Severe Acute Malnutrition, Sickle Cell Anemia
Conditions
Keywords
sickle cell disease, sub-Saharan Africa, malnutrition, low-income settings, severe acute malnutrition, sickle cell anemia, Nigeria
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.
Interventions
DRUGhydroxyurea (20mg/kg/day)
Treatment of severe malnutrition in children with SCA in northern Nigeria
DIETARY_SUPPLEMENTReady-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
Sponsors
Aminu Kano Teaching Hospital
Murtala Muhammad Specialist Hospital
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Allocation was concealed from all other study personnel, except statisticians.
Intervention model description
A 12-week, open label, randomized controlled feasibility trial in children with sickle cell anemia between 5 and 12 years of age to treat uncomplicated severe malnutrition.
Eligibility
Sex/Gender
ALL
Age
5 Years to 12 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| Change in Mean Corpuscular Volume | 12 weeks | Adherence to hydroxyurea was evaluated based on change in mean corpuscular volume |
| 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. |
| 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). |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Nigeria, United States
Participant flow
Recruitment details
The first participant was enrolled in the Management of Severe Acute Malnutrition in Children With Sickle Cell Disease Greater Than 5 Years of Age Living in Northern Nigeria study in August 2021. Recruitment took place at Aminu Kano Teaching Hospital and Murtala Muhammad Specialist Hospital in Kano, Nigeria. Enrollment for children with SCD (either the Ready-to-Use Therapeutic Food arm or the Ready-to-Use Therapeutic Food and Hydroxyurea arm) and siblings without SCD ended in May 2022.
Pre-assignment details
The feasibility trial's primary objectives are to evaluate the intervention's feasibility and safety in children with sickle cell anemia.
Participants by arm
| Arm | Count |
|---|---|
| SCD - Ready-to-use Therapeutic Food and Hydroxyurea Children (5-12 years old) with SCA and severe malnutrition randomly allocated to receive Ready-to-use therapeutic food and hydroxyurea (20mg/kg/day)
hydroxyurea (20mg/kg/day): Treatment of severe malnutrition in children with SCA in northern Nigeria
Ready-to-use therapeutic food: Treatment of severe malnutrition in children with SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food | 55 |
| SCD - Ready-to-use Therapeutic Food Alone Children (5-12 years old) with SCA and severe malnutrition randomly allocated to receive Ready-to-use therapeutic food alone
Ready-to-use therapeutic food: Treatment of severe malnutrition in children with SCA in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food | 54 |
| Siblings Without SCD non-SCD siblings(5-12 years old) with severe malnutrition.
Ready-to-use therapeutic food: Treatment of severe malnutrition in children without SCD in northern Nigeria with an additional 500-1000 calories from ready-to-use-therapeutic food | 22 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | A participant was administratively withdrawn due to a calculated BMI z-score >-3.0. | 1 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | SCD - Ready-to-use Therapeutic Food and Hydroxyurea | SCD - Ready-to-use Therapeutic Food Alone | Siblings Without SCD | Total |
|---|---|---|---|---|
| Age, Continuous | 10.2 years | 10.5 years | 8.2 years | 10.1 years |
| Body Mass Index, kg/m^2, mean (std. dev.) | 12 kg/m^2 STANDARD_DEVIATION 0.6 | 12.1 kg/m^2 STANDARD_DEVIATION 0.6 | 11.7 kg/m^2 STANDARD_DEVIATION 0.6 | 12 kg/m^2 STANDARD_DEVIATION 0.6 |
| Body Mass Index z-score, mean (std. dev.) | -3.64 Z-score STANDARD_DEVIATION 0.49 | -3.66 Z-score STANDARD_DEVIATION 0.44 | -3.6 Z-score STANDARD_DEVIATION 0.5 | -3.65 Z-score STANDARD_DEVIATION 0.46 |
| Height, cm, mean (std. dev.) | 123.5 centimeters STANDARD_DEVIATION 10.1 | 124.1 centimeters STANDARD_DEVIATION 9.5 | 123.5 centimeters STANDARD_DEVIATION 12.3 | 123.7 centimeters STANDARD_DEVIATION 10.2 |
| Hemoglobin, g/dl, mean (std. dev.) | 7.4 g/dl STANDARD_DEVIATION 1 | 7.3 g/dl STANDARD_DEVIATION 1.1 | 10.8 g/dl STANDARD_DEVIATION 1 | 7.9 g/dl STANDARD_DEVIATION 1.7 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Race/Ethnicity, Customized Fulani | 4 Participants | 2 Participants | 0 Participants | 6 Participants |
| Race/Ethnicity, Customized Hausa | 49 Participants | 51 Participants | 22 Participants | 122 Participants |
| Race/Ethnicity, Customized Kanuri | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 26 Participants | 27 Participants | 14 Participants | 67 Participants |
| Sex: Female, Male Male | 29 Participants | 27 Participants | 8 Participants | 64 Participants |
| Weight, kg, mean (std. dev.) | 18.4 kg STANDARD_DEVIATION 3.5 | 18.7 kg STANDARD_DEVIATION 3.5 | 18.1 kg STANDARD_DEVIATION 4.2 | 18.5 kg STANDARD_DEVIATION 3.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 56 | 0 / 54 | 0 / 22 |
| other Total, other adverse events | 2 / 56 | 4 / 54 | 0 / 22 |
| serious Total, serious adverse events | 1 / 56 | 0 / 54 | 0 / 22 |
Outcome results
Primary
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.
Time frame: Baseline to 12 weeks
Population: The final analysis included 54 participants from each arm with sickle cell anemia and severe acute malnutrition. We did not measure fetal hemoglobin in children without SCD.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Change in Fetal Hemoglobin Level Percentage | 3.9 percentage of fetal hemoglobin |
| Eligible Children Aged 5-12 Years Old Without SCD | Change in Fetal Hemoglobin Level Percentage | 2.2 percentage of fetal hemoglobin |
Primary
Change in Mean Corpuscular Volume
Adherence to hydroxyurea was evaluated based on change in mean corpuscular volume
Time frame: 12 weeks
Population: The final analysis included 54 participants from each arm with sickle cell anemia and severe acute malnutrition. We did not include the siblings' change in mean corpuscular volume - since none of the siblings without sickle cell disease received hydroxyurea.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Change in Mean Corpuscular Volume | 5.4 fl | Standard Deviation 12.7 |
| Eligible Children Aged 5-12 Years Old Without SCD | Change in Mean Corpuscular Volume | -1.0 fl | Standard Deviation 10.9 |
Primary
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.
Time frame: 6 months
Population: Children aged 5-12 years with SCA were evaluated for eligibility. Siblings of enrolled participants aged 5-12 years old without SCD were also evaluated for eligibility.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Enrollment Rate at the End of the 6-month Recruitment Period | Eligible | 111 participants |
| Eligible Children Aged 5-12 Years With SCA | Enrollment Rate at the End of the 6-month Recruitment Period | Randomized | 110 participants |
| Eligible Children Aged 5-12 Years With SCA | Enrollment Rate at the End of the 6-month Recruitment Period | Unable to randomize | 1 participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Enrollment Rate at the End of the 6-month Recruitment Period | Eligible | 22 participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Enrollment Rate at the End of the 6-month Recruitment Period | Randomized | 22 participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Enrollment Rate at the End of the 6-month Recruitment Period | Unable to randomize | 0 participants |
Primary
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).
Time frame: Feasibility over 12-week Period [Time Frame: 3 months]
Population: The final analysis included 54 participants from each arm with sickle cell anemia and severe acute malnutrition. The feasibility trial's primary objectives are to evaluate the intervention's feasibility and safety in children with sickle cell anemia. We, therefore, did not include the outcomes for the siblings in these main results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Fetal Hemoglobin Levels at Exit | 12.2 percentage of fetal hemoglobin |
| Eligible Children Aged 5-12 Years Old Without SCD | Fetal Hemoglobin Levels at Exit | 9.4 percentage of fetal hemoglobin |
Primary
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).
Time frame: Feasibility over 12-week Period [Time Frame: 3 months]
Population: The final analysis included 54 participants from each arm with sickle cell anemia and severe acute malnutrition. The feasibility trial's primary objectives are to evaluate the intervention's feasibility and safety in children with sickle cell anemia. We, therefore, did not include the outcomes for the siblings in these main results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Mean Corpuscular Volume Values at Exit | 88.5 fl | Standard Deviation 14.7 |
| Eligible Children Aged 5-12 Years Old Without SCD | Mean Corpuscular Volume Values at Exit | 85.4 fl | Standard Deviation 11.4 |
Primary
Number of Missed Visits
Adherence to monthly visits was assessed based on the number of missed visits
Time frame: 12 weeks
Population: Per-protocol analysis of participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Number of Missed Visits | 0 missed visits |
| Eligible Children Aged 5-12 Years Old Without SCD | Number of Missed Visits | 0 missed visits |
| Siblings Without SCD | Number of Missed Visits | 0 missed visits |
Primary
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.
Time frame: 12 weeks
Population: The final analysis included 54 participants with sickle cell anemia and severe acute malnutrition randomized to receive hydroxyurea in addition to ready-to-use therapeutic food. The other arms did not receive hydroxyurea, and therefore, adherence to hydroxyurea cannot be evaluated.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Percentage of Hydroxyurea Pills Returned | 4.4 percentage of hydroxyurea pills returned |
Primary
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.
Time frame: 12 weeks
Population: The final analysis included 54 participants with sickle cell anemia from each arm with sickle cell anemia and severe acute malnutrition, along with 22 non-SCD siblings with severe acute malnutrition.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Percentage of Ready-to-use Therapeutic Food Sachets Returned as Empty. | 99.02 percentage of empty sachets |
| Eligible Children Aged 5-12 Years Old Without SCD | Percentage of Ready-to-use Therapeutic Food Sachets Returned as Empty. | 99.03 percentage of empty sachets |
| Siblings Without SCD | Percentage of Ready-to-use Therapeutic Food Sachets Returned as Empty. | 99.02 percentage of empty sachets |
Primary
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.
Time frame: 12 weeks
Population: The analysis included participants with sickle cell anemia and severe acute malnutrition. The feasibility trial's primary objectives are to evaluate the intervention's feasibility and safety in children with sickle cell anemia.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Retention Over 12-week Period | Voluntarily withdrew from the trial | 0 participants |
| Eligible Children Aged 5-12 Years With SCA | Retention Over 12-week Period | Involuntary withdrawal from the trial | 1 participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Retention Over 12-week Period | Voluntarily withdrew from the trial | 0 participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Retention Over 12-week Period | Involuntary withdrawal from the trial | 0 participants |
| Siblings Without SCD | Retention Over 12-week Period | Voluntarily withdrew from the trial | 0 participants |
| Siblings Without SCD | Retention Over 12-week Period | Involuntary withdrawal from the trial | 0 participants |
Primary
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).
Time frame: Feasibility over 12-week Period [Time Frame: 3 months]
Population: The final analysis included 54 participants from each arm with sickle cell anemia and severe acute malnutrition. The feasibility trial's primary objectives are to evaluate the intervention's feasibility and safety in children with sickle cell anemia. We, therefore, did not include the outcomes for the siblings in these main results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Total Hemoglobin Levels at Exit | 8.3 g/dl | Standard Deviation 1.1 |
| Eligible Children Aged 5-12 Years Old Without SCD | Total Hemoglobin Levels at Exit | 7.7 g/dl | Standard Deviation 1.3 |
Secondary
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.
Time frame: 12 weeks
Population: The final analysis included 54 participants with sickle cell anemia from each arm with sickle cell anemia and severe acute malnutrition, along with 22 non-SCD siblings with severe acute malnutrition.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eligible Children Aged 5-12 Years With SCA | Percentage of Participants Maintaining a BMI Z-score Less Than -3.0 | 66.7 percentage of participants |
| Eligible Children Aged 5-12 Years Old Without SCD | Percentage of Participants Maintaining a BMI Z-score Less Than -3.0 | 55.6 percentage of participants |
| Siblings Without SCD | Percentage of Participants Maintaining a BMI Z-score Less Than -3.0 | 30.1 percentage of participants |