Optimizing the Dose of Tafenoquine for the Radical Cure of Plasmodium Vivax Malaria in Southeast Asia
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 820
- 试验地点
- 11
- 主要终点
- Microscopy positive P. vivax recurrence after radical treatment up to month 4
研究概览
简要总结
Tafenoquine was recently approved by regulatory authorities in the USA and Australia. Tafenoquine is an alternative radical curative treatment to primaquine acting against the dormant liver stage of Plasmodium vivax (the hypnozoite). Tafenoquine (an 8-aminoquinoline) has the substantial advantage of single dosing as compared to a 14-day course of primaquine to achieve radical cure. The recommended tafenoquine dose is 300 mg, which was shown to be significantly worse in radical curative efficacy to a total primaquine dose of 3.5 mg/kg in Southeast Asia. The cure rate of tafenoquine 300 mg in Southeast Asian study sites was only 74%. The comparator 3.5 mg/kg total primaquine dose is the standard and most commonly used dose globally, but in Southeast Asia and the Western Pacific, higher doses of primaquine are needed for radical cure. This study aims to determine the optimal dose of tafenoquine in Southeast Asia.
Addendum for Indonesia: The INSPECTOR trial results showed that tafenoquine 300mg was not efficacious for radical cure (79% probability for recurrence after treatment). The comparator arm, low-dose primaquine 3.5mg/kg divided equally over 14 days, showed a 48% probability of recurrence after treatment). The standard of care for radical cure in Indonesia is high-dose primaquine 7mg/kg divided in 7 daily doses).
详细描述
Study design
A total of 700 participants will be enrolled and randomized to one of two arms: the currently recommended tafenoquine dose (TQ-current; e.g., 300mg adult dose) or a 50% higher tafenoquine dose (TQ-higher; e.g., 450mg adult dose). Doses will be equal to 100, 150, 200, 300, or 450 mg, given as a single dose. Each arm will have 350 participants. Recruitment will be conducted competitively across participating countries, depending on malaria caseloads and the recruitment strategy, until the target sample size is reached.The schizonticidal agent used will be determined by the study site. Tafenoquine will be given concomitantly with the schizonticidal agent on the day of enrolment. The participant will follow up daily until the malaria smear is negative for asexual parasites or until the schizonticidal treatment is completed, whichever occurs last. Follow up will continue on days 7, 14, 21, and 28 then every month until month 4. Participants will be instructed to follow up in between visits if they are feeling unwell. Treatment allocation will be double-blind.
Recruitment
Potential participants will be recruited from the outpatient setting at the following sites:
- Mahidol Oxford Tropical Medicine Research Unit, Cambodia
- Lao Oxford Mahosot Hospital Wellcome Trust Research Unit, Lao PDR
- Mahidol Vivax Research Unit, Thailand
- Shoklo Malaria Research Unit, Thailand
- Oxford University Clinical Research Unit, Vietnam
- Oxford University Clinical Research Unit, Indonesia
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
- Single (Outcomes Assessor)
盲法说明
Single (Outcomes Assessor) This is a double-blind randomized superiority trial. The laboratory staff responsible for reading the malaria blood smear slides will be blinded to treatment allocation.
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with symptomatic P. vivax mono-infection as diagnosed by microscopy
- •Fever or history of fever in the previous 7 days
- •Quantitative G6PD activity ≥70% of the population median
- •Weight >10 kg and ≥2 years old
- •Ability to understand the study instructions and provide written informed consent.
- •Willing to be followed for 4 months
排除标准
- •Pregnancy
- •Lactation
- •Hb < 8 g/dL
- •Severe malaria
- •Blood transfusion in the last 4 months
- •History of allergic response to an 8-aminoquinoline or the nationally recommended schizonticide (e.g., chloroquine, artemether-lumefantrine)
- •Any previous history of a haemolytic event Presence of any condition which in the judgement of the investigator would place the patient at undue risk or interfere with the results of the study (e.g. chronic disease, medications that potentiate or inhibit CYP2D6 or CYP2C8 isoenzyme function)
研究组 & 干预措施
Tafenoquine 50% higher dose (TQ-higher)
Arm 2
- >10 kg to ≤20 kg 150 mg
- >20 kg kg ≤35 kg 300 mg
- >35 kg 450 mg
Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands.
