Post-discharge Malaria Chemoprevention(PMC) Study

Study Overview
=================
Brief Summary
-----------------
This study evaluates the efficacy and safety of 3 months of malaria chemoprevention post-discharge using dihydroartemisinin piperaquine (DHA-P) in children under 5 years of age admitted with severe anemia. One half will receive monthly DHA-P and the other half placebo.

Detailed Description
-----------------
Children hospitalized with severe anemia 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 with monthly 3-day treatment courses of artemether-lumefantrine (AL) in children with severe malarial anemia prevented 31% of deaths and readmissions. This study is a confirmatory efficacy trial in Kenya and Uganda to determine the efficacy and safety of malaria chemoprevention post-discharge. We hypothesize that an additional three months of malaria chemoprevention with monthly 3-day treatment courses with DHA-piperaquine (each providing about 4 weeks of post-treatment prophylaxis) provided during the post-discharge period to children recently admitted with severe anemia is superior to reduce all-cause readmission and mortality rates by 6 months compared with 2 weeks of post-treatment prophylaxis provided by the single course of oral AL when given as part of the standard in-hospital care around the time of discharge.

Official Title
-----------------
Malaria Chemoprevention With Monthly Treatment With Dihydroartemisinin-piperaquine for the Post-discharge Management of Severe Anaemia in Children Aged Less Than 5 Years in Uganda and Kenya: A Two-arm Randomised Placebo Controlled Trial

Conditions
-----------------
Malaria, Severe Anemia

Intervention / Treatment
-----------------
* Drug: dihydroartemisinin-piperaquine
* Drug: dihydroartemisinin-piperaquine placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pre-study screening Haemoglobin <5.0 g/dl or PCV < 15%, or requirement for blood transfusion for other clinical reasons on or during admission to the hospital Aged less than 59.5 months Body weight >5 kg Resident in catchment area Enrolment in study(t=0) Fulfilled the pre-study screening eligibility criteria Aged < 59.5 months Clinically stable, able to take oral medication Subject completed blood transfusion(s) or became clinically stable without transfusion Able to feed (for breastfeeding children) or eat (for older children) Absence of know cardiac problems Provision of informed consent by parent or guardian Randomisation (t=2 weeks) Fulfilled enrolment eligibility criteria and was enrolled during recent admission Aged <60 months Still clinically stable, able to take to oral medication, able to feed (for breastfeeding children) or eat (for older children) and able to sit unaided (for older children who were already able to do so prior to hospitalisation) Exclusion Criteria: Pre-study screening Recognised specific other cause of severe anaemia (e.g. trauma, haematological malignancy, known bleeding disorder) Known sickle cell disease Anticipated to reach the 5th birthday (60 months of age) within 2 weeks from enrolment (i.e. prior to randomization) Child will reside for more than 25%of the 6 months study period (i.e. 6 weeks or more) outside of catchment area Enrolment in study (t=0) Previous enrolment in the present study Known hypersensitivity to study drug Sickle cell disease Use or known need at the time of enrolment for concomitant prohibited medication during the 14 weeks PMC treatment period. Ongoing or planned participation in another clinical trial involving ongoing or scheduled treatment with prohibited medicinal products or active follow-up during the course of the study (6 months from enrolment) A known need at the time of enrolment for scheduled surgery during the subsequent course of the study (6 months from enrolment) Suspected non-compliance with the follow-up schedule Know heart conditions, or family history of congenital prolongation of the QTc interval. Taking medicinal products that are known to prolong the QTc interval Randomisation (t=2 weeks) Used dihydroartemisinin since enrolment Use or known need at the time of randomisation for concomitant prohibited medication during the 14 weeks PMC treatment period. Enrolled, or known agreement to enrol into another clinical trial involving ongoing or scheduled treatment with medicinal products during the course of the study (6 months from enrolment) A known need at the time of randomisation for scheduled surgery during the subsequent course of the study (6 months from enrolment) Suspected non-compliance with the follow-up schedule Withdrawal of consent since enrolment

