Field Study of the Pharmacokinetics and Pharmacodynamics of Artemisinin-based Combination Therapy for Gametocyte Clearance and Post-treatment Chemoprotection in Zambian Children With Uncomplicated Falciparum Malaria
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 182
- 试验地点
- 1
- 主要终点
- Incidence of reinfection during the 9-week follow-up period
研究概览
简要总结
Single-center phase II/III clinical investigation of the pharmacokinetics and pharmacodynamics of artemether-lumefantrine and dihydroartemisinin-piperaquine for gametocyte clearance and post-treatment chemoprotection in Zambian children with uncomplicated falciparum malaria.
详细描述
Artemisinin-based combination therapies (ACTs) are the first-line agents for uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted ACT in sub-Saharan Africa for case management. Dihydroartemisinin-piperaquine (DP) is increasingly used for mass drug administration in malaria eliminating regions, and is being explored as a candidate for intermittent preventive therapy. AL and DP possess similar clinical efficacy against uncomplicated falciparum malaria in areas of drug susceptible parasites. However, AL appears to clear gametocytes (the transmissible stage of the malaria parasite) more rapidly than DP, while DP confers a longer duration of post-treatment protection against reinfection. It is not known whether the observed difference in gametocyte clearance between AL and DP is due to pharmacokinetic (PK) and/or pharmacodynamic (PD) differences of the artemisinin derivatives, PK/PD features of the non-artemisinin companions, or contributions from both. The longer duration of protection against reinfection provided by DP is due to the long elimination half-life of the partner drug, but further characterization of its relative benefit in high-transmission settings compared to AL is needed to inform malaria drug policy. The investigators are conducting a single-center randomized controlled clinical trial comparing the efficacies of AL and DP for gametocyte clearance and post-treatment chemoprotection among 6- to 59-month-old children with uncomplicated falciparum malaria in a high malaria transmission area of northern Zambia. Children with microscopy-confirmed Plasmodium falciparum monoinfection will be admitted for 72 hours for directly observed therapy with either AL or DP and serial sampling for parasite clearance and multi-dose PK measurements. Twenty children from each arm will be recruited to an intensive PK subgroup. Participants will be followed for 9 weeks for outcome assessment according to World Health Organization-defined clinical endpoints and to measure clearance of the long-acting partner drugs. Parasite genotyping will be done to distinguish recrudescence from reinfection and query genetic markers of drug resistance. Participants will contribute fecal specimens to help investigate bidirectional associations between the intestinal microbiota and antimalarial drug pharmacokinetics, as well as enterotype association with risk of reinfection.
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 (Investigator, Outcomes Assessor)
盲法说明
Participants and clinical trial nurses and pharmacists will be aware of the treatment assignment.
入排标准
- 年龄范围
- 6 Months 至 59 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Weight ≥10 kg
- •Any indication for malaria diagnostic testing as determined by a treating provider (e.g., fever or history of fever)
- •P. falciparum parasitemia (by microscopy) of any density not meeting criteria for severe malaria
- •Ability to swallow oral medication
- •Ability and willingness of parents or guardians to comply with study protocol for the duration of the study and to comply with the study follow-up visit schedule
- •Residence within hospital catchment area
- •Signed informed consent obtained from a legal representative of the participant
排除标准
- •Complicated or severe falciparum malaria as defined by WHO criteria
- •Hemoglobin concentration < 7 g/dL
- •Use of any drug with antimalarial activity within the prior 4 weeks
- •History of hypersensitivity reaction or intolerance to AL or DP
- •Co-infection with Plasmodium spp. other than P. falciparum as determined by microscopy
- •Confirmed or suspected concurrent acute infection other than malaria (e.g. measles, acute lower respiratory tract infection)
- •Current therapy with QT interval-prolonging agents
- •Family history of sudden cardiac death or personal history of cardiac disease
- •Residence outside the study area, or plan to leave the study area
- •Residence in foster care or otherwise under government supervision
- •Previous enrollment in the study, or enrollment in any other investigational drug trial during the previous 30 days
- •Presence of any other condition or abnormality that in the opinion of the investigator would compromise the safety of the participant or the quality of the data
研究组 & 干预措施
Artemether-lumefantrine
Standard 6-dose regimen
干预措施: Artemether-lumefantrine (Drug)
Dihydroartemisinin-piperaquine
Standard 3-dose regimen
干预措施: Dihydroartemisinin-piperaquine (Drug)
结局指标
主要结局
Incidence of reinfection during the 9-week follow-up period
时间窗: 9 weeks
Primary measure of the post-treatment chemoprotective effect of the drugs
Area-under-the-curve (AUC) of the gametocyte concentration-time curve
时间窗: 72 hours
Primary gametocyte-related pharmacodynamic (PD) endpoint of the study
Treatment outcome
时间窗: 9 weeks
Defined according to World Health Organization (WHO) classification as adequate clinical and parasitological response, early treatment failure, late clinical failure, or late parasitological failure corrected by genotyping to distinguish reinfection from recrudescent infection.
次要结局
- Elimination half-life of the gametocyte concentration-time curve(72 hours up to 9 weeks for those with persistent gametocytemia)
- Elimination half-life of the asexual parasite concentration-time curve(72 hours)
- Change over time of the gametocyte sex ratio (female:male)(72 hours up to 9 weeks for those with persistent, emergent, or recurrent gametocytes)
- Allele frequency of genetic markers of parasite drug resistance in initial vs. recurrent parasites and fast vs. slow clearing parasites(9 weeks)
- Incidence of treatment-emergent adverse events (safety and tolerability)(9 weeks)