Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria
Condition: Malaria, Vivax
MeSH terms: Malaria; Malaria, Vivax
Intervention: Tafenoquine; Matched-Placebo for Tafenoquine; Primaquine; Matched-Placebo for Primaquine; Dihydroartemisinin-piperaquine (DHA-PQP); ACT plus PQ (Rescue medication); PQ (End of study treatment)
Intervention description: This intervention is provided as tablet containing 150 mg of tafenoquine. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.; This intervention contains tafenoquine matched-placebo. Two tablets of this formulation will be administered orally with water as a single dose after a meal. Dose will be taken at least 3 hours after DHA-PQP.; This intervention is provided as over-encapsulated tablet containing 15 mg of primaquine. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).; This intervention contains primaquine matched-placebo. One capsule of this formulation will be administered orally with water as a single dose after a meal for 14 days. Dose will be taken at least 3 hours after DHA-PQP (Days 1, 2 and 3).; This formulation is provided as tablet containing 320 mg of piperaquine tetrasphosphate (as the tetrahydrate; PQP) and 40 mg dihydroartemisinin (DHA). This tablet will be administered orally as single dose for 3 days. For subjects weighing <75 kg, 3 tablets will be administered per day. For subjects weighing >=75 kg, 4 tablets will be administered per day. Dose will be taken at least 3 hours after last food intake. No food will be allowed for at least 3 hours after dosing.; Subjects with relapse during the 180 day follow up period will be given an ACT plus PQ 0.5 mg/kg for 14 days as rescue medication.; Subjects who do not relapse during the study will receive PQ 0.5mg/kg for 14 days at the end of the study.
Intervention MeSH terms: Primaquine; Piperaquine; Artenimol; Tafenoquine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 150.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Safety; Artemisinin Combination Therapy; Efficacy; Tafenoquine; Superiority; Primaquine; Radical cure; Vivax; ACT; Plasmodium vivax malaria; Dihydroartemisinin-piperaquine

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).