Comparison of Three Drug Combinations for Intermittent Treatment of Malaria in Children
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Intermittent preventive treatment (IPT) offers a way of preventing malaria infection without
      compromising the development of malaria immunity or encouraging drug resistance. The effect
      of IPT in children in the prevention of malaria has been evaluated in a number of trials in
      areas of seasonal malaria transmission. Results from these trials have shown that IPTc
      provided between 40% - 86% protection against clinical malaria. In 2006, a trial that
      compared two methods of IPTc delivery was carried out in Upper River Division, The Gambia.
      Preliminary results of the trial have shown that the treatment was very effective as only 4%
      (45/1133) of the children seen at the end of year cross-sectional survey were parasitaemic.
      Tolerability was assessed in a subset of 1100 children and the results showed that about
      13.5% of children developed mild to moderate vomiting. Malaise was present in about 10% of
      the study subjects. Severe adverse events were rare. Thus it is important to investigate if
      other drug regimens might be equally effective in preventing malaria but less likely to cause
      adverse events. During the 2007 malaria transmission season, 1009 children aged 1-5 years
      will be individually randomized to receive amodiaquine plus SP, piperaquine plus SP or
      Artekin TM (dihdroartemisinin plus piperaquine) at monthly intervals on three occasions
      during the months of September, October, and November. To determine the prevalence of side
      effects following drug administration participants in each treatment group will be visited at
      home three and seven days after each round of drug administration and a side effects
      questionnaire completed. To help establish whether these adverse events are drug related, the
      same questionnaire will be administered after each treatment round, to 286 age-matched
      children who are not part of the trial. The primary ends points will be the incidence of
      adverse events.
    

Detailed description: 
      Objectives

      Primary Objective To determine the safety and tolerability of amodiaquine(AQ) (three days)
      plus sulfadoxine-pyrimethamine(SP) (one day), piperaquine(PQP) (three days) plus SP (one
      day), and Artekin TM (PQP plus dihydroartemisinin, DHA) (3 days) when used for seasonal IPT
      in children.

      Secondary Objective To determine the efficacy of AQ (three days) plus SP (one day), PQP
      (three days) plus SP (one day) and Artekin TM (3 days) when used for seasonal IPT in
      children.

      3.4 Randomisation Open-label, individual randomisation was carried out three weeks before the
      first dose of IPTc administration in September 2007. Study subjects were individually
      randomised into either the AQ plus SP, PQP plus SP or ArtekinTM treatment groups in a 1:1:1
      fashion. An independent statistician generated the randomizing subject study number (SSN)
      that assigned each SSN to one of the treatment groups. A photo ID card was given to all
      participants to facilitate identification at every contact, at home or in the health centres.

      3.5 Drug distribution at the health centres Study subjects and their parents were informed
      about the date of treatment approximately one week before any intervention. Treatment is
      scheduled to be given during the months of September, October and November. Drugs are to be
      given at the nearest health centre by a designated member of staff. Tablets are crushed,
      mixed with honey or suspended in water and given on a spoon. Staff who administer drugs at
      the health centre play no further part in the trial. All participants are kept under
      observation for 30 minutes after drugs are taken. In case of vomiting, the drug is
      re-administrated. At the time of each monthly drug administration, a brief clinical
      assessment is carried out. Children who are febrile are screened for malaria using a rapid
      antigen test. Children found to have malaria are treated with Lumefantrine-artemether
      (CoartemTM, Norvatis Pharma., Basel Switzerland).

      3.7 Morbidity surveillance during the rainy season Passive surveillance for malaria will be
      maintained throughout the transmission season. Parents/guardians are being encouraged to take
      their children to the health centre identified as being closest to their home at any time
      that their child becomes unwell. Project staff are based at each of these health facilities
      to identify children in the trial and to ensure that they are seen, properly investigated and
      treated promptly. At each clinic visit, axillary temperature is recorded using a digital
      thermometer and haemoglobin concentration measured using a Hemocue machine. A dipstick for
      diagnosis of malaria is to be used if fever (axillary temperature of ³ 37.5°C) or a history
      of fever within the previous 48 hours is present. In such cases, a thick blood smear is also
      be collected for subsequent confirmation of the diagnosis. Study subjects with documented
      fever (axillary temperature of ³ 37.5°C) or history of recent fever and malaria parasitaemia
      are treated with Coartem. The treatment of study subjects seen at the health centres for
      other conditions is being carried out in accordance with national guidelines.

