Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria
Condition: Malaria, Vivax
MeSH terms: Malaria; Malaria, Vivax; Hemolysis
Intervention: Tafenoquine; Tafenoquine Placebo; Chloroquine; Primaquine; Primaquine Placebo
Intervention description: Tafenoquine will be supplied as a dark pink, capsule-shaped, film-coated tablet that is plain on both sides. Each tablet will contain 150mg TQ.; Placebo TQ tablets will be supplied as a dark pink, capsule-shaped, film-coated tablet that is plain on both sides, with common excipients of appropriate quality.; One of two formulations of commercially available generic chloroquine may be utilized in this study:
tablets containing 500 mg chloroquine phosphate (equivalent to 300 mg chloroquine free base); or,
tablets containing 250 mg chloroquine phosphate (equivalent to 155 mg chloroquine free base).; Commercially available primaquine containing primaquine phosphate united states pharmacopeia (USP), 26.3 mg (equivalent to primaquine base 15 mg) will be utilized in this study. Primaquine, a pink film-coated tablet imprinted W on one side and P97 on the other side. The PQ tablets for this study have been over-encapsulated in a Swedish orange size B supro capsule.; Placebo to match PQ will be supplied as Swedish orange size B supro capsules with common excipients of appropriate quality.
Intervention MeSH terms: Chloroquine; Primaquine; Tafenoquine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 251.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Tafenoquine; Plasmodium vivax; Hemolysis; Primaquine; Chloroquine; Glucose-6-phosphate dehydrogenase (G6PD); Relapse

Summary:

      This is a prospective, double-blind, double-dummy, multicenter, comparative study. A total of
      300 subjects will be randomized to treatment on Day 1, of which a minimum of 50 female
      subjects must be enrolled that display moderate glucose-6-phosphate dehydrogenase (G6PD)
      deficiency (>=40% - <70% of the site median G6PD value). Subjects must have a blood smear
      that is positive for P. vivax at entry. Subjects will be randomized 2:1 to receive
      tafenoquine (TQ)/chloroquine(CQ) or the active comparator primaquine (PQ)/CQ. All subjects
      will receive CQ on Days 1 to 3, followed by TQ or PQ and matching placebo beginning on Day 1
      or 2. Tafenoquine, or matching placebo, will be given as a single, 300mg dose. Subjects will
      receive PQ (15mg once daily) or matching placebo for 14 days. The duration of the study is
      180 days, including screening and randomization to treatment (Day 1), three in-hospital days
      (Days 1-3), four out-patient visits while on treatment with study medication (Days 5, 8, 11
      and 15) and seven follow-up visits (Days 22, 29, 60, 90, 120, 150 and 180).

      The primary safety data collected in this study will help to understand the hemolysis risk to
      both G6PD-normal and G6PD-deficient subjects. The efficacy data produced from this study will
      support the results for sister study TAF112582, the pivotal phase III efficacy and safety
      study of the TQ program.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A female is eligible to enter and participate in the study if she is non-pregnant,
             nonlactating and if she is of: a. Non-childbearing potential defined as:
             post-menopausal (12 months of spontaneous amenorrhea or <6 months of spontaneous
             amenorrhea with serum follicle-stimulating hormone >40 milli-International units per
             milliliter [mIU/mL]), or pre-menopausal and has had a hysterectomy or a bilateral
             oophorectomy (removal of the ovaries) or a bilateral tubal ligation, negative
             pregnancy test or, b. Child-bearing potential, has a negative 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 medication: 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; 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 medication, throughout the study and for a period of 90 days after stopping
             study medication.

          -  The subject has a glucose 6-phosphate dehydrogenase (G6PD) value (measured by a
             quantitative spectrophotometric phenotype assay) as follows: Female subjects must have
             an enzyme level >= 40 percent of the site median value for G6PD normal males. Male
             subjects must have an enzyme level >= 70 percent of the site median value for G6PD
             normal males.

          -  The subject has a screening hemoglobin (Hb) value as follows: Any subject with a G6PD
             value >=70 percent of the site median value must have a screening Hb value >=7 g/dL;
             Female subjects with a G6PD value is >=40 - <70 percent of the site median value must
             have a screening Hb value >=8 g/dL.

          -  The subject has a QT duration corrected for heart rate by Fridericia's Formula (QTcF)
             <450 milisecond (msec). Reading based on an average of triplicate Electrocardiograms
             (ECGs) obtained over a brief recording period by machine or manual over-read.

          -  The subject has a positive malarial smear for P. vivax .

          -  The subject has a parasite density of >100 and <100,000 per microliter (μL).

          -  Male or female subject aged 16 years or older (18 years or older in Ethiopia) at the
             time of signing the informed consent.

          -  The subject agrees to G6PD genotyping.

          -  The subject is willing and able to comply with the study protocol.

          -  The subject or parent/legal guardian, as applicable, has given written informed, dated
             consent; and the subject has given written assent, if applicable, to participate in
             the study.

        Exclusion Criteria:

          -  The subject has a mixed malaria infection (identified by a malarial smear or rapid
             diagnostic test).

          -  The subject has severe P. vivax malaria as defined by World Health Organization (WHO)
             criteria.

          -  The subject has a history of allergy to chloroquine, mefloquine, tafenoquine,
             primaquine, or to any other 4- or 8-aminoquinoline.

          -  The subject has a liver alanine aminotransferase (ALT) >2 x upper limit of normal
             (ULN).

          -  The subject has severe vomiting (no food or inability to take food during the previous
             8 hours).

          -  The subject has a clinically significant concurrent illness (e.g., pneumonia,
             septicemia), pre-existing condition (e.g., renal disease, malignancy), condition that
             may affect absorption of study medication (e.g., vomiting, severe diarrhea), or
             clinical signs and symptoms of severe cardiovascular disease (e.g., uncontrolled
             congestive heart failure, severe coronary artery disease).

          -  The subject has a history of porphyria, psoriasis, or epilepsy.

          -  The subject has a history of significant ocular disease (e.g. surgery to the globe,
             glaucoma, diabetic retinopathy) or has evidence of corneal or retinal abnormalities
             identified in the clinical screening ophthalmologic examination.

          -  The subject has taken anti-malarials (e.g., artemisinin-based combination therapies,
             mefloquine, primaquine, or any other 4- or 8-aminoquinoline) within 30 days prior to
             study entry.

          -  The subject has taken or will likely require during the study the use of medications
             from the following classes: Histamine-2 blockers and antacids; Drugs with hemolytic
             potential; Drugs known to prolong the QTcF interval; The biguanides phenformin and
             buformin (but excluding metformin); Drugs that are substrates of the renal
             transporters OCT2, MATE1 AND MATE-2K and have a narrow therapeutic index (for example,
             the anti-arrhythmic agents dofetilide, procainamide and pilsicainide)

          -  The subject has received treatment with any investigational drug within 30 days of
             study entry, or within 5 half-lives, whichever is longer.

          -  The subject has a recent history of illicit drug abuse or heavy alcohol intake, such
             that full participation in the study could be compromised.