Extended Duration Artemether-lumefantrine Treatment for Malaria in Children
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 305
- 试验地点
- 2
- 主要终点
- AUC0-8h for Artemether
研究概览
简要总结
This project determines the pharmacokinetic/pharmacodynamic (PK/PD) of an extended artemether-lumefantrine (AL) dosing regimen in HIV-infected children on efavirenz (EFV)-based antiretroviral therapy (ART) that is designed to improve the PK exposure and treatment efficacy of this artemisinins-based combination therapy (ACT) regimen. Our overarching goal is to inform the best treatment guidelines for young children in Africa. HIV-infected and HIV-uninfected children were enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes.
详细描述
This is a prospective multi-site study to evaluate the PK/PD of extended duration AL in HIV-infected children on EFV-based ART and HIV-uninfected children not on ART. AL is the first-line treatment for malaria in Uganda. No change in standard of care treatment was made for the purposes of this study except for the extension of AL to 5-day dosing. This study enrolled a) HIV-infected children, and b) HIV-uninfected children. All participants may be enrolled through Tororo District Hospital (TDH) or Masafu General Hospital (MGH) in Busia, or other referral centers the area. we used a design where children were randomized to either 3-day or 5-day AL and then for subsequent episodes of malaria, should they occur. Conservatively, assuming each enrolled child participates for only a single episode of malaria, up to 60 (30 HIV-infected on 3-day and 30 HIV-infected on 5-day) and 100 (50 HIV-uninfected on 3-day and 50 HIV-uninfected on 5-day) subjects were enrolled for each of the intensive study groups. 16 (9 HIV-infected on 3-day and 7 HIV-infected on 5-day) and 120 (60 HIV-uninfected on 3-day and 60 HIV-uninfected on 5-day) subjects were enrolled for each of the population study groups. Enrollment of HIV-infected subjects for population PK study groups was not halted due to the lack of HIV-infected children in the study area. Comparisons of AL PK exposure were made among and between a) HIV-infected children with malaria receiving EFV-based ART and b) HIV-uninfected children who are not on ART. Comparisons were based on an intensive PK design for AL area under the concentration-time curve (AUC) estimations.
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
- 6 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1, All participants:
- •Residency within 60 km of the study clinics either at TDH or at MGH
- •Agreement to come to clinic for all follow-up clinical and PK evaluations
- •Provision of informed consent
- •Weight ≥6 kg
- •Presentation with uncomplicated falciparum malaria as indicated by positive smear for malaria parasites along with clinical evidence of infection (fever or history of fever in the past 24 hours)
- •Willingness to undergo intensive PK sampling and/or population PK sampling during episode(s) of malaria.
- •2 HIV-infected participants:
- •Confirmed HIV infection (positive rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
- •On stable EFV-based ART for at least 10 days prior to enrollment
- •Age 3 years to 18 years
- •3 HIV-uninfected participants:
- •Confirmed HIV negative test (negative rapid HIV test to be confirmed by Western Blot or HIV RNA after enrollment)
- •Age 6 months to 18 years
排除标准
- •History of significant comorbidities such as malignancy, active tuberculosis or other World Health Organization (WHO) stage 4 disease
- •Current infection with non-P. falciparum species
- •Receipt of any medications known to affect CYP450 metabolism (except ART) within 14 days of study enrollment (see 4.2.2)
- •Hemoglobin < 7.0 g/dL
- •For the population PK study, prior treatment for malaria within 14 days of enrollment
- •For the intensive PK study, prior treatment for malaria within 28 days of enrollment
- •Signs or evidence of complicated malaria, defined as unarousable coma or any two of the following symptoms: Recent febrile convulsions, altered consciousness, lethargy, unable to drink, unable to stand/sit due to weakness, severe anemia (Hb < 5.0 gm/dL), respiratory distress, jaundice (see Appendix D)
- •History of toxicity to AL
- •The following medications are disallowed within 3 weeks prior to receiving study drug:
- •Carbamazepine
- •Clarithromycin
- •Erythromycin (oral)
- •Ketoconazole
- •Phenobarbital
- •Phenytoin
- •Rifabutin
- •Halofantrine
- •Any other medication known to significantly affect CYP450 metabolism.
- •Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.
研究组 & 干预措施
HIV-infected 3-day AL
Standard 3-day twice daily (BID) regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-infected and stabilized on EFV-based ART.
干预措施: Artemether-lumefantrine (Drug)
HIV-infected 5-day AL
Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-infected and stabilized on EFV-based ART.
干预措施: Artemether-lumefantrine (Drug)
HIV-uninfected 3-day AL
Standard 3-day BID regimen of artemether-lumefantrine for uncomplicated malaria, given over 4 days (Study Days 0, 1, 2 and 3) so that sampling will begin in the morning of day 3. These participants are HIV-uninfected.
干预措施: Artemether-lumefantrine (Drug)
HIV-uninfected 5-day AL
Extended 5-day BID regimen of artemether-lumefantrine, given over 6 days (Study Days 0, 1, 2, 3, 4, and 5) so that sampling will begin in the morning of day 5. These participants are HIV-uninfected.
干预措施: Artemether-lumefantrine (Drug)
结局指标
主要结局
AUC0-8h for Artemether
时间窗: 0-8hr
Area under the plasma concentration versus time curve (AUC) from 0 to 8hr post last dose for artemether (ARM)
AUC0-21d
时间窗: Study day 0-day21
Area under the plasma concentration versus time curve (AUC) from time 0 to day 21 for lumefantrine
Recurrent Parasitemia Following Treatment by Day 42 (Recrudescence or New Infection)
时间窗: up to study day 42
Recurrent malaria determined by microscopy (thick blood smears), loop mediated isothermal amplification (LAMP), or rapid diagnostic test (RDT).
AUC0-8h for Dihydroartemisinin
时间窗: 0-8hr
Area under the plasma concentration versus time curve (AUC) from time 0 to 8hr post last dose for Dihydroartemisinin (DHA)
Cmax for Lumefantrine
时间窗: 0-21 days
Maximal concentration post last dose for lumefantrine
Cmax for Artemether
时间窗: 0-8hr
Maximal concentration post last dose for artemether
Cmax for Dihydroartemisinin
时间窗: 0-8hr
Maximal concentration post last dose for dihydroartimisinin (DHA)
次要结局
- Number of Participants With Serious Adverse Events(study day 0-42)