Phase 3
N=150
Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria
Malaria, Vivax
Bottom Line
View on ClinicalTrials.gov: NCT02802501 ↗Enrolled (actual)
150
Serious AEs
3.1%
Results posted
Jul 2020
Primary outcome: Primary: Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone — 12; 22 Percentage of participants — p=<0.001
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Tafenoquine (Drug); Matched-Placebo for Tafenoquine (Drug); Primaquine (Drug); Matched-Placebo for Primaquine (Drug); Dihydroartemisinin-piperaquine (DHA-PQP) (Drug); ACT plus PQ (Rescue medication) (Drug); PQ (End of study treatment) (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- Male
- Sponsor
- GlaxoSmithKline
- Primary completion
- Aug 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone |
12; 22 | <0.001 sig |
| SECONDARY Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and Primaquine+DHA-PQP |
22; 52 | — |
| SECONDARY Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Primaquine With DHA-PQP and DHA-PQP Alone |
12; 52 | — |
| SECONDARY Percentage of Participants With Relapse-free Efficacy at Four Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone |
16; 28 | — |
| SECONDARY Time to Relapse of P. Vivax Malaria |
81.5; 96.0; NA | — |
| SECONDARY Time to Fever Clearance |
16.5; 15.8; 16.8 | — |
| SECONDARY Time to Parasite Clearance |
18.1; 18.1; 18.0 | — |
| SECONDARY Number of Participants With Recrudescence |
0; 0; 0 | — |
| SECONDARY Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Double-blind Treatment Phase |
41; 41; 34; 1; 2; 2 | — |
| SECONDARY Number of Participants With Chemistry Values Outside Clinical Concern Range |
1; 3; 0; 1; 0; 0 | — |
| SECONDARY Number of Participants With Hematology Values Outside Clinical Concern Range |
0; 0; 0; 3; 4; 2 | — |
| SECONDARY Number of Participants With Electrocardiogram (ECG) Values Outside Clinical Concern Range-QT Interval Corrected Using Fredericia's Formula (QTcF) |
2; 3; 1 | — |
| SECONDARY Change From Baseline in QT Interval Corrected by Fridericia's Formula (QTcF) |
35.3; 44.5; 40.8; 11.5; 12.2; 16.5 | — |
| SECONDARY Number of Participants With Worst Case Body Temperature Results Relative to Normal Range Post-Baseline Relative to Baseline |
42; 38; 42; 3; 7; 5 | — |
| SECONDARY Number of Participants With Worst Case Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Results Relative to Normal Range Post-Baseline Relative to Baseline |
0; 1; 0; 19; 21; 25 | — |
| SECONDARY Number of Participants With Worst Case Pulse Rate Results Relative to Normal Range Post-Baseline Relative to Baseline |
19; 26; 23; 25; 23; 26 | — |
| SECONDARY Number of Participants With Worst Case Respiratory Rate Results Relative to Normal Range Post-Baseline Relative to Baseline |
0; 0; 0; 41; 41; 40 | — |
| SECONDARY Number of Participants With Gastrointestinal AEs |
5; 4; 3; 6; 5; 1 | — |
| SECONDARY Change From Baseline in Methemoglobin/ Total Hemoglobin |
-0.13; -0.07; -0.06; -0.16; -0.04; 0.01 | — |
| SECONDARY Number of Participants With Protocol-defined SAE (Hemoglobin Drop) |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Oral Clearance (CL/F) of Tafenoquine When Co-administered With DHA-PQP |
— | — |
| SECONDARY Volume of Distribution (V/F) of Tafenoquine When Co-administered With DHA-PQP |
— | — |
Summary
Tafenoquine (TQ) is an 8-aminoquinoline anti-malarial drug which is in development as a single-dose treatment for the radical cure of P.vivax malaria when given with standard doses of chloroquine. Currently, the only available drug for radical cure is primaquine (PQ) which requires administration over 14 days, resulting in poor compliance. In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance. This study will evaluate the efficacy and safety of a single dose of tafenoquine when co-administered with an ACT (i.e. DHA-PQP). This single-center, double-blind, double-dummy, randomized study will test the superiority of DHA-PQP plus TQ against DHA-PQP alone in the prevention of P. vivax malaria relapse at 6 months. The study will be conducted in male Indonesian soldiers diagnosed with P.vivax malaria on return from deployment to a malarious region of Indonesia. A PQ plus DHA-PQP comparator arm is included to provide an informal comparison against the standard 14 day treatment for P.vivax malaria in Indonesia. Subjects who are glucose-6-phosphate dehydrogenase deficient (G6PD deficient) will be excluded due to the risk of acute hemolysis following dosing with 8-aminoquinolines drugs. Subjects who have a recurrence of P.vivax malaria during the study will be treated with an ACT plus PQ (0.5mg/kg for 14 days), in line with local treatment guidelines. At the end of the 6 month follow up period, any subject who has not relapsed will be given open label PQ (0.5mg/kg daily for 14 days) to minimize the likelihood of relapse after the study. Approximately 200 subjects will be screened to achieve 150 randomized subjects. The total duration of study for each subject will be 180-195 days. This study is being carried out to support registration of TQ in Indonesia and other countries where ACTs are first line therapy.
