Delivery of Malaria Chemoprevention in the Post-discharge Management of Children With Severe Anaemia in Malawi

Study Overview
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Brief Summary
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Background and rationale: Children hospitalised with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No strategy specifically addresses this post-discharge period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly 3-day treatment courses of artemether-lumefantrine (AL) in children with severe malarial anaemia prevented 31% of deaths and readmissions. The effect was in addition to the effect of insecticide-treated bednets. There is now need to design and evaluate effective delivery mechanism for PMC within the health system.

Detailed Description
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Objectives: The primary objective of the trial is to determine the optimum PMC delivery mechanism by comparing community- versus health facility-based strategies in order to inform policy. Study Type: This is a single-centre, matched, cluster randomized, 5-arm, factorial design trial comparing the uptake of PMC-DHP delivered through health facility or community-based approaches with or without SMS/HSA reminders. Site: 90 villages in the catchment areas of Zomba Central hospital in southern Malawi Study Population: Inclusion criteria: convalescent children aged less than 5 years and weighing >5 kg admitted with severe anaemia (haemoglobin<5g/dL / Ht<15%); clinically stable, able to take or switch to oral medication; post-transfusion Hb >5g/dL. Exclusion criteria: blood loss due to trauma, malignancy, known bleeding disorders or sickle cell trait, known hypersensitivity to study drug, known heart conditions, non-resident in study area, previous participation in study, known need at enrolment for prohibited medication and scheduled surgery during the course of the study. HIV infection and cotrimoxazole prophylaxis are not exclusion criteria Study Interventions: All children will receive Dihydroartemisinin-piperaquine (3-day treatment courses, given 2,6 and 10 weeks after discharge) either: at discharge + SMS Reminder; at discharge + No SMS Reminder; at discharge + HSA Reminder; at OPD + SMS Reminder; or at OPD + No SMS Reminder Outcome Measures: Primary: 100% of PMC drugs uptake (defined as administration of all 3-day treatment courses, given 2, 6 and 10 weeks after discharge) assessed by unannounced spot checks. Follow-up procedures: Children will be followed up for 15 weeks by passive case detection in 2 phases: Pre-PMC (2 weeks between hospital admission and 2 weeks post-discharge); PMC (2-14 weeks post-discharge) Sample Size: A sample size of 75 children per arm (375 total children) allows for a detection of 25% increase in uptake from 50% to 75% with 10% loss to follow-up (power 90%, α=0.05). Data Analysis: The % of children receiving IPTpd according to schedule will be compared by relative risks (95% CI), adjusted for prognostic factors at baseline using log binomial or Poisson regression with adjustment for cluster effects

Official Title
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Malaria Chemoprevention With Monthly Treatment With Dihydroartemisinin-Piperaquine for the Post-discharge Management of Severe Anaemia in Children Less Than 5 Years in Malawi

Conditions
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Malaria, Severe Anemia

Intervention / Treatment
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* Drug: dihydroartemisinin-piperaquine
* Other: message(SMS) reminder
* Other: Health worker reminder
* Other: short message(SMS) reminder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Haemoglobin <5.0g/dl or PCV <15%, or requirement for blood transfusion for other clinical reasons on or during admission to the hospital Age between 4 months (inclusive) and 59 months (inclusive) Body weight >5kgs Screening (in-hospital): Fulfilled the pre-study screening eligibility criteria Clinically stable, able to switch to oral medication Subject completed blood transfusion(s) in accordance with routine hospital practice Able to feed (for breastfed children) or eat (for older children) Absence of known cardiac problems Provision of informed consent by parent or guardian Randomization (at discharge): Fulfilled screening eligibility criteria Still clinically stable, able to take oral medication, able to feed (for breastfed children) or eat (for older children) and able to sit unaided (for older children who were able to do so prior to hospitalization Exclusion Criteria: Recognised specific other cause of severe anaemia (e.g. trauma, haematological malignancy, known bleeding disorder) Known sickle cell Child will reside for more than 25% of the 3.5months study period (i.e. 3 weeks or more) outside of catchment area Enrolment in the study (t=0) at discharge Previous enrolment in the present study Known hypersensitivity to study drug Sickle cell disease Known need at the time of enrolment for concomitant prohibited medication during the 14 weeks PMC treatment period. On-going or planned participation into another clinical trial involving on-going or scheduled treatment with medicinal products during the course of the study (3.5 months from enrolment) Known need, or scheduled surgery during the course of the study (3.5 months) Suspected non-compliance with the follow-up schedule Known heart conditions, or family history of congenital prolongation of the QTc interval

Ages Eligible for Study
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Minimum Age: 4 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Drug + short message(SMS) reminder<br>dihydroartemesinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrolment) with SMS reminders prior to each treatment course | Drug: dihydroartemisinin-piperaquine<br> <br> Other: short message(SMS) reminder<br> <br> |
| Other: Drug + no short message(SMS) reminder<br>dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrolment) without SMS reminders prior to each treatment course. | Drug: dihydroartemisinin-piperaquine<br> <br> |
| Other: Drug+ Health worker reminder<br>dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrolment) with Health surveillance assistants reminders prior to each treatment course. | Drug: dihydroartemisinin-piperaquine<br> <br> Other: Health worker reminder<br>* Health surveillance assistants reminders prior to each treatment course<br>|
| Other: Drug at hospital + SMS reminder<br>dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrolment) collected at the outpatient department without an SMS reminders prior to each treatment course. | Drug: dihydroartemisinin-piperaquine<br> <br> |
| Other: Drug at Hospital+no SMS reminder<br>dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrolment) collected at the outpatient department with a short message reminder prior to each treatment course | Drug: dihydroartemisinin-piperaquine<br> <br> Other: message(SMS) reminder<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of those with 100 % uptake of PMC drugs during the 15 weeks of the study period. | 100 % uptake is defined as administration of all study drugs and compliance to study visits during the course of 15 weeks. | 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of those with 60% uptake of PMC drugs during the 15 weeks of the study period. | 60 % uptake is defined as administration of 6 or more [but less than 9] of the daily dosages out of the total of 9 during the 15 week study period. | 15 weeks | 
| Proportion of those with 30 % uptake of PMC drugs during the 15 week trial period. | 30 % PMC uptake is defined as administration of 3 or more [but less than 6] of the daily dosages out of the total of 9 during the 15 week trial period. | 15 weeks | 
| Proportion of those with <30% uptake of PMC drugs during the 15 week trial period. | <30 % PMC uptake is defined as administration of less than 3 of the daily dosages out of the total of 9 assessed during the 15 week trial period. | 15 weeks |