Study 13: Hypothesis
Severe malaria can progress rapidly and patients become too sick to take medication by mouth. Untreated severe malaria leads to death. Treated late, there may be neurological damage. A single pre-referral dose of artesunate, given rectally, could enable patients with severe malaria to reach definitive care at a healthcare facility (hospital, dispensary, or other clinic) alive.
Artesunate, a derivative of artemisinin (also known as qinghaosu), is a rapidly and reliably effective antimalarial drug, from one of most important group of compounds for treatment of malaria. It has special properties that make it useful in severe malaria, in particular its ability to kill young ring forms of the P falciparum parasites, preventing them from growing to the mature, pathogenic stages that cause complications (1). Several hospital-based studies in the late 1990’s had demonstrated the ability of artesunate given as a suppository in a single dose to reduce parasitaemia by 97-99% within 24 hours (2) (3) (4).
It was hypothesized that the speed and efficiency of artesunate in killing parasites might convert into a clinical benefit, saving lives. But, as the artemisinins are neurotoxic in high doses, artesunate could cause neurotoxicity (5) (6). On the other hand, as malaria causes neurological damage if treated late, early treatment might help prevent serious permanent neurological damage.
The purpose of Study 13, a community-based study, therefore was to determine whether a single dose of rectal artesunate given to patients who could not take oral medications could save lives in very remote communities far from health facilities. Patients often cannot reach such facilities quickly and self-medication is common. As patients in these villages do not have any treatment until they get to a health facility, the trial was a randomised, placebo-controlled trial, with all patients referred to the nearest hospital.
Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria
Barnes KI, Mwenechanya J, Tembo M et al. Efficacy of rectal artesunate in the initial treatment of moderately severe malaria in African children and adults. Lancet 2004; 363: 1598-1605.
Simpson JA et al. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Medicine 2006; 3: e444 (doi: 10.1371).
Brewer TG, Peggins JO, Grate SJ et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 1994; 88: S33-S36 (Suppl 1).
WHO Informal Consultation on clinical neurological investigations required for patients treated with artemisinin compounds and derivatives. 1998.