Overview

This trial is active, not recruiting.

Condition malaria, vivax
Treatments tafenoquine, tafenoquine placebo, chloroquine, primaquine, primaquine placebo
Phase phase 3
Sponsor GlaxoSmithKline
Collaborator Medicines for Malaria Venture
Start date April 2015
End date November 2016
Trial size 300 participants
Trial identifier NCT02216123, 116564

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, investigator)
Primary purpose treatment
Arm
(Experimental)
All subjects will receive one of two formulations of CQ from Days 1 to 3 (600 mg [2×CQ 300 mg] on Day 1, 600 mg on Day 2 and 300 mg on Day 3, each once daily [OD] orally; OR, 620 mg [4×CQ 155 mg] on Day 1, 620 mg on Day 2 and 310 mg on Day 3, each once daily [OD] orally). Tafenoquine 300mg (2×TQ 150 mg) will be given as a single oral dose on Day 1 or Day 2. Primaquine matching placebo will be given OD orally beginning on Day 1 or Day 2 and continue for 14 days total dosing. All subjects will be followed-up till 180 days.
tafenoquine
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.
chloroquine
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).
primaquine placebo
Placebo to match PQ will be supplied as Swedish orange size B supro capsules with common excipients of appropriate quality.
(Experimental)
All subjects will receive one of two formulations of CQ from Days 1 to 3 (600 mg [2×CQ 300 mg] on Day 1, 600 mg on Day 2 and 300 mg on Day 3, each once daily [OD] orally; OR, 620 mg [4×CQ 155 mg] on Day 1, 620 mg on Day 2 and 310 mg on Day 3, each once daily [OD] orally). Primaquine 15mg will be given OD orally beginning on Day 1 or Day 2 and continue for 14 total dosing. Tafenoquine matching placebo will be given as a single oral dose on Day 1 or Day 2. All subjects will be followed-up till 180 days.
tafenoquine placebo
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.
chloroquine
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).
primaquine
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.

Primary Outcomes

Measure
Proportion of all subjects with Plasmodium vivax (P. vivax) experiencing clinically relevant hemolysis
time frame: Up to Day 180
Proportion of female subjects with P. vivax who are moderately (40-70 percent) G6PD deficient experiencing clinically relevant hemolysis
time frame: Up to Day 180

Secondary Outcomes

Measure
Proportion of subjects with relapse-free efficacy six months post-dosing
time frame: After Day 32 of the study Up to day 180
Proportion of subjects with relapse-free efficacy four months post-dosing
time frame: After Day 32 of the study Up to day 120
Time to relapse
time frame: After Day 32 of the study Up to day 180
Parasite clearance time
time frame: Up to day 180
Fever clearance time
time frame: Up to day 180
Gametocyte clearance time
time frame: Up to day 180
Proportion of subjects with recrudescence
time frame: Up to Day 32
Incidence of genetically homologous and genetically heterologous P. vivax infections
time frame: Up to Day 180
Healthcare resource use for P. vivax relapses
time frame: Up to day 180
Population pharmacokinetic profile profile for tafenoquine
time frame: Days 2, 3, 8, 15, 29 and 60
Proportion of P. falciparum malaria
time frame: Up to Day 180
Safety as assessed by adverse events
time frame: Up to Day 180
Safety as assessed by Electrocardiogram (ECG)
time frame: 12 hours after first dose of blinded study medication, Day 29, at relapse or premature withdrawal visit, assessed Up to Day 180
Adverse events caused by treatment to prevent P. vivax relapses, especially hemolytic anemia
time frame: Up to Day 180
Safety as assessed by clinical chemistry parameters
time frame: Assessed up to Day 120, and at relapse or premature withdrawal visit
Safety as assessed by clinical hematology parameters
time frame: Assessed up to Day 120, and at relapse or premature withdrawal visit
Safety as assessed by clinical urinalysis
time frame: Assessed up to Day 120, and at relapse or premature withdrawal visit
Over-the-counter medications purchased during the study for P. vivax relapses
time frame: Up to day 180
Any travel or other costs incurred in seeking or receiving healthcare during the study for P. vivax relapses
time frame: Up to day 180
Time lost from normal occupation during the study due to P. vivax relapses
time frame: Up to day 180
Correlation between tafenoquine plasma concentration and P. vivax relapses at 4 and 6 month, if data permit
time frame: Up to Day 180
Correlation between tafenoquine plasma concentration and change in methemoglobin, if data permit
time frame: Up to Day 180
Correlation between tafenoquine plasma concentration and change in hemoglobin, if data permit
time frame: Up to Day 180
Safety as asessed by vital signs
time frame: Up to Day 180

Eligibility Criteria

Male or female participants at least 16 years old.

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.

Additional Information

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
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by GlaxoSmithKline.