A Single Center Phase 1 Double Blind Study to Evaluate the Effect of Losmapimod on Cardiac Conduction as Compared to Placebo and Moxifloxacin in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- Losmapimod
- Conditions
- Acute Coronary Syndrome
- Sponsor
- GlaxoSmithKline
- Enrollment
- 56
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- 8 years ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •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%)
Exclusion Criteria
- •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
Arms & Interventions
Losmapimod 7.5 mg
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
Intervention: Losmapimod
Losmapimod 20 mg
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
Intervention: Losmapimod
Moxifloxacin 400 mg
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
Intervention: Moxifloxacin
Placebo
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
Intervention: Losmapimod matched Placebo
Placebo
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
Intervention: Moxifloxacin Placebo
Outcomes
Primary Outcomes
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
Time Frame: Baseline and Day 5 of the corresponding study period
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
Secondary Outcomes
- 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)
- Clinical monitoring/observation(Up to Day 49)
- 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)
- 12-lead ECGs measurements to assess safety and tolerability of losmapimod and moxifloxacin(Up to Day 49)
- 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)
- Maximum observed plasma concentration (Cmax) 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)
- Clinical laboratory test measurements to assess safety and tolerability of losmapimod and moxifloxacin(Up to Day 49)
- Time to Cmax (Tmax) 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)
- Number of subjects with adverse events(Up to Day 49)
- Blood pressure measurements to assess safety and tolerability of losmapimod and moxifloxacin(Up to Day 49)
- HR measurements to assess safety and tolerability of losmapimod and moxifloxacin(Up to Day 49)
- Model parameters appropriate for concentration-QT analysis of losmapimod, metabolite and moxifloxacin (e.g. slope and intercept)(Day 5 of all 4 study period)
- Physical examination findings to assess safety and tolerability of losmapimod and moxifloxacin(Up to Day 49)