A Study to Evaluate the Effect of Losmapimod on Cardiac Conduction as Compared to Placebo and Moxifloxacin

NCT01756495 | Completed Phase 1

• 1 other identifier: 116628
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a double-blind, 4-period, randomized, cross-over study conducted in healthy adult subjects. The purpose of this study is to characterize the effect of orally administered losmapimod on the electrocardiogram (ECG) parameters with a focus on cardiac repolarization as measured by the corrected QT interval (QTc) duration, compared with placebo and moxifloxacin. Moxifloxacin (Avelox) is a drug with a known potential to create a mild QTc interval prolongation; therefore, it will serve as a positive control to validate the ability of this study to detect a change in the QTc interval. All subjects will participate in 4 study periods separated by a minimum washout period of 5 days. Each subject will receive one of 4 regimens (A = Losmapimod 7.5 milligram \[mg\] Twice daily \[BID\] x 5 days, B = Losmapimod 20 mg Once daily \[QD\] x 5 days, C = moxifloxacin 400 mg on Day 5, D = Losmapimod matched placebo and moxifloxacin placebo x 5 days) in each of the 4 planned study periods in a randomized, cross-over fashion. Subjects will be assigned to one of four treatment sequences following a Williams design (ABDC, BCAD, CDBA, DACB). Follow-up visit will occur 10 to 14 days after end of Period 4

Conditions

Acute Coronary Syndrome

Keywords

QTc,; GW856553 .; P38,

Outcome Measures

Primary Outcomes (1)

• Change from baseline in QT interval corrected for heart rate by Fridericia's formula (QTcF) at each time point for losmapimod 20 mg QD on Day 5 as compared with time matched placebo

  Triplicate ECGs will be collected at three baseline pre-dose time points (at -45 min, -30 min and -15 min) on Day 1 of the corresponding study period. Period baseline will be the average of triplicate pre-dose assessments. Triplicate Holter ECGs measurements will be evaluated at 14 post-dose time points (0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 hours) on Day 5 of the corresponding study period and will be averaged prior to calculation of changes from period baseline and statistical analyses

  Baseline and Day 5 of the corresponding study period

Secondary Outcomes (15)

• Change from baseline in QTcF at each time point for losmapimod 7.5 mg BID on Day 5 as compared with time-matched placebo

  Baseline and Day 5 of the corresponding study period

• Change from baseline in QTcF at each time point for moxifloxacin 400 mg single dose as compared with time-matched placebo

  Baseline and Day 5 of the corresponding study period

• Change from baseline in QT interval corrected for heart rate by Bazett's formula (QTcB) at each time point for losmapimod (7.5 mg BID and 20 mg QD) and moxifloxacin (400 mg) on Day 5 as compared with time matched placebo

  Baseline and Day 5 of all 4 study period

• Change from baseline at each time point on Day 5 for other cardiac electrophysiological parameters: QT, PR, QRS, heart rate (HR) and ECG waveform morphology for losmapimod (7.5 mg BID and 20 mg QD) and moxifloxacin

  Baseline and Day 5 of all 4 study period

• Area under the plasma concentration-time curve (AUC) of losmapimod and its metabolite GSK198602 at doses of 7.5 mg BID and 20 mg QD, as well as 400 mg single dose of moxifloxacin

  0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and approximately 24 hours post-dose on Day 5 of all 4 study period

Study Arms (4)

Losmapimod 7.5 mg

EXPERIMENTAL

Each subject will receive losmapimod 7.5 mg BID orally for 5 days, in one of the 4 study periods (per randomization sequence) separated by a minimum washout period of 5 days

Drug: Losmapimod

Losmapimod 20 mg

EXPERIMENTAL

Each subject will receive losmapimod 20 mg QD orally for 5 days, in one of the 4 study periods (per randomization sequence) separated by a minimum washout period of 5 days

Drug: Losmapimod

Moxifloxacin 400 mg

ACTIVE COMPARATOR

Each subject will receive moxifloxacin 400 mg orally on Day 5, in one of the 4 study periods (per randomization sequence) separated by a minimum washout period of 5 days

Drug: Moxifloxacin

Placebo

PLACEBO COMPARATOR

Each subject will receive losmapimod matched placebo and moxifloxacin placebo orally for 5 days, in one of the 4 study periods (per randomization sequence) separated by a minimum washout period of 5 days

Drug: Losmapimod matched Placebo; Drug: Moxifloxacin Placebo

Interventions

Losmapimod DRUG

Wet granulation formulation, Film coated white, 7 mm round, biconvex, plain faced Tablet of 7.5 mg or 10 mg unit dose strength. Taken orally 7.5 mg BID / 20 mg QD for 5 days in one of the 4 study periods

Losmapimod 20 mg; Losmapimod 7.5 mg

Moxifloxacin DRUG

17.2mm x 7.1 mm capsule shaped pink biconvex tablet of 400 mg unit dose strength. Taken orally 400 mg on Day 5 in one of the 4 study periods

Moxifloxacin 400 mg

Losmapimod matched Placebo DRUG

Direct compression formulation (visually matched to GW856553), Film coated white, 7 mm round, biconvex, plain faced Tablet. Taken orally for 5 days in one of the 4 study periods

Placebo

Moxifloxacin Placebo DRUG

16 mm x 8 mm capsule shaped to white film coated tablet. Taken orally for 5 days in one of the 4 study periods

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac safety monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures
• Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent
• A female subject is eligible to participate if she is of
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] \>40 MIU/mL and estradiol \<40 pg/mL \[\<147 pmol/L\] is confirmatory)
• Child-bearing potential and is abstinent or agrees to use one of the allowed contraception methods with a failure rate of \<1% (Oral contraceptive, either combined or progestogen alone, Injectable progestogen, Implants of etonogestrel or levonorgestrel, Estrogenic vaginal ring, Percutaneous contraceptive patches, Intrauterine device \[IUD\] or intrauterine system \[IUS\], Male partner sterilization \[vasectomy with documentation of azoospermia\] prior to the female subject's entry into the study, and this male is the sole partner for that subject, Male condom combined with a female diaphragm, either with or without a vaginal spermicide \[foam, gel, cream or suppository\], Male condom combined with a vaginal spermicide \[foam, gel, cream or suppository\]) for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit
• Body weight \>=50 kg and Body mass index (BMI) within the range 19 to 28 kg/m\^2 (inclusive)
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5 x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)

You may not qualify if:

• Subjects with cardiac conduction abnormalities on the screening 12-lead ECG denoted by any of the following
• QTcB or QTcF \>450 msec
• PR interval \>200 msec or \<=110 msec
• evidence of second- or third- degree atrioventricular block (AVB)
• clinically significant pathological Q-waves (defined as Q-wave \>40 msec or depth greater than 0.4 to 0.5 mV)
• evidence of ventricular pre-excitation
• electrocardiographic evidence of complete left bundle branch block (LBBB), right bundle branch block (RBBB), incomplete LBBB
• intraventricular conduction delay with QRS duration \>110 msec
• bradycardia as defined by sinus rate \<45 beats per minute (BPM) or tachycardia as defined by sinus rate \>100 BPM
• Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination or ECG
• Subjects with a personal or family history of QTc prolongation, symptomatic cardiac arrhythmias or cardiac arrest
• History of hypersensitivity to moxifloxacin or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• A positive pre-study drug/alcohol screen

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
• Results for study 116628 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Acute Coronary Syndrome

Interventions

6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; Moxifloxacin

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2012
• First Posted: December 27, 2012
• Study Start: January 10, 2013
• Primary Completion: April 23, 2013
• Study Completion: April 23, 2013
• Last Updated: June 7, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)