Optimizing Malaria Treatment for HIV-Malaria Co-Infected Individuals by Addressing Drug Interactions Between Artemether-Lumefantrine and Efavirenz; a Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 入组人数
- 888
- 试验地点
- 2
- 主要终点
- Measure of malaria treatment outcome adjusted by genotyping and classified as reinfection or recrudescence.
研究概览
简要总结
Optimal is a Randomized clinical trial to optimize treatment of malaria in HIV -malaria co infected patients. It has been demonstrated that, when the antimalarial drug Artemether Lumefantrine is co administered with Efavirenz based ART in HIV-malaria co-infected individuals, sub therapeutic levels of the drug are achieved hence resulting in poor malaria treatment outcomes.
The study then hypothesizes that, : HIV-malaria co-infected individuals receiving efavirenz-based ART plus a double-dose or 5-day course of artemether-lumefantrine will achieve higher and adequate artemether-lumefantrine serum concentrations with adequate 42-day treatment outcomes compared to individuals with HIV-malaria co-infection receiving efavirenz-based ART plus a standard-dose of artemether-lumefantrine.
详细描述
Malaria and HIV have significant interactions at various levels. The geographical and epidemiological overlap increases risk for co-infection and co-treatment. The immune suppression due to HIV increases malaria incidence, severity and risk for poor treatment outcomes including mortality and adverse pregnancy outcomes such as anemia and low birth weight. Malaria infection increases HIV viral replication. Both malaria and HIV are treated with combination therapy to enhance treatment outcomes and reduce risk for development of resistance, consequently creating potential for drug-drug interactions (DDIs) when the two diseases are treated concomitantly. Previous studies demonstrated significant reduction in systemic exposure to Artemether, its metabolite dihydroartemisinin, and the long acting partner drug lumefantrine when the ACT artemether-lumefantrine was co-administered with efavirenz-based ART to HIV-malaria co-infected individuals.
Exposure to sub therapeutic antimalarial drug concentrations poses a risk for poor malaria treatment outcomes such as prolonged morbidity, anemia, death and poor birth outcomes for pregnant women plus increased economic costs and risk for drug resistance. There are currently limited drug options available for both malaria and HIV treatment especially in sub-Saharan Africa, thus the need to protect drug effectiveness. There are very scanty data on effects of drug interactions on malaria clinical outcomes, and such studies would be unethical currently. Despite these gaps, co-administration of antimalarial and antiretroviral drugs occurs with no guidance on therapeutic interventions to overcome these deleterious effects. Data are therefore urgently needed to optimize treatment of malaria for HIV-malaria co-infected individuals.
General Objective: To utilize innovative interventions to overcome drug interactions between artemether-lumefantrine and efavirenz to guide malaria treatment for individuals co-infected with HIV and malaria.
Specific objectives:
Objectives
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 (Investigator)
盲法说明
study physicians and laboratory technicians will be blinded to treatment group assignments.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent
- •Willing and able to comply with study treatment and procedures
- •Age above 18 years
- •Confirmed HIV positive and receiving efavirenz or dolutegravir based ART for objectives 3 and 4
- •Confirmed Malaria blood film positive without evidence for severe malaria for objectives 3 and 4
- •Confirmed Malaria blood film negative for objectives 1 and 2
排除标准
- •Serum alanine transaminase levels above 3x upper limit of normal
- •Serum creatinine levels above 2x upper limit of normal
- •Use of known inducers/inhibitors of CYP or glucuronyl transferase UGT1A1 within past 2 months (e.g. anticonvulsants, TB medications, HIV agents for prophylaxis, azole antifungals)
- •Pregnant women or female subjects who are unwilling to use a suitable contraceptive method for the duration of the study (condom, diaphragm, IUD or contraceptive implant)
- •Likely to be poorly adherent based on clinician's medical judgement
- •Known to be current injection drug user
- •Administration of any additional antimalarial drugs that are not study drugs within 24 hours before study enrollment and during the course of the study.
- •Presence of any non-malarial febrile illness which may interfere with the classification of malaria treatment outcome
- •Movement away from the study area interfering with follow-up assessment
- •Patients with contraindications to taking the study drugs
- •Evidence of QT prolongation on ECG (rate adjusted QT interval>45ms (men (or >470ms for women
研究组 & 干预措施
Standard dose of Artemether lumefantrine
Dose comparison-concurrent control In this arm, Participants receiving Efavirenz400mg based ART will be randomized to standard dose Artemether Lumefantrine when treating uncomplicated malaria in HIV-malaria co-infected participants
干预措施: Artemether-lumefantrine (Drug)
Double dose Artemether lumefantrine
Dose comparison concurrent control In this arm, Participants receiving Efavirenz based ART will be randomized to double dose Artemether Lumefantrine when treating uncomplicated malaria in HIV-malaria co-infected participants
干预措施: Artemether-lumefantrine (Drug)
5 day course of Artemether lumefantrine
Dose comparison concurrent control In this arm, Participants receiving Efavirenz based ART will be randomized to 5 day course of Artemether Lumefantrine as opposed to the standard 3day course when treating uncomplicated malaria in HIV-malaria co-infected participants
干预措施: Artemether-lumefantrine (Drug)
结局指标
主要结局
Measure of malaria treatment outcome adjusted by genotyping and classified as reinfection or recrudescence.
时间窗: Day 42
The Primary outcome measure will be the malaria treatment outcome adjusted by genotyping and classified as reinfection or recrudescence. Treatment outcomes will be classified on the basis of an assessment of the parasitological and clinical outcomes of antimalarial treatment according to the latest WHO guidelines. Thus, all patients will be classified as having early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response. Clinical Treatment outcomes will be assessed according to WHO criteria as; early treatment failure and late treatment failure. Parasitological treatment outcomes will be classified as late parasitological failure and adequate clinical and parasitological response.
次要结局
- Measuring level of Hemoglobin(Hemoglobin will be measured from on follow-up days; 7, 14, 21 and 28.)
- Change in Clearance [Cl/F] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)(over 120hours)
- Change Maximum concentration [Cmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine(over 120hours)
- Change in Area under the time-concentration curve [AUC] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine(over 120hours)
- Change in Time to maximum concentration [Tmax] of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)(over 120hours)
- Change in Trough concentration [Ctrough]) of the antimalarials (Artemether, dihydroartemisinin [DHA], lumefantrin and desbutylumefantrine)(over 120hours)
- Prolongation of the QT interval(Over 35days)
- Change in the level on the liver enzymes ALT and ALP(Over 35days)
- Change in creatinine and urea levels(Over 35days)