Malaria Clinical Trial
Official title:
Prospective Assessment of Relapse Characteristics of Plasmodium Ovale and Antimalarial Treatment Efficacy of Artemether-lumefantrine for Mixed Species and Non-falciparum Malaria in Gabon
Malaria is a protozoan infection transmitted by anopheline mosquitoes. The most severe forms
are caused by Plasmodium (P) falciparum and to a much lesser extent by P. vivax.
Although the interest in research on malaria has increased during the last years, yet little
research is conducted on the "neglected" malaria species P. ovale and P. malariae. P. ovale
being first described in 1922, it still remains unclear whether it displays dormant
pre-erythrocytic liver stages, so called hypnozoites, or not. Primaquine, the only marketed
drug with liver stage activity at present, can cause severe hemolysis in glucose-6-phosphate
dehydrogenase (G6PD) deficient persons and methemoglobinemia. Because G6PD is widely spread
in Central Africa, it is important to explore whether additional intake of liver-active
medication is really needed and on this account further research to investigating new
treatment options with liver stage activity should be conducted.
While, due to widespread resistance, treatment recommendations for P. falciparum and mixed
infections have switched from chloroquine to the safer applicable artemisinin-based
combination therapies (ACTs), World Health Organization (WHO) guidelines still suggest
chloroquine as first line treatment for P. malariae and P. ovale mono infections. Further
studies assessing alternative treatment options are largely missing.
Summing up the current situation for both topics shows the need for further research.
Therefore this study aims to assess the evidence and characterize the frequency of relapses
in P. ovale infections with respect to differences between its subspecies as well as the
effectiveness of the ACT artemether-lumefantrine in P. malariae and P. ovale mono- and mixed
infections.
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.
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