      3.8 End of malaria transmission season cross-sectional survey Children enrolled in the study
      will be seen at the OPD clinic at the end of malaria transmission season for examination by a
      study physician and a finger-prick blood sample will be obtained for preparation of a thick
      blood smear and determination of haemoglobin concentration. A standardized questionnaire will
      be administered to the parents/guardians of the study subject, to collect information
      regarding illness that had occurred since the last visit, symptoms experienced, use of
      healthcare facilities and use of medicines. Information on the use of bed nets will be
      collected again at this visit.

      3.10. Assessment of adverse events To determine the prevalence of minor side effects
      following drug administration such as headache, fever, weakness, abdominal pain, anorexia,
      nausea, vomiting, diarrhoea, rash, itching or sleep disorder participants in each treatment
      group are to be visited at home three and seven days after each round of drug administration
      and a side effects questionnaire completed. Field workers who complete these questionnaires
      will be unaware of the treatment group to which the child belongs. To help establish whether
      these adverse events are drug related, the same questionnaire will be administered once after
      each treatment round, to 286 children who are not part of the trial, recruited from nearby
      villages and matched for age to children in the trial.

      Any serious adverse event that occurs during the study period will be reported to the Local
      Safety Monitor and Chairman of DSMB.

      Primary end-point:

      - Incidence of any adverse events during the observation period.

      Secondary endpoints:

        -  Mean Hb (g/dl) at the end of malaria transmission.

        -  Prevalence of malaria parasitaemia at the end of the malaria transmission season.

        -  Number of OPD attendances with malaria that meet the case definitions as indicated below
           during the surveillance period.

      Data management and analysis All baseline, surveillance and laboratory data will be collected
      on forms designed for the trial. Field and laboratory staff will be trained to follow the
      procedures set out in a series of Standard Operating Procedures (SOPs). Key data will be
      double entered and inconsistencies checked; range checks will be used for standard variables.
      Primary analyses will be performed on an intention to treat (ITT) basis. Any child who
      receives a first dose of drug will be included in the ITT analysis. Children who are
      randomised but who do not receive any mediation will not be included in this analysis.

      Sample size calculations Drugs for IPT need to be acceptable and have low frequency of
      adverse events. If the frequency of adverse events is 20% in the SP/AQ group, a trial with
      286 children per arm has 90% power to detect a halving in the frequency of adverse events,
      using a significance level of 0.05, or a reduction to 9% or less if a significance of 0.025
      is used (to preserve an overall type 1 error rate of 5% for the primary endpoint when there
      are 2 comparisons, each alternative drug group with SP/AQ). If the frequency of adverse
      events is 15%, a reduction to 5% or less can be detected with the same power, and if the
      frequency is 10% a reduction to 2% or less can be detected. Based on experience from several
      studies the drop-out rate is not expected to exceed 15% and is likely to be less. Allowing
      for 15% drop out, a sample size of 286*3/(1-0.15)=1009 is needed.

      Withdrawal during the study:

      Study subjects may be withdrawn from the study for any one of the following reasons.

        1. Withdrawal of parental / legal guardian's consent.

        2. Serious adverse event attributable to the study drug.

        3. Loss to follow-up.

      Children who develop adverse events attributable to study drugs should not receive further
      doses but should be followed-up to monitor safety until the resolution of the adverse
      reaction.
    

Intervention name(s): SP, amodiaquine, piperaquine, dihdroartemisinin; intermittent preventive treatment; Du-Cotecxin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): once every month during september, October and November; SP(500mg sulfadoxine/25mg pyrimethamine)1.25mg SP per kg stat Amodiaquine (200mg base) 25mg/kg over 3 days Piperaquine (320 mg per tablet) 16.8 g/kg daily for 3 days Du-Cotecxin ( 40mg dihydroartemisinin(DHA)/320mg piperaquine(PQP))PQP/DHA 1.6/12.8mg/kg once daily for 3 days; Du-Cotecxin (40mg dihydroartemisinin (DHA/320mg Piperaquine (PQP) PQP/DHA 1.6/12.8mg/kg once daily for 3 days
Other intervention name(s): Fansidar; Du-Cotecxin; SP; Du-Cotecxin; SP
Intervention MeSH terms: Piperaquine; Amodiaquine; Artenimol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: safety; tolerability; efficacy; intermittent prevetive treatment; children