Management of Severe Acute Malnutrition in SCD, in Northern Nigeria

Phase 2

Completed

• Conditions: Sickle Cell Anemia; Severe Acute Malnutrition
• Interventions: Drug: hydroxyurea (20mg/kg/day); Dietary Supplement: Ready-to-use therapeutic food

• Registration Number: NCT03634488
• Lead Sponsor: Vanderbilt University Medical Center

Brief Summary

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 nutrition feasibility trial is to identify whether families of children with sickle cell disease (SCD) 5 years and older 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 and older with and without SCD, in a low-resource setting.

Detailed Description

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) 5 years and older. 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 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 up to 150 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 SCD 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 100 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-01-30
• Study First Submitted QC: 2018-08-14
• Study First Posted: 2018-08-16
• Study Start: 2021-08-18
• Primary Completion: 2022-10-05
• Study Completion: 2022-11-09
• Results First Submitted: 2023-10-06
• Status Verified: 2024-02
• Results First Submitted QC: 2024-02-29
• Last Update Submitted: 2024-02-29
• Results First Posted: 2024-03-27
• Last Update Posted: 2024-03-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 132

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)

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SCD - Ready-to-use therapeutic food and Hydroxyurea	hydroxyurea (20mg/kg/day)	50-75 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)
SCD - Ready-to-use therapeutic food alone	Ready-to-use therapeutic food	50-75 children (5-12 years old) with SCA and severe malnutrition will be randomly allocated to receive ready-to-use therapeutic food alone
Non-SCD siblings with severe malnutrition	Ready-to-use therapeutic food	To decrease the likelihood of sharing limited food resources, we will enroll up to 100 malnourished non-SCD siblings.
SCD - Ready-to-use therapeutic food and Hydroxyurea	Ready-to-use therapeutic food	50-75 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)

Primary Outcome Measures

Name	Time	Method
Change in Mean Corpuscular Volume	12 weeks	Adherence to hydroxyurea was evaluated based on change in mean corpuscular volume
Enrollment Rate at the End of the 6-month Recruitment Period	6 months	Recruitment Feasibility: The primary outcome is the proportion of eligible individuals that agree to be included, referred to as the recruitment rate. Children with severe malnutrition who qualified and agreed to participate were invited to sign a consent and assent for study recruitment to this study.
Retention Over 12-week Period	12 weeks	The primary outcome is the proportion of participants who completed the 12-week trial, known as the retention rate for the trial.
Percentage of Ready-to-use Therapeutic Food Sachets Returned as Empty.	12 weeks	Adherence to the ready-to-use therapeutic food was evaluated based on the percentage of empty food sachets returned at each visit.
Number of Missed Visits	12 weeks	Adherence to monthly visits was assessed based on the number of missed visits
Percentage of Hydroxyurea Pills Returned	12 weeks	Adherence to hydroxyurea was evaluated based on the percentage of hydroxyurea pills returned for the group randomized to both ready-to-use therapeutic food and hydroxyurea.
Fetal Hemoglobin Levels at Exit	Feasibility over 12-week Period [Time Frame: 3 months]	The primary outcome is the proportion of eligible individuals who adhere to therapy (Ready-to-use therapeutic food and hydroxyurea). The adherence rate for hydroxyurea was determined based on the fetal hemoglobin levels at exit (12 weeks).
Mean Corpuscular Volume Values at Exit	Feasibility over 12-week Period [Time Frame: 3 months]	The primary outcome is the proportion of eligible individuals who adhere to therapy (Ready-to-use therapeutic food and hydroxyurea). The adherence rate for hydroxyurea was determined based on mean corpuscular volume (MCV) values at exit (12 weeks).
Change in Fetal Hemoglobin Level Percentage	Baseline to 12 weeks	The primary outcome is the proportion of eligible individuals who adhere to therapy (Ready-to-use therapeutic food and hydroxyurea). The adherence rate for hydroxyurea was determined based on the change in fetal hemoglobin level percentage.
Total Hemoglobin Levels at Exit	Feasibility over 12-week Period [Time Frame: 3 months]	The primary outcome is the proportion of eligible individuals who adhere to therapy (Ready-to-use therapeutic food and hydroxyurea). The adherence rate for hydroxyurea was determined based on the total hemoglobin levels at exit (12 weeks).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Maintaining a BMI Z-score Less Than -3.0	12 weeks	As a secondary outcome, we assessed the percentage of participants with and without SCA who continued to have a body mass index z-score of \<-3.0 at the end of the 12 weeks of treatment. Using the World Health Organization (WHO) growth reference, anthropometric measurements were converted to age and sex-specific z-scores. Anthropometric Indices (BMI-for-age (BMIZ), were calculated using WHO 2007 R Macro Package to assess growth and development of the children. Severe malnutrition/wasting (SAM) was defined as a body mass index (BMI) z-score \<-3.0.

Trial Locations

Locations (3)

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Murtala Mohammad Specialist Hospital; 🇳🇬 Kano, Nigeria

Aminu Kano Teaching Hospital; 🇳🇬 Kano, Nigeria