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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
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.
研究の種類
研究の種類
参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
サンプリング方法
調査対象母集団
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
グループ/コホートの数
コホートと介入
グループ/コホートグループ/コホート |
介入・治療介入・治療 |
|---|---|
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Study subjects
Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
|
Intravenous Artesunate 2.4 mg/kg
|
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Absolute reduction of lactate
時間枠：12 hours
|
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
|
12 hours
|
二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Time needed until a plasma lactate concentration <2 mmol/L
時間枠：42 days
|
42 days
|
|
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Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
時間枠：12 hours
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at 12 hours after initial treatment and coma recovery time defined as GCS>10 or BCS>3 and GCS=15 and BCS=5
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12 hours
|
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Base excess clearance after 12 hours
時間枠：42 days
|
Base excess clearance after 12 hours as proportion of the base excess at presentation
|
42 days
|
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Time until a base excess concentration ≥ minus 2 mmol/L
時間枠：42 days
|
42 days
|
|
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Time to resuming the ability to sit, eat, drink, stand unsupported and walk
時間枠：42 days
|
42 days
|
|
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The parasite clearance half-life
時間枠：48 hours
|
48 hours
|
|
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The parasite clearance ratios at H28 and H48 compared to parasite count on admission
時間枠：48 hours
|
48 hours
|
|
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The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
時間枠：7 days
|
7 days
|
|
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Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
時間枠：H0
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H0
|
|
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Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
時間枠：H6
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H6
|
|
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Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
時間枠：H12
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H12
|
|
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Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
時間枠：H48
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H48
|
|
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Time until resolution of fever
時間枠：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
時間枠：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
時間枠：42 days
|
42 days
|
|
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Prevalence of neurological sequelae assessed by neurological examination at discharge
時間枠：42 days
|
42 days
|
|
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Prevalence of neurological sequelae assessed by neurological examination at day 7
時間枠：7 days
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7 days
|
|
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Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
時間枠：14 days
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14 days
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|
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Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
時間枠：28 days
|
28 days
|
|
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Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
時間枠：42 days
|
42 days
|
|
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Severity of neurological sequelae assessed by neurological examination at discharge
時間枠：42 days
|
42 days
|
|
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Severity of neurological sequelae assessed by neurological examination at day 7
時間枠：7 days
|
7 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 14
時間枠：14 days
|
14 days
|
|
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Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
時間枠：28 days
|
28 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
時間枠：42 days
|
42 days
|
|
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Proportion treated with quinine
時間枠：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
時間枠：42 days
|
42 days
|
|
|
Day 7, 14 hemoglobin or hematocrit levels
時間枠：42 days
|
and in addition at day 28 and 42 if abnormal at day 14 or day 28 respectively
|
42 days
|
|
Creatinine levels daily
時間枠：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
時間枠：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
時間枠：42 days
|
42 days
|
|
|
outcome of pregnancy during hospitalization
時間枠：42 days
|
If pregnant
|
42 days
|
|
Time until discharge
時間枠：42 days
|
42 days
|
協力者と研究者
協力者
協力者
捜査官
捜査官
- 主任研究者：Prof. Arjen M Dondorp, MD、Mahidol Oxford Research Unit (MORU)
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (実際)
一次修了
研究の完了 (実際)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
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