Clinical trial NCT02216123: Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB-252263, WR238605) Versus Primaquine in Subjects With Plasmodium Vivax Malaria
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria, Vivax
Keywords: Tafenoquine
Plasmodium vivax
Hemolysis
Primaquine
Chloroquine
Glucose-6-phosphate dehydrogenase (G6PD)
Relapse
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2014-08-13
Enrollment: 251
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Percentage of Participants With Clinically Relevant Hemolysis.
timeFrame: Up to Day 180
measure: Percentage of Female Participants With Moderate Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency Experiencing Clinically Relevant Hemolysis.
timeFrame: Up to Day 180
Secondary outcomes:
measure: Rate of Relapse-free Efficacy at Six Months Post Dose
timeFrame: 6 months post dose
measure: Rate of Relapse-free Efficacy at Four Months Post Dose
timeFrame: 4 months post dose
measure: Time to Relapse of P. Vivax Malaria
timeFrame: Up to Day 180
measure: Time to Parasite Clearance
timeFrame: Up to Day 180
measure: Time to Fever Clearance
timeFrame: Up to Day 9
measure: Time to Gametocyte Clearance
timeFrame: Up to Day 180
measure: Number of Participants With Recrudescence
timeFrame: Up to Day 32
measure: Number of Participants With Genetically Homologous and Genetically Heterologous P. Vivax Infections
timeFrame: Up to Day 180
measure: Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range
timeFrame: Up to Day 120
measure: Number of Participants With Hematology Laboratory Data Outside the Reference Range
timeFrame: Up to Day 120
measure: Number of Participants With Abnormal Urinalysis Dipstick Results
timeFrame: Up to Day 120
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Up to Day 180
measure: Number of Participants With Electrocardiogram (ECG) Findings
timeFrame: Up to Day 29
measure: Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP)
timeFrame: Baseline and up to Day 180
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline and up to Day 180
measure: Change From Baseline in Temperature
timeFrame: Baseline and up to Day 180
measure: Number of Participants With P. Falciparum
timeFrame: Up to Day 180
measure: Number of Participants With Keratopathy
timeFrame: Up to Day 180
measure: Number of Participants With Change in Best Corrected Visual Acuity Test Scores
timeFrame: Baseline and up to Day 180
measure: Number of Participants With Retinal Changes From Baseline
timeFrame: Baseline and up to Day 180
measure: Change From Baseline in Percent Methemoglobin
timeFrame: Baseline and up to Day 120
measure: Cost Associated With Relapse Episode of P Vivax Malaria
timeFrame: Up to Day 180
measure: Cost Associated With a Hemolysis Event
timeFrame: Up to Day 180
measure: Cost Incurred With Purchase of Medications Associated With Relapse Episode of P. Vivax Malaria
timeFrame: Up to Day 180
measure: Cost Incurred With Purchase of Medications Associated With Hemolysis Event
timeFrame: Up to Day 180
measure: Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to Relapse Episode of Malaria
timeFrame: Up to Day 180
measure: Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to a Hemolysis Event
timeFrame: Up to Day 180
measure: Number of Participants With Action Taken to Treat Relapse Episode of P. Vivax Malaria
timeFrame: Up to Day 180
measure: Number of Participants With Action Taken to Treat a Hemolysis Event
timeFrame: Up to Day 180
measure: Oral Clearance (CL/F) of TQ
timeFrame: Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180
measure: Volume of Distribution (Vc/F) of TQ
timeFrame: Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180
Other outcomes:
Locations:
city: Manaus
country: Brazil
facility: GSK Investigational Site
state: Amazonas
city: Cali
country: Colombia
facility: GSK Investigational Site
city: Monteria
country: Colombia
facility: GSK Investigational Site
city: Gondar
country: Ethiopia
facility: GSK Investigational Site
city: Jimma
country: Ethiopia
facility: GSK Investigational Site
city: Iquitos
country: Peru
facility: GSK Investigational Site
state: Loreto
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Mae Sot
country: Thailand
facility: GSK Investigational Site
city: Tak
country: Thailand
facility: GSK Investigational Site
city: Ho Chi Minh
country: Vietnam
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.