TMC435-TiDP16-C117: The Effect of TMC435 on the Results of Electrocardiograms (Electric Recording of the Heart) in Healthy Volunteers

A Double-blind, Double-dummy, Randomized, 4-period Cross-over, Placebo- and Positive-controlled Study to Evaluate the Effect of TMC435 on the QTc Interval in Healthy Subjects

The purpose of this study is to evaluate the effect of TMC435 on the results of electrocardiograms (ECGs) in healthy volunteers. An electrocardiogram is an electric recording of the heart. TMC435 is being investigated for the treatment of chronic hepatitis C virus infection.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: TMC435; Drug: TMC435; Drug: Placebo for TMC435; Drug: Placebo for TMC435; Drug: Placebo for TMC435; Drug: Placebo for moxifloxacin; Drug: Moxifloxacin

Detailed Description

This is a double-blind, double-dummy, randomized, 4-period cross-over, placebo- and positive-controlled, Phase I study. This means neither the study doctor nor the participants know in which treatment session you will receive which active medication or matching placebo. Every participant will receive 4 treatment sessions (Treatments A, B, C and D) in a different order. The order in which you receive the treatment sessions is determined by chance, like tossing a coin. The purpose of the study is to evaluate the effect of TMC435 on the results of electrocardiograms (electric recording of the heart). Two dose regimens of TMC435 will be tested, ie, 150 mg once daily (the dose that will be given to patients) and 350 mg once daily (a dose higher than the one that will be given to patients), administered for 7 days. A single dose of 400 mg moxifloxacin will be used as a positive control to assess trial sensitivity. The trial population will consist of 60 healthy volunteers of which approximately 18 will be females. In each treatment, dummy capsules will be added in order to have the same number of capsules in each treatment. Treatment A will consist of 150 mg TMC435 once daily for 7 days (2 capsules of TMC435 and 2 capsules placebo on days 1-7, 1 placebo tablet for moxifloxacin on Day 7). Treatment B will consist of 350 mg TMC435 once daily for 7 days (4 capsules of TMC435 on Days 1-7, 1 placebo tablet for moxifloxacin on Day 7). Treatment C will consist of 400 mg moxifloxacin on Day 7 (4 capsules of placebo for TMC435 on Days 1-7, 1 moxifloxacin tablet on Day 7). In Treatment D only placebo will be given (4 capsules of placebo for TMC435 on Days 1-7, 1 placebo tablet for moxifloxacin on Day 7). There will be a washout period of at least 10 days between subsequent treatments. A pharmacogenomic blood sample (DNA sample, blood sample from which your genetic information can be analyzed) will be collected from all volunteers and will be analyzed upon observation of irregular electrocardiogram during the study. The purpose is to see if irregularities in the electrocardiogram can be linked to genetic variants. DNA samples may also be analyzed for additional genes related to pharmacokinetics (what the body does with the drug), pharmacodynamics (what the drug does to your body) or safety and tolerability of TMC435 during the study, as necessary. Two oral doses of TMC435 (150 or 350 mg) or placebo will be given once daily for 7 consecutive days. A single dose of moxifloxacin 400 mg will be administered orally on Day 7 in one of the treatment sessions only.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-smokers for at least six months
• Have a body mass index of 18.0 to 30.0 kg per square meter
• Be healthy on the basis of physical examination, medical history, vital signs, and clinical laboratory tests performed at screening.

Exclusion Criteria:

