Safety, Pharmacokinetics, and Preliminary Efficacy of Tafenoquine for the Treatment of Vivax Malaria in Papua New Guinean Children
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Pharmacokinetic: Distribution half-life
研究概览
简要总结
Plasmodium vivax is the most geographically widespread malaria species and the second largest contributor to symptomatic malaria worldwide. It accounts for half of all malaria cases outside Africa, with an estimated 14.3 million clinical vivax malaria cases reported annually, contributing to an annual cost of US$359 million. Children are most vulnerable to infection, with P. vivax prevalence peaking between 2 to 6 years of age. In Papua New Guinea (PNG), there are >1.5 million suspected P. vivax cases annually, and while P. falciparum infections are the most prevalent, P. vivax transmission is the most intense in the world. P. vivax in PNG provides a unique epidemiological setting in which to assess innovative treatments in children.
The complex biology of P. vivax represents a challenge for malaria control and chemotherapy, especially dormant liver-stage parasites (hypnozoites) which can reactivate (relapse) and cause disease at a time remote from the primary infection. Hypnozoite relapse is the primary cause of vivax malaria in endemic regions and is resistant to most antimalarial drugs. Identifying effective treatments for radical cure, the complete elimination of parasites (both blood- and liver-stage), is therefore a priority. The World Health Organization (WHO) recommends a 14-day radical cure regimen for uncomplicated vivax malaria; comprised of blood stage treatment (chloroquine or artemisinin combination therapy (ACT)) and 14 days of the 8-aminoquinoline drug primaquine (PQ; 0.25-0.5 mg/kg/day) for liver-stage cure. More recently, the 8-aminoquinoline tafenoquine has garnered interest as an alternative radical cure agent to primaquine. However, there is limited data on the pharmacokinetics, tolerability and radical cure efficacy of tafenoquine in children.
The overall aim of the study is to characterise the pharmacokinetic profile of tafenoquine (and primary metabolite) in Papua New Guinean children.
详细描述
This is an open-label study to evaluate the pharmacokinetic disposition of tafenoquine, with and without coadministration of fat, in healthy Papua New Guinean children. This study represents the first part of a multi-phase evaluation of tafenoquine in PNG children (preliminary efficacy study registered separately).
In this study, healthy PNG children aged 5-12 year will be eligible for inclusion into the study providing they have normal G6PD activity (>70% enzyme activity) and no history of previous hypersensitivity to 8-aminoquinoline drugs. All participants will be admitted to the Alexishafen Health Centre for the first 2-4 days of the study, to facilitate blood sampling and clinical monitoring.
After admission, baseline demographic and medical history will be taken, and the participants will undergo a full clinical assessment to establish baseline safety indices. The 30 participants will then be randomized 1:1 to receive either:
Group A: single dose tafenoquine (10 mg/kg) with water (and cracker biscuits (2% fat), to mitigate gastrointestinal complaints, or Group B: single dose tafenoquine (10 mg/kg) with 250mL of chocolate flavoured mild (9% fat; and cracker biscuits (2% fat)).
For pharmacokinetic analysis, venous blood samples will be collected (via indwelling cannula) at 8 time points within the first 48-hours of drug administration, with further finger prick samples collected on days 3, 4, 7, 14, 28, 42 and 56. Both dried blood spot and plasma samples will be collected at all time points for pharmacokinetic analyses.
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
- None
入排标准
- 年龄范围
- 5 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •have a normal glucose-6-phosphate-dehydrogenase (G6PD) activity (>70% enzyme activity) as confirmed by quantitative SD Biosensor
- •are Rapid Diagnostic Test negative for malaria
- •have not received treatment with any antimalarial in the previous 4-weeks
- •have no signs or symptoms of significant morbidity
- •have no history of hypersensitivity to primaquine
- •are able to attend all scheduled follow-up visits
排除标准
- •have G6PD activity <70%
- •test positive for malaria by rapid diagnostic test
- •have receive treatment with an antimalarial in the previous 4-weeks
- •have signs or symptoms of significant morbidities
- •have a history of primaquine related hypersensitivity
- •cannot, or are not willing, to attend all scheduled follow-up visits
研究组 & 干预措施
Group A
Single-dose tafenoquine as 10 mg/kg taken with water and a low-fat meal (3 plain cracker biscuits; 2% fat)
干预措施: Single dose tafenoquine (10 mg/kg) given with water (Drug)
Group B
Single-dose tafenoquine as 10mg/kg taken with 250 mL chocolate flavoured milk (9% fat) and a low-fat meal (3 plain cracker biscuits; 2% fat).
干预措施: Single dose tafenoquine (10 mg/kg) given with fat (Drug)
结局指标
主要结局
Pharmacokinetic: Distribution half-life
时间窗: 56-days after drug administration
Pharmacokinetic parameters of tafenoquine and 5,6-orthoquinone tafenoquine, will be ascertained using a nonlinear mixed-effects modelling approach (NONMEM), based on drug concentrations determined from venous blood samples collected at baseline (Day 0), 2, 4, 8, 12, 18, 24, 36 and 48 hours from a sampling cannula with capillary finger-prick samples at Days 3, 4, 7, 14, 28, 42 and 56.
Pharmacokinetic: Terminal elimination half-life
时间窗: 56-days after drug administration
Pharmacokinetic: Absorption half-life
时间窗: 56-days after drug administration
Pharmacokinetics: Clearance
时间窗: 56-days after drug administration
Pharmacokinetics: Volume of distribution
时间窗: 56-days after drug administration
Pharmacokinetics: Maximal concentration
时间窗: 56-days after drug administration
Pharmacokinetics: Area under concentration-time curve
时间窗: 56-days after drug administration
次要结局
- Safety: Change in haemoglobin over 28 days(28-days from drug administration)
- Safety: Change in methaemoglobin over 28 days(28-days from drug administration)
- Safety: Change in hepatorenal function over 7 days(7-days from drug administration)
- Safety: Change in rate corrected QTc over 28 days(28-days from drug administration)
- Tolerability: Taste and tolerability assessment(1-day following drug administration)
- Safety and tolerability: Number of participants with treatment-related adverse events as assessed by standardised questionnaire(56-days after drug administration)