Conditions: Sickle Cell Anemia Severe Acute Malnutrition
Keywords: sickle cell disease sub-Saharan Africa malnutrition low-income settings severe acute malnutrition sickle cell anemia Nigeria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 132
Healthy volunteers: yes

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.

Arms:
arm 1: 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) arm 2: 50-75 children (5-12 years old) with SCA and severe malnutrition will be randomly allocated to receive ready-to-use therapeutic food alone arm 3: To decrease the likelihood of sharing limited food resources, we will enroll up to 100 malnourished non-SCD siblings.

Interventions: intervention 1: hydroxyurea (20mg/kg/day) intervention 2: Ready-to-use therapeutic food
Intervention descriptions: intervention 1: Treatment of severe malnutrition in children with SCA in northern Nigeria intervention 2: 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

Protocol document:
Prot_000.pdf: 
Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
Page 1 of 32 
 
 
 
 
 
ID: 170577  
Management of Severe Acute Malnutrition in SCD, in 
Northern Nigeria  
NCT03634488 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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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 
 
Principal Investigator: Dr. Michael R. DeBaun, M.D., M.P.H. 
Professor of Pediatrics and Medicine 
JC Peterson Endowed Chair in Pediatrics 
Vice Chair of Clinical Research in Pediatrics 
Vanderbilt University School of Medicine 
2200 Children’s Way, 11206DOT 
Nashville, TN, 37232-9000 
 
Co-Principal Investigator: Dr. Sari A. Acra, M.D. 
Professor of Clinical Pediatrics, Gastroenterology 
Division Chief, Medical Director, Director Fellowship Program 
Vanderbilt University School of Medicine 
2200 Children’s Way, 10th Floor, Doctors’ Office Tower 
Nashville, TN, 37232-9000 
 
 
 
 
 
Study coordinator:  
Leshana Saint-Jean, PhD 
Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease 
2525 West End Ave, Ste 750 VIGH 
Nashville, TN 37203 
Email : leshana.saint.jean@vumc.org 
 
Protocol version: 06/01/2022 
 
 
 
 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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Study Roster 
Principal Investigators: 
Michael R. DeBaun, MD, MPH  
Principal Investigator (Contact)  
Vanderbilt University School of Medicine  
Monroe Carell Jr. Children’s Hospital at Vanderbilt Email: m.debaun@vumc.org 
Phone: 615-875-3040 
Dr. Sari A. Acra, M.D. 
Co-Principal Investigator 
Professor of Clinical Pediatrics, Gastroenterology 
Division Chief, Medical Director, Director Fellowship Program 
Vanderbilt University School of Medicine 
2200 Children’s Way, 10th Floor, Doctors’ Office Tower 
 
Nashville, TN, 37232-9000 
Email : sari.acra@vumc.org 
 
Virginia Stallings, MD 
Co-Principal Investigator  
Nutrition pediatrician and Jean A. Cortner Endowed Chair in the Division of Gastroenterology, 
Hepatology and Nutrition at Children's Hospital of Philadelphia. Research Director in the 
Nutrition Center 
Email : stallingsv@email.chop.edu 
 
Study Coordinator 
Leshana Saint-Jean, PhD 
Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease 
2525 West End Ave, Ste 750 VIGH 
Nashville, TN 37203 
Email : leshana.saint.jean@vumc.org 
Clinical Sites in northern Nigeria (Kano):  
1. Aminu Kano Teaching Hospital  
2. Murtala Muhammad Specialist Hospital  
Study personnel conducts activity at both all study sites. 
Site PI : Shehu Umar Abdullahi, MD, 
FWACPaed Consultant Pediatrician 
Aminu Kano Teaching Hospital School of 
Medicine Department of Pediatrics Zaria 
Road, P.M.B 3452 Kano, NGA: Nigeria 
Phone: 234-802-326-8363 Email: 
dr_suak@yahoo.com 
Site PI : Safiya Gambo, MBBS, FWACP 
Pediatrician, Site Investigator II Murtala 
Mohammed Specialist Hospital 
Department of Pediatrics Kano, Nigeria 
Phone: 234-803-314-9383 Email: 
saphiaaa01@gmail.com 
Saifuddeen Sani Adamu 
Research Coordinator 
Aminu Kano Teaching Hospital 
Bilya Sani Musa Research Coordinator 
Aminu Kano Teaching Hospital 
Administrative Department Zaria Road, 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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Phone: +2347030159400 
 
P.M.B 3452 Kano, NGA: Nigeria Phone: 
234-803-600-5052 Fax: 234-646-63454 
Email: bilyasani@yahoo.com 
Awwal Inuwa Gambo Research 
Coordinator Address: No. 1 Indus close, 
off Euphrates Crescent Maitama to Midel 
Centre, Plot 14, Off Oladipo Diya Way 
Gudu District, Abuja. Nigeria Phone: 234-
8052886441 Email: 
awwalgambo@gmail.com 
 
 
 
 
 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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Table of Contents 
Section Title 
Page 
  
 
1.0 PROJECT SUMMARY 
 
5 
2.0 BACKGROUND  
 
6 
3.0 SPECIFIC AIMS 
 
9 
4.0 APPROACH 
 
11 
 4.1 Study methods 
11 
 4.2 Procedures 
15 
 
5.0 SAMPLE SIZE AND STATISTICAL ANALYSIS 
 
21 
6.0 STUDY COORDINATION 
 
23 
7.0 REFERENCES 
 
26 
 
 
 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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1. PROJECT SUMMARY 
 
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 we 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 our 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. We 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 a nutritional supplement (Plumpy’nut) and 
moderate fixed-dose hydroxyurea therapy is superior to a nutritional supplement alone, 
we will randomly allocate 150 children between 5 and 12 years of age with SCA and 
severe uncomplicated malnutrition to each of the two arms. In aim 1, we 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, we 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, we will screen and treat up to 100 
malnourished non-SCD siblings of the trial participants. After completion of this feasibility 
trial, we 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. 
 
 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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2. BACKGROUND 
Significance: High burden of sickle cell disease (SCD) and severe malnutrition in 
Sub-Saharan Africa Approximately 80% of all children born with SCD live in Africa.1 The 
most populous country in Africa, Nigeria, has approximately 150,000 born each year with 
sickle cell anemia (SCA), 50% of the newborns with SCD in the world, as compared to 
about 1,800 births with SCA in the USA 2 The highest prevalence of global childhood 
malnutrition is estimated to occur in low- and middle-income countries, with a prevalence 
of approximately 8% in sub-Saharan Africa. Case-fatality rates among hospitalized 
children with severe malnutrition can be as high as 20-60%,3,4  and children with severe 
malnutrition have 9.4-fold higher odds of dying compared to non-malnourished children.5 
Malnutrition in children is also associated with significant long-term morbidities including 
poor cognitive development, impaired behavioral development, heightened anxiety levels, 
depression, and low self-esteem.6-11 Severe malnutrition is associated with high mortality 
in children under 5 years of age; however, data on morbidity and mortality specifically in 
children with SCD and children above 5 years of age are lacking. 
 
Malnutrition is associated with adverse events in SCD Reduced growth and delayed 
maturation have been previously described in children with SCD12,13 due to multifactorial 
causes, including poor dietary intake (which decreases as the individual gets older),14 
hyper-metabolism and increased nutrient demand,15,16 increased hemolysis causing a 
compensatory increase in reticulocyte production to maintain tissue oxygenation,17 and 
poverty. Individuals with SCD are more prone to infections with encapsulated organisms 
due to auto-splenectomy, which occurs as a result of repeated splenic infarction.18 
Several interventional studies demonstrated that zinc and micronutrient supplementation 
(vitamins A, B and magnesium) given to children with SCD leads to improvement in 
growth, decreased emergency room visits, decreased acute vaso-occlusive pain 
episodes, and reduced rates of infection.14-16 Amino acids, particularly L-arginine and its 
precursor L-glutamine, are critical for growing children and are a key component for 
immunological, inflammatory, intestinal permeability and healing responses.19-21 An in-
vitro study demonstrated increased usage of glutamine by sickled erythrocytes for nucleic 
acid (antioxidant) production.22 In July 2017, the U.S. Food and Drug Administration 
(FDA) approved Endari (L-glutamine oral powder) for the treatment of SCD in adults and 
children > 5 years of age.23  
 
Hydroxyurea therapy is associated with increased weight gain in children with SCD 
A recent review of hydroxyurea in children with SCD enumerates that fetal hemoglobin 
(HbF) induction that results in (1) decreased sickle polymerization; (2) decreased 
inflammation based on lower neutrophil and reticulocyte counts from ribonucleotide 
reductase inhibition and marrow cytotoxicity; (3) decreased adhesiveness and improved 
rheology of circulating neutrophils and reticulocytes; (4) reduced hemolysis through 
improved erythrocyte hydration, macrocytosis, and reduced intracellular sickling; and (5) 
nitric oxide (NO) release with potential local vasodilatation and improved vascular 
response.24 Multiple studies have demonstrated that hydroxyurea therapy, an anti-
metabolite chemotherapeutic agent, approved for secondary prevention of acute vaso-
occlusive pain, is associated with increased BMI and linear growth in children with SCD 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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when compared to children with SCD not treated with hydroxyurea.25-27 Given that 
hydroxyurea therapy is associated with decreased inflammation, increased hemoglobin, 
and increased weight gain when compared to children not on hydroxyurea, we postulate 
our global hypothesis is biologically plausible for treatment of uncomplicated severe 
malnutrition. 
 
Outpatient community-based therapeutic care of severe malnutrition in children is 
safe Several studies have demonstrated the safety of outpatient treatment of 
uncomplicated severe malnutrition in children below 5 years of age in low-resource 
settings, using ready-