MalariaARIMTIANCT02640495
Artemisinin Resistance In Malaria Treated With IV Artesunate
An observational study of Malaria, run by University of Oxford.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 months and older
- Conditions the study is for
- Malaria
- What is being tested?
- Intravenous Artesunate as part of standard medical practice
- Type of treatment
- Injection or infusion
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Oct 2015to Dec 2017
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
Who may be able to join
- 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
Show all 21Show fewer
- 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
Who cannot join
- History of 2 or more doses of parenteral antimalarial treatment in the previous 24 hours
- History of allergy or known contraindication to artemisinins
About this study
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)
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.
Read the 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
- Being tested
- Intravenous Artesunate as part of standard medical practice
- Keywords
- Treatment Efficacy, drug resistance, Artemisinin
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intravenous Artesunate as part of standard medical practiceDrug
Intravenous Artesunate 2.4 mg/kg
| Study group | Role | What they receive |
|---|---|---|
| Study subjects | Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate. Receives: Drug: Intravenous Artesunate as part of standard medical practice |
What is being measured
The primary outcome is the main question the study is designed to answer.
Absolute reduction of lactate
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
Measured: 12 hours
Secondary outcomes (33)
Time needed until a plasma lactate concentration <2 mmol/L
Measured: 42 days
Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
at 12 hours after initial treatment and coma recovery time defined as GCS>10 or BCS>3 and GCS=15 and BCS=5
Measured: 12 hours
Base excess clearance after 12 hours
Base excess clearance after 12 hours as proportion of the base excess at presentation
Measured: 42 days
Time until a base excess concentration ≥ minus 2 mmol/L
Measured: 42 days
Time to resuming the ability to sit, eat, drink, stand unsupported and walk
Measured: 42 days
The parasite clearance half-life
Measured: 48 hours
The parasite clearance ratios at H28 and H48 compared to parasite count on admission
Measured: 48 hours
The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
Measured: 7 days
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
Measured: H0
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
Measured: H6
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
Measured: H12
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
Measured: H48
Time until resolution of fever
(time until tympanic temperature first <37.5 Celsius and below 37.5C for 24 h)
Measured: 14 days
Proportion of patients developing new malaria
Proportion of patients developing new malaria severity signs as defined in the 2014 WHO severe malaria guidelines
Measured: 42 days
Proportion of patients developing new neurological signs assessed by neurological examination during hospitalization
Measured: 42 days
Prevalence of neurological sequelae assessed by neurological examination at discharge
Measured: 42 days
Prevalence of neurological sequelae assessed by neurological examination at day 7
Measured: 7 days
Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
Measured: 14 days
Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Measured: 28 days
Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Measured: 42 days
Severity of neurological sequelae assessed by neurological examination at discharge
Measured: 42 days
Severity of neurological sequelae assessed by neurological examination at day 7
Measured: 7 days
Severity of neurological sequelae assessed by neurological examination at day 14
Measured: 14 days
Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Measured: 28 days
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Measured: 42 days
Proportion treated with quinine
as a rescue treatment, antibiotics, blood products, anticonvulsants, renal replacement therapy, mechanical ventilation therapy, vasopressive drugs and oxygen therapy
Measured: 42 days
In hospital mortality
Measured: 42 days
Day 7, 14 hemoglobin or hematocrit levels
and in addition at day 28 and 42 if abnormal at day 14 or day 28 respectively
Measured: 42 days
Creatinine levels daily
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
Measured: 42 days
Bilirubin, Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase levels daily
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
Measured: 42 days
Plasma biomarkers of severe (artemisinin resistant) malaria
Measured: 42 days
outcome of pregnancy during hospitalization
If pregnant
Measured: 42 days
Time until discharge
Measured: 42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Dec 2015 (estimated)
- Study startOct 2015
- Primary completionDec 2017
- Study completionDec 2017
Why it stopped: Due to the relative low incidence of severe malaria in Southeast Asia.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MalariaStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Mahidol Oxford Tropical Medicine Research Unit, Oxford University Clinical Research Unit, Vietnam
- Responsible party
- Sponsor
- Investigators
- Prof. Arjen M Dondorp, MD, Principal investigator, Mahidol Oxford Research Unit (MORU)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02640495
- Sponsor's protocol ID
- BAKMAL1504
- Acronym
- ARIMTIA
- Status last verified
- Aug 2018
- First submitted
- 16 Nov 2015
- Last updated
- 22 Aug 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02640495
- Acronym / sponsor ID
- ARIMTIA / BAKMAL1504
- Conditions
- Malaria
- Keywords
- Treatment Efficacy, drug resistance, Artemisinin
- Study type
- Observational
- Recruitment status
- WithdrawnReason stopped: Due to the relative low incidence of severe malaria in Southeast Asia.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- Mahidol Oxford Tropical Medicine Research Unit, Oxford University Clinical Research Unit, Vietnam
- Study start
- Oct 2015 (actual)
- Primary completion
- Dec 2017 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 29 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Study subjects | – | Drug: Intravenous Artesunate as part of standard medical practicePatients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate. |
Who may qualify
- Ages
- 6 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients admitted with malaria, caused by Plasmodium falciparum, treated with parenteral artesunate.
