A Randomized, Placebo-Controlled Study to Evaluate the Effect of Tafenoquine (SB252263) on the Electrocardiogram (ECG) With Focus on Cardiac Repolarization (QTc Duration) in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- Placebo for Tafenoquine
- Conditions
- Malaria, Vivax
- Sponsor
- GlaxoSmithKline
- Enrollment
- 260
- Locations
- 1
- Primary Endpoint
- Change from baseline in QTcF for 1200 mg dose of tafenoquine compared to baseline
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This will be a randomized, single-blind, placebo controlled, parallel group study. Approximately 260 subjects will be enrolled in five groups. This study is designed to compare the effects of tafenoquine, administered as single dose as well as administered over three consecutive days, on the changes in QT duration to those observed in subjects dosed with either moxifloxacin or placebo.
Detailed Description
SB-252263 (tafenoquine, TQ) is a new 8-aminoquinoline antimalarial drug being developed by GlaxoSmithKline (GSK) and the Medicines for Malaria Venture with the assistance and historical support of the Walter Reed Army Institute of Research. Tafenoquine has been shown to be effective in the treatment of plasmodial infections in vitro, in pre-clinical models in vivo, and during early phase clinical studies for radical cure and eradication of liver hypnozoites in patients infected with Plasmodium vivax. This study is designed to compare the effects of tafenoquine mono-therapy, administered as a single dose or administered on 3 consecutive days, on the changes in QT duration to those observed in subjects dosed with either Avelox (moxifloxacin hydrochloride) or placebo. This will be a randomized, single-blind, placebo controlled, parallel group study. Parallel group design is chosen because tafenoquine has a long half-life, about 14 to 19 days, and therefore a cross-over design is not a practical alternative. Moxifloxacin will be used as a positive control in order to validate the sensitivity of the study in detecting QTc change. Moxifloxacin has been shown to prolong the QT interval in a dose-dependent manner in patients and healthy volunteers, and the QTc prolongation has been well quantified.
Investigators
Eligibility Criteria
Inclusion Criteria
- •AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and baseline ECG 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 and the 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:
- •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 the protocol 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 90 days post-last dose.
- •Body weight ≥50 kg for men and ≥45 kg for women and BMI within the range 18.5 to 31.0 kg/m2 (inclusive).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion Criteria
- •Documented Glucose-6-phosphate dehydrogenase (G6PD) deficiency, determined by a quantitative assay of enzyme activity.
- •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).
- •History of thalassaemia; or current or past history of methemoglobinemia or methemoglobin percentage above the reference range at screening.
- •A positive pre-study drug/alcohol screen.
- •A positive test for HIV antibody.
- •History of 2nd degree or higher AV block.
- •Donation of blood or blood products in excess of 500 mL within a 56 day period prior to enrolment.
- •Subjects with a hemoglobin values outside the normal range. 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 50-100bpm for female subjects or 45-100 bpm for male subjects.
Arms & Interventions
Group 1
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on three consecutive days of dosing
Intervention: Placebo for Tafenoquine
Group 1
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on three consecutive days of dosing
Intervention: Placebo for moxifloxaxin
Group 2
Subjects in group 2 receive 400mg of tafenoquine and placebo for moxifloxacin on three consecutive days of dosing
Intervention: Tafenoquine 1200mg
Group 2
Subjects in group 2 receive 400mg of tafenoquine and placebo for moxifloxacin on three consecutive days of dosing
Intervention: Placebo for Tafenoquine
Group 3
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for tafenoquine and 400mg moxifloxacin.
Intervention: moxifloxacin
Group 3
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for tafenoquine and 400mg moxifloxacin.
Intervention: Placebo for Tafenoquine
Group 3
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for tafenoquine and 400mg moxifloxacin.
Intervention: Placebo for moxifloxaxin
Group 4
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 300mg of tafenoquine
Intervention: Tafenoquine 300mg
Group 4
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 300mg of tafenoquine
Intervention: Placebo for Tafenoquine
Group 4
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 300mg of tafenoquine
Intervention: Placebo for moxifloxaxin
Group 5
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 600mg of tafenoquine
Intervention: Tafenoquine 600mg
Group 5
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 600mg of tafenoquine
Intervention: Placebo for Tafenoquine
Group 5
Subjects in group 1 receive placebo for tafenoquine and placebo for moxifloxacin on days 1 and 2. On day 3, subjects receive placebo for moxifloxacin and 600mg of tafenoquine
Intervention: Placebo for moxifloxaxin
Outcomes
Primary Outcomes
Change from baseline in QTcF for 1200 mg dose of tafenoquine compared to baseline
Time Frame: Day 1, Day 2, day 3, Day 4, Day 5 and Day 6
Contineous QTcF will be electronically recorded using holtor monitors. The primary comparison of interest is the mean time-matched change from baseline in QTcF for the difference tafenoquine-placebo for 1200mg dose of tafenoquine at each timepoint.
Secondary Outcomes
- Change from Baseline in QTcF, QTcB, QTcI, QT, and HR for moxifloxacin(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Change from Baseline in QTcB, QTcI, QT, and HR for 1200mg dose of tafenoquine(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Change from Baseline in QTcF, QTcB, QTcI, QT, and HR for placebo(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Change from Baseline in QTcF QTcB, QTcI, QT, and HR for 300 mg single dose of tafenoquine(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Plasma concentrations and derived pharmacokinetic parameters AUC(0-t), Cmax, and tmax of tafenoquine(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Safety and tolerability of tafenoquine as assessed by 12-lead ECGs, vital signs, adverse events, and clinical laboratory tests(Day 1, Day 2 and Day 3)
- Plasma concentrations and derived pharmacokinetic parameters AUC(0-t), Cmax, and tmax of moxifloxacin(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)
- Change from Baseline in QTcF QTcB, QTcI, QT, and HR for 600 mg single dose of tafenoquine(Day 1, Day 2, day 3, Day 4, Day 5 and Day 6)