• Use of disallowed therapies, including over-the-counter products and dietary supplements
• Any skin condition likely to interfere with ECG electrode placement or adhesion
• History or evidence of current use of alcohol or recreational or narcotic drug use
• Clinically relevant abnormality on ECG at screening or history of clinically relevant heart rhythm disturbances.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 001; TMC435 2 capsules of 75 mg once daily for 7 days in Treatment A	Drug: TMC435; 2 capsules of 75 mg once daily for 7 days in Treatment A; Drug: TMC435; 2 capsules of 75 mg and 2 capsules of 100 mg once daily for 7 days in Treatment B
Other: 002; Placebo for TMC435 2 placebo capsules once daily for 7 days in Treatment A	Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment C; Drug: Placebo for TMC435; 2 placebo capsules once daily for 7 days in Treatment A; Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment D
Other: 003; Placebo for moxifloxacin 1 placebo tablet on Day 7 of Treatments A B and D	Drug: Placebo for moxifloxacin; 1 placebo tablet on Day 7 of Treatments A, B and D
Experimental: 004; TMC435 2 capsules of 75 mg and 2 capsules of 100 mg once daily for 7 days in Treatment B	Drug: TMC435; 2 capsules of 75 mg once daily for 7 days in Treatment A; Drug: TMC435; 2 capsules of 75 mg and 2 capsules of 100 mg once daily for 7 days in Treatment B
Other: 005; Placebo for TMC435 4 placebo capsules once daily for 7 days in Treatment C	Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment C; Drug: Placebo for TMC435; 2 placebo capsules once daily for 7 days in Treatment A; Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment D
Other: 006; Moxifloxacin 1 tablet of 400 mg on Day 7 of Treatment C	Drug: Moxifloxacin; 1 tablet of 400 mg on Day 7 of Treatment C
Placebo Comparator: 007; Placebo for TMC435 4 placebo capsules once daily for 7 days in Treatment D	Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment C; Drug: Placebo for TMC435; 2 placebo capsules once daily for 7 days in Treatment A; Drug: Placebo for TMC435; 4 placebo capsules once daily for 7 days in Treatment D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in QT/QTc interval for TMC435 therapeutic dose versus placebo	24-hour measurement on Day 7 of Treatment Session A and D
Change in QT/QTc interval for TMC435 supratherapeutic dose versus placebo	24-hour measurement on Day 7 of Treatment Session B and D

Secondary Outcome Measures

Outcome Measure	Time Frame
RR interval, HR, PR interval, QRS interval and ECG morphology	1-hour predose measurement on Day 1 of every treatment session
RR interval, HR, PR interval, QRS interval and ECG morphology	24-hour measurement on Day 7 of every treatment session
Pharmacokinetics of 150 mg TMC435 once daily for 7 days	Predose on Day 1 of every treatment and on Days 5 and 6 of Treatments A and B. 24 hour profile on Day 7 of Treatment A and B
Pharmacokinetics of 350 mg TMC435 once daily for 7 days	Predose on Day 1 of every treatment and on Days 5 and 6 of Treatments A and B. 24 hour profile on Day 7 of Treatment A and B
Changes from baseline for electrocardiogram (ECG) and physical examination	During all treatment sessions: Daily safety ECG from Day -1 to Day 9 with on Day 1 and 7 an additional safety ECG at 5h timepoint plus at screening and follow-up visits. Physical examination at screening, on Day 8 and at the follow-up visits
Number of participants with adverse events and severity of adverse events	From signing of informed consent onwards until last trial-related visit
Changes from baseline and percentage of subjects with abnormal values for laboratory parameters	At screening, on Days -1, 1, 5, 8 of all treatment sessions and at the follow-up visits
Changes from baseline and percentage of subjects with abnormal values for pulse and blood pressure	At screening, daily from Day -1 to Day 9 with a second measurement on Day 7 of all treatment sessions and at the follow-up visits
Difference of QTc between moxifloxacin treatment and placebo treatment as a measure for trial sensitivity	On Day 7 of Treatment C and D, at the 2, 3, 4 and 5 hour timepoints

Collaborators and Investigators

• Sponsor: Tibotec Pharmaceuticals, Ireland

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: December 30, 2010
• First Submitted That Met QC Criteria: December 30, 2010
• First Posted (Estimate): January 4, 2011

Study Record Updates

• Last Update Posted (Estimate): May 6, 2013
• Last Update Submitted That Met QC Criteria: May 3, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: HCV; Hepatitis C; TMC435; Moxifloxacin; ECG; QT; QTc; TMC435-TiDP16-C117; TMC435-C117
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Protease Inhibitors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Simeprevir
• Other Study ID Numbers: CR017491; TMC435-TiDP16-C117 (Other Identifier: Tibotec Pharmaceuticals, Ireland)