A Study to Evaluate the Effect of Losmapimod on Cardiac Conduction as Compared to Placebo and Moxifloxacin
Status: | Completed |
---|---|
Conditions: | Cardiology |
Therapuetic Areas: | Cardiology / Vascular Diseases |
Healthy: | No |
Age Range: | 18 - 65 |
Updated: | 6/8/2017 |
Start Date: | January 10, 2013 |
End Date: | April 23, 2013 |
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
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
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
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
1. 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)
2. 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
1. QTcB or QTcF >450 msec
2. PR interval >200 msec or <=110 msec
3. evidence of second- or third- degree atrioventricular block (AVB)
4. clinically significant pathological Q-waves (defined as Q-wave >40 msec or depth
greater than 0.4 to 0.5 mV)
5. evidence of ventricular pre-excitation
6. electrocardiographic evidence of complete left bundle branch block (LBBB), right
bundle branch block (RBBB), incomplete LBBB
7. intraventricular conduction delay with QRS duration >110 msec
8. 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
- A positive test for Human immunodeficiency virus (HIV) antibody result within 3
months of screening
- History of regular alcohol consumption within 6 months of the study defined as (For
US sites) an average weekly intake of >14 drinks for males or >7 drinks for females.
One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150
mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer)
- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day
- Unable to refrain from the use of prescription or non-prescription drugs, including
vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is
longer) prior to the first dose of study medication, unless in the opinion of the
Investigator and GSK Medical Monitor the medication will not interfere with the study
procedures or compromise subject safety
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period
- Pregnant females as determined by positive serum human chorionic gonadotropin (hCG)
test at screening or prior to dosing
- Lactating females
- Unwillingness or inability to follow the procedures outlined in the protocol
- Subject is mentally or legally incapacitated
- History of sensitivity to heparin or heparin-induced thrombocytopenia
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