Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children.
BACKGROUND
Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.


METHODS
A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.


RESULTS
Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.


CONCLUSIONS
This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.


BACKGROUND
Current Controlled Trials Identifier ISRCTN37517549.
Department of Medicine, Makerere University, Kampala, Uganda. cmaiteki@yahoo.com
Catherine
C
Maiteki-Sebuguzi
Prasanna
P
Jagannathan
Vincent M
VM
Yau
Tamara D
TD
Clark
Denise
D
Njama-Meya
Bridget
B
Nzarubara
Ambrose O
AO
Talisuna
Moses R
MR
Kamya
Philip J
PJ
Rosenthal
Grant
G
Dorsey
Sarah G
SG
Staedke
D000655:Amodiaquine / Q000008:administration & dosage / Q000009:adverse effects*; D000855:Anorexia / Q000139:chemically induced; D000962:Antimalarials / Q000009:adverse effects*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects*; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects*; D005449:Fluorenes / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000188:drug therapy*; D018908:Muscle Weakness / Q000139:chemically induced; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects*; D016037:Single-Blind Method; D013413:Sulfadoxine / Q000008:administration & dosage / Q000009:adverse effects*; D014454:Uganda
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D011739:Pyrimethamine