Thorough QT/QTc Study of Multiple Oral Doses of NOMAC-E2 (Org 10486 0 + Org 2317) in Healthy Women (Study 292011)(P05802)

Study Overview
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Brief Summary
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The trial is a single-center randomized, double-blind, double-dummy, placebo and positive controlled, parallel group clinical trial. This trial investigated whether NOMAC-E2 (Org 10486 -0 + Org 2317), a new combined hormonal contraceptive, has potential to delay cardiac repolarization. The primary measure of cardiac repolarization in this trial is the Fridericia corrected QT interval (QTcF). QTcF represents the duration of ventricular depolarization and subsequent repolarization. A delay in cardiac repolarization creates an electrophysiological environment that favors the development of cardiac arrhythmias, most clearly torsade de pointes (TdP), but possibly other ventricular tachyarrhythmias. The primary aim of this study is to investigate, if the administration of a therapeutic (2.5/1.5 mg) or supra-therapeutic (higher than required for treatment: 12.5/7.5 mg) dose of NOMAC-E2 administered over a period of 14 days will prolong the mean QTcF interval to values above the accepted threshold of regulatory concern. In addition, a single dose of moxifloxacin will be administered in order to prove that sensitivity of the applied assay is sufficient to detect the prolongation of the QTcF-interval. Secondary aims of this study are to evaluate the relation between concentrations of NOMAC (therapeutic and supra-therapeutic) after steady state has been reached in the subject's body, the time matched change in Estradiol E1 and E2 in relation to baseline and the QTcF intervals after multiple dose administration of NOMAC-E2. Finally, the safety and tolerability of different treatments are investigated. A total of 189 subjects will participate in this trial. The entire study duration is about 9 weeks with a 4-week screening period, 14-day treatment period and a follow-up period of about 3 weeks.

Official Title
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A Randomized, Double-blind, Placebo and Positive Controlled, Parallel Group Trial to Investigate the Effect of Multiple Doses of NOMAC-E2 on QT/QTc Interval in Healthy Women

Conditions
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Contraception

Intervention / Treatment
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* Drug: Moxifloxacin
* Drug: NOMAC-E2 (Org 10486-0 + Org 2317)
* Drug: Moxifloxacin placebo
* Drug: NOMAC-E2 placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female (aged 18-50 years) with a body mass index (BMI) of 17 <= BMI <= 29 kg/m^2 at screening; Able and willing to use non-hormonal contraceptives during the trial from at least 2 weeks prior to Day 1 up to and including follow-up; Able and willing to sign the Informed Consent Form prior to screening evaluations; Subject is in a good age-appropriate healthy condition as established by medical history, physical examination, cardiac monitoring, electrocardiogram, results of biochemistry, hematology and urinalysis testing within 4 weeks prior to treatment as judged by the investigator; Normal 12-lead automatic ECG at screening and admission; Subject has a normal blood pressure at screening and admission; Subject smokes less than 5 cigarettes or equivalent per day and is capable of not smoking from 48 hours prior drug administration on Day -1 and Day 14 until the last ECG has been taken on respectively Day 1 and Day 15; Able to refrain from all use of (methyl)xanthines (e.g. coffee, tea, cola, chocolate) from 48 hours prior to drug administration on Day -1 and Day 14 until the last ECG has been taken on respectively Day 1 and Day 15; Able to refrain from alcohol containing beverages from 24 hours prior to drug administration on Day -1 and Day 14 until the last ECG has been taken on respectively Day 1 and Day 15; Able to refrain from all use of grapefruit containing products from 14 days prior to first NOMAC-E2 dosing until the last ECG has been taken; Easy venous accessibility. Exclusion Criteria: History of sensitivity/idiosyncrasy to the applied drugs or chemically related compounds or excipients which may be employed in the study or to any other unknown drug used in the past Use of any drug or substance within one week and hormonal contraception within 2 weeks prior to the first treatment day, except for paracetamol or topical medication without systemic exposure Present use or use during 2 months prior to the start of treatment of any drugs interfering with the trial medication; Clinically relevant history or presence of any medical disorder, potentially interfering with this trial (according to the investigator) Known or suspected pregnancy History of/or current abuse of drugs or alcohol or solvents, or positive drug or alcohol screen at screening and admission, as judged by the (sub-)investigator Positive test result on hepatitis B surface antigen, hepatitis C antibody, or HIV 1/2 serology Participation in an investigational drug trial within 90 days prior to treatment Donation of blood within 90 days prior to treatment Contraindications for contraceptive steroids Breastfeeding or within 2 months after stopping breastfeeding prior to the start of trial medication. Present use or use within one month prior to treatment or within 10 half-lives in case the half-life > 3 days of any agent that is known to prolong the QT/QTc interval History of/or current risk factors for Torsade de Pointes (TdP) or life-threatening ventricular arrhythmia (e.g. heart failure, hypokaliemia, hypomagnesaemia, hypocalcaemia, family history of long or short QT syndrome, loss of consciousness)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Once daily intake (orally) of 5 NOMAC-E2 placebo tablets from Day -1 to Day 14. Once daily intake (orally) of one moxifloxacin placebo capsule at Day -1. Once daily intake (orally) of one moxifloxacin capsule of 400 mg at Day 14. | Drug: Moxifloxacin<br>* Capsules containing 400 mg moxifloxacin, on Day 14 only<br>* Other names: Avelox®;Drug: Moxifloxacin placebo<br>* Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only<br>Drug: NOMAC-E2 placebo<br>* Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.<br>|
| Experimental: Group B<br>Once daily intake (orally) of 4 NOMAC-E2 placebo tablets and 1 NOMAC-E2 (2.5/1.5 mg) tablet from Day 1 to Day 14. Once daily intake (orally) of 5 NOMAC-E2 placebo tablets and 1 moxifloxacin placebo capsule at Day -1. Once daily intake (orally) of 1 moxifloxacin placebo capsule at Day 14. | Drug: NOMAC-E2 (Org 10486-0 + Org 2317)<br>* Tablets containing 2.5 mg NOMAC and 1.5 mg E2, once daily dosing, orally taken. Daily dose either NOMAC-E2 2.5/1.5 mg or 12.5/7.5 mg.<br>Drug: Moxifloxacin placebo<br>* Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only<br>Drug: NOMAC-E2 placebo<br>* Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.<br>|
| Experimental: Group C<br>Once daily intake (orally) of 5 NOMAC-E2 (2.5/1.5 mg) tablets from Day 1 to Day 14. Once daily intake (orally) of 5 NOMAC-E2 placebo tablets and 1 moxifloxacin placebo capsule at Day -1. Once daily intake (orally) of 1 moxifloxacin placebo capsule at Day 14 | Drug: NOMAC-E2 (Org 10486-0 + Org 2317)<br>* Tablets containing 2.5 mg NOMAC and 1.5 mg E2, once daily dosing, orally taken. Daily dose either NOMAC-E2 2.5/1.5 mg or 12.5/7.5 mg.<br>Drug: Moxifloxacin placebo<br>* Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only<br>Drug: NOMAC-E2 placebo<br>* Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.<br>|
| Placebo Comparator: Group D<br>Once daily intake (orally) of 5 NOMAC-E2 placebo tablets from Day -1 to Day 14. Once daily intake (orally) of 1 moxifloxacin placebo capsule at Days -1 and 14. | Drug: Moxifloxacin placebo<br>* Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only<br>Drug: NOMAC-E2 placebo<br>* Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate whether once daily multiple therapeutic and supra-therapeutic doses of NOMAC-E2 prolong the mean QTcF interval at steady state to the threshold of regulatory concern compared to placebo |  | 16 days | 
| Establish assay sensitivity after single dose of 400 mg moxifloxacin |  | 16 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| evaluate the relation between steady state concentrations of NOMAC, time matched change from baseline in E1 and E2 and the QTcF intervals after multiple dosing of NOMAC-E2 |  | 16 days | 
| Investigate safety and tolerability of the various treatments |  | 64 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Electrocardiography, Pharmacokinetics