Clinical trial NCT02164812: Study to Determine the Effect of Efavirenz on the ECG QTcF Interval in Healthy Subjects
Official title: A Study to Determine the Concentration-Electrocardiographic Effects of Efavirenz in Healthy Subjects Enriched for CYP2B6 Polymorphisms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV/AIDS
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2014-06-17
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP

Brief summary: The purpose of this study is to determine whether multiple doses of Efavirenz has an effect on the QTc interval (corrected by Fridericia) in CYP2B6 \*1/\*6 and \*6/\*6 healthy subjects.

Detailed description: CYP = Cytochrome p-450

Primary Purpose: Other: This is a Phase 1 clinical pharmacology thorough QT study being conducted as a post marketing requirement

Eligibility criteria: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Healthy volunteers, ages 18 to 49 years old
* BMI 18 to 32 kg/m2
* Women must not be pregnant or breastfeeding

Exclusion Criteria:

* A personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, presyncope or syncopal episodes, or additional risk factors for torsades de pointes (eg, heart failure)
* History of hypokalemia, personal history or family history of prolonged QT interval, or family history of sudden cardiac death at a young age
* Any of the following on 12-lead electrocardiogram (ECG) prior to study drug administration: PR ≥210 msec, QRS ≥120 msec, QT ≥500 msec, QTcF ≥450 msec, HR \<45 bpm
* Second or third degree heart block prior to study drug
* Positive urine screen for drugs of abuse
* Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or Human Immunodeficiency Virus (HIV)-1, -2 antibody
* Any of the following lab results outside of the ranges specified below prior to dosing: Alanine aminotransferase (ALT) \>upper limit of normal (ULN), aspartate aminotransferase (AST) \>ULN, Total bilirubin \>ULN, Direct bilirubin \>ULN, Creatinine \>ULN, Serum potassium \<lower limit of normal (LLN), Serum magnesium \<LLN
* History of allergy to Moxifloxacin, Efavirenz or related compounds

Primary outcomes:
measure: Difference from placebo of Efavirenz (EFV) in change from period-specific baseline in the QT interval corrected for heart rate (HR) via Fridericia's method (QTcF) at postdose extraction times (ΔΔQTcF)
timeFrame: Days 1, 2, 5, 6, 19 and 20
Secondary outcomes:
measure: Difference from placebo of EFV in change from period-specific baseline in other ECG parameters: HR, PR, QRS, and uncorrected QT following 14 days of dosing
timeFrame: Days 1, 5 and 19
measure: Difference from placebo of Moxifloxacin in change from period-specific baseline in QTcF (ΔΔQTcF) following a single dose
timeFrame: Days 1, 5 and 19
measure: Number and percent of subjects having a maximum QTcF, HR, PR, and QRS outside of pre-specified categories and those having a maximum ΔQTcF outside of pre-specified categories
timeFrame: Days 1, 5 and 19
measure: Time of maximum observed plasma concentration (Tmax) of EFV
timeFrame: Days 1, 2, 19 and 20
measure: Maximum observed plasma concentration (Cmax) of EFV
timeFrame: Days 1, 2, 19 and 20
measure: Trough observed plasma concentration 24 h after a dose (C24) of EFV
timeFrame: Days 1, 2, 19 and 20
measure: Area under the concentration-time curve in one dosing interval (AUC(TAU)) of EFV
timeFrame: Days 1, 2, 19 and 20
measure: Safety based on incidence of AEs, SAEs, AEs leading to discontinuation, marked laboratory abnormalities, findings on 12-lead safety ECG measurements and physical examinations, and abnormalities in vital sign measurements exceeding pre-defined thresholds
timeFrame: Up to 30 days after discontinuation of dose (approximately 52 days)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Parexel International - Baltimore Epcu
state: Maryland
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Abdelhady AM, Shugg T, Thong N, Lu JB, Kreutz Y, Jaynes HA, Robarge JD, Tisdale JE, Desta Z, Overholser BR. Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers. J Cardiovasc Electrophysiol. 2016 Oct;27(10):1206-1213. doi: 10.1111/jce.13032. Epub 2016 Jul 25.