Management of Severe Acute Malnutrition in SCD, in Northern Nigeria

Study Overview
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Brief Summary
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Except for children with HIV, all recommendations for treatment of childhood malnutrition are for children < 5 years of age. The overall goal of this randomized controlled nutritional feasibility trial is to identify whether families of children with sickle cell anemia (SCA) > 5 years of age agree to participate over a 12-week period. The investigators will also establish a safety protocol for monitoring potential complications associated with treating severe malnutrition in children > 5 years of age with and without SCA, in a low-resource setting.

Detailed Description
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The overall goal of this feasibility trial is to determine the acceptability of a randomized controlled trial to ascertain the optimal strategy for the treatment of severe malnutrition in children with sickle cell disease (SCD) older than 5 years of age. No international standard or evidence-based guidelines exist for the treatment of severe malnutrition (defined as BMI Z-score below -3) in children with SCD. With an expanding pediatric population of more than 75 million in Nigeria, coupled with decreasing childhood infectious disease-related mortality, the next emerging threats to preventable childhood deaths are non-communicable diseases. Data from our ongoing NIH-funded randomized controlled primary stroke prevention trial in Nigeria (NCT02560935), in which the investigators evaluated children with SCD between 5 and 12 years of age, demonstrated that 29% (230/803) of the cohort met criteria for severe malnutrition. Approximately 92% of the cohort in northern Nigeria identified as having severe malnutrition was below the 5th percentile for weight of children with SCD living in the US, Canada, or Europe. These data indicate older children with SCD living in northern Nigeria are undernourished when compared to children living with SCD in high-resource settings. A potentially unique attribute to treating malnutrition in children with SCD is the use of FDA approved anti-metabolite, hydroxyurea, to prevent vaso-occlusive pain events in children. The beneficial effects of hydroxyurea include, but are not limited to, decreased inflammation and increased hemoglobin levels. Preliminary evidence in this cohort of older children with sickle cell anemia (SCA) in northern Nigeria reveals that moderate fixed-dose hydroxyurea (20 mg/kg/day) significantly increases BMI in children with severe malnutrition. The investigators propose a randomized controlled feasibility trial in older children (5 to 12 years of age) with SCA living in northern Nigeria. In preparation for a definitive phase III trial to determine if ready-to-use therapeutic food and moderate fixed-dose hydroxyurea therapy is superior to ready-to-use therapeutic food alone, the investigators will randomly allocate 100 children between 5 and 12 years of age with SCA and severe uncomplicated malnutrition to each of the two arms. In aim 1, the investigators will assess the feasibility (rate of recruitment, retention, and adherence) of a randomized controlled trial (RCT) in children with SCA and severe malnutrition to a 12-week intervention period. For aim 2, the investigators will establish the safety protocol to monitor for unknown rates of complications associated with treating malnutrition in children with SCD. To decrease the likelihood of sharing limited food resources in a poor family and to determine the specificity of malnutrition for children with SCD in northern Nigeria, the investigators will screen and treat up to 150 malnourished non-SCD siblings of the trial participants. After completion of this feasibility trial, the investigators will use the acquired knowledge to design a phase III trial to definitively determine the optimal treatment strategy for severe malnutrition in older children with SCD living in Africa, potentially affecting thousands of children in this region.

Official Title
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Management of Severe Acute Malnutrition in Children With Sickle Cell Disease Greater Than 5 Years of Age Living in Northern Nigeria

Conditions
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Sickle Cell Anemia, Severe Acute Malnutrition

Intervention / Treatment
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* Drug: hydroxyurea (20mg/kg/day)
* Dietary Supplement: Ready-to-use therapeutic food


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: confirmed diagnoses of SCA, comparison children without SCD severe malnutrition defined as a BMI z-score < -3 age between 5 and 12 years (assessment can take place up until the 13th birthday) pass the appetite test uncomplicated malnutrition (good appetite, alert, no signs of infection of respiratory distress) Exclusion Criteria: children with complicated severe acute malnutrition children with electrolyte disturbances (serum Na, K, PO4) at baseline children on disease-modifying therapy (hydroxyurea or regular blood transfusion therapy) children enrolled in other studies children with diabetes and other chronic illnesses children with known HIV infection children with a known allergy to dairy or peanuts.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A 12-week, open label, randomized controlled feasibility trial in children with SCA between 5 and 12 years of age to treat uncomplicated severe malnutrition.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ready-to-use therapeutic food and Hydroxyurea<br>50 children (5-12 years old) with SCA and severe malnutrition will be randomly allocated to receive Ready-to-use therapeutic food and hydroxyurea (20mg/kg/day) | Drug: hydroxyurea (20mg/kg/day)<br>* Treatment of severe malnutrition in children with SCA in northern Nigeria<br>* Other names: hydrea;Dietary Supplement: Ready-to-use therapeutic food<br>* Treatment of severe malnutrition in children with SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeautic food<br>* Other names: RUTF;|
| Placebo Comparator: Ready-to-use therapeutic food alone<br>50 children (5-12 years old) with SCA and severe malnutrition will be randomly allocated to receive Ready-to-use therapeutic food alone | Dietary Supplement: Ready-to-use therapeutic food<br>* Treatment of severe malnutrition in children with SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeautic food<br>* Other names: RUTF;|
| Placebo Comparator: non-SCD AND severe malnutrition<br>To decrease the likelihood of sharing limited food resources, we will enroll up to 100 malnourished non-SCD siblings. | Dietary Supplement: Ready-to-use therapeutic food<br>* Treatment of severe malnutrition in children with SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeautic food<br>* Other names: RUTF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapy Acceptance and Adherence over 12-week Period | The primary outcome is the proportion of eligible individuals that agree to be included, referred to as the recruitment rate, the retention rate for the trial, and the adherence rates to both the protocol and to therapy (Ready-to-use therapeutic food and hydroxyurea). | Feasibility over 12-week Period [Time Frame: 4 months] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nutritional Safety protocol for Children with Sickle Cell Anemia and Severe Malnutrition | The outcome for safety is our ability to identify serious adverse events (SAE), defined as death, ICU admission, or life-threatening infection in a timely manner and monitor such events. We will assess the percentage of children with SAEs during the study period (expressed as a point estimate ± 95% CIs), and also the rate of events (events/person year) | 6 months | 
| Feasibility of a Definitive Phase III Trial for Hydroxyurea and Nutritional Therapy to Treat Severe Malnutrition in Sickle Cell Disease | Not a secondary outcome; however as an overall objective of the study, the investigators will prepare a manual of operations and case report forms for the proposed trial. Investigators will also solidify working relationships with our colleagues and collaborators at sites in Kano, Nigeria; and develop and organize all committees, collaborators and study procedures necessary for initiation of a successful, definitive, Phase III Trial | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, sub-Saharan Africa, malnutrition, low-income settings, severe acute malnutrition, sickle cell anemia, Nigeria