A Study to Evaluate the Effect of Intravenous Zanamivir on Cardiac Conduction in Healthy Volunteers

Study Overview
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Brief Summary
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Approximately 40 healthy subjects will be enrolled. Each subject will participate in the study for approximately 9 weeks. There will be four treatment sequences with a 5-7 day washout between treatments. Subjects will be admitted to the clinical unit on Day-1 of each dosing period and will remain in the unit until Day 2. Each subject will receive a single dose of each of the four treatments on Day 1 of each treatment period in a randomized fashion. Subjects will be discharged from the clinical research unit after the completion of all assessments on Day 2 of each period and return approximately 5-7 days later for the next dose period. Serial pharmacokinetic samples will be collected for up to 24 hours following each treatment.

Official Title
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A Phase I, Randomized, Placebo-Controlled, Four-Way Crossover Study to Evaluate the Effect of Intravenous (IV) Zanamivir on Cardiac Conduction as Assessed by 12-lead Electrocardiogram (ECG) With Moxifloxacin as a Positive Control in Healthy Volunteers

Conditions
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Influenza, Human

Intervention / Treatment
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* Drug: 600 mg zanamivir + moxifloxacin placebo
* Drug: 1200 mg zanamivir + moxifloxacin placebo
* Drug: zanamivir placebo + moxifloxacin placebo
* Drug: zanamivir placebo + 400 mg moxifloxacin


Participation Criteria
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Eligibility Criteria
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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 monitoring. Male or female between 18 and 55 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 or of child-bearing potential and agrees to use one of the contraception methods listed in the protocol. Body weight greater than or equal to 50 kg for men and greater than or equal to 45 kg for women and BMI within the range 18.5-31.0 kg/m2 (inclusive). AST, ALT, alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated bilirubin >1.5x upper limit of normal (ULN) is acceptable if bilirubin is fractionated and direct bilirubin <35%). Capable of giving written informed consent, which includes agreement to comply with the requirements and restrictions listed in the consent form Exclusion Criteria: The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. 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). 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. 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. A history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >14 drinks/week for men or >7 drinks/week for women. Has a history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening. Pregnant females as determined by positive serum or urine human chorionic gonadotrophin (hCG) test at screening or prior to dosing. Lactating females. Unwillingness or inability to follow the procedures outlined in the protocol. 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 should be excluded. Subjects with active peptic ulcer disease or a history of upper gastrointestinal bleeding A creatinine clearance less than 80mL/min as determined by Cockcroft-Gault equation. History/evidence of clinically significant pulmonary disease, renal or hepatobiliary diseases. Subjects with a history of nephrolithiasis will be excluded. A positive pre-study Human immunodeficiency virus (HIV) antibody test, a positive Hepatitis B surface antigen or Hepatitis C antibody result within 3 months of screening. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Subjects with a hemoglobin <11 g/dL. A single repeat is allowed for eligibility determination. The subject's systolic blood pressure is outside the range of 90-140mmHg, or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 45-100bpm for female subjects or 45-100 bpm for male subjects. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination) per protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Treatment A will include combination of zanamivir 600 mg IV plus placebo for moxifloxacin | Drug: 600 mg zanamivir + moxifloxacin placebo<br>* zanamivir 600 mg IV over 30 min x 1 dose + moxifloxacin placebo administered orally x 1 dose<br>|
| Experimental: Treatment B<br>Treatment A will include combination of zanamivir 1200 mg IV plus placebo for moxifloxacin | Drug: 1200 mg zanamivir + moxifloxacin placebo<br>* zanamivir 1200 mg IV over 30 min x 1 dose + moxifloxacin placebo administered orally x 1 dose<br>|
| Experimental: Treatment C<br>Treatment C will include zanamivir placebo plus placebo for moxifloxacin | Drug: zanamivir placebo + moxifloxacin placebo<br>* zanamivir placebo IV over 30 min x 1 dose + moxifloxacin placebo administered orally x 1 dose<br>|
| Experimental: Treatment D<br>Treatment D will include moxifloxacin plus zanamivir placebo | Drug: zanamivir placebo + 400 mg moxifloxacin<br>* moxifloxacin 400 mg administered orally x 1 dose + zanamivir placebo IV over 30 min x 1 dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in QTcF for zanamivir |  | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in QTcB |  | 9 weeks | 
| Change from baseline in QTci |  | 9 weeks | 
| Change from baseline in QT |  | 9 weeks | 
| Change from baseline in Heart Rate |  | 9 weeks | 
| Pharmacokinetic parameters of Area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of maximum observed concentration from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of time of occurrence of cmax from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of systemic clearance of parent drug from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of volume of distribution in terminal phase from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of terminal phase half-life from serum zanamivir concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of Area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of maximum observed concentration (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of time of occurrence of cmax (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of systemic clearance of parent drug (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of volume of distribution in terminal phase (if needed) from plasma moxifloxacin concentration-time data |  | 9 weeks | 
| Pharmacokinetic parameters of terminal phase half-life (if needed) from plasm moxifloxacin concentration-time data |  | 9 weeks | 
| Safety and tolerability of zanamivir as assessed by change from baseline in 12-lead Electrocardiograms (ECG) |  | 9 weeks | 
| Safety and tolerability of zanamivir as assessed by change from baseline in blood pressure and heart rate |  | 9 weeks | 
| Safety and tolerability of zanamivir as assessed by change from baseline in the collection of adverse events |  | 9 weeks | 
| Safety and tolerability of zanamivir as assessed by change from baseline in toxicity grading of clinical laboratory tests |  | 9 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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zanamivir, influenza, 12-lead ECG, cardiac repolarization, QTc, GR121167