干预措施: Tafenoquine (Drug)
Tafenoquine standard dose (TQ-current)
Arm 1
- >10 kg to ≤20 kg 100 mg
- >20 kg kg ≤35 kg 200 mg
- >35 kg 300 mg
Tafenoquine will be given as 100 mg coated tablets. Tablets will be given, and dosing will be based on weight bands.
干预措施: Tafenoquine (Drug)
Tafenoquine standard dose (TQ-current)
Arm 1
- >10 kg to ≤20 kg 100 mg
- >20 kg kg ≤35 kg 200 mg
- >35 kg 300 mg
Tafenoquine will be given as 100 mg coated tablets. Tablets will be given, and dosing will be based on weight bands.
干预措施: Artemether 20 mg-Lumefantrine 120 mg (Drug)
Tafenoquine 50% higher dose (TQ-higher)
Arm 2
- >10 kg to ≤20 kg 150 mg
- >20 kg kg ≤35 kg 300 mg
- >35 kg 450 mg
Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands.
干预措施: Chloroquine (Drug)
Tafenoquine standard dose (TQ-current)
Arm 1
- >10 kg to ≤20 kg 100 mg
- >20 kg kg ≤35 kg 200 mg
- >35 kg 300 mg
Tafenoquine will be given as 100 mg coated tablets. Tablets will be given, and dosing will be based on weight bands.
干预措施: Chloroquine (Drug)
Primaquine standard high-dose (PQ)
Arm 3 (Indonesia site only) Primaquine will be given once daily over 7 days (7mg/kg total dose divided 1mg/kg/day).
干预措施: Primaquine (Drug)
Tafenoquine 50% higher dose (TQ-higher)
Arm 2
- >10 kg to ≤20 kg 150 mg
- >20 kg kg ≤35 kg 300 mg
- >35 kg 450 mg
Tafenoquine will be given as 100 mg coated tablets. Whole tablets will be given, and dosing will be based on weight bands.
干预措施: Artemether 20 mg-Lumefantrine 120 mg (Drug)
结局指标
主要结局
Microscopy positive P. vivax recurrence after radical treatment up to month 4
时间窗: At month 4
次要结局
- The probability of treatment failure defined as by the probability of one or more of the observed recurrences within 4 months being a relapse, using time-to-event and estimated identity-by-descent of recurring parasite genotypes compared to enrolment(At Day 0, 7, 14, 21, and 28; Month 2, 3, and 4)
- Sub-microscopic P. vivax recurrence after radical treatment between day 28 and month 4(At Day 28; Month 4)
- Tafenoquine metabolites identification in red blood cell and urine at days 1, and 2 or 3(At Day 1, 2, and 3)
- Sub-microscopic P. vivax recurrence with very low parasite density after radical cure treatment at days 14 and 21(At Day 14 and 21)
- Number of serious adverse events (e.g., hospitalization for symptomatic hemolysis or methemoglobinemia)(At Days 1, 2, 7, 14 and Months 1, 2, 3, 4)
- Number of adverse events (e.g., gastrointestinal symptoms)(At Days 1, 2, 7, 14 and Months 1, 2, 3, 4)
- Methemoglobin levels measured by pulse oximetry at day 7(At Day 7)
- Tafenoquine AUC and t1/2 as estimated from plasma tafenoquine concentrations at days 0, 1, 2, and 7, and monthly visits until month 4(At Day 0, 1, 2, and 7; Month 1, 2, 3, and 4)
- Plasma tafenoquine concentrations at days 0, 1, 2, and 7, and at monthly visits until month 4(At Day 0, 1, 2, and 7; Month 1, 2, 3, and 4)
- Microscopy positive P. vivax recurrence after radical treatment comparing primaquine and the tafenoquine groups in Indonesia only(At months 1, 2, 3 and 4)