Kintampo Trial of Combination Therapy for Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 4

Summary: 
      Case management is one of the key strategies for malaria control in most endemic countries.
      Plasmodium falciparum malaria is becoming resistant to commonly used and cheap antimalarial
      drugs such as chloroquine, amodiaquine, and sulfadoxine-pyrimethamine (SP). Thus the safety
      and efficacy of new anti-malarial drugs need to be tested in sites with well-characterised
      malariometric indices in order to make appropriate treatment policies.

      Artemisinin-based combination chemotherapies have been documented to consistently produce
      faster relief of clinical symptoms and parasite clearance in uncomplicated falciparum malaria
      than any other currently used antimalarial drugs. So far, artesunate-amodiaquine (AS-AQ) and
      artemether-lumefantrine (AR-LM) are the only two registered fixed-dose artemisinin
      combination chemotherapies produced at industrial scale, with good manufacturing practices
      and already used in Africa. Several African countries, including Ghana, are therefore
      introducing either AS-AQ or AR-LM as first-line antimalarials or evaluating the case for such
      a change. Clearly, a direct comparison of both the safety and efficacy profiles of the two
      combinations under different epidemiological conditions is urgently needed to guide informed
      decisions on the most appropriate antimalarial first-line treatment regimen.

      This study aims to evaluate the efficacy and safety of artesunate-amodiaquine combination
      therapy, artemether-lumefantrine, and artesunate-lapdap in an open-labelled, randomised,
      non-inferiority drug trial.

      The study results will inform future decisions on first- and second-line treatments for
      uncomplicated P. falciparum malaria with respect to efficacy and safety in Ghana.
    

Detailed description: 
      A study funded by the GMP-LSHTM in the Kintampo district of Ghana is currently assessing the
      efficacy of SP as part of a comprehensive process of characterising the site into the
      patterns of seasonal dynamics of P. falciparum transmission, infection, and morbidity. The
      initial results from this study have demonstrated a high parasitological failure rate(18%) on
      day 14 of treatment, an indication that SP is no longer suitable for use in Ghana. Artesunate
      combination therapies (ACTs) have been found to be efficacious and safe, producing rapid
      clearance of parasites and malaria symptoms; they are very well tolerated. Lapdap is a newly
      registered, relatively cheap antimalarial with short half-life and has been found to be
      highly efficacious in strict trial conditions for treatment of acute uncomplicated falciparum
      infections in endemic sites in Africa. Despite the rapid clearance of lapdap, children
      treated with this drug did not have higher incidence of malaria episodes than those treated
      with SP though haematological adverse effects have been documented to be more common with
      lapdap than with SP. At present, the fixed-dose combination regimens of
      artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AR-LM) are the only two
      registered artemisinin combination chemotherapies produced at industrial scale, with good
      manufacturing practices and already used in Africa. Several African countries are introducing
      either AS-AQ or AR-LM as first-line antimalarials or evaluating the case for such a change.
      Ghana, has just changed its antimalarial drug policy to artesunate-amodiaquine combination
      therapy (AS-AQ) as first line drug. The selection of this new ACT has been driven partly by
      cost of treatment, but a critical look at the safety and efficacy of ACTs in Ghana has yet to
      be done.

      This study aims to evaluate the efficacy and safety of artesunate-amodiaquine combination
      therapy (AS-AQ), Artemether-lumefantrine (Coartem), and Artesunate-lapdap) in a drug
      non-inferiority study.

      Objectives

      Primary objective:

      • To evaluate the efficacy of artesunate-amodiaquine versus artemether-lumefantrine, versus
      artesunate-lapdap in the treatment of children aged 6 months to ten years, infected with
      uncomplicated falciparum malaria, at the paediatric outpatient clinic in the Kintampo
      hospital.

      Secondary objectives:

      • To evaluate the safety of artesunate-amodiaquine versus artemether-lumefantrine, versus
      artesunate-lapdap in the treatment of children 6 months to ten years with uncomplicated
      falciparum malaria.

      Study design and methods

      Study site: This study is being conducted in Kintampo district in the middle belt of Ghana
      where the investigators in the Kintampo Health Research Centre are located. Kintampo Health
      Research Centre (KHRC), one of three research centres under the Health Research Unit (HRU) of
      the Ghana Health Service, Ghana, lies within the forest-savannah, transitional ecological
      zone in the Brong Ahafo Region of Ghana.

      Study design:

      This is a randomised, open-labelled, non-inferiority drug trial. At the Kintampo district
      hospital, 510 paediatric outpatients (refer sample size calculation) with uncomplicated P.
      falciparum malaria and aged between 6 months and 10 years will be recruited and randomly
      assigned to one of the three study arms: (i) Artesunate-Amodiaquine (AS-AQ), (ii)
      Artemether-Lumefantrine (AR-LM), or (iii) Artesunate-lapdap (AS-LP). The classification of
      clinical and parasitological responses will follow the relevant WHO protocol for areas of
      intense transmission. Follow-up, however, will be extended beyond day 14 up to day 28 to
      increase the sensitivity of the in vivo test. PCR-based genotyping comparing pairs of
      parasite isolates from day 0 and day of asexual parasite reappearance will be used to
      distinguish between recrudescence and re-infection.
    

Intervention name(s): artesunate-amodiaquine; coartem; artesunate-lapdap
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Artesunate; Amodiaquine; Artemether, Lumefantrine Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: antimalarial drugs; efficacy; safety; trial