A Study to Evaluate the Effect of GSK1322322 on Cardiac Conduction as Assessed by 12-lead Electrocardiogram in Healthy Volunteers

NCT01803399 | Withdrawn Phase 1

• 1 other identifier: 112166
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a randomized, partially-blinded, placebo and moxifloxacin-controlled, single dose, 4-period, balanced crossover study. The primary objective of this study is to separately assess the effects of a therapeutic and supratherapeutic dose of GSK1322322 on the cardiac conduction (corrected QT interval \[QTc\]) compared with placebo in eligible healthy male and female subjects. Avelox (moxifloxacin hydrochloride) will be used as an open-label positive control in order to validate the sensitivity of the study in detecting QTc change. Approximately 56 healthy subjects will participate in the study for approximately 9 weeks i.e. 30 day Screening period, 4-week Treatment period, and a 7-10 day Follow-up period. There will be 4 treatment periods separated by at least 1 week. Subjects will be admitted to the clinical unit on Day -1 of each dosing period. Each subject will receive each of the four treatment sequences (GSK1322322 1200 milligram \[mg\] intravenous \[IV\] over 60 minutes x 1 dose, GSK1322322 3000 mg IV over 60 minutes x 1 dose, GSK1322322 Placebo IV over 60 minutes x 1 dose, moxifloxacin 400 mg administered orally x 1 dose) on Day 1 of each Treatment period in a randomized fashion. Twelve-lead electrocardiogram (ECG), continuous Holter monitoring, laboratory tests, vital sign measurements, and serial pharmacokinetic samples will be collected for up to 24 hours following each treatment. If no clinically significant abnormalities are noted, subjects will be discharged from the clinical research unit after the completion of all assessments on Day 2 in each period and return approximately one week later for the next dosing period. Each individual subject will follow the same dosing schedule at every period. A Follow-up visit will be conducted 7-10 days after administration of the last dose of study medication in treatment period 4.

Conditions

Infections, Bacterial

Keywords

cardiac repolarization; oral; QTc; GSK1322322; antibiotic; 12-lead ECG; placebo; IV; moxifloxacin

Outcome Measures

Primary Outcomes (1)

• Change from baseline in QT duration corrected for heart rate by Fridericia's formula (QTcF) for GSK1322322 as compared with time-matched placebo

  Triplicate 12-lead Holter ECG measurements for each subject at each time point will be averaged

  Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period

Secondary Outcomes (8)

• Change from baseline in QT duration corrected for heart rate by Bazett's formula (QTcB), Individual (linear) QT correction (QTci), QT, and heart rate (HR)

  Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period

• Change from baseline in QTcB, QTci, QT, and HR

  Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period

• Plasma concentrations and selected pharmacokinetic (PK) parameters of moxifloxacin

  Day 1: 15 minutes pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period

• Plasma concentrations and selected PK parameters of GSK1322322/moxifloxacin

  Day 1: 15 minutes pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period

• Safety and tolerability of GSK1322322 as assessed by change from baseline in 12-lead ECGs

  Screening, Day 1 (pre-dose (x3) [mean value as baseline] and 0.5, 1, 1.5, 4, 8, 12 hours post-dose) of each treatment period, and Week 9

Study Arms (4)

GSK1322322 1200 mg Arm

EXPERIMENTAL

Each subject will receive a single dose of GSK1322322 1200 mg IV over 60 minutes on Day 1 of one of the 4 treatment periods

Drug: GSK1322322 1200 mg

GSK1322322 3000 mg Arm

EXPERIMENTAL

Each subject will receive a single dose of GSK1322322 3000 mg IV over 60 minutes on Day 1 of one of the 4 treatment periods

Drug: GSK1322322 3000 mg

Placebo Arm

PLACEBO COMPARATOR

Each subject will receive a single dose of GSK1322322 Placebo IV over 60 minutes on Day 1 of one of the 4 treatment periods

Drug: Placebo

Moxifloxacin 400 mg Arm

ACTIVE COMPARATOR

Each subject will receive a single dose of moxifloxacin 400 mg administered orally on Day 1 of one of the 4 treatment periods

Drug: Moxifloxacin

Interventions

GSK1322322 1200 mg DRUG

GSK1322322 will be supplied as white to slightly colored lyophilized powder 400 mg/vial for injection. Single dose of GSK1322322 1200 mg (3 vials) will be administered IV over 60 minutes

GSK1322322 1200 mg Arm

GSK1322322 3000 mg DRUG

GSK1322322 will be supplied as white to slightly colored lyophilized powder 400 mg/vial for injection. Single dose of GSK1322322 3000 mg (8 vials) will be administered IV over 60 minutes

GSK1322322 3000 mg Arm

Placebo DRUG

Placebo will be supplied as 0.9% sodium chloride solution. Single dose of placebo will be administered IV over 60 minutes

Placebo Arm

Moxifloxacin DRUG

Moxifloxacin will be supplied as oblong, dull red film coated tablets of 400 mg strength. Single dose of moxifloxacin 400 mg will be administered orally

Moxifloxacin 400 mg Arm

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 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 feels that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures
• Male or female (of non childbearing potential) 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 milli international units \[mIU\]/millilitre \[mL\] and estradiol \<40 picograms \[pg\]/mL or \<147 picomole \[pmol\]/litre \[L\] is confirmatory)
• Male subjects with female partners of child-bearing potential must agree to use one of the following contraception methods from the time of the first dose of study medication until the final follow up visit - Condom plus partner use of a highly effective contraceptive; Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Body weight \>=50 kilograms (kg) for men and \>=45 kg for women and body mass index (BMI) within the range 18.5-31.0 kg/(square metre) 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%) at screening and check-in (repeat allowed at check-in only)
• Serum Potassium, Calcium and Magnesium lab parameters within normal limits at screening and check-in (repeat allowed at check-in only)
• QTcB \<450 milliseconds (msec) at screening and check-in
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

You may not qualify if:

• History/evidence of any arrhythmia (for example, first, second or third degree heart block, atrial fibrillation, supraventricular tachycardia, sinus bradycardia, junctional rhythm) or clinically significant cardiac disease or procedure(mitral valve regurgitation, heart murmur, angina/ischemia, congenital heart abnormalities, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PCTA). Personal or family history of long QT syndrome
• Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy, inflammatory bowel disease or pancreatitis. Subjects with active peptic ulcer disease or a history of upper gastrointestinal bleeding
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams 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
• A positive pre-study Hepatitis B surface antigen, positive Hepatitis C antibody result, or a positive test for Human Immunodeficiency Virus (HIV) antibody within 3 months of screening
• A positive pre-study drug/alcohol screen
• 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 GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety due to potential drug interaction
• History of sensitivity to any of the study medications, quinolone antibiotics, (including moxifloxacin), 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 mL within a 56 day period
• Pregnant females as determined by positive (serum or urine) 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

MeSH Terms

Conditions

Bacterial Infections

Interventions

GSK1322322; Moxifloxacin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

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: February 28, 2013
• First Posted: March 4, 2013
• Study Start: August 1, 2014
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: January 28, 2015

Record last verified: 2015-01