Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria
Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria
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.
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.