Artemisone for the Treatment of Uncomplicated Falciparum Malaria in Western Cambodia
Artemisone for the Treatment of Uncomplicated Falciparum Malaria in Western Cambodia
It has now been demonstrated clearly that in Western Cambodia parasitological responses to
 artesunate and artemether containing treatment regimens for uncomplicated falciparum malaria
 are slower than elsewhere in the world. Median parasite clearance time (PCT) in patients
 treated with artesunate 4 mg/kg/day was 78 hours and with 2 mg/kg/day 82 hours, compared to
 54 and 48 hours, respectively, in Western Thailand; at 72hours peripheral blood parasitaemia
 was still detectable in 55% of patients in Western Cambodia, compared to 7.5% in Western
 Thailand. Although occasional poor responses to artesunate have been described previously the
 current reports suggest a consistent problem. These antimalarials are central to current
 treatment strategies, and so spread of parasites with reduced artemisinin susceptibility
 outside this area would be a disaster. A recent consensus meeting Pnomh Penh agreed that this
 should indeed be termed resistance, and represented a major threat to malaria control.
 Radical containment measures would be needed. This study aims to address whether a
 semi-synthetic or fully synthetic peroxide antimalarial would be more effective than
 artesunate and could therefore be used in Cambodia as part of the elimination strategy.
 Artemisone is a semisynthetic derivative of dihydroartemisinin, which importantly changes its
 tertiary structure. This drug has also shown promising efficacy for the treatment of
 uncomplicated falciparum malaria in phase II trials in Thailand and seems to be at least as
 efficacious as artesunate. No significant toxicity has been reported for artemisone and it is
 very well tolerated. If sensitivity for artemisone has remained intact in Western Cambodia,
 this will have important implications for the strategies available for containment of the
 threatening problem of artesunate resistance in Western Cambodia. It will also have important
 implications for further development of these drugs for the use in artemisinin combination
 therapies (ACTs).
This is a small detailed randomised open-label clinical trial comparing the efficacy of oral
 artemisone with oral artesunate in the treatment of uncomplicated falciparum malaria in
 Western Cambodia. A detailed pharmacokinetic-pharmacodynamic evaluation and in vitro
 sensitivity for the study drugs will be part of the assessments. The overall design and
 proposed conduct is very similar to the recently completed studies of high dose
 artesunate.Fever patients in the villages surrounding Pailin (or equivalent study site) in
 Western Cambodia will be screened with a PfHRP2-based malaria rapid test (Paracheck) by the
 village malaria workers. In case of a positive test result, the patient will be transported
 by the study team to the hospital, full consent (as described above) and enrolment procedures
 will be conducted. It will be made clear from the outset that refusal to participate will in
 no way jeopardize subsequent antimalarial treatment.Eligibility can only be confirmed by a
 medically qualified investigator. Subjects who fulfil all the inclusion criteria and have
 none of the exclusion criteria will be randomised to one of the three treatment arms
 according to the randomisation schedule. Subject numbers will be will be assigned when the
 subject is enrolled after screening and prior to randomisation.Patients will be randomized in
 blocks of 15 to receive either artemisone 4 mg/kg/day for 3 days plus mefloquine 15mg/kg on
 day 3 and 10mg/kg on day 4 (N=50) or artesunate 4mg/kg/day for 3 days plus mefloquine 15mg/kg
 on day 3 and 10mg/kg on day 4 (N=25.
Inclusion Criteria:

 -  Age ≥ 16 years

 -  Full written informed consent is obtained

 -  Willingness and ability to comply with the study protocol for the duration of the
 trial including agreement to 5 days hospitalisation.

 -  History of fever or presence of fever (tympanic or axillary temperature at >37.5 °C).

 -  Peripheral blood P.falciparum parasitaemia between 10,000/uL and 200,000/uL. (Mixed
 malaria infection included)

 Exclusion Criteria:

 -  Known hypersensitivity to the study drugs.

 -  Any antimalarial drug treatment in the 48 hours prior to enrolment.

 -  Clinical and/or laboratory features of severe malaria (as defined by WHO).

 -  Gastrointestinal dysfunction that could alter absorption or motility (i.e. active
 peptic ulcer, inflammatory bowel disease, malabsorption syndromes, intestinal
 sub-occlusion or previous major gastrointestinal surgery).

 -  Presence of intercurrent illness or any condition which in the judgement of the
 investigator would place the subject at undue risk or interfere with the results of
 the study.

 -  Splenectomy.

 -  Pregnant or lactating women. Serum test for β-HCG to be performed on any woman of
 child bearing age unless menstruating.

 -  Taking any contraindicated medicines (as listed in the most up to date product
 information)

 -  Participation in a clinical study within the previous 12 weeks

 -  Any other condition in the opinion of the investigator makes the patient unsuitable to
 be a subject