Ages Eligible for Study
-----------------
Maximum Age: 60 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: dihydroartemisinin-piperaquine<br>dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrollment) | Drug: dihydroartemisinin-piperaquine<br>* Children in both arms will receive standard in-hospital care for severe anaemia (blood transfusion, often combined with quinine or artesunate IV/IM). All children will then receive a 3-day course of AL (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication, and will be completed at home after discharge. At 2 weeks after enrolment surviving children will be randomized to receive either a standard 3-day courses of dihydroartemisinin-piperaquine (Eurartesim®, Sigma Tau, Italy) or an identical placebo regimen at 2, 6 and 10 weeks after enrolment.<br>* Other names: Eurartesim;|
| Placebo Comparator: dihydroartemisinin-piperaquine Placebo<br>Placebo comparator (matching tablets containing no active ingredients) | Drug: dihydroartemisinin-piperaquine placebo<br>* Children will receive standard in-hospital care for severe anaemia (blood transfusion, often combined with quinine or artesunate IV/IM). All children will then receive a 3-day course of AL (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication, and will be completed at home after discharge. At 2 weeks after enrolment surviving children will be randomized to receive either a standard 3-day courses of dihydroartemisinin-piperaquine (Eurartesim®, Sigma Tau, Italy) or an identical placebo regimen at 2, 6 and 10 weeks after enrolment.<br>* Other names: Eurartesim placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause deaths or all-cause re-admissions by 26 weeks from randomization (composite primary outcome). | Primary outcome | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Readmission due to severe malaria (defined as any treatment with parenteral quinine or artesunate, or presence of severe anaemia and treatment with oral antimalarials) by 26 weeks from randomization |  | 26 weeks from randomization | 
| All-cause readmission by 26 weeks from randomization |  | 26 weeks from randomization | 
| Readmissions due to severe anaemia (defined as Haemoglobin (Hb) <5g/dL or packed-cell volume (PCV) <15% or requirement for blood transfusion based on other clinical indication)by 26 weeks from randomization |  | 26 weeks from randomization | 
| Readmission due to severe malarial anaemia (severe anaemia plus parenteral or oral antimalarial treatment)by 26 weeks from randomization |  | 26 from randomization | 
| Readmission due to severe anaemia or severe malaria (composite outcome)by 26 weeks from randomization |  | 26 weeks from randomization | 
| All-cause mortality by 26 weeks from randomization |  | 26 weeks from randomization | 
| Clinic visits because of smear of rapid diagnostic test (RDT) confirmed non-severe malaria by 26 weeks from randomization |  | 26 weeks from randomization | 
| Readmission due to severe malaria-specific anaemia (severe anaemia plus parenteral or oral antimalarial treatment and parasite density >5000/microlitre) by 26 weeks from randomization |  | 26 weeks from randomization | 
| Readmission due to severe disease other than severe anaemia and severe malaria by 26 weeks from randomization |  | 26 weeks from randomization | 
| Non-severe all-cause sick-child clinic visits by 26 weeks from randomization |  | 26 weeks from randomization | 
| Non-malaria sick child clinic visits by 26 weeks from randomization |  | 26 weeks from randomization | 
| Malaria infection at 6 month |  | 6 month | 
| Hb at 6 months |  | 6 months | 
| Any anaemia (Hb<11 g/dL), mild anaemia (Hb 8.0-10.99 g/dl) moderate anaemia (Hb 5.0-7.99 g/dL) and severe anaemia (Hb<5 g/dL) at 6 months |  | 6 months | 
| Weight-for-age, height-for-age, and height-for-weight Z-scores, standard deviation (SD) scores of reference population) at 6 months |  | 6 months | 
| Serious adverse events, excluding primary and secondary efficacy outcomes, by 26 weeks from randomization |  | 26 weeks from randomization | 
| Serious adverse events within 7 days after the start of each course of PMC, excluding primary and secondary efficacy outcomes. |  | 26 weeks from randomization | 
| Adverse events by 26 weeks from randomization |  | 26 weeks from randomization | 
| Adverse events within 7 days after start of each course of PMC. |  | 7 days post drug administration | 
| Corrected QT interval (QTc) prolongation measured by electro cardio gram (ECG)4-6 hours after 3rd dose of each course |  | 4-6 hours after 3rd dose of each course | 
| Patients costs of receiving the intervention |  | 26 weeks after randomization | 
| Patients costs related to treatment of the primary disease, readmission or death |  | 26 weeks after randomization | 
| The costs of the health care system of providing the intervention |  | 26 weeks after randomization | 
| The costs of the health system of treating the primary disease and anaemia, as well as treatment of readmissions or costs related to fatalities |  | 26 weeks after randomization |