Artemisinin Resistance In Malaria Treated With IV Artesunate

NCT ID: NCT02640495

Last Updated: 2018-08-22

Basic Information

• Recruitment Status: WITHDRAWN
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-10-31
• Study Completion Date: 2017-12-31

Brief Summary

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.

Detailed Description

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.

Conditions

Malaria

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

Study subjects

Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.

Intravenous Artesunate as part of standard medical practice

Intervention Type: DRUG

Intravenous Artesunate 2.4 mg/kg

Interventions

Intravenous Artesunate as part of standard medical practice

Intravenous Artesunate 2.4 mg/kg

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 6 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mahidol Oxford Tropical Medicine Research Unit

OTHER

Sponsor Role: collaborator

Oxford University Clinical Research Unit, Vietnam

OTHER

Sponsor Role: collaborator

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Prof. Arjen M Dondorp, MD

Role: PRINCIPAL_INVESTIGATOR

Mahidol Oxford Research Unit (MORU)

Other Identifiers

BAKMAL1504

Identifier Type: -

Identifier Source: org_study_id