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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00779532
First received: October 23, 2008
Last updated: October 16, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Contraception
Drug: Moxifloxacin
Drug: NOMAC-E2 (Org 10486-0 + Org 2317)
Drug: Moxifloxacin placebo
Drug: NOMAC-E2 placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • 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 [ Time Frame: 16 days ] [ Designated as safety issue: Yes ]
  • Establish assay sensitivity after single dose of 400 mg moxifloxacin [ Time Frame: 16 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 [ Time Frame: 16 days ] [ Designated as safety issue: Yes ]
  • Investigate safety and tolerability of the various treatments [ Time Frame: 64 days ] [ Designated as safety issue: Yes ]

Enrollment: 189
Study Start Date: May 2008
Study Completion Date: November 2008
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A

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
Capsules containing 400 mg moxifloxacin, on Day 14 only
Other Name: Avelox®
Drug: Moxifloxacin placebo
Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only
Drug: NOMAC-E2 placebo
Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.
Experimental: Group B

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)
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.
Drug: Moxifloxacin placebo
Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only
Drug: NOMAC-E2 placebo
Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.
Experimental: Group C

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)
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.
Drug: Moxifloxacin placebo
Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only
Drug: NOMAC-E2 placebo
Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.
Placebo Comparator: Group D

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
Moxifloxacin-placebo capsule taken orally, Day -1 and Day 14 only
Drug: NOMAC-E2 placebo
Tablets containing NOMAC-E2 placebo, once daily dosing, orally taken.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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)
  Contacts and Locations
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, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided by Merck Sharp & Dohme Corp.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00779532     History of Changes
Other Study ID Numbers: P05802, EudraCT # 2008-001649-25, 292011
Study First Received: October 23, 2008
Last Updated: October 16, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Merck Sharp & Dohme Corp.:
Electrocardiography
Pharmacokinetics

Additional relevant MeSH terms:
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Anti-Bacterial Agents
Anti-Infective Agents
Antineoplastic Agents
Contraceptive Agents
Contraceptive Agents, Female
Contraceptives, Oral
Contraceptives, Oral, Combined
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014