Three Alternative Drug Regimens for Malaria Seasonal Preventive Treatment in Senegal

Study Overview
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Brief Summary
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The purpose of this trial is to compare the acceptability, efficacy and safety of three alternative drug regimens for use for seasonal Intermittent Preventive Treatment to prevent malaria in children. Children aged 2 months to 5 years will be randomized to receive IPT with one of three regimens during the transmission season: sulfadoxine-pyrimethamine (SP) plus amodiaquine, show to be highly effective for IPT in a recent trial; SP plus piperaquine, used for malaria prophylaxis in China for many years; or Duocotexcin (a combination of piperaquine with an artemisinin).

Detailed Description
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In areas of seasonal malaria transmission the burden of severe disease and mortality due to malaria is mainly among children under 5 years of age. Intermittent preventive treatment (IPT) with antimalarial drugs given to all children once a month during the transmission season is a promising new strategy for malaria prevention. Seasonal IPT with sulfadoxine-pyrimethamine (SP) and one dose of artesunate resulted in a 90% reduction in incidence of clinical malaria in a recent trial in Senegal (Cisse et al., Lancet 2006). An important consideration is the possible impact of seasonal IPT on the emergence and spread of drug resistant parasite genotypes, the choice of drug regimen is therefore critical. A second trial in Senegal showed that a combination of two non-artemisinin drugs with relatively long half lives (SP and amodiaquine (AQ) over three days) was more effective than SP with artesunate and more effective than AQ with artesunate, in preventing malaria; and very few children developed parasitaemia, so that the potential for drug resistant genotypes to emerge and spread was low. Although SP+AQ was more efficacious than the artemisinin-containing regimens tested, it was associated with a higher frequency of adverse events, especially vomiting, and AQ has a bitter unpleasant taste, and therefore we have concerns about the acceptability of AQ for widespread use for IPT. It is important to select a drug regimen that is not only effective but safe and acceptable to the community. Each treatment is a 3-dose regimen over 3 days, the first dose will be supervised and the other 2 doses given by the mother or carer. One month after each treatment round, children will be visited at home to check for malaria symptoms, children with fever or a history of fever in the last 48 hours will be asked to give a finger prick blood sample for malaria diagnosis. One month after the last treatment all children will be asked to give a finger prick blood sample for parasitology and haemoglobin, axillary temperature will be measured. The child's carer will be interviewed about compliance and adverse events. The endpoints will be the cumulative incidence of malaria, the proportion of children experiencing moderate and severe adverse events, compliance with and acceptability of the regimen, the prevalence of parasitaemia, and the proportion of children carrying parasite genotypes associated with resistance to sulfadoxine or pyrimethamine at the end of the transmission season. Since acceptability is difficult to assess in the formal setting of a trial, and because the method of delivery may affect compliance and acceptability, drug treatments will be delivered by community workers replicating the conditions under IPT would be delivered routinely in Senegal. Treatments will be administered at home by local community workers, each worker covering a circuit of approximately 60-80 children. The community worker circuit will be the unit of randomization, for simplicity in the field to minimise allocation errors, and to avoid contamination due to sharing of tablets within a household.

Official Title
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Randomized Trial of Effectiveness and Acceptability of Three Alternative Regimens for Malaria Seasonal Intermittent Preventive Treatment in Senegal

Conditions
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Malaria

Intervention / Treatment
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* Drug: sulfalene-pyrimethamine plus amodiaquine
* Drug: dihydroartemisinin plus piperaquine
* Drug: sulfadoxine pyrimethamine plus piperaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 2 to 59 months in September 2007 Exclusion Criteria: history of allergy to study drugs

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>sulfalene pyrimethamine plus amodiaquine | Drug: sulfalene-pyrimethamine plus amodiaquine<br>* Monthly treatments during the malaria transmission season<br>* Other names: Dualkin;|
| Active Comparator: 2<br>dihydroartemisinin piperaquine | Drug: dihydroartemisinin plus piperaquine<br>* Monthly treatments during the transmission season<br>* Other names: Duo cotexcin;|
| Active Comparator: 3<br>sulfadoxine-pyrimethamine plus piperaquine | Drug: sulfadoxine pyrimethamine plus piperaquine<br>* Monthly treatments during the malaria transmission season<br>* Other names: piperaquine phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of malaria |  | Four months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events reported by the mother: vomiting, headache, fever, nausea, diarrhea |  | within 4 days of the start treatment | 
| Prevalence of P.falciparum parasitaemia |  | Measured by microscopy 1 month after the last treatment, in December | 
| Haemoglobin concentration |  | Measured 1 month after the last treatment, in December | 
| The proportion of children carrying P.falciparum genotypes associated with resistance to sulfadoxine and pyrimethamine |  | Measured in December | 
| Compliance with the treatment regimen |  | Recorded 4 days after the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, IPT, preventive treatment