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.
Přehled studie
Postavení
Podmínky
Intervence / Léčba
Detailní popis
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.
Typ studie
Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Metoda odběru vzorků
Studijní populace
Popis
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
Studijní plán
Jak je studie koncipována?
Detaily designu
Kohorty a intervence
Skupina / kohorta |
Intervence / Léčba |
|---|---|
|
Study subjects
Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
|
Intravenous Artesunate 2.4 mg/kg
|
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Absolute reduction of lactate
Časové okno: 12 hours
|
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
|
12 hours
|
Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
|
Time needed until a plasma lactate concentration <2 mmol/L
Časové okno: 42 days
|
42 days
|
|
|
Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
Časové okno: 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
Časové okno: 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
Časové okno: 42 days
|
42 days
|
|
|
Time to resuming the ability to sit, eat, drink, stand unsupported and walk
Časové okno: 42 days
|
42 days
|
|
|
The parasite clearance half-life
Časové okno: 48 hours
|
48 hours
|
|
|
The parasite clearance ratios at H28 and H48 compared to parasite count on admission
Časové okno: 48 hours
|
48 hours
|
|
|
The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
Časové okno: 7 days
|
7 days
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
Časové okno: H0
|
H0
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
Časové okno: H6
|
H6
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
Časové okno: H12
|
H12
|
|
|
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
Časové okno: H48
|
H48
|
|
|
Time until resolution of fever
Časové okno: 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
Časové okno: 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
Časové okno: 42 days
|
42 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at discharge
Časové okno: 42 days
|
42 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 7
Časové okno: 7 days
|
7 days
|
|
|
Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
Časové okno: 14 days
|
14 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Časové okno: 28 days
|
28 days
|
|
|
Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Časové okno: 42 days
|
42 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at discharge
Časové okno: 42 days
|
42 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 7
Časové okno: 7 days
|
7 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 14
Časové okno: 14 days
|
14 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Časové okno: 28 days
|
28 days
|
|
|
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Časové okno: 42 days
|
42 days
|
|
|
Proportion treated with quinine
Časové okno: 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
Časové okno: 42 days
|
42 days
|
|
|
Day 7, 14 hemoglobin or hematocrit levels
Časové okno: 42 days
|
and in addition at day 28 and 42 if abnormal at day 14 or day 28 respectively
|
42 days
|
|
Creatinine levels daily
Časové okno: 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
Časové okno: 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
Časové okno: 42 days
|
42 days
|
|
|
outcome of pregnancy during hospitalization
Časové okno: 42 days
|
If pregnant
|
42 days
|
|
Time until discharge
Časové okno: 42 days
|
42 days
|
Spolupracovníci a vyšetřovatelé
Sponzor
Spolupracovníci
Vyšetřovatelé
- Vrchní vyšetřovatel: Prof. Arjen M Dondorp, MD, Mahidol Oxford Research Unit (MORU)
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Aktuální)
Dokončení studie (Aktuální)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Odhad)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
Další identifikační čísla studie
- BAKMAL1504
Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .