Management of Severe Acute Malnutrition in SCD, in Northern Nigeria

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

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Anemia; Severe Acute Malnutrition
• Intervention / Treatment: Drug: hydroxyurea (20mg/kg/day); Dietary supplement: Ready-to-use therapeutic food

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.

• Study Type: Interventional
• Enrollment (Actual): 132
• Phase: Phase 2

Contacts and Locations

Study Locations

• Nigeria
  • Kano, Nigeria
    • Aminu Kano Teaching Hospital
  • Kano, Nigeria
    • Murtala Mohammad Specialist Hospital
• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232-9000
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 10 years (Child)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SCD - Ready-to-use therapeutic food and Hydroxyurea; 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)	Drug: hydroxyurea (20mg/kg/day); Treatment of severe malnutrition in children with SCA in northern Nigeria; Other Names: hydrea; Dietary supplement: Ready-to-use therapeutic food; Treatment of severe malnutrition in children with and without SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food; Other Names: RUTF
Placebo Comparator: SCD - Ready-to-use therapeutic food alone; 50-75 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; Treatment of severe malnutrition in children with and without SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food; Other Names: RUTF
Placebo Comparator: Non-SCD siblings with severe malnutrition; 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; Treatment of severe malnutrition in children with and without SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food; Other Names: RUTF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enrollment Rate at the End of the 6-month Recruitment Period	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.	6 months
Retention Over 12-week Period	The primary outcome is the proportion of participants who completed the 12-week trial, known as the retention rate for the trial.	12 weeks
Percentage of Ready-to-use Therapeutic Food Sachets Returned as Empty.	Adherence to the ready-to-use therapeutic food was evaluated based on the percentage of empty food sachets returned at each visit.	12 weeks
Number of Missed Visits	Adherence to monthly visits was assessed based on the number of missed visits	12 weeks
Percentage of Hydroxyurea Pills Returned	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.	12 weeks
Change in Mean Corpuscular Volume	Adherence to hydroxyurea was evaluated based on change in mean corpuscular volume	12 weeks
Change in Fetal Hemoglobin Level Percentage	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.	Baseline to 12 weeks
Mean Corpuscular Volume Values at Exit	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).	Feasibility over 12-week Period [Time Frame: 3 months]
Fetal Hemoglobin Levels at Exit	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).	Feasibility over 12-week Period [Time Frame: 3 months]
Total Hemoglobin Levels at Exit	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).	Feasibility over 12-week Period [Time Frame: 3 months]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Maintaining a BMI Z-score Less Than -3.0	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.	12 weeks

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Aminu Kano Teaching Hospital; Murtala Muhammad Specialist Hospital
• Investigators: Principal Investigator: Michael DeBaun, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2021
• Primary Completion (Actual): October 5, 2022
• Study Completion (Actual): November 9, 2022

Study Registration Dates

• First Submitted: January 30, 2018
• First Submitted That Met QC Criteria: August 14, 2018
• First Posted (Actual): August 16, 2018

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: malnutrition; sickle cell disease; sub-Saharan Africa; severe acute malnutrition; sickle cell anemia; Nigeria; low-income settings
• Additional Relevant MeSH Terms: Hematologic Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Malnutrition; Severe Acute Malnutrition; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: 170577

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes