Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania

Study Overview
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Brief Summary
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Background: In high-transmission settings, up to 70% of school-aged children harbour malaria parasites which is mostly asymptomatic, thus, from an epidemiological point of view, they contribute significantly as reservoir to onward malaria transmission to others. In endemic areas, malaria accounts for around 50% of the mortality, 13-50% of all school absenteeism, and causes anaemia in approximately 85 million school-aged children of sub Saharan Africa that also impairs the cognitive development of children. Intermittent preventive treatment (IPT) of pregnant women as well as seasonal malaria chemoprevention in children under the age of five have been implemented in several sub-Saharan countries and have proven to be very effective. However, none of these IPT strategies is targeting school children. A clinical trial is being conducted to expand the IPT by testing effectiveness and safety of two antimalarial drugs Dihydroartemisinin-piperaquine (DP) and Artesunate-amodiaquine (ASAQ) in preventing malaria related morbidity in school aged children (IPTsc) living in high endemic areas. Methods: A randomized, open label, controlled trial will enrol 1602 school children aged 5-15 years, who will receive either DP or ASAQ or control (no drug ), using a balanced block design with the standard of care arm as reference. The interventional treatments are given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects. All study-arms receive bed nets, early diagnosis and care for malaria, and praziquantel and albendazole as mass treatment for helminthiasis. The primary endpoint are change from baseline in mean haemoglobin concentration at months 12 and 20 of follow-up and clinical malaria incidence from month 0 till months 12 and 20 of follow up. Adverse events will be monitored throughout the study. Mixed design methods will be used to assess the acceptability, cost-effectiveness and feasibility of this IPTsc as part of a more comprehensive school children health package. Discussion: The national school health programme (NSHP), Tanzania, combines schistosomiasis and soil transmitted helminthes (STH) control package under national schistosomiasis and STH control programme (NSSCP). Malaria intervention using IPTsc strategy may be integrated in NSHP with the same platform as NSSCP, however, there is limited systematic evidence to assess the operational feasibility of this approach. School aged children are a reachable target population in any endemic malaria setting. The suggested strategy will provide effective protection against malaria, hasten either the elimination process and/or diminish the reservoir and burden.

Official Title
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Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania: A Controlled Randomised Trial

Conditions
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Malaria,Falciparum, Anemia

Intervention / Treatment
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* Drug: Dihydroartemisinin-piperaquine
* Drug: Artesunate-amodiaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Includes parental/guardian informed consent Assent by primary school children aged 11 years and above. Aged 5-15 years. Currently, lives within the pre-defined catchment area of Muheza District. Will remain within the same area throughout the study period (preferably class five and below). Exclusion Criteria: Students at class 6 and 7 Currently enrolled in another study or participated in another investigational drug study within the last 30 days. Known to have heart disease or a known cardiac ailment. Reports known hypersensitivity to the study drugs. Not willing to undergo all study procedures including physical examination and to provide blood samples as per this study protocol. Having clinical features of severe anaemia Febrile due to non-malaria illness at the time of recruitment. Has apparent severe infection or any condition that requires hospitalization Illness or conditions like hematologic, cardiac, renal, hepatic diseases which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency and SS sickle cell. Body weight < 14 k

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 15 Years

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
Interventional Model Description: A randomized, controlled, open label study assessing the effectiveness and safety of 2 antimalarial drugs for IPTsc, namely DP and ASAQ by a 3-arm trial using a balanced block design with the standard of care arm as reference.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DP<br>Dihydroartemisinin-piperaquine (DP), antimalarial drug to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects. | Drug: Dihydroartemisinin-piperaquine<br>* Dihydroartemisinin-piperaquine (DP). One of the Artemisinin combination therapy(ACTs), indicated for treatment of uncomplicated malaria. It will to be given every 4 months 3 rounds for a year.<br>|
| Active Comparator: ASAQ<br>Artesunate-amodiaquine (ASAQ), antimalarial drugs to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects. | Drug: Artesunate-amodiaquine<br>* Artesunate-amodiaquine (ASAQ). One of the Artemisinin combination therapy(ACTs), indicated for treatment of uncomplicated malaria. It will to be given every 4 months 3 rounds for a year.<br>|
| No Intervention: Control<br>No intervention drugs will be given, but normal routine standard of care will be provided. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in mean haemoglobin concentration at months 12 and 20 of follow-up | Will measure change from baseline haemoglobin concentration at month 12 (intervention period) and at month 20 (post intervention period to assess rebound effect) [Note: a trend of change at each visit will also be assessed with respect to malaria seasonality] | at months 0, 12 and 20 | 
| Clinical malaria incidence from month 0 till months 12 and 20 of follow up | number of symptomatic malaria episodes during and after intervention period | at months 0, 12 and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of asymptomatic malaria infections at month 0, 12 and 20 of follow up | to be measured from microscopic detection of malaria parasite on blood slides | from month 0 till month12 and 20 | 
| Prevalence of PCR confirmed sub-microscopic parasitaemia at months 0,12 and 20 of follow up | Polymerase chain reaction (PCR) confirmed from random subset of finger prick dry blood spots samples | at months 0, 12 and 20 | 
| Prevalence of soil transmitted helminths and schistosomiasis | A stool sample will be used to determine prevalence (defined as adult or eggs) of STH and S. mansoni infection determined by duplicate Kato-Katz thick smears technique. Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium) | at baseline, at month 12 and month 20. | 
| Prevalence of schistosomiasis | Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium) for confirmation. | at baseline, at month 12 and month 20. | 
| Prevalence of validated common P. falciparum polymorphisms known to be associated with drug sensitivity at baseline, at months 12 and 20 | from random subset of finger prick dry blood spots samples | at baseline, at month 12 and 20. | 
| Proportion of children seropositive for Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20 | from random subset of finger prick dry blood spots samples, Antibody responses to P. falciparum blood-stages antigens, apical membrane antigen (AMA-1) and merozoite surface protein (MSP-119) will be determined. | at baseline, at month 12 and 20. | 
| Change in serum antibody responses to Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20 | From random subset of finger prick dry blood spots samples to be eluted for ELISA | at baseline, at month 12 and 20. | 
| Percentages of school children with malnutrition through WHO's BMI z-score | weight in kilograms and height in meters will be combined to report BMI in kg/m^2 | at month 0, 12, and 20 | 
| Relative risk (RR), for all adverse events categorised to severity at month 12 and 20 | Adverse events will be detected throughout the study, Each intervention arm will be compared to control arm to determine risk of an adverse event among the two arms. Also events in two intervention arms will be compared to each other to assess risk in the two intervention arms. | at month 12 and 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive, Malaria, school children, randomized controlled trial, safety, effectiveness, Dihydroartemisinin-piperaquine, Artesunate-amodiaquine, malaria serology, drug resistance