Eligibility Criteria
Inclusion Criteria
- Male subjects >=18 years at the time of signing the informed consent.
- The subject has a positive Giemsa smear for P. vivax (mixed infection with P.falciparum is acceptable).
- The subject has a parasite density of >20 per microliter.
- Glucose-6-phosphate dehydrogenase (G6PD) normal using a suitable qualitative assessment, for example, nicotinamide adenine dinucleotide phosphate (NADPH) qualitative fluorescent spot test (Trinity Biologicals, United States of America).
- The subject has a QTcF of 2 times upper limit of Normal (ULN).
- Any clinically significant concurrent illness (for example, pneumonia, septicemia), significant pre-existing conditions (for example, renal disease, malignancy, Type 1 diabetes), conditions that may affect absorption of study treatment (for example, vomiting, severe diarrhea), or clinical signs and symptoms of severe cardiovascular disease (for example, uncontrolled congestive heart failure, severe coronary artery disease).
- History of hypersensitivity, allergy or adverse reactions to Dihydroartemisinin (DHA) or other artemisinins, piperaquine, tafenoquine or primaquine.
- Subject has previously received treatment with tafenoquine, or has received treatment with any other investigational drug within 30 days of study entry or within 5 half-lives, whichever is longer.
- Subject has taken anti-malarials (for example, ACTs, mefloquine, primaquine, quinacrine) or drugs with anti-malarial activity within the past 30 days.
- Subjects who will likely require the use of medications from the prohibited medications list or have taken them in the past 30 days which include the following medications and medication classes: Drugs with hemolytic potential, Drugs known to prolong the QT corrected (QTc) interval including: Antiarrhythmics; Neuroleptics and antidepressive agents; Certain antimicrobial agents, including agents of the following classes: macrolides, fluroquinolones imidazole and triazole antifungal agents and also pentamidine and saquinavir; Certain non-sedating antihistamines; Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.
- The biguanides: phenformin and buformin (but excluding metformin).
- Drugs that are substrates of the renal transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 2 (MATE1) and multidrug and toxin extrusion protein 2 (MATE2) and have a narrow therapeutic index (for example, the antiarrhythmic agents: dofetilide, procainamide and pilsicainide).
- Anticipated to be unable to consume daily study treatment under direct supervision by the research team.
- Previous participation in the present clinical trial, that is, subjects experiencing relapse during or after the study period may not be enrolled as a new subject.
- History of illicit drug abuse or heavy alcohol intake, such that full participation in the study could be compromised.
- Any contraindication in the opinion of the Investigator to DHA-PQP or primaquine administration such as: Family history of sudden unexplained death (DHA-PQP); Known congenital QT corrected (QTc) prolongation (DHA-PQP); Known history of a medical condition known to prolong the QT interval: for example, myxoedema, cardiomyopathies, recent myocardial infarction (DHA-PQP); History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia (DHA-PQP); Cardiac illnesses predisposing to arrhythmias for example, severe hypertension, left ventricular hypertrophy, cardiomyopathies, cardiac failure with reduced ejection fraction (DHA-PQP); Presence of an electrolyte disturbance particularly hypokalemia, hypocalcemia, hypomagnesemia (DHA-PQP); Rheumatoid arthritis, lupus erythematosus and other systemic conditions that may cause granulocytopenia (primaquine); History of hemolytic anemia, methemoglobinemia and leucopenia (primaquine).
Data sourced from ClinicalTrials.gov (NCT02802501). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.