Malaria, Vivax
Conditions
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.
Interventions
Single dose of Tafenoquine give on Day 3 only
Single dose of Tafenoquine given on Day 3 only
DRUGTafenoquine 1200mg
400mg Dose of Tafenoquine given on each of the three consecutive dosing days
DRUGmoxifloxacin
moxifloxacine given on Day 3 only
DRUGPlacebo for Tafenoquine
Placebo given on all three days to all groups except for group 5 on Day 3
DRUGPlacebo for moxifloxaxin
Placebo for moxifloxacin, given to all groups on all days except for Group 3 on Day 3
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in QTcF for 1200 mg dose of tafenoquine compared to baseline | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | electronic ECGs collected using holter monitors will be analysed to measure QTcF QTcB, QTcI, QT, and Heart Rate (HR) |
| 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 | electronic ECGs collected using holter monitors will be analysed to measure QTcF QTcB, QTcI, QT, and Heart Rate (HR) |
| 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 | electronic ECGs collected using holter monitors will be analysed to measure QTcF QTcB, QTcI, QT, and Heart Rate (HR) |
| 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 | electronic ECGs collected using holter monitors will be analysed to measure QTcF QTcB, QTcI, QT, and Heart Rate (HR) |
| 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 | Safety and tolerability of tafenoquine as assessed by 12-lead ECGs, vital signs, adverse events, and clinical laboratory tests |
| 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 | electronic ECGs collected using holter monitors will be analysed to measure QTcF QTcB, QTcI, QT, and Heart Rate (HR) |
| 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 | Blood samples will be collected at pre-dose on Days 1 and 2, and Day 3: pre-dose, 1, 2, 3, 4, 5, 6, 9, 12, 15, 20, 24, 36, 48 and 72 hours post Day 3 dose, to measure plasma concentrations and derived pharmacokinetic parameters AUC(0-t), Cmax, and tmax of moxifloxacin |
| 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 | Blood samples will be collected at pre-dose on Days 1 and 2, and Day 3: pre-dose, 1, 2, 3, 4, 5, 6, 9, 12, 15, 20, 24, 36, 48 and 72 hours post Day 3 dose, to measure plasma concentrations and derived pharmacokinetic parameters AUC(0-t), Cmax, and tmax of tafenoquine |
Countries
United States
Outcome results
None listed