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Study of resistance to artesunate of malaria parasite
ISRCTN ISRCTN64835265
DOI 10.1186/ISRCTN64835265
ClinicalTrials.gov identifier
EudraCT number
Public title Study of resistance to artesunate of malaria parasite
Scientific title Clinical investigation of in-vivo and in vitro susceptibility of P. falciparum to artesunate in Western Thailand
Acronym N/A
Serial number at source Version 12 Dec 2007
Study hypothesis Has the resistance to artemisinins in P. falciparum emerged in Thailand?
Lay summary Not provided at time of registration
Ethics approval Ethics approval received from Mahidol University Ethical Committee on the 20th December 2007 (ref: MUTM 2007-130).
Study design Pharmacokinetic and dynamic study of artesunate in two randomly assigned treatment groups.
Countries of recruitment Thailand
Disease/condition/study domain Malaria/uncomplicated/resistance
Participants - inclusion criteria 1. 40 patients with uncomplicated falciparum malaria
2. Aged greater than or equal to 15 years, either sex
3. Symptomatic of malaria infection, i.e., history of fever or presence of fever greater than 37.5°C
4. Microscopic confirmation of asexual stages of P. falciparum with parasitaemia greater than 10,000/ml
5. Written informed consent to participate in trial
Participants - exclusion criteria 1. Pregnancy or lactation (urine test for beta-human chorionic gonadotropin [β-HCG] to be performed on any woman of child bearing age unless menstruating)
2. P. falciparum asexual stage parasitaemia greater than or equal to 4% red blood cells (175,000/µl)
3. History of treatment with antimalarials (except chloroquine [CQ] or sulfadoxine-pyrimethamine [SP]) in the previous 48 hours
4. Microscopy indicates a mixed infection
5. Signs or symptoms indicative of severe malaria:
5.1. Impaired consciousness (Glasgow Coma Scale [GCS] less than 15)
5.2. Bleeding disorder (severe nosebleed, bleeding gums, frank haematuria, bleeding from venepuncture sites)
5.3. Respiratory distress (deep breathing or respiratory rate [RR] greater than 30)
5.4. Shock (circulatory collapse with systolic blood pressure [SBP] less than 80 mmHg)
5.5. Hyperparasitaemia (see above)
5.6. Acidosis (bicarbonate [HCO3-] less than 15 mmol/L)
5.7. Renal insufficiency (creatinine greater than 3 mg/dL)
5.8. Severe jaundice (total bilirubin greater than 2.5 mg/dL)
5.9. Severe anaemia (haematocrit [Hct] less than 20% in adults or less than 15% in children)
5.10. Severe hypoglycaemia (glucose less than 40 mg/dL)
6. Known hypersensitivity to artemisinin derivatives or mefloquine
7. History of convulsions or neuropsychiatric disorder
8. History of splenectomy
Anticipated start date 01/01/2008
Anticipated end date 01/06/2008
Status of trial Completed
Patient information material Not available in web format, please use the contact details below to request a patient information sheet.
Target number of participants 40
Interventions Patients will be randomised in blocks of 10 to receive either:
1. Artesunate (Guilin Pharmaceutical Company, PRC) orally (po) 2 mg/kg/day for 7 days
2. Artesunate (Guilin Pharmaceutical Company, PRC) po 4 mg/kg/day for 3 days plus mefloquine 15 mg/kg on day 3 and 10 mg/kg on day 4

On enrolment a detailed history and full clinical examination will be performed and recorded on a standard Case Report Form (CRF). The patient will then be weighed. A Teflon® heparinised sampling catheter will be inserted in a forearm vein.

Baseline blood samples will be taken as described below. Part of the blood sample will be taken at baseline for immediate culture (for an in-vitro susceptibility test) and also storage of parasites (cryopreserved in liquid nitrogen), parasite deoxyribonucleic acid [DNA] and messenger ribonucleic acid [mRNA]. On admission 5 ml blood will be collected for parasite count (thin and thick films stained by Giemsa's method), and routine biochemistry (sodium, potassium, chloride, calcium, blood urea nitrogen, creatinine, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, glucose and total carbon dioxide) and haematology (haematocrit, haemoglobin, white blood cell count with differentiation, platelets). An additional 5 ml of blood will be collected in a sterile heparinised tube for parasite culture and cryopreservation, and 2 ml for assessment of drug levels (artesunate and mefloquine).

The total amount of blood taken for study purposes will be 12 ml on admission and about 10 to 20 ml during follow-up (dependent on the parasite clearance time; blood collection for parasitaemia during hospitalisation will stop when the patient is parasite negative).

Sampling (2 ml):
1. Parasite counts: 0, 4, 8, 12, 18, 24 hours then 6 hourly until parasite clearance
2. Drug levels: plasma samples will be taken. Most are fixed times but for artesunate there is a population PK component so random times within time-bins are proposed. In children capillary whole blood sampling for mefloquine may need to be substituted.

Patients will remain in hospital for 7 days or longer if parasites have not cleared. They will then be followed up to Day 63 and at each weekly visit will have a haematocrit and parasite count checked.
Primary outcome measure(s) A population based pharmacokinetic-pharmacodynamic modelling approach will be used to describe the antimalarial effect of artesunate in patients with acute falciparum malaria. The objective of the modelling exercise is to characterise the relationship between pharmacokinetic variables (areas under curve [AUC], Cmax) and parasite clearance measures (parasite clearance time [PCT], parasite reduction ratio [PRR]), completed with in vitro susceptibility and molecular markers of resistance.
Secondary outcome measure(s) Parasitological efficacy
Sources of funding The Wellcome Trust South-East Asia (SEA) Programme (Thailand)
Trial website
Publications 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19641202
Contact name Prof  Francois  Nosten
  Address Shoklo Malaria Research Unit (SMRU)
68/30 Baan Tung Road
  City/town Mae Sot
  Zip/Postcode 63110
  Country Thailand
  Tel +66 (0)55 545 021
  Fax +66 (0)55 545 020
  Email SMRU@tropmedres.ac
Sponsor University of Oxford (UK)
  Address Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)
Churchill Hospital
Old Road
Headington
  City/town Oxford
  Zip/Postcode OX3 7LJ
  Country United Kingdom
  Tel +44 (0)1865 857431
  Fax +44 (0)870 133 7250
  Email paul.hogben@ndm.ox.ac.uk
  Sponsor website: http://www.ccvtm.ox.ac.uk/
Date applied 22/01/2008
Last edited 21/03/2013
Date ISRCTN assigned 25/01/2008
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