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

NCT02216123 | Completed Phase 3 Results DMC

• 1 other identifier: 116564
• Study Type: interventional
• Target: 251
• Locations: 6 countries
• Sites: 10

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

Keywords

Tafenoquine; Plasmodium vivax; Hemolysis; Primaquine; Chloroquine; Glucose-6-phosphate dehydrogenase (G6PD); Relapse

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Clinically Relevant Hemolysis.

  Clinically relevant hemolysis is defined as a decrease in hemoglobin of \>=30% or \>3 grams per deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. The percentage of participants with clinically relevant hemolysis has been summarized. Safety Population comprised of all randomized participants who received at least one dose of blinded study medication.

  Up to Day 180

• Percentage of Female Participants With Moderate Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency Experiencing Clinically Relevant Hemolysis.

  Clinically relevant hemolysis is defined as a decrease in hemoglobin of \>=30% or \>3 g/dL from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL at any visit after the first dose of study medication. Despite additional efforts, no females with moderate G6PD-deficiency were enrolled that experienced clinically-significant hemolysis during the study; hence, the end point could not be estimated.

  Up to Day 180

Secondary Outcomes (31)

• Rate of Relapse-free Efficacy at Six Months Post Dose

  6 months post dose

• Rate of Relapse-free Efficacy at Four Months Post Dose

  4 months post dose

• Time to Relapse of P. Vivax Malaria

  Up to Day 180

• Time to Parasite Clearance

  Up to Day 180

• Time to Fever Clearance

  Up to Day 9

Study Arms (2)

Tafenoquine+ Chloroquine

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.

Drug: Tafenoquine; Drug: Chloroquine; Drug: Primaquine Placebo

Primaquine+ Chloroquine

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.

Drug: Tafenoquine Placebo; Drug: Chloroquine; Drug: Primaquine

Interventions

Tafenoquine 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.

Tafenoquine+ Chloroquine

Tafenoquine Placebo 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.

Primaquine+ Chloroquine

Chloroquine 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+ Chloroquine; Tafenoquine+ Chloroquine

Primaquine 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.

Primaquine+ Chloroquine

Primaquine Placebo DRUG

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

Tafenoquine+ Chloroquine

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Medicines for Malaria Venture: collaborator

Study Sites (10)

GSK Investigational Site

Manaus, Amazonas, 69040-000, Brazil

Location

GSK Investigational Site

Cali, Colombia

Location

GSK Investigational Site

Montería, Colombia

Location

GSK Investigational Site

Gonder, Ethiopia

Location

GSK Investigational Site

Jimma, Ethiopia

Location

GSK Investigational Site

Iquitos, Loreto, Iqui 01, Peru

Location

GSK Investigational Site

Bangkok, 10400, Thailand

Location

GSK Investigational Site

Mae Sot, 63110, Thailand

Location

GSK Investigational Site

Tak, 63170, Thailand

Location

GSK Investigational Site

Ho Chi Minh City, Vietnam

Location

Related Publications (1)

• 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.

  PMID: 30650326 DERIVED

MeSH Terms

Conditions

Malaria, Vivax; Hemolysis; Recurrence

Interventions

tafenoquine; Chloroquine; Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2014
• First Posted: August 13, 2014
• Study Start: April 30, 2015
• Primary Completion: November 4, 2016
• Study Completion: November 4, 2016
• Last Updated: May 16, 2018
• Results First Posted: May 16, 2018

Record last verified: 2018-02

Locations

BR (1); PE (1); CO (2); TH (3); VN (1); ET (2)