Clinical trial NCT03217851: Prevalence Survey of Antimalarial Drug Resistance Markers
Official title: Prevalence Survey of Plasmodium Falciparum Antimalarial Drug Resistance Markers in Greater Mekong Subregion
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Malaria
Keywords: Plasmodium falciparum
Prevalence Survey
Antimalarial Drug
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol University
name: Worldwide Antimalarial Resistance Network
name: Mahidol Oxford Tropical Medicine Research Unit
name: Myanmar Oxford Clinical Research Unit
name: Shoklo Malaria Research Unit
name: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit
name: Oxford University Clinical Research Unit, Vietnam
name: Cambodia Oxford Medical Research Unit
First posted: 2017-07-14
Enrollment: 4000
Sex: ALL
Minimum age (years): 6
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients age 6 months - 75 years presenting at study site with confirmed P. falciparum infection

Brief summary: Study is cross-sectional and observational with one-time dried-blood spot sample collection from persons with laboratory-confirmed uncomplicated Plasmodium falciparum malaria (mixed or monoinfection). Samples will be analysed for the presence of molecular markers of resistance to ACT partner drugs (gene amplifications and/or other mutations in pfmdr1, gene amplifications of pfpm2, and additional mutations which may be identified during the course of the trial) in the first instance. Testing to detect additional markers of antimalarial drug resistance will also be performed where feasible. Prevalence of mutations will be summarized and mapped to provide intelligence on antimalarial drug resistance in the region of interest.

Detailed description: Malaria Malaria is caused by a mosquito-borne, protozoan parasite belonging to the genus Plasmodium. Of the five species of Plasmodium that infect humans, Plasmodium falciparum is the most deadly and is responsible for the majority of malaria disease and death. Every year, falciparum malaria causes disease in hundreds of millions of people living in the tropics and subtropics, killing a million or more according to some estimates. The vast majority of these deaths occur in sub-Saharan Africa, mostly among young children and infants. When treated with effective antimalarial drugs, malaria can be cured completely.

Antimalarial drug resistance The emergence in Southeast Asia and the subsequent global spread of drug resistant malaria was a major factor contributing to the failure of the first global malaria eradication campaign in the mid-20th century (1). The widespread implementation of highly effective artemisinin-based combination therapy (ACT) for malaria has contributed to significant gains in global control and elimination efforts and has brought malaria eradication back on the agenda, 40 years after the first global malaria eradication campaign was abandoned (2). However the gains seen in the past decade are now at risk as parasite resistance to artemisinin compounds has been confirmed in Southeast Asia and threatens Africa once again (3-8). In the absence of effective vaccines, it is critical to prolong the usable life of antimalarial drugs by judicious implementation of treatment strategies.

Primary Objective To measure prevalence of established and candidate molecular markers of drug resistant malaria in Greater Mekong Subregion

Secondary Objective To map the geographical and temporal changes in prevalence of molecular markers of antimalarial drug resistance in Greater Mekong Subregion

Funder: EXPERTISE FRANCE Grant reference number: Expertise France reference 15SANIN211

Eligibility criteria: Inclusion Criteria:

* Patients (6 months - 75 years) with confirmed uncomplicated P. falciparum infection
* Written informed consent obtained (by parents/guardian in case of children less than 18 years old)

Exclusion Criteria:

Patients presenting signs of severe malaria\* will be excluded from the survey to prevent any delay in the management of the patient.

\*Guideline for the treatment of Malaria-3rd edition, WHO (27) Severe falciparum malaria is 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.

* Impaired consciousness: A Glasgow comma score \< 11 in adults or Blantyre coma score \< 3 in children
* Prostration: Generalized weakness so that the person is unable to sit, stand or walk without assistance.
* Multiple convulsions: More than two episodes within 24 h
* Acidosis: A base deficit of \> 8 mEq/L or, if not available a plasma bicarbonate level of \< 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured breathing).
* Hypoglycaemia: Blood or plasma glucose \< 2.2 mmol/L (\<40 mg/dL)
* Severe malarial anaemia: Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% in children \< 12 years of age (\< 7 g/dL and \< 20%, respectively, in adults) with a parasite count \> 10,000/µL
* Renal impairment: Plasma or serum creatinine \> 265 µmol/L (3 mg/dL) or blood urea \> 20 mmol/L
* Jaundice: Plasma or serum bilirubin \> 50 µmol/L (3 mg/dL) with a parasite count \> 100,000/ µL
* Pulmonary oedema: Radiologically confirmed or oxygen saturation \< 92% on room air with a respiratory rate \> 30/min, often with chest indrawing and crepitations on auscultation
* Significant bleeding: Including recurrent or prolonged bleeding from the nose, gums or venepuncture site; haematemesis or melaena
* Shock: Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure \< 70 mm Hg in children or \< 80 mm Hg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill)
* Hyperparasitaemia: P.falciparum parasitaemia \> 10%

Primary outcomes:
measure: Prevalence and geospatial trends of molecular markers, information to assist definition of treatment policies
timeFrame: 3 years
Secondary outcomes:
measure: Visualization and dissemination of molecular marker prevalence data to inform public health officials, researchers, policymakers and key stakeholders
timeFrame: 3 years
Other outcomes:
Locations:
city: Mae Sot
country: Thailand
facility: Shoklo Malaria Research Unit
state: Tak
Study officials:
affiliation: Shoklo Malaria Research Unit
name: Francois Nosten, Prof
role: STUDY_DIRECTOR
affiliation: Myanmar Oxford Clinical Research Unit
name: Frank Smithuis, Prof
role: STUDY_DIRECTOR
affiliation: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit
name: Mayfong Mayxay, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Oxford University Clinical Research Unit, Vietnam
name: Nguyen Thanh Thuy Nhien, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Mahidol Oxford Clinical Research Unit
name: Arjen M. Dondorp, PhD
role: PRINCIPAL_INVESTIGATOR
References: