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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 251
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Clinically Relevant Hemolysis.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Tafenoquine (Drug)
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.
干预措施: Chloroquine (Drug)
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.
干预措施: Primaquine Placebo (Drug)
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.
干预措施: Tafenoquine Placebo (Drug)
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.
干预措施: Chloroquine (Drug)
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.
干预措施: Primaquine (Drug)
结局指标
主要结局
Percentage of Participants With Clinically Relevant Hemolysis.
时间窗: Up to Day 180
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.
Percentage of Female Participants With Moderate Glucose-6 Phosphate Dehydrogenase (G6PD) Deficiency Experiencing Clinically Relevant Hemolysis.
时间窗: Up to Day 180
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.
次要结局
- Rate of Relapse-free Efficacy at Six Months Post Dose(6 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)
- Time to Gametocyte Clearance(Up to Day 180)
- Rate of Relapse-free Efficacy at Four Months Post Dose(4 months post dose)
- Number of Participants With Recrudescence(Up to Day 32)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs(Up to Day 180)
- Number of Participants With Hematology Laboratory Data Outside the Reference Range(Up to Day 120)
- Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP)(Baseline and up to Day 180)
- Change From Baseline in Temperature(Baseline and up to Day 180)
- Number of Participants With Genetically Homologous and Genetically Heterologous P. Vivax Infections(Up to Day 180)
- Change From Baseline in Pulse Rate(Baseline and up to Day 180)
- Number of Participants With Retinal Changes From Baseline(Baseline and up to Day 180)
- Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range(Up to Day 120)
- Number of Participants With Abnormal Urinalysis Dipstick Results(Up to Day 120)
- Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to Relapse Episode of Malaria(Up to Day 180)
- Oral Clearance (CL/F) of TQ(Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180)
- Number of Participants With Electrocardiogram (ECG) Findings(Up to Day 29)
- Cost Associated With a Hemolysis Event(Up to Day 180)
- Cost Incurred With Purchase of Medications Associated With Hemolysis Event(Up to Day 180)
- Number of Participants With Action Taken to Treat Relapse Episode of P. Vivax Malaria(Up to Day 180)
- Number of Participants With Action Taken to Treat a Hemolysis Event(Up to Day 180)
- Number of Participants With P. Falciparum(Up to Day 180)
- Number of Participants With Keratopathy(Up to Day 180)
- Number of Participants With Change in Best Corrected Visual Acuity Test Scores(Baseline and up to Day 180)
- Change From Baseline in Percent Methemoglobin(Baseline and up to Day 120)
- Cost Associated With Relapse Episode of P Vivax Malaria(Up to Day 180)
- Number of Participants or Care Givers Who Had Taken Time Off From Normal Occupation Due to a Hemolysis Event(Up to Day 180)
- Cost Incurred With Purchase of Medications Associated With Relapse Episode of P. Vivax Malaria(Up to Day 180)
- Volume of Distribution (Vc/F) of TQ(Day 2, Day 3, Day 8, Day 15, Day 29, Day 60 and Day 180)