Relapses in Plasmodium Ovale and Efficacy of Artemether-lumefantrine for Mixed Species and Non-falciparum Malaria

Although P. ovale hypnozoites have never been demonstrated by biological experiments and findings in the literature about relapses are controversial, a 14 days primaquine standard therapy is recommended for every patient suffering from P. ovale infection. As there is no clear evidence of relapses of P. ovale it is of importance to conclusively analyze clinical evidence for its relapse potential to evaluate the necessity for further anti-relapse treatment options.

Moreover, summarizing the actual situation shows the need for further evaluation of the clinical use of ACTs in non-falciparum infections:

• Firstly, molecular diagnostic methods indicate that P. malariae and P. ovale are more prevalent than previously thought. In many settings malaria is treated on clinical suspicion. Diagnosis by microscopy is difficult if parasitemia is low and differentiation of species requires experience. This leads to the assumption that P. malariae and P. ovale infections are already blindly treated with the common ACTs recommended for P. falciparum malaria. The evaluation of artemisinin based combination therapies for non-falciparum malaria is therefore essential.
• Secondly, combination therapies have proven to be protective for the emergence of resistant parasites and in Asia combination therapy could even reduce resistance. As chloroquine-resistant P. malariae parasites have been reported, a combination therapy should be implemented in order to stop the emergence and spread of further resistance. Additionally, artemisinins can, in contrast to chloroquine, reduce transmissibility by their gametocytocidal activity.

A uniform treatment algorithm for all four Plasmodium species would simplify and facilitate treatment of malaria. With the reduction of chloroquine use in settings of poor quality diagnosis, the risk of fatal treatment failure due to wrongly administered chloroquine to chloroquine-resistant P. falciparum would be decreased. Finally, if no 8-aminoquinoline treatment was necessary for P. ovale infections, this could improve the safety and compliance of treatment.

The study is designed as an open label prospective study with a within group design. Patients enrolled will receive oral artemether-lumefantrine tablets as a 6 dose regimen over 3 consecutive days (Day 0, 1 and 2). Dosage depends on the patient's weight is according to the manufacturers recommendations. Patients will be followed for 42 days. If P. ovale is diagnosed at baseline, a one-year follow-up will be conducted every second week.

Parasite density, expressed as the number of parasites per microliter (µl) of blood, will be measured regularly to determine parasite clearance time (PCT).

Blood smears preparation, staining, examination and interpretation will be done according to the Lambaréné method. Thick and thin blood films for parasite count and species diagnosis should be obtained and examined at screening on D0 to confirm inclusion/exclusion criteria. Thick blood films will be examined every 24h following first dose administration and until the parasites have cleared. Thick and thin blood films will be also examined on Days 7, 14, 21, 28, 35 and 42 or on any other day if the patient spontaneously returns. For participants with P. ovale infection at baseline, reading of thick and thin blood films will be continued every second week for up to one year. In case of reappearance of parasites, Coartem will be administered again and Follow-up will be continued as scheduled.

Diagnosis of P. ovale will be effected by PCR. Furthermore, genotyping studies will be used to differentiate a new infection from relapse or recrudescence and to confirm microscopic diagnosis of species. Plasma samples will be collected and stored for further pharmacokinetic analysis 7 days after treatment initiation.

To determine the efficacy clinically, body temperature and clinical signs and symptoms of malaria will be assessed. Safety assessments include physical examination, vital signs and hematology.

Adverse Events and Serious Adverse Events will be ascertained. The investigator or his / her staff will notify the Independent Ethics Committee of all Serious Adverse Events as soon as possible and in accordance with local regulations.