Ph 2B/3 Tafenoquine (TFQ) Study in Prevention of Vivax Relapse
Condition: Malaria, Vivax
MeSH terms: Malaria; Malaria, Vivax
Intervention: Chloroquine 600mg; Chloroquine 300mg; Tafenoquine 50mg; Tafenoquine 100mg; Tafenoquine 300mg; Tafenoquine 600mg; Primaquine 15mg; Chloroquine 600mg (Part 2 ); Chloroquine 300mg (Part 2 ); Tafenoquine 300mg (Part 2); Primaquine 15mg (Part2 )
Intervention description: 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial; 300mg Chloroquine given to each subject on Day 3 of the trial; single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2; single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2; single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2; single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2; 15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.; 600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.; 300mg Chloroquine given to each subject on Day 3 of the trial.; single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2.; 15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.
Intervention MeSH terms: Chloroquine; Chloroquine diphosphate; Primaquine; Tafenoquine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 851.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No

Summary:

      The purpose of this two part study is to test the safety and efficacy of Tafenoquine (with
      Cholorquine) as a radical cure for Plasmodium vivax (P.vivax) malaria relative to the control
      Chloroquine.Part 1 aims to select an efficacious and well tolerated dose that can be
      co-administered with Chloroquine. Part 2 will investigate the safety and efficacy of the
      selected dose (300 mg tafenoquine) in the treatment and radical cure of Plasmodium Vivax
      Malaria.
    

Eligibility criteria:

        Inclusion Criteria: - Positive Giemsa smear for P. vivax

          -  Parasite density >100 and <200,000/μL

          -  ≥16 years

          -  A female is eligible if she is non-pregnant, nonlactating and if she is of: -
             non-child bearing potential defined as: post-menopausal (12 months of spontaneous
             amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating
             hormone >40 mIU/mL), pre-menopausal and has had a hysterectomy or a bilateral
             oophorectomy (removal of the ovaries) or a bilateral tubal ligation with medical
             report verification, negative pregnancy test or,

          -  child-bearing potential, has a negative serum pregnancy test at screening, and agrees
             to comply with one of the following during the treatment stage of the study and for a
             period of 90 days after stopping study drug:

          -  Use of oral contraceptive, either combined or progestogen alone used in conjunction
             with double barrier method as defined below

          -  Use of an intrauterine device with a documented failure rate of <1% per year

          -  Use of depo provera injection (part 2)

          -  Double barrier method consisting of spermicide with either condom or diaphragm

          -  Male partner who is sterile prior to the female subject's entry into the study and is
             the sole sexual partner for that female.

          -  Complete abstinence from intercourse for 2 weeks prior to administration of study
             drug, throughout the study and for a period of 90 days after stopping study drug.

          -  A signed and dated informed consent is obtained from the subject or the subject's
             legal representative prior to screening.

        NB Assent is obtained from subjects <18 years, where applicable and written or oral
        witnessed consent has been obtained from parent or guardian.

          -  The subject is able to understand and comply with protocol requirements, instructions
             and protocol-stated restrictions and is likely to complete the study as planned.

          -  Willing to be hospitalized for 3 days and return to clinic for all follow-up visits
             including Day 180

          -  QTc <450 msec at screening, based on a single QTcF value at screening (part 1 only) or
             as an average of triplicate Electrocardiogram obtained over a brief recording period
             by machine or manual over-read if first is >450 msec.- Exclusion Criteria: - Mixed
             malaria infections (e.g. identified by Giemsa-stained smear or rapid diagnostic test)

          -  Severe vivax malaria as defined by World Health Organisation criteria.

          -  Severe vomiting (no food or inability to take food during previous 8 hours)

          -  Screening haemoglobin concentration <7 g/dL.

          -  Glucose 6-phosphate dehydrogenase deficiency, assessed by a quantitative
             spectrophotometric phenotype assay:

        Part 1 - Males: Any subject with an enzyme level <70% of the site median value for Glucose
        6-phosphate dehydrogenase normals will be excluded. Females: Those females with a screening
        Hb ≥ 10 g/dL will only be excluded if their enzyme level is <70% of the site median value
        for Glucose 6-Phosphate dehydrogenase normals. hose females with Hb ≥7 but < 10 g/dL will
        be excluded if an enzyme level is not > 90% of the site median value for Glucose
        6-Phosphate dehydrogenase normals.

        Part 2 - Any subject with enzyme level <70% of the site median value for Glucose
        6-phosphate dehydrogenase normals will be excluded

          -  Liver function test alanine transaminase >2x Upper Limit of Normal

          -  Any clinically significant concurrent illness (e.g. pneumonia, septicaemia),
             pre-existing conditions (e.g. renal disease, malignancy), conditions that may affect
             absorption of study medication (e.g. vomiting or severe diarrhea) or clinical signs
             and symptoms of severe cardiovascular disease (e.g. uncontrolled congestive heart
             failure or severe coronary artery disease). These abnormalities may be identified on
             the screening history and physical or laboratory examination.

          -  Subject has taken antimalarials (e.g. ACT, mefloquine, primaquine, chloroquine) or
             drugs with anti-malarial activity within the past 30 days by history.

          -  History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or to any other
             4- or 8-aminoquinolines.

          -  Any contraindications to chloroquine or primaquine administration including a history
             of porphyria, psoriasis or epilepsy (please refer to chloroquine and primaquine
             locally approved prescribing information).

          -  Subject who has previously received study medication for this protocol (all parts) or
             has received treatment with any other investigational drug within 30 days or 5
             half-lives (whichever is longer) preceding the first dose of study medication.

          -  History of illicit drug abuse or heavy alcohol intake within 6 months of the study.

          -  Subjects who have taken or will likely require the use of medications from the
             prohibited medication list which include the following classes: Histamine-2 blockers
             and antacids.

          -  Drugs with haemolytic potential.

          -  Drugs known to prolong the QTc interval