Clinical trial NCT02451904: Severe and Cerebral Malaria Investigated Through Host Metabolomics
Official title: Microvascular and Metabolic Dysregulation in the Pathogenesis of Severe and Cerebral Malaria Investigated Through Host Metabolomics
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Severe Malaria
Keywords: Pathogenesis
Microvascular function
Metabolic dysregulation
Metabolomics
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Chittagong Medical College and Hospital
First posted: 2015-05-22
Enrollment: 840
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: In total, up to 840 patients may be enrolled in this study.

Brief summary: * The aim is to describe disease mechanisms of severe and cerebral malaria and identify new targets for adjunctive therapies.
* Despite treatment between 10-30% of patients with severe malaria die.
* Metabolic acidosis and cerebral malaria are major complications associated with mortality across all age groups. Still, their underlying pathogenesis remains incompletely understood.
* Using a metabolomics approach, this study aims to characterise the spectrum of acids accumulating during acidosis, and investigate patterns of metabolic dysregulation associated with coma and seizures.


Eligibility criteria: Severe/Cerebral Malaria:

* Any P. falciparum parasitaemia detected by asexual stages on a peripheral blood-slide or a positive rapid diagnostic test in combination with one or more Modified WHO Criteria for Severe Malaria (Hien et al, 1996)
* \< 24 hours after treatment commencement with either parenteral artemisinin or quinine
* Age \> 12 years
* Full informed written consent obtained

Uncomplicated malaria:

* Any level of Plasmodium parasitaemia, detected by asexual stages on a peripheral blood-slide or a positive rapid diagnostic test without any of the complications of severe malaria stated above.
* Age \> 12 years
* Full informed written consent obtained

Sepsis:

* Clinical signs of infection in combination with any two of the following signs:

  1. Heart rate \> 90 beats per minute;
  2. Respiratory rate \> 20 breaths per minute, a PaCO2 of \< 32 mmHg, or the use of mechanical ventilation for an acute respiratory process;
  3. Tympanic temperature \> 38°C or \< 36 °C;
  4. White-cell count of \> 12x109/L or \< 4x109/L, or a differential count showing 10% immature neutrophils ;
* Negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria
* \[As bacterial culture is not routinely available at the study site, positivity of cultures is not required\]
* Age \> 12 years
* Full informed written consent obtained

Acidosis:

* Clinical suspicion of metabolic acidosis in combination with any of the following:

  1. Peripheral venous bicarbonate \< 15 mmol/L
  2. Peripheral venous base excess \< -3 mmol/L
* Negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria; and not meeting any of the inclusion criteria for sepsis as stated above.
* Age \> 12 years
* Full informed written consent obtained

Encephalitis:

* GCS \< 11/15
* Documented fever \> 38°C
* Onset of symptoms \< 2 weeks, with an indication a lumbar puncture as part of the diagnostic work up
* Negative peripheral blood slide for any stages of malaria parasites or a negative rapid diagnostic test for falciparum and vivax malaria
* Age \> 12 years
* Full informed written consent obtained

Healthy volunteers:

* No chronic or acute disease
* No fever in the past 2 weeks
* Age \> 16 years
* Full informed written consent obtained

Exclusion Criteria:

* Known pre-existing chronic medical conditions including advanced hepatic disease.

Primary outcomes:
measure: Characterisation of patterns of metabolic dysregulation in severe malaria
timeFrame: 4-6 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Chittagong
country: Bangladesh
facility: Chittagong Medical College Hospital (CMCH)
Study officials:
affiliation: Mahidol Oxford Tropical Medicine Research Unit
name: Prof. Arjen M. Dondorp, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dondorp A, Nosten F, Stepniewska K, Day N, White N; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005 Aug 27-Sep 2;366(9487):717-25. doi: 10.1016/S0140-6736(05)67176-0.
citation: Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ; AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 13;376(9753):1647-57. doi: 10.1016/S0140-6736(10)61924-1. Epub 2010 Nov 7.
citation: Leopold SJ, Ghose A, Allman EL, Kingston HWF, Hossain A, Dutta AK, Plewes K, Chotivanich K, Day NPJ, Tarning J, Winterberg M, White NJ, Llinas M, Dondorp AM. Identifying the Components of Acidosis in Patients With Severe Plasmodium falciparum Malaria Using Metabolomics. J Infect Dis. 2019 May 5;219(11):1766-1776. doi: 10.1093/infdis/jiy727.