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

NCT ID: NCT02216123

Last Updated: 2018-05-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 251 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2016-11-04

Brief 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.

Conditions

Malaria, Vivax

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Tafenoquine+ Chloroquine

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.

Group Type: EXPERIMENTAL

Tafenoquine

Intervention Type: DRUG

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

Intervention Type: DRUG

One of two formulations of commercially available generic chloroquine may be utilized in this study:

1. tablets containing 500 mg chloroquine phosphate (equivalent to 300 mg chloroquine free base); or,

2. tablets containing 250 mg chloroquine phosphate (equivalent to 155 mg chloroquine free base).

Primaquine Placebo

Intervention Type: DRUG

Placebo to match PQ will be supplied as Swedish orange size B supro capsules with common excipients of appropriate quality.

Primaquine+ Chloroquine

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.

Group Type: EXPERIMENTAL

Tafenoquine Placebo

Intervention Type: DRUG

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

Intervention Type: DRUG

One of two formulations of commercially available generic chloroquine may be utilized in this study:

1. tablets containing 500 mg chloroquine phosphate (equivalent to 300 mg chloroquine free base); or,

2. tablets containing 250 mg chloroquine phosphate (equivalent to 155 mg chloroquine free base).

Primaquine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Chloroquine

One of two formulations of commercially available generic chloroquine may be utilized in this study:

1. tablets containing 500 mg chloroquine phosphate (equivalent to 300 mg chloroquine free base); or,

2. tablets containing 250 mg chloroquine phosphate (equivalent to 155 mg chloroquine free base).

Intervention Type: DRUG

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.

Intervention Type: DRUG

Primaquine Placebo

Placebo to match PQ will be supplied as Swedish orange size B supro capsules with common excipients of appropriate quality.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Manaus, Amazonas, Brazil

GSK Investigational Site

Cali, , Colombia

GSK Investigational Site

Montería, , Colombia

GSK Investigational Site

Gonder, , Ethiopia

GSK Investigational Site

Jimma, , Ethiopia

GSK Investigational Site

Iquitos, Loreto, Peru

GSK Investigational Site

Bangkok, , Thailand

GSK Investigational Site

Mae Sot, , Thailand

GSK Investigational Site

Tak, , Thailand

GSK Investigational Site

Ho Chi Minh City, , Vietnam

Countries

Brazil; Colombia; Ethiopia; Peru; Thailand; Vietnam

References

Llanos-Cuentas A, Lacerda MVG, Hien TT, Velez ID, Namaik-Larp C, Chu CS, Villegas MF, Val F, Monteiro WM, Brito MAM, Costa MRF, Chuquiyauri R, Casapia M, Nguyen CH, Aruachan S, Papwijitsil R, Nosten FH, Bancone G, Angus B, Duparc S, Craig G, Rousell VM, Jones SW, Hardaker E, Clover DD, Kendall L, Mohamed K, Koh GCKW, Wilches VM, Breton JJ, Green JA. Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019 Jan 17;380(3):229-241. doi: 10.1056/NEJMoa1802537.

Reference Type: DERIVED

PMID: 30650326 (View on PubMed)

Other Identifiers

116564

Identifier Type: -

Identifier Source: org_study_id