Artemisinin Resistance In Malaria Treated With IV Artesunate
Artemisinin Resistance In Malaria Treated With IV Artesunate
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.
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.
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