Artemisinin Resistance In Malaria Treated With IV Artesunate (ARIMTIA)
A Multicenter, Prospective, Observational Study to Assess the Efficacy of Artesunate in Malaria Treated With Parenteral Artesunate in Areas With Artemisinin Resistance A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)
The spread of artemisinin resistant falciparum malaria presents new challenges to both the control and treatment of malaria. Loss of ring stage susceptibility to the artemisinins might jeopardize the use of parenteral artesunate as the first line drug for the treatment of severe falciparum malaria.
The purpose of this study is to assess the effect of artemisinin resistance (defined by a Kelch13 mutation with known functional significance) in P. falciparum malaria requiring parenteral artesunate treatment on lactate clearance parameters.
研究概览
详细说明
The investigators propose a multi-center observational study to assess the effect of artemisinin resistance (as defined by the presence of relevant Kelch13 mutations) on the efficacy of parenteral artesunate for the treatment of malaria, stratified for disease severity on admission.
The patients will receive the standard intravenous treatment for severe malaria (parenteral artesunate). Primary endpoints will be the plasma lactate concentration at 12 hours as a proportion of the plasma lactate at the start of treatment. Secondary endpoints will be improvement of Glasgow or Blantyre Coma Scores and other indicators of neurological recovery or deterioration, parasite clearance rates, time until resolution of fever, development of new severity or neurological signs under treatment, development of severe anemia, renal and hepatic injury, total duration of hospitalization , outcome of pregnancy in pregnant female patients, mortality rates and the necessity to treat with antibiotics, need for renal replacement therapy, mechanical ventilation, blood transfusion and rescue treatments.
On admission blood will be taken for the determination of genetic markers of antimalarial resistance (including Kelch13 mutations of known functional significance) and in vitro sensitivity tests to artemisinins and other antimalarials. Additional blood samples will be used for measuring plasma organic acid biomarkers of severe falciparum malaria measured by mass spectrometry. Difference in the kinetics of these acids will be an additional endpoint. Difference in the transcriptome of p. falciparum will be assessed by RNA measurements at baseline and 3 timepoints during treatment.
The proposed sites in Vietnam and Cambodia have been chosen based on the prevalence of artemisinin resistant falciparum malaria, incidence of severe malaria and local experience in participating in clinical trials.
Interim analysis:
To ensure timely recognition of the effect of artemisinin resistance on the outcome in malaria treated with parenteral artesunate, an interim analysis will be performed after the inclusion of 60 patients or one malaria transmission season (whatever comes first). An independent Data Safety Board will assess whether the difference in outcome between infections with artemisinin resistant versus sensitive strains warrants early termination and reporting of the study.
研究类型
参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
取样方法
研究人群
描述
Inclusion Criteria:
- Male or female, aged over 6 months old
Acute severe P. falciparum malaria or another indication to treat with IV artesunate. Defined as one or more of the following, occurring in the absence of an identified alternative cause, and in the presence of P. falciparum asexual parasitaemia:
- Prostration OR obtundation
- BCS<3 (preverbal children) or GCS<11 (adults)
- Convulsion in last 24 hours
- Suspected acidosis, manifesting as acidotic breathing
- Respiratory distress manifesting clinically (nasal flaring/indrawing) or oxygen saturation <92% or respiratory rate >30/min
- History of anuria
- Jaundice and/or hemoglobinuria
- Hemoglobin <7 g/dl or hematocrit <20%
- Significant bleeding including recurrent or prolonged bleeding from nose gums or venipuncture sites; hematemesis or melena
- Shock defined as systolic blood pressure <70 mm Hg (children) OR <80 mm Hg (adults)
- P. falciparum parasitaemia >10%
Indication for parenteral antimalarial treatment (as assessed by clinician) other than nausea and vomiting. These may include laboratory findings such as:
- Creatinine >2.5 mg/dL (>220uM/L) or blood urea >56mg/dL (>20 mM/L)
- Glucose <4.0 mmol/L (<72mg/dL)
- Bilirubin > 3 mg/dL (>50uM/L)
- Hemoglobin <7g/dL or Hematocrit <20%
