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Artemisinin Resistance In Malaria Treated With IV Artesunate (ARIMTIA)

20 augustus 2018 bijgewerkt door: University of Oxford

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.

Studie Overzicht

Toestand

Ingetrokken

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

6 maanden en ouder (Kind, Volwassen, Oudere volwassene)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Bemonsteringsmethode

Niet-waarschijnlijkheidssteekproef

Studie Bevolking

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

Beschrijving

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

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / Cohort
Interventie / Behandeling
Study subjects
Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
Geneesmiddel: Intravenous Artesunate as part of standard medical practice
Intravenous Artesunate 2.4 mg/kg

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Absolute reduction of lactate
Tijdsspanne: 12 hours
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
12 hours

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Time needed until a plasma lactate concentration <2 mmol/L
Tijdsspanne: 42 days
42 days
Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 42 days
42 days
Time to resuming the ability to sit, eat, drink, stand unsupported and walk
Tijdsspanne: 42 days
42 days
The parasite clearance half-life
Tijdsspanne: 48 hours
48 hours
The parasite clearance ratios at H28 and H48 compared to parasite count on admission
Tijdsspanne: 48 hours
48 hours
The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
Tijdsspanne: 7 days
7 days
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
Tijdsspanne: H0
H0
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
Tijdsspanne: H6
H6
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
Tijdsspanne: H12
H12
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
Tijdsspanne: H48
H48
Time until resolution of fever
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 42 days
42 days
Prevalence of neurological sequelae assessed by neurological examination at discharge
Tijdsspanne: 42 days
42 days
Prevalence of neurological sequelae assessed by neurological examination at day 7
Tijdsspanne: 7 days
7 days
Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
Tijdsspanne: 14 days
14 days
Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Tijdsspanne: 28 days
28 days
Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Tijdsspanne: 42 days
42 days
Severity of neurological sequelae assessed by neurological examination at discharge
Tijdsspanne: 42 days
42 days
Severity of neurological sequelae assessed by neurological examination at day 7
Tijdsspanne: 7 days
7 days
Severity of neurological sequelae assessed by neurological examination at day 14
Tijdsspanne: 14 days
14 days
Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Tijdsspanne: 28 days
28 days
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Tijdsspanne: 42 days
42 days
Proportion treated with quinine
Tijdsspanne: 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
Tijdsspanne: 42 days
42 days
Day 7, 14 hemoglobin or hematocrit levels
Tijdsspanne: 42 days
and in addition at day 28 and 42 if abnormal at day 14 or day 28 respectively
42 days
Creatinine levels daily
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 42 days
42 days
outcome of pregnancy during hospitalization
Tijdsspanne: 42 days
If pregnant
42 days
Time until discharge
Tijdsspanne: 42 days
42 days

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

University of Oxford

Medewerkers

Oxford University Clinical Research Unit, Vietnam
Mahidol Oxford Tropical Medicine Research Unit

Onderzoekers

  • Hoofdonderzoeker: Prof. Arjen M Dondorp, MD, Mahidol Oxford Research Unit (MORU)

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

1 oktober 2015

Primaire voltooiing (Werkelijk)

1 december 2017

Studie voltooiing (Werkelijk)

1 december 2017

Studieregistratiedata

Eerst ingediend

16 november 2015

Eerst ingediend dat voldeed aan de QC-criteria

22 december 2015

Eerst geplaatst (Schatting)

29 december 2015

Updates van studierecords

Laatste update geplaatst (Werkelijk)

22 augustus 2018

Laatste update ingediend die voldeed aan QC-criteria

20 augustus 2018

Laatst geverifieerd

1 augustus 2018

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • BAKMAL1504

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