Malaria, Vivax
Conditions
Keywords
Malaria, Artemisinin-based Combination Therapies (ACT)
Brief summary
This will be a single-centre, 5-cohort, randomized open-label, parallel-group study in healthy volunteer subjects. This study aims to provide sufficient pharmacokinetic (PK) evidence to support the safe usage of Tafenoquine (TQ) in studies and markets where the Artemisinin-based Combination Therapies (ACTs) are the standard of care for patients with Plasmodium vivax malaria (i.e., co administration with TQ). The objective of this study is to assess the pharmacokinetics, safety and tolerability of TQ when co-administered with the chosen ACTs (AL and DHA + PQP), administered concomitantly in healthy subjects. Specifically, the study will evaluate whether there are drug-drug interactions between TQ and each of the ACTs and if these interactions are considered to be clinically significant. The co-primary objectives of this study are to characterize both the effects of a 300 milligram (mg) single dose of TQ on the pharmacokinetics; changes in (area under the concentration-time curve from 0 to time t) AUC (0-t), AUC (0-infinity), and maximum observed concentration (Cmax) of each of the two Artemisinin-based Combination Therapies (ACT) according to their prescribed dose when co-administered as well as the effects of the ACTs on the PK of TQ. A total of 120 subjects (24 subjects in each of 5 cohorts) are planned to be enrolled in order to ensure a target sample size of at least 22 subjects completing the study per cohort. All subjects will arrive in the unit at least 24 hours prior to dosing and be discharged after 72-hour post first dose assessments have been completed. Subjects will return for outpatient visits on Days 7, 14, 21, 28, and 56 after first dose.
Interventions
DRUGTafenoquine
A dark pink, capsule-shaped, film-coated tablet containing 150mg tafenoquine. To be administered orally
DRUGDihydroartemisinin + Piperaquine tetraphosphate
White, oblong, biconvex, film-coated tablet with a break-line and marked on one side with two σ letters containing 320 mg piperaquine tetraphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). To be administered orally
Light yellow, round tablet with NC debossed on one side and CG on the other, containing 20 mg artemether and 120 mg lumefantrine. To be administered orally
Sponsors
Medicines for Malaria Venture
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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. A subject with a clinical abnormality or laboratory parameter(s), which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the Investigator and GlaxoSmithKline (GSK) Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects whose laboratory values are outside the normal ranges will be excluded from enrolment. * Male or female aged between 18 and 65 years of age inclusive, at the time of signing the informed consent. * Alanine Aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x Upper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * QTcF \<440 milliseconds (msec) based on averaged corrected QT interval (QTc) values of triplicate electrocardiogram (ECGs) obtained over a brief recording period at screening and no history of additional risk factors for Torsades des Pointes (e.g., heart failure or family history of Long QT Syndrome). * 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 \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; 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 per (MIU)/ millilitre (mL) and estradiol \<40 picograms (pg)/mL (\<147 picomoles (pmol)/liter \[L\]) is confirmatory\]. \[Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.\]; Child-bearing potential with negative pregnancy test as determined by serum or urine human chorionic gonadotropin (hCG) test at screening or prior to dosing AND Agrees to use one of the contraception methods 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 56-days post first dose. OR has only same-sex partners, when this is her preferred and usual lifestyle. * Body Mass Index (BMI) within the range 18.5 to 31.0 kilogram/square meter (kg/m\^2) (inclusive) and body weight between \>=36kilogram (kg) and \<=100kg. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratios of Geometric mean (90% [confidence interval] CI) for DHA+PQP AUC and Cmax for treatment groups: Cohort 1 (TQ + DHA+PQP) versus (vs.) cohort 3 (DHA+PQP) | Up to Day 56 | Blood samples will be collected on Day 1 (Pre-dose, 1, 2, 4, 6, 12 hours), Day 2 (24 hours), Day 3 (48, 48.5, 49, 49.5, 50, 51, 52, 54, 56, 60 hours), Day 4 (72 hours), Days 7, 14, 21, 28 and 56. |
| Ratios of geometric mean [90% CI] for A/DHA/L AUC and Cmax for treatment groups: Cohort 2 (TQ + AL) vs. cohort 4 (AL). | Up to Day 56 | Blood samples will be collected on Day 1 (Pre-dose, 1, 2, 4, 6, 12 hours), Day 2 (24 hours), Day 3 (48, 60, 60.5, 61, 61.5, 62, 64 hours), Day 4 (66, 68, 72 hours), Days 7, 14, 21, 28 and 56. |
| Ratios of geometric mean [90% CI] for TQ AUC and Cmax for treatment groups: Cohort 1 (TQ + DHA+PQP) vs. cohort 5 (TQ). | Up to Day 56 | Blood samples will be collected on Day 1 (Pre-dose, 1, 2, 4, 6, 12 hours), Day 2 (24 hours), Day 3 (48, 48.5, 49, 49.5, 50, 51, 52, 54, 56, 60 hours), Day 4 (72 hours), Days 7, 14, 21, 28 and 56. |
| Ratios of geometric mean [90% CI] for TQ AUC and Cmax for treatment groups: Cohort 2 (TQ + AL) vs. cohort 5 (TQ). | Up to Day 56 | Blood samples will be collected on Day 1 (Pre-dose, 1, 2, 4, 6, 12 hours), Day 2 (24 hours), Day 3 (48, 60, 60.5, 61, 61.5, 62, 64 hours), Day 4 (66, 68, 72 hours), Days 7, 14, 21, 28 and 56. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum change from baseline in QT interval corrected for heart rate by Fridericia's formula (QTcF) for all cohorts | Day 1 to Day 56 | The baseline measurement will be the average of the triplicate measurements taken on pre-dose Day 1. |
| Pharmacokinetic endpoints including changes in time to Cmax (Tmax) and apparent terminal phase half-life (t½) for TQ, as data permit. | Up to Day 56 | — |
| Change from baseline in QTcF at 52-hours post-first dose for subjects who receive DHA+PQP (cohort 1 and 3) | Pre-dose (Day 1) and 52-hours post-dose ( Day 3) | The baseline measurement will be the average of the triplicate measurements taken on pre-dose Day 1. |
| Pharmacokinetic endpoints including changes in Tmax and t½ for each of the ACTs, as data permit. | Up to Day 56 | — |
| Changes in safety laboratory measures (including haemoglobin change from baseline [mean of pre-dose and Day-1 results]) | Day -1 to Day 28 | Laboratory assessments will include haematology, clinical chemistry and urinalysis. |
| Frequency of adverse events (AEs) | Day -1 to Day 56 | An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
Countries
United States
Outcome results
None listed