Randomized Study of the Tolerability and Efficacy of Artemether-Lumefantrine Versus Artesunate Plus Amodiaquine Coadministered for the Treatment of Uncomplicated Falciparum Malaria in Zanzibar
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 408
- Primary Endpoint
- PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine (AA) or Coartem® (CO)
Study Overview
Brief Summary
The primary objective of the study was to determine PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine or Coartem®.
Secondary objectives were to determine safety and possible selection of mutations related to the resistance of the tested drugs.
Detailed Description
Combination therapy, the new strategy for malaria treatment, is based on the hypothesis that two (or more) components of different mechanisms of action protect each other from development of resistance. Artemisinin as well as its two derivatives, e.g. artemether and artesunate, constitute a family of compounds with several attractive features for such a combination, due mainly to their rapid onset of effective action against multidrug-resistant P. falciparum and their gametocytocidal effect, which potentially reduces transmission of resistant alleles. There also appears to be no cross-resistance with other known anti-malarials. Because of the short half-life of this family of compounds, their use as mono-therapy requires multiple daily doses over a period of 7 days. Combining them with longer acting partner -drugs allows for a reduction in treatment duration while simultaneously enhancing the efficacy and reducing the likelihood of resistance development.
As of October 2001 the following anti-malarial drugs were recommended for malaria treatment in Zanzibar:
- Artesunate (AS)+ Amodiaquine (AQ) - "first line" (AA)
- Lumefantrine-artemether (Co-artem®) (CO) - "second line"
- Quinine, if failure or contra indication of 1 & 2, or for treatment of severe malaria
- Sulfadoxine-pyrimethamine (SP) for Intermittent Presumptive Treatment in pregnancy (IPT)
The move that the Zanzibar Ministry of Health has taken with this new treatment policy/strategy provided a unique opportunity to investigate the potential value of combination therapy when introduced on a large scale. Using artemisinine derivatives in combination with anti-malarials with longer half-lives is thought to be highly effective and considerably prevent the development of parasite resistance to the individual drugs. This study therefore provided baseline data on the efficacy of the new treatment policy and also for future monitoring of the policy in Zanzibar.
All children presenting with clinical signs of malaria at the study site were considered possible study subjects. The guardians of these children were informed about the study orally in Swahili for providing informed consent. Those who were willing to participate in the study were treated according to local standard procedure. The patient was tested for parasites using light microscopy on Giemsa stained blood films. A detailed clinical history, a clinical examination including an axillary temperature, was assessed. Haemoglobin was assessed and blood samples were collected on filter paper for each child for genotyping of the parasites as well as for determining blood levels of different antimalarial drugs.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Masking Description
The AQ+AS (AA) group received their drugs under direct observation once daily for 3 days. The Coartem (CO) group received their drugs twice daily, the second (evening) dose also under supervision. Drug treatment was thus not be blinded.
Eligibility Criteria
- Ages
- 6 Months to 59 Months (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Children age 6-59 months and body weight ≥6 kg (AQ+AS); 9-59 months and body weight ≥9 kg (AL)
- •Fever or history of fever in the preceding 24 hours
- •Parasitemia ≥2000 ≤200.000 parasites per µl
- •Informed consent given by the child's parent or other adult guardian
Exclusion Criteria
- •Signs of severe malaria or other danger signs, such as: 1.Unconsciousness;
- •Not able to sit or stand; 3.Severe anaemia (Hb ≤ 5 g/dl); 4.Convulsions;
- •Shock (systolic BP<50 mmHg);
- •Not able to drink or breastfeed;
- •Vomiting 3 times or more the past 24 hrs
- •Other diseases associated with fever
- •History of allergy to test drugs
- •History of intake of any drugs other than paracetamol and aspirin within 3 days
Arms & Interventions
Artemether-lumefantrine (AL)
One tablet of artemether-lumefantrine (Coartem®) was administered twice daily for 3 days to children with a body weight of 9 to <15 kg, and 2 tablets were administered twice daily for 3 days to children with a body weight of >15 to 25 kg. All doses were taken under direct observation.
Intervention: Artemether-lumefantrine (Drug)
Artesunate + Amodiaquine (AA)
Artesunate + amodiaquine (ASAQ) was administered as follows: 4 mg/kg body weight of artesunate plus 10 mg/kg body weight of amodiaquine once daily for 3 days under direct observation.
Intervention: Coadministered Artesunate plus Amodiaquine (Drug)
Outcomes
Primary Outcomes
PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine (AA) or Coartem® (CO)
Time Frame: 42 days
Comparing PCR adjusted parasitological cure rate (PCR-APCR) between the two treatment options up to day 42. Parasitological cure will be adjusted using PCR genotyping of msp2 marker. Recrudescence is defined as the presence of at least one matching allelic band, and reinfection as the absence of any matching allelic band on day 0 and day of recurring parasitaemia. Patients with recurrent parasitaemia having missing filter paper sample or negative PCR results will be considered uncertain with regards to PCR adjusted outcome.
Secondary Outcomes
- Fever clearance(42 days)
- Safety of treatment with Artesunate + Amodiaquine (AA) or Coartem® (CO): Proportion of subjects with adverse events(42 days)
- Gametocyte carriage(42 days)
- Hemoglobin(42 days)
- Selection of mutations in P. falciparum related to the resistance of the study drugs(42 days)
- Parasite clearance(42 days)
Investigators
Professor Anders Björkman
Professor
Karolinska Institutet