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)
Condition: P. Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional
Phase: Phase 4

Summary: 
      Background: Malaria by P falciparum is a public health problem in more than 100
      municipalities of Colombia. The country is using the artemether+lumefantrine (AM+L) fixed
      combination for uncomplicated P falciparum malaria but it is ideal to have different types of
      formulations with similar efficacy that may be used in diverse circumstances. One alternative
      of treatment is using preparations containing artesunate and amodiaquine (AS+AQ) in fixed
      combination, which can be given in a simpler dosing regimen. In order to assess the efficacy
      of that combination in an area with suspected risk of resistance to amodiaquine an open
      controlled clinical trial was carried out in Colombia. Methods: The study was done in Choco,
      a high endemic area for malaria by P falciparum, from August 2008 and September 2009.
      Patients diagnosed with uncomplicated malaria (n=210) malaria were randomized in two arms,
      one receiving AS+AQ and the other AM+L. The main clinical results was parasitological cure,
      i.e. a negative blood smears, that was assessed, for both groups, at days 1, 2, 3, 7, 14, 21
      and 28 after the onset of treatment. Results: There were no losses at follow up. The mean age
      of the enrolled study subjects was of 37.5 years without differences between study arms. Both
      therapies were very well tolerated in general. The efficacy for AS+AQ was 100%, and 99% for
      AM+L (p>0.1). In average, patients in the AS+AQ arm became negative for P falciparum
      parasites and gametocytes earlier than those at the AM+L arm. Blood smears became negative
      after one day of treatment with AS+AQ and after two days of treatment with AM+L. Gametocytes
      disappeared after 2 days of treatment in the AS+AQ arm compared to 4 days in the AM+L arm.
      Conclusions: In this study, the efficacy of the AS+AQ combination was similar to that of the
      AM+L. This finding do not support the hypothesis that there is a level of resistance to
      amodiaquine that prevents its use combined with artemisinin derived.
    

Detailed description: 
      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.
    

Intervention name(s): Artemeter plus lumefantrina vs artesunato plus amodiquina
Intervention type(s): Drug
Intervention description(s): 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)
Intervention MeSH terms: Artesunate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: uncomplicated P. falciparum malaria; Colombia