Clinical trial NCT02640495: Artemisinin Resistance In Malaria Treated With IV Artesunate
Official title: 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)
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Malaria
Keywords: Treatment Efficacy
drug resistance
Artemisinin
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
name: Oxford University Clinical Research Unit, Vietnam
First posted: 2015-12-29
Enrollment: 0
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.

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.

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

Primary outcomes:
measure: Absolute reduction of lactate
timeFrame: 12 hours
Secondary outcomes:
measure: Time needed until a plasma lactate concentration <2 mmol/L
timeFrame: 42 days
measure: Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
timeFrame: 12 hours
measure: Base excess clearance after 12 hours
timeFrame: 42 days
measure: Time until a base excess concentration ≥ minus 2 mmol/L
timeFrame: 42 days
measure: Time to resuming the ability to sit, eat, drink, stand unsupported and walk
timeFrame: 42 days
measure: The parasite clearance half-life
timeFrame: 48 hours
measure: The parasite clearance ratios at H28 and H48 compared to parasite count on admission
timeFrame: 48 hours
measure: The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
timeFrame: 7 days
measure: Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
timeFrame: H0
measure: Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
timeFrame: H6
measure: Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
timeFrame: H12
measure: Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
timeFrame: H48
measure: Time until resolution of fever
timeFrame: 14 days
measure: Proportion of patients developing new malaria
timeFrame: 42 days
measure: Proportion of patients developing new neurological signs assessed by neurological examination during hospitalization
timeFrame: 42 days
measure: Prevalence of neurological sequelae assessed by neurological examination at discharge
timeFrame: 42 days
measure: Prevalence of neurological sequelae assessed by neurological examination at day 7
timeFrame: 7 days
measure: Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
timeFrame: 14 days
measure: Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
timeFrame: 28 days
measure: Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
timeFrame: 42 days
measure: Severity of neurological sequelae assessed by neurological examination at discharge
timeFrame: 42 days
measure: Severity of neurological sequelae assessed by neurological examination at day 7
timeFrame: 7 days
measure: Severity of neurological sequelae assessed by neurological examination at day 14
timeFrame: 14 days
measure: Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
timeFrame: 28 days
measure: Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
timeFrame: 42 days
measure: Proportion treated with quinine
timeFrame: 42 days
measure: In hospital mortality
timeFrame: 42 days
measure: Day 7, 14 hemoglobin or hematocrit levels
timeFrame: 42 days
measure: Creatinine levels daily
timeFrame: 42 days
measure: Bilirubin, Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase levels daily
timeFrame: 42 days
measure: Plasma biomarkers of severe (artemisinin resistant) malaria
timeFrame: 42 days
measure: outcome of pregnancy during hospitalization
timeFrame: 42 days
measure: Time until discharge
timeFrame: 42 days
Other outcomes:
Locations:
Study officials:
affiliation: Mahidol Oxford Research Unit (MORU)
name: Prof. Arjen M Dondorp, MD
role: PRINCIPAL_INVESTIGATOR
References: