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Artemisinin Resistance In Malaria Treated With IV Artesunate (ARIMTIA)

20. August 2018 aktualisiert von: 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.

Studienübersicht

Status

Zurückgezogen

Bedingungen

Intervention / Behandlung

Detaillierte Beschreibung

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.

Studientyp

Beobachtungs

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

6 Monate und älter (Kind, Erwachsene, Älterer Erwachsener)

Akzeptiert gesunde Freiwillige

Nein

Studienberechtigte Geschlechter

Alle

Probenahmeverfahren

Nicht-Wahrscheinlichkeitsprobe

Studienpopulation

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

Beschreibung

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

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

Kohorten und Interventionen

Gruppe / Kohorte
Intervention / Behandlung
Study subjects
Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
Arzneimittel: Intravenous Artesunate as part of standard medical practice
Intravenous Artesunate 2.4 mg/kg

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Absolute reduction of lactate
Zeitfenster: 12 hours
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
12 hours

Sekundäre Ergebnismessungen

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

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

University of Oxford

Mitarbeiter

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

Ermittler

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

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn (Tatsächlich)

1. Oktober 2015

Primärer Abschluss (Tatsächlich)

1. Dezember 2017

Studienabschluss (Tatsächlich)

1. Dezember 2017

Studienanmeldedaten

Zuerst eingereicht

16. November 2015

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

22. Dezember 2015

Zuerst gepostet (Schätzen)

29. Dezember 2015

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

22. August 2018

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

20. August 2018

Zuletzt verifiziert

1. August 2018

Mehr Informationen

Begriffe im Zusammenhang mit dieser Studie

Schlüsselwörter

Zusätzliche relevante MeSH-Bedingungen

Andere Studien-ID-Nummern

  • BAKMAL1504

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