A Trial of Four Drug Regimens for the Prevention of Malaria in Senegalese Children
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      A recent study has shown that the administration of a single dose of
      sulfadoxine/pyrimethamine plus artesunate to Senegalese children on three occasions during a
      short malaria transmission season reduced the incidence of clinical attacks of malaria by
      86%. However, use of this drug regimen led to the selection of parasites with molecular
      markers of resistance to pyrimethamine and sulfadoxine. Therefore, a trial of three
      alternative regimens has been undertaken to see if these are as effective and safe as the
      drug combination used in the initial study but less likely to select for drug resistance.
    

Detailed description: 
      Background:

      In countries of the Sahel and sub-Sahel, malaria transmission is highly seasonal with nearly
      all episodes of malaria occuring during a few months of the year. However, mortality and
      morbidity from malaria may be very high during this period, especially in children who are
      the most vulnerable group. It has been shown previously in The Gambia and elsewhere in West
      Africa that regular administration of anti-malarial drugs throughout the period of malaria
      transmission (chemoprophylaxis) reduces mortality and morbidity substantially but
      chemoprophylaxis is difficult to sustain. Intermittent preventive treatment (IPT) differs
      from chemoprophylaxis in that drugs are given at less frequent intervals and drug
      concentrations fall below the inhibitory level between administrations. IPT was used first to
      protect pregnant women from malaria and this approach has proved very effective. More
      recently, the IPT concept has been applied to the prevention of malaria in infants, drugs
      being given at the same time as infant vaccines are administered. However, in areas of
      seasonal malaria, such as Senegal, only a small proportion of cases of severe malaria occur
      during the first year of life. In such areas, older children require protection. Intermittent
      preventive treatment in children (IPTc) is a potential way of doing this. IPTc involves the
      administration of drugs to all children in the age group at risk on two or three occasions
      during the period of high malaria transmission. In a recent study in Senegal it was shown
      that the administration of a single dose of sulfadoxine/pyrimethamine (SP) plus artesunate to
      children aged 6 weeks to 59 months reduced the incidence of clinical attacks of malaria by
      86%. However, administration of these drugs was associated with selection of parasites with
      molecular markers of resistance to pyrimethamine and to sulfonamides. The aim of the new
      study was to investigate alternative drug regimens which might be equally effective but less
      likely to select for drug resistance.

      Objective:

      The object of the study was to find the most effective drug regimen for use in intermittent
      preventive treatment in children in Senegal.

      Study Area:

      The study was conducted in Niakhar, a rural area in central Senegal where the previous trial
      of IPTc had been conducted. In this area, malaria transmission is very seasonal with nearly
      all cases occuring during a three to four month period of the year. The entomological
      inoculation rate in the area is 10 infectious bites per person per year.

      Study Population:

      All children aged 1 - 5 years residing in the study area were eligible to join the trial.

      Study Procedure:

      Following village meetings, the families of all eligible children were contacted and asked if
      they wished their child to join the study. If they wished to do so, informed consent was
      obtained and the child randomised to one of four treatment arms. At the beginning and at the
      end of the malaria transmission season, children were examined and a finger prick blood
      sample was obtained for determination of haemoglobin and preparation of blood films for
      microscopy. A drop of blood was collected on filter paper for subsequent molecular studies.

      Following initial evaluation children were treated with one of four drug regimens. These were
      SP + 1 dose of artesunate (the regimen used in the initial trial), SP + three doses of
      artesunate, SP + 3 doses of amodiaquine and 3 doses of amodiaquine and artesunate. Initial
      drug administration was given under observation. Treatment was repeated on two further
      occasions at monthly intervals. The health assistants responsible for giving drugs were not
      blinded to the study group but they played no further part in the trial. Staff who made
      observations in the field, for example on the prevalence of side effects, and laboratory
      staff were blind to the study code.

      The incidence of clinical attacks of malaria in children in each randomisation group was
      measured during the period of the malaria transmission. Weekly home visits were made to
      detect any children who were sick and children in the study who attended one of the clinics
      in the study area with a febrile illness were identified.

      Blood films were stained with Giemsa and examined by two microscopists. DNA was extracted
      from filter papers obtained from parasitaemic children and examined for mutations in the dhfr
      and dhps genes which are associated with resistance to pyrimethamine and sulfonamides
      respectively.

      All serious adverse events were noted and reported to the Data Safety and Monitoring Board
      (DSMB). Home visits were made to the first 100 children in each arm of the trial seven days
      after drug administration to enquire about any side effects associated with drug
      administration.

      Trial End-Points:

      The primary end-point of the trial was the prevalence of markers of drug resistance to
      pyrimethamine and sulfonamides at the end of the malaria transmission season. Secondary
      end-points were the incidence of clinical attacks of malaria and the incidence of side
      effects.

      Sample Size:

      Sample size was calculated on the basis of a comparison of the three new drug regimens with
      the one used in the previous trial (SP + 1 dose of artesunate). It was assumed that about 20%
      of children in the SP + 1 dose of artesunate group would have Plasmodium falciparum
      parasitaemia at the end of the malaria transmission season providing around 100% samples for
      molecular studies. Assuming that the prevalence of resistance mutations at the dhfr codons
      108, 59 and 51 was about 90%, 500 children would be needed in each study arm to give a trial
      with 90% power to detect a 20% reduction in the prevalence of resistance mutations in
      children receiving the new drug combinations at a 5% level of significance. Allowing for a
      loss to follow-up of about 10% a sample size of 2,200 was selected.

      Monitoring:

      The trial was monitored by a clinical monitor provided by the IPTi consortium. A DSMB
      reviewed the study protocol, standard operating procedures and approved the analytical plan.
    

Intervention name(s): Pyrimethamine/sulfadoxine; Amodiaquine; Artesunate
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Artesunate; Pyrimethamine; Sulfadoxine; Amodiaquine; Fanasil, pyrimethamine drug combination
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single
Primary purpose: Prevention
Keywords: Malaria; Children; Intermittent preventive treatment; Senegal