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

Condition(s) targeted: Malaria, Vivax

Intervention: Tafenoquine (Drug); Tafenoquine Placebo (Drug); Chloroquine (Drug); Primaquine (Drug); Primaquine Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Overall contact:
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com

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.

Official title: A Randomized, Double-Blind, Double Dummy, Comparative, Multicenter Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in the Treatment of Subjects With Plasmodium Vivax Malaria

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

Proportion of all subjects with Plasmodium vivax (P. vivax) experiencing clinically relevant hemolysis

Proportion of female subjects with P. vivax who are moderately (40-70 percent) G6PD deficient experiencing clinically relevant hemolysis

Secondary outcome:

Proportion of subjects with relapse-free efficacy six months post-dosing

Proportion of subjects with relapse-free efficacy four months post-dosing

Time to relapse

Parasite clearance time

Fever clearance time

Gametocyte clearance time

Proportion of subjects with recrudescence

Incidence of genetically homologous and genetically heterologous P. vivax infections

Healthcare resource use for P. vivax relapses

Population pharmacokinetic profile profile for tafenoquine

Proportion of P. falciparum malaria

Safety as assessed by adverse events

Safety as assessed by Electrocardiogram (ECG)

Adverse events caused by treatment to prevent P. vivax relapses, especially hemolytic anemia

Safety as assessed by clinical chemistry parameters

Safety as assessed by clinical hematology parameters

Safety as assessed by clinical urinalysis

Over-the-counter medications purchased during the study for P. vivax relapses

Any travel or other costs incurred in seeking or receiving healthcare during the study for P. vivax relapses

Time lost from normal occupation during the study due to P. vivax relapses

Correlation between tafenoquine plasma concentration and P. vivax relapses at 4 and 6 month, if data permit

Correlation between tafenoquine plasma concentration and change in methemoglobin, if data permit

Correlation between tafenoquine plasma concentration and change in hemoglobin, if data permit

Safety as asessed by vital signs

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Both.

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.

US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com

GSK Investigational Site, Cali, Colombia; Not yet recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com

GSK Investigational Site, Iquitos, Loreto Iqui 01, Peru; Recruiting
US GSK Clinical Trials Call Center, Phone: 877-379-3718, Email: GSKClinicalSupportHD@gsk.com
EU GSK Clinical Trials Call Center, Phone: +44 (0) 20 8990 4466, Email: GSKClinicalSupportHD@gsk.com

Starting date: April 2015
Last updated: June 25, 2015