Clinical trial NCT02802501: Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria
Official title: Study 200894: A Double-blind, Double-dummy, Randomized, Parallel Group, Placebo-controlled Superiority Study to Evaluate the Efficacy and Safety of Tafenoquine (SB-252263, WR238605) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria, Vivax
Keywords: Safety
Artemisinin Combination Therapy
Efficacy
Tafenoquine
Superiority
Primaquine
Radical cure
Vivax
ACT
Plasmodium vivax malaria
Dihydroartemisinin-piperaquine
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2016-06-16
Enrollment: 150
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 In Indonesia, chloroquine has been replaced by artemisinin-based combination therapy (i.e. ACTs) due to widespread chloroquine resistance.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 \<450 millisecond (msec). Note: Reading based on an average of triplicate ECGs obtained over a brief recording period by machine.
* The subject is willing and able to comply with the study protocol.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

Exclusion Criteria:

* Severe P.vivax malaria as defined by World Health Organization (WHO) criteria.
* Severe vomiting (no food or inability to take food during the previous 8 hours).
* Screening hemoglobin (Hb) concentration \<8 grams per deciliter.
* Liver function test ALT \>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).

Primary outcomes:
measure: Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone
timeFrame: 6 months post-dose
Secondary outcomes:
measure: Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Tafenoquine With DHA-PQP and Primaquine+DHA-PQP
timeFrame: 6 months post-dose
measure: Percentage of Participants With Relapse-free Efficacy at Six Months After Administration of Primaquine With DHA-PQP and DHA-PQP Alone
timeFrame: 6 months post-dose
measure: Percentage of Participants With Relapse-free Efficacy at Four Months After Administration of Tafenoquine With DHA-PQP and DHA-PQP Alone
timeFrame: 4 months post-dose
measure: Time to Relapse of P. Vivax Malaria
timeFrame: Up to Day 180
measure: Time to Fever Clearance
timeFrame: Up to Day 7
measure: Time to Parasite Clearance
timeFrame: Up to Day 8
measure: Number of Participants With Recrudescence
timeFrame: Up to Day 14
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Double-blind Treatment Phase
timeFrame: Up to Day 180
measure: Number of Participants With Chemistry Values Outside Clinical Concern Range
timeFrame: Up to Day 120
measure: Number of Participants With Hematology Values Outside Clinical Concern Range
timeFrame: Up to Day 120
measure: Number of Participants With Electrocardiogram (ECG) Values Outside Clinical Concern Range-QT Interval Corrected Using Fredericia's Formula (QTcF)
timeFrame: Up to Day 28
measure: Change From Baseline in QT Interval Corrected by Fridericia's Formula (QTcF)
timeFrame: Baseline (Day 1), Day 3: 4 hours post DHA-PQP dose, Days 7 and 28
measure: Number of Participants With Worst Case Body Temperature Results Relative to Normal Range Post-Baseline Relative to Baseline
timeFrame: Baseline (Day 1) and up to Day 180
measure: 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
timeFrame: Baseline (Day 1) and up to Day 180
measure: Number of Participants With Worst Case Pulse Rate Results Relative to Normal Range Post-Baseline Relative to Baseline
timeFrame: Baseline (Day 1) and up to Day 180
measure: Number of Participants With Worst Case Respiratory Rate Results Relative to Normal Range Post-Baseline Relative to Baseline
timeFrame: Baseline (Day 1) and up to Day 180
measure: Number of Participants With Gastrointestinal AEs
timeFrame: Up to Day 180
measure: Change From Baseline in Methemoglobin/ Total Hemoglobin
timeFrame: Baseline (Day 1) and Days 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,18,20,21,22,24,26,28 and 60
measure: Number of Participants With Protocol-defined SAE (Hemoglobin Drop)
timeFrame: Days 3, 5, 7, and 14
measure: Oral Clearance (CL/F) of Tafenoquine When Co-administered With DHA-PQP
timeFrame: Up to Day 60
measure: Volume of Distribution (V/F) of Tafenoquine When Co-administered With DHA-PQP
timeFrame: Up to Day 60
Other outcomes:
Locations:
city: Jakarta
country: Indonesia
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: