | 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). |
| 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 | 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). |
| 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) | Any clinically significant observations, as determined by the Investigator, in results of clinical laboratory tests, 12-lead ECGs, vital sign measurements, or physical examination findings will be recorded as Adverse events (AEs). At several time points before and after study drug administration, participants will be asked nonleading questions to determine the occurrence of AEs. In addition, all AEs reported spontaneously during the course of the study will be recorded. A treatment-emergent AE (TEAE) is defined as any event not present prior to the first administration of the study drug or any event already present that worsens in either severity or frequency following exposure to the study drug. |
| Maximum observed plasma concentration (Cmax) for E4 | from 1 hour 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 | — |
| 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 | — |
| 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 | Continuous 12-lead ECG (Holters) recordings will be performed. Baseline will be the average of the derived ECG intervals from the 3 predose ECGs extracted at -45, -30, and -15 minutes. |
Countries
United States
Outcome results
None listed