Key inclusion criteria (21 listed)
- 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:
Key exclusion criteria (2 listed)
- History of 2 or more doses of parenteral antimalarial treatment in the previous 24 hours
- History of allergy or known contraindication to artemisinins
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intravenous Artesunate as part of standard medical practiceIntravenous Artesunate 2.4 mg/kg | Drug | Study subjects |
Primary outcome
Absolute reduction of lactate
Time frame: 12 hours
Absolute reduction of lactate at 12 hours after the first artesunate treat-ment compared to baseline.
33 secondary outcomes
Time needed until a plasma lactate concentration <2 mmol/L
Time frame: 42 days
Change in Glasgow Coma Score (GCS) or Blantyre Coma Score (BCS)
Time frame: 12 hours
Base excess clearance after 12 hours
Time frame: 42 days
Time until a base excess concentration ≥ minus 2 mmol/L
Time frame: 42 days
Time to resuming the ability to sit, eat, drink, stand unsupported and walk
Time frame: 42 days
The parasite clearance half-life
Time frame: 48 hours
The parasite clearance ratios at H28 and H48 compared to parasite count on admission
Time frame: 48 hours
The parasite clearance time for parasite count to fall to 50%, 90% and 99% of initial parasite density
Time frame: 7 days
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at baseline
Time frame: H0
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H6
Time frame: H6
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H12
Time frame: H12
Differences in transcriptome patterns between artemisinin resistant parasites and artemisinin sensitive parasites at H48
Time frame: H48
Time until resolution of fever
Time frame: 14 days
Proportion of patients developing new malaria
Time frame: 42 days
Proportion of patients developing new neurological signs assessed by neurological examination during hospitalization
Time frame: 42 days
Prevalence of neurological sequelae assessed by neurological examination at discharge
Time frame: 42 days
Prevalence of neurological sequelae assessed by neurological examination at day 7
Time frame: 7 days
Prevalence of neurological sequelae assessed by neurologicalexamination at day 14
Time frame: 14 days
Prevalence of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Time frame: 28 days
Prevalence of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Time frame: 42 days
Severity of neurological sequelae assessed by neurological examination at discharge
Time frame: 42 days
Severity of neurological sequelae assessed by neurological examination at day 7
Time frame: 7 days
Severity of neurological sequelae assessed by neurological examination at day 14
Time frame: 14 days
Severity of neurological sequelae assessed by neurological examination at day 28 if day 14 is abnormal
Time frame: 28 days
Severity of neurological sequelae assessed by neurological examination at day 42 if day 28 is abnormal
Time frame: 42 days
Proportion treated with quinine
Time frame: 42 days
In hospital mortality
Time frame: 42 days
Day 7, 14 hemoglobin or hematocrit levels
Time frame: 42 days
Creatinine levels daily
Time frame: 42 days
Bilirubin, Alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase levels daily
Time frame: 42 days
Plasma biomarkers of severe (artemisinin resistant) malaria
Time frame: 42 days
outcome of pregnancy during hospitalization
Time frame: 42 days
Time until discharge
Time frame: 42 days
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Prof. Arjen M Dondorp, MD principal investigator
Mahidol Oxford Research Unit (MORU)
Questions about this trial
What is this clinical trial studying?
An observational study of Malaria, run by University of Oxford.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 22 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Absolute reduction of lactate (time frame: 12 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2018.