- P. falciparum parasitaemia >4%
- Venous plasma lactate >5 mM, Base deficit of >8meq/L or bicarbonate <15mM
- Written informed consent or consent by locally accepted representative in the case of patients rendered incapable of providing consent due to illness
Exclusion Criteria:
- History of 2 or more doses of parenteral antimalarial treatment in the previous 24 hours
- History of allergy or known contraindication to artemisinins
学习计划
研究是如何设计的？
设计细节
队列和干预
团体/队列 |
干预/治疗 |
|---|---|
|
Study subjects
Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
|
Intravenous Artesunate 2.4 mg/kg
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Absolute reduction of lactate
大体时间：12 hours
|
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
|
12 hours
|
次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Time needed until a plasma lactate concentration <2 mmol/L
大体时间：42 days
|
42 days
|
|
|
Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
大体时间：12 hours
|
at 12 hours after initial treatment and coma recovery time defined as GCS>10 or BCS>3 and GCS=15 and BCS=5
|
12 hours
|
|
Base excess clearance after 12 hours
大体时间：42 days
|
Base excess clearance after 12 hours as proportion of the base excess at presentation
|
42 days
|
|
Time until a base excess concentration ≥ minus 2 mmol/L
大体时间：42 days
|
42 days
|
|
|
Time to resuming the ability to sit, eat, drink, stand unsupported and walk
大体时间：42 days
|
42 days
|
|
|
The parasite clearance half-life
大体时间：48 hours
|
48 hours
|
|
|
The parasite clearance ratios at H28 and H48 compared to parasite count on admission
大体时间：48 hours
|
48 hours
|
|
|
The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
大体时间：7 days
|
7 days
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
大体时间：H0
|
H0
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
大体时间：H6
|
H6
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
大体时间：H12
|
H12
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
大体时间：H48
|
H48
|
|
|
Time until resolution of fever
大体时间：14 days
|
(time until tympanic temperature first <37.5 Celsius and below 37.5C for 24 h)
|
14 days
|
|
Proportion of patients developing new malaria
大体时间：42 days
|
Proportion of patients developing new malaria severity signs as defined in the 2014 WHO severe malaria guidelines
|
42 days
|
|
Proportion of patients developing new neurological signs assessed by neurological examination during hospitalization
大体时间：42 days
|
42 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at discharge
大体时间：42 days
|
42 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 7
大体时间：7 days
|
7 days
|
|
|
Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
大体时间：14 days
|
14 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
大体时间：28 days
|
28 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
大体时间：42 days
|
42 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at discharge
大体时间：42 days
|
42 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 7
大体时间：7 days
|
7 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 14
大体时间：14 days
|
14 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
大体时间：28 days
|
28 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
大体时间：42 days
|
42 days
|
|
|
Proportion treated with quinine
大体时间：42 days
|
as a rescue treatment, antibiotics, blood products, anticonvulsants, renal replacement therapy, mechanical ventilation therapy, vasopressive drugs and oxygen therapy
|
42 days
|
|
In hospital mortality
大体时间：42 days
|
42 days
|
|
|
Day 7, 14 hemoglobin or hematocrit levels
大体时间：42 days
|
and in addition at day 28 and 42 if abnormal at day 14 or day 28 respectively
|
42 days
|
|
Creatinine levels daily
大体时间：42 days
|
during the first four days and thereafter on day 7 and 14 and in addition on day 28 and 42 if abnormal on day 14 or day 28 respectively
|
42 days
|
|
Bilirubin, Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase levels daily
大体时间：42 days
|
during the first four days and thereafter on day 7, 14 and in addition on day 28 and 42 if abnormal on day 14 or 28 respectively
|
42 days
|
|
Plasma biomarkers of severe (artemisinin resistant) malaria
大体时间：42 days
|
42 days
|
|
|
outcome of pregnancy during hospitalization
大体时间：42 days
|
If pregnant
|
42 days
|
|
Time until discharge
大体时间：42 days
|
42 days
|
合作者和调查者
合作者
调查人员
- 首席研究员：Prof. Arjen M Dondorp, MD、Mahidol Oxford Research Unit (MORU)
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (实际的)
研究完成 (实际的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (估计)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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