Efficacy Study of Amodiaquine-Artesunate and Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria
Condition: Malaria, Falciparum
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional

Summary: 
      In the Democratic Republic of Congo (DRC), malaria is an important cause of morbidity and
      mortality. It is estimated that malaria is responsible for 30% of admissions to hospital
      averaged throughout the country and for 25-30% mortality in children under five.

      In 2005, DRC adopted artesunate and amodiaquine (ASAQ) as first-line anti-malarial treatment.
      As WHO recommended that the efficacy of antimalarial drugs was monitored regularly to avoid
      an upsurge of mortality and morbidity due to continued use of ineffective drugs, a
      randomized, non-inferiority open-label trial was conducted in Katanga, in order to compare
      the efficacy of the fixed-dose formulation ASAQ versus artemether-lumefantrine (AL),

      Children aged six and 59 months with uncomplicated Plasmodium falciparum malaria were
      enrolledand randomly allocated into one of the two regimens. The risk of recurrent
      parasitaemia by day 42, both unadjusted and adjusted by PCR genotyping to distinguish
      recrudescence from new infection, was analysed.

      Between April 2008 and March 2009, 301 childrenwere included: 156 with ASAQ and 145 with AL.
      No early treatment failures were reported. Among the 256 patients followed-up at day 42, 32
      patients developed late clinical or parasitological failure (9.9% (13/131) in the ASAQ group
      and 15.2% (19/125) in the AL group). After PCR correction, cure rates were 98.3% (95%CI,
      94.1-99.8) in the ASAQ group and 99.1% (95%CI, 94.9-99.9) in the AL group (difference -0.7%,
      one sided 95%CI -3.1). Kaplan-Meier PCR-adjusted cure rates were similar. Both treatment
      regimens were generally well tolerated.

      Both ASAQ and AL are highly effective and currently adequate as the first-line treatment of
      uncomplicated falciparum malaria in this area of Katanga, DRC. However, in a very large
      country such as DRC, and because of possible emergence of resistance from other endemic
      regions, surveillance of efficacy of artemisinin-based combination treatments, including
      other evaluations of the resistance of ASAQ, need to be done in other provinces.
    

Detailed description: 
      Study design and site An open randomized study was conducted to test the hypothesis that the
      risk of recurrent parasitaemia after 42 days is not inferior in the group receiving
      artesunate and amodiaquine (ASAQ) regimen compared to the group receiving
      artemether-lumefantrine (AL) regimen.

      The patients were recruited from the outpatient department of the general reference hospital
      of Pweto, health district of Pweto, province of Katanga, Democratic Republic of Congo (DRC),
      between April 2008 and March 2009.

      Procedures Children aged between six and 59 months and with a body weight ≥ 5kg were eligible
      for enrolment if they had P. falciparum infections (density threshold at inclusion between
      2,000 and 200,000/µl), fever or history of fever in the previous 24 hours, no signs of severe
      malaria, no reported hypersensitivities of the studied drugs, and no serious concomitant
      febrile illness.

      The children included were randomized in one of the two treatment arms, in a 1:1 ratio
      without any stratification. The randomization list was generated by a computer in blocks of
      six. Treatment allocations were kept in sealed and numbered opaque envelopes. Participants
      were enrolled in the same order in which they were diagnosed.

      ASAQ (ASAQ Winthrop®, Sanofi-Aventis) was administered once daily for three days, as follows:
      one tablet of artesunate 25mg/amodiaquine 67.5 mg for children between 5 to 8.9 kg,
      artesunate 50mg/amodiaquine 135 mg for children between 9 to 17.9 kg. One tablet of
      artemether 20 mg/lumefantrine 120 mg; (Coartem® Novartis Pharma, Basel, Switzerland) was
      administered twice daily for three days to children with a body weight of 5 to 14.9 kg and
      two tablets were administered twice daily for three days to children with a body weight of 15
      to 24.9 kg. All doses of drugs were administered under direct observation for the three days.
      Full doses of drugs were re-administered if a patient vomited within 30 min after receipt.
      Patients who vomited more than twice were excluded from the study.

      Signs of severe malaria or any other serious health condition (i.e. severe malnutrition),
      intake of anti-malarial treatment in the last seven days, and mixed malaria infection were
      also exclusion criteria.

      Clinical assessment (including measurement of axillary temperature), tick and thin smears and
      haemoglobin measurement were performed on days 2, 3, 7, 14, 21, 28, 35 and 42 or any day in
      between in the event of illness.

      Malaria outcome classification Outcomes were classified according to 2009 WHO guidelines as
      adequate clinical and parasitological response (ACPR), early treatment failure (ETF), late
      clinical failure (LCF), late parasitological failure (LPF) or follow-up interrupted.

      Follow-up interrupted included treatment protocol violation, lost to follow-up, use of other
      anti-malarials (such as quinine) outside the study protocol or withdrawal of consent
      prohibiting further follow-up.

      Drug tolerability was also assessed clinically. An adverse event was defined as any
      undesirable symptom in a patient during the study regardless of whether it was related to the
      treatment.

      PCR genotyping In areas of intense transmission, where multiple genotype infections are
      common , a second episode of malaria or a recurrent parasitaemia during the drug-free
      follow-up period may be due to the same infection or a different infection (a recrudescence,
      thus a treatment failure, or a new infection, respectively). To distinguish these two events,
      polymorphic P. falciparum genes, such as the merozoite surface protein 1 and 2 genes (msp1
      and msp2) and the glutamate-rich protein gene (glurp) were genotyped by PCR, as previously
      described. PCR analyses, conducted at the Epicentre research base, Mbarara, Uganda, were
      performed using paired samples from all patients experiencing late clinical or parasitologic
      failure. Blood was collected on filter paper (Whatman FTA® Cards) on the day of enrollment
      and the day treatment failure occurred. The genotypic profiles for pre- and post-treatment
      parasites were compared; patients in which pre- and post-treatment genotypes were identical
      were considered as recrudescences and patients in which pre- and post-treatment genotypes
      were different were considered as new infections.

      All ETFs were considered to be due to recrudescence. Patients meeting the criteria for LCF or
      LPF in whom genotyping was done; according to the results, patients were classified as either
      (i) resolved by PCR and further categorized as recrudescences or new infections or (ii)
      unsuccessfully genotyped with the reason recorded (missing sample, PCR not done or result
      inconclusive).

      Statistical analysis The primary outcome was the PCR-adjusted parasitological cure rate up to
      day 42 of the follow-up period. Two analytical approaches were used to assess efficacy data.
      First a per protocol (PP) analysis was performed including only the patients who were
      followed throughout the protocol, defined follow-up period and in whom a clear treatment
      outcome can be determined. The risk of failure for each treatment group was calculated as the
      proportion of patients classified as failure (the numerator) divided by the number of
      patients in the evaluable population (the denominator). In the second approach, survival
      analysis was performed and patients with incomplete follow-up who did not reach the primary
      outcome interest were included in the analysis as non-failures, but censored on the last day
      of follow-up. The risk of failure was calculated using the Kaplan-Meier product limit formula
      with data censored for patients who were not classified as failures and with interrupted
      follow-up. Patients wrongly included, who did not meet study inclusion criteria, were
      excluded from both analyses.

      In the PP analysis (adjusting by genotyping), the evaluable population included only patients
      classified as ACPR, ETF or LCF/LPF due to recrudescence. In the survival analysis, the
      evaluable population for adjusted and unadjusted calculations included all patients enrolled
      in the study, with the exception that LCF/LPF outcomes with unsuccessful genotyping outcomes
      were excluded from the adjusted calculations. For the unadjusted calculations, patients with
      follow-up interrupted and non-falciparum new infections were censored on the last day of
      observation. For the adjusted calculations, censored patients also included those with new P.
      falciparum infections.

      Other variables, such as the baseline characteristics of the patients of the two treatment
      arms, were compared using the chi2 test or Fisher's exact test for variables and Student's
      test for continuous variables.

      Data were double entered and validated using Epidata version 3.1 (Odense, Danemark). All
      analyses were performed with Stata, version 10 (Stats-Corp, College Station, Texas). A
      p-value < 0.05 was considered statistically significant.
    

Intervention name(s): ASAQ Winthrop® Sanofi Aventis; Coartem®, Novartis
Intervention type(s): Drug; Drug
Intervention description(s): Artesunate 25mg / amodiaquine 67.5mg: 1 tab/day for 3 days in children 5 to 8.9 kg Artesunate 50mg / amodiaquine 135mg: 1 tab/day for 3 days in children 9 to 17.9 kg; artemether 20 mg / lumefantrine 120 mg co-formulated tablets given as six twice-daily doses over three days:
tab/dose for children 5 to 14.9 kg (total 6 tabs)
tabs/dose for children 15 to 24.9 kg (total 12 tabs)
Other intervention name(s): COARSUCAM 25 mg/67,5 mg; COARSUCAM 50 mg/135 mg; COARSUCAM 100 mg/270 mg; RIAMET
Intervention MeSH terms: Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malaria; Plasmodium falciparum; Children; Efficacy; Uncomplicated malaria