Clinical trial NCT01424540: Cross-Over Study to Assess the Cardiovascular Effects of GSK2336805
Official title: A Randomized, Double Blind, Single Dose, Cross-Over Study to Assess the Cardiovascular Effects of GSK2336805 in Healthy Adult Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-08-29
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a single-center, randomized, two part, double-blind, crossover study in healthy adult subjects to assess the effect of a single dose of GSK2336805 150mg on cardiac function comparing with placebo using echocardiography as a primary assessment modality


Eligibility criteria: Inclusion Criteria:

* Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin less than or equal to 1.5xUpper Limit of Normal (ULN).
* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including \[medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included at the discretion of the Investigator only if 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, oophorectomy, or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea.

Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the follow up visit.

* Body weight greater than or equal to 50 kilogram (kg) for men and 45 kg for women. Body mass index (BMI) between 18.5-30 inclusive will be allowed.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Subject has demonstrated an adequate echocardiographic window.
* QTcB less than 450 milliseconds (msec).

Exclusion Criteria:

* A positive pre-study Hepatitis B surface antigen,positive Hepatitis C antibody, or a positive test for HIV 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.
* History of regular alcohol consumption within 6 months of the study.
* 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).
* 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.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mililiters within a 56 day period.
* Pregnant females as determined by positive \[serum or urine\] 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.
* Subjects who have asthma or a history of asthma.
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
* Consumption of red wine, seville oranges, grapefruit or grapefruit juice \[and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices\] from 7 days prior to the first dose of study medication.
* Left ventricular ejection fraction less than 55% at screening.
* The subject's systolic blood pressure is outside the range of 90-140, or diastolic blood pressure is outside the range of 45-90 or heart rate is outside the range of 50-100beats per minute for female subjects or 45-100 beats per minute for male subjects.
* Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination):

Males-Heart rate less than 45 and greater than 100 beats per minute (bpm). Females-Heart rate less than 50 and greater than 100 bpm Evidence of previous myocardial infarction (Does not include ST segment changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block \[2nd degree or higher\], Wolf Parkinson White \[WPW\] syndrome). Sinus Pauses greater than 3 seconds. Any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety for the individual subject. Non-sustained or sustained ventricular tachycardia ( greater than or equal to 3 consecutive ventricular ectopic beats).

Primary outcomes:
measure: Number of subjects with a change in ejection fraction greater than 10 percent
timeFrame: 10 hours
Secondary outcomes:
measure: Number of subjects with electrocardiogram (ECG) parameters out of range
timeFrame: 3 hours
measure: Number of subjects with vital signs out of range
timeFrame: 24 hours
measure: Number of subjects with adverse events
timeFrame: 24 hours
measure: Number of subjects using concurrent medication
timeFrame: 24 hours
measure: Number of subjects with laboratory values out of range
timeFrame: 24 hours
measure: Area under the curve (0-24)
timeFrame: 24 hours
measure: Maximum observed concentration (Cmax)
timeFrame: 24 hours
measure: Terminal phase half-life
timeFrame: 24 hours
measure: Lag time before observation of drug concentrations in sampled matrix
timeFrame: 24 hours
measure: Time of occurrence of Cmax
timeFrame: 24 hours
measure: Concentration at 24 hours
timeFrame: 24 hours
measure: Correlation between concentration and various safety parameters
timeFrame: 24 hours
measure: B-type natriuretic peptide (BNP) lab result
timeFrame: 24 hours
measure: Troponin lab results
timeFrame: 24 hours
Other outcomes:
Locations:
city: Buffalo
country: United States
facility: GSK Investigational Site
state: New York
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Wilfret DA, Adkison KK, Jones LA, Lou Y, Gan J, Spreen W. Echocardiogram study to evaluate the effect of the novel hepatitis C virus NS5A inhibitor GSK2336805 on cardiac contractility in healthy subjects. Antimicrob Agents Chemother. 2013 Oct;57(10):5141-3. doi: 10.1128/AAC.00668-13. Epub 2013 Jul 15.