A Study to Evaluate the Pharmacokinetics of a Single Dose of Tafenoquine Co-administered With Either Artemether + Lumefantrine or Dihydroartemisinin + Piperaquine Tetraphosphate

NCT02184637 | Completed Phase 1

• 1 other identifier: 200951
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria, Vivax

Keywords

Malaria; Artemisinin-based Combination Therapies (ACT)

Outcome Measures

Primary Outcomes (4)

• 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)

  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.

  Up to Day 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).

  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.

  Up to Day 56

• Ratios of geometric mean [90% CI] for TQ AUC and Cmax for treatment groups: Cohort 1 (TQ + DHA+PQP) vs. cohort 5 (TQ).

  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.

  Up to Day 56

• Ratios of geometric mean [90% CI] for TQ AUC and Cmax for treatment groups: Cohort 2 (TQ + AL) vs. cohort 5 (TQ).

  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.

  Up to Day 56

Secondary Outcomes (6)

• 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

• 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

• Frequency of adverse events (AEs)

  Day -1 to Day 56

• Maximum change from baseline in QT interval corrected for heart rate by Fridericia's formula (QTcF) for all cohorts

  Day 1 to Day 56

Study Arms (5)

Cohort 1- TQ w/DHA+PQP

EXPERIMENTAL

Tafenoquine (TQ) will be co-administered with Dihydroartemisinin + Piperaquine tetraphosphate (DHA+PQP) on Day 1. DHA+PQP alone will be administered at 24 hours (h) (Day 2) and 48 h (Day 3) post first dose administration.

Drug: Tafenoquine; Drug: Dihydroartemisinin + Piperaquine tetraphosphate

Cohort 2 - TQ w/AL

EXPERIMENTAL

Tafenoquine co-administered with Artemether + Lumefantrine (AL) on Day 1. AL alone will be administered at 8h (Day 1), 24h and 36h (Day 2), 48h and 60 h (Day 3) post first dose administration.

Drug: Tafenoquine; Drug: Artemether + Lumefantrine

Cohort 3 - DHA+PQP alone

EXPERIMENTAL

Dihydroartemisinin + Piperaquine tetraphosphate (DHA+PQP) will be administered on Day 1 and at 24 hours (Day 2) and 48 hours (Day 3) post first dose administration

Drug: Dihydroartemisinin + Piperaquine tetraphosphate

Cohort 4 - AL alone

EXPERIMENTAL

Artemether + Lumefantrine will be administered on Day 1 and 8h, 24 and 36h (Day 2), 48h and 60 h(Day 3) post first dose administration

Drug: Artemether + Lumefantrine

Cohort 5 - TQ alone

EXPERIMENTAL

A single dose of Tafenoquine will be administered on Day 1

Drug: Tafenoquine

Interventions

Tafenoquine DRUG

A dark pink, capsule-shaped, film-coated tablet containing 150mg tafenoquine. To be administered orally

Cohort 1- TQ w/DHA+PQP; Cohort 2 - TQ w/AL; Cohort 5 - TQ alone

Dihydroartemisinin + Piperaquine tetraphosphate DRUG

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

Cohort 1- TQ w/DHA+PQP; Cohort 3 - DHA+PQP alone

Artemether + Lumefantrine DRUG

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

Cohort 2 - TQ w/AL; Cohort 4 - AL alone

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.
• The subject's average triplicate (at screening after approximately 5 minutes at rest in the semi-supine position) systolic blood pressure is outside the range of 80-140 millimeters of mercury (mmHg), or diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside the range of 40-100 beats per minute (bpm).
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
• Lactating females.
• Criteria Based Upon Medical Histories:
• 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 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 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• 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.
• History of thalassaemia; or current or past history of methemoglobinemia or methemoglobin percentage above the reference range at screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Medicines for Malaria Venture: collaborator

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (1)

• Green JA, Mohamed K, Goyal N, Bouhired S, Hussaini A, Jones SW, Koh GC, Kostov I, Taylor M, Wolstenholm A, Duparc S. Pharmacokinetic Interactions between Tafenoquine and Dihydroartemisinin-Piperaquine or Artemether-Lumefantrine in Healthy Adult Subjects. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7321-7332. doi: 10.1128/AAC.01588-16. Print 2016 Dec.

  PMID: 27697758 DERIVED

Related Links

• Results for study 200951 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Malaria, Vivax; Malaria

Interventions

tafenoquine; artenimol; Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2014
• First Posted: July 9, 2014
• Study Start: July 31, 2014
• Primary Completion: April 8, 2015
• Study Completion: April 8, 2015
• Last Updated: July 13, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

US (1)