Assessment of the Therapeutic Efficacy and Tolerability of the Artesunate/Amodiaquina Combination and Artemether/Lumefantrine Combination, Treatment of Uncomplicated P. Falciparum Malaria in the Department of Chocó (Colombia)

Design: An open-labeled, randomized and controlled clinical trial with follow-up in days 1, 2, 3, 4, 7, 14, 21 and 28 was carried out in adult patients with uncomplicated P. falciparum malaria. This type of study has been validated by PAHO and has been used by the Amazon Network for the Surveillance of Antimalarial Drug (RAVREDA) to evaluate the efficacy of antimalarial treatment in the Americas region. This study is a simplified version with monthly follow-up by a Data Safety Monitoring Board (DSMB) of the status of therapeutic failures to assure that the study progress does not result unethical.

Study area: The study area was in Department of Chocó, which is located west in the Pacific region of the country, has an approximate extension of 47,000 Km2, equivalent to 4% of the country's total extension. Chocó has 31 Municipalities for a total of 454,030 inhabitants, according to the 2005 Survey. From this population, 90% is black, 6% mulatto or white, and the remaining 4% natives. The great part of the population has its settling in the river and sea zones, which constitutes an important aspect to consider in communications, culture and socioeconomic development of the region. The temperature ranges between 26º and 30ºC. Patients were recruited from two municipalities, Quibdo and Tado.

Inclusion Criteria. Age > 18 years, fever (axillary temperature >37.5º C) or history of fever during the prior 48 hours in absence of another obvious cause (such as pneumonia, otitis media), a non-mixed P. falciparum infection with 250 and 100,000 asexual parasites/µl to be determined by a thick film or thick film and blood smear microscopic test.

Exclusion Criteria. Not being able to drink, vomiting (more than twice within the prior 24 hours), recent history of seizures (1 or more in the previous 24 hours), alteration of the consciousness level, not being able to seat or stand up, signs of serious malaria (World Health Organization criteria), other chronic or severe diseases (i.e., cardiac, renal and hepatic diseases, HIV/AIDS, severe malnutrition), history of hypersensibility to any of the study drugs or drugs used as alternative treatment (i.e. mefloquine, artesunate, quinine or tetracycline/clindamycin), and suspicion of pregnancy or pregnancy (based on a urine pregnancy test).

Study arms and treatments. Two study arms were considered: Group 1 received the combination AQ+AS (COARSUCAM®) which was administered orally at an initial dose of 2 tablets (200 mg AQ/540 mg AS) followed by 2 additional doses of 2 tablets at 24 and 48 hours (6 tablets in 48 hours).

Group 2 received the combination Artemeter+lumefantrina (COARTEM®) administered orally at an initial dose of 4 tablets (80 mg artemeter/480 mg lumefantrina) followed by 5 additional doses of 4 tablets at 8, 24, 36, 48, and 60 hours (24 tablets in 60 hours)

Sample size. The sample size was estimated based on the expected proportion of failures for each one of the treatments in this population. Assuming a similar efficacy for both treatments (7) and considering a proportion of failures to treatment of 5% (range 1-11%) in a population of infinite size, a 5% significance level and a maximum tolerable error of +4%, a total of 100 study subjects are required to be included in each group. If 5% of the study subjects are lost in a 28 days study, a total of 105 will be needed in each group. All included subjects signed the Informed Consent.

Randomization. The assignment of treatments was made through a negative coordinated type sampling scheme (7) which consists in generating a list of randomized numbers from a normal distribution [0,1] and order the study subjects regarding this new list. These ordered study subjects were systematically chosen (in this case applying a ½ sampling fraction, i.e., 1 of every two for each treatment arm, since there were two arms) with an initial number randomly generated through a Bernoulli distribution. This process ensures a balanced allocation to the study arms.

Main outcomes. failure to take the drug on any of the first three days, parasitemia on day 2 greater than that on day 0, presence of parasitemia on day 7, diagnosis of severe malaria at any point after day 0, recurrent parasitemia after day 7 up to day 28 (8-11).

Analysis. Data were double-entered, and validated using Epi info© 2000 and the analysis was done using Stata™ 10.0. Per protocol analysis included patients who were properly randomised, had received the study drugs according to the protocol, and for whom data were available on the primary end point. All statistical tests were two-sided and an α-level <0.05 was considered a statistically significant result. For comparisons of continuous variables between groups, the t-test was used and for comparisons between more than two groups, one-way analysis of variance was used after assuring normality and homogeneity of variances assumptions were satisfied. For comparison of categorical variables, the chi-square test was used with the exact extension invoked when there were small numbers in the cells. The end points were any of the following: failure to take the drug on any of the first three days, parasitaemia on day 2 greater than that on day 0, presence of parasitaemia on day 7, diagnosis of severe malaria at any point after day 0, recurrent parasitaemia after day 7 up to day 28.