Clinical trial NCT01521377: QTc Study GSK573719+GW642444
Official title: A Randomised, Placebo-controlled, Incomplete Block, Four Period Crossover , Repeat Dose Study to Evaluate the Effect of the Inhaled GSK573719/Vilanterol Combination and GSK573719 Monotherapy on Electrocardiographic Parameters, With Moxifloxacin as a Positive Control, in Healthy Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: LAMA
Respiratory
COPD
Tolerability
Beta-2 Agonist
Safety
Pharmacokinetics
Pharmacodynamics
LABA
Muscarinic Receptor Agonist
Healthy subjects
Moxifloxacin
Anticholinergic
GW642444
GSK573719
QTc
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-01-30
Enrollment: 100
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 randomized, placebo controlled, four period incomplete block,crossover thorough QT study to estimate the effect of repeat dose GSK573719/GW642444M (Vilanterol) combination and GSK573719 monotherapy on the QTc interval in healthy male and female subjects compared with placebo. At least 100 subjects will receive, four of five possible, 10-day repeat dose treatments. Treatments are placebo with a moxifloxacin placebo on day 10, placebo with moxifloxacin (400mg) on day 10, GSK573719/Vilanterol combination (125/25μg) with moxifloxacin placebo on day 10, GSK573719/Vilanterol combinatio (500/100μg) with moxifloxacin placebo on day 10, or GSK573719 (500μg) with a moxifloxacin placebo on day 10. All treatments are double blind except for moxifloxacin (400mg) and moxifloxacin placebo controls, given as a single-blind single dose on Day 10 of the appropriate treatment period.

Primary endpoints are individual time-matched changes from baseline QTcF for GSK573719/Vilanterol combination (125/25μg) and GSK573719 (500μg), 0-24 hours after dosing on Day 10. Secondary endpoints will include individual time-matched changes from baseline in QTcF for GSK573719/Vilanterol combination (500/100μg) and moxifloxacin (400mcg) 0-24 hours after dosing on Day 10. Also changes from baseline in QTci, QTcB, QT, QRS, RR, PR and ventricular rate at each time point after 10 days dosing of each GSK573719 and GSK573719/Vilanterol treatment and single dose moxifloxacin (400mg). Maximal change from baseline 0-24hours after dosing on day 10 will be derived for QTcF, QTci and QTcB for each treatment. Plasma concentrations on Day 10 (0-24 hours) and pharmacokinetic parameters of GSK573719 and Vilanterol will also be derived. Key assessments: 12- lead electrocardiogram (ECG), pharmacokinetics. Safety will be assessed by blood pressure, heart rate, clinical laboratory safety tests and collection of adverse events (AEs).


Eligibility criteria: Inclusion Criteria:

* Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* 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 believes that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* 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 \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \<40 pg/ml (\<147 pmol/L) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
  * Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 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 after the Follow Up visit
* AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Body weight ≥ 45 kg and BMI within the range 18 - 29.5 kg/m2 (inclusive).
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* No significant abnormality on 12-lead ECG at screening, including the following specific requirements:

  * Ventricular rate ≥ 40 beats per minute
  * PR interval ≤ 210msec
  * Q waves \< 30msec (up to 50 ms permitted in lead III only)
  * QRS interval to be ≥ 60msec and \< 120msec
  * The waveforms must enable the QT interval to be clearly defined
  * QTcF interval must be \< 450msec (machine or manual reading).
* A 24 hour Holter ECG at screening that demonstrates no clinically significant abnormalities or finding that could interfere with interpretation of the study results, when assessed by an appropriately trained and experienced reviewer
* Subjects who are able to use the Novel DPIsatisfactorily.
* Capable of giving written informed consent and a signed and dated written informed consent is obtained, which includes compliance with the requirements and restrictions listed in the consent form.
* Normal spirometry (FEV1 ≥ 80% of predicted, FEV1/FVC ≥ 70%).
* Non-smokers (never smoked or not smoking for \>6 months with \<10 pack years history (Pack years = (cigarettes per day smoked/20) x number of years smoked)).
* Available to complete the study.

Exclusion Criteria:

* History or presence of any medically significant disease, or any disorder that would introduce additional risk or interfere with the study procedures or outcome. In particular, a family history of QT prolongation, of early or sudden cardiac death or of early cardiovascular disease.
* History of symptomatic arrhythmias.
* A supine blood pressure that is persistently higher than 140/90 millimetres of mercury (mmHG) at screening.
* A supine mean heart rate outside the range 40-90 beats per minute (BPM) at screening.
* History of tendon disease/disorder related to quinolone treatment.
* History of sensitivity to any of the study medications, 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. In particular, the subject has a known allergy or hypersensitivity to quinolones, ipratropium bromide, tiotropium, atropine and any of its derivatives. Or any adverse reaction including immediate or delayed hypersensitivity to any β2 agonist or sympathomimetic drug,
* Severe Milk Protein allergy
* 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 HIV antibody.
* History of regular alcohol consumption within 6 months of the study defined as:

  * an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 ml) of beer, 1 glass (125ml) of wine or 1 (25 ml) measure of 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: 3 months, 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.
* 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.
* Consumption of seville oranges, pummelos (members of the grapefruit family) or grapefruit juice from 7 days prior to the first dose of study medication.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 3 month period.
* Pregnant females as determined by positive serum β-HCG test at screening or serum/ urine β-HCG prior to dosing.
* Lactating females.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Subject is mentally or legally incapacitated.
* Urinary cotinine levels indicative of smoking or history or regular use

Primary outcomes:
measure: Change from baseline in QTcF Interval with GSK573719/ Vilanterol 125/25mcg
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline in QTcF Interval with GSK573719 500 mcg
timeFrame: Screening, Day 1, and Day 10
Secondary outcomes:
measure: Change from baseline in QTcF interval with GSK573719/Vilanterol 500/100mcg
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline in QTci and QTcB interval for GSK573719/Vilanterol 125/25mcg and 500/100mcg as compared with timematched placebo.
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline in QTci and QTcB interval for GSK573719 500mcg as compared with time-matched placebo.
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline in QTcF interval for moxifloxacin as compared with time-matched placebo.
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline in QTci and QTcB interval for moxifloxacin as compared with time-matched placebo.
timeFrame: Screening, Day 1, and Day 10
measure: Change from baseline at each timepoint on Day 10 for other cardiac electrophysiological parameters: QT, QRS, RR, PR and ventricular rate for each active treatment compared with placebo.
timeFrame: Screening, Day 1, and Day 10
measure: Plasma concentrations of GSK573719 and Vilanterol and derived pharmacokinetic parameters including Cmax, tmax and AUC(0-τ).
timeFrame: Screening, Day 1, and Day 10
measure: Plasma concentrations of GSK573719 and derived pharmacokinetic parameters including Cmax, tmax and AUC(0-τ).
timeFrame: Screening, Day 1, and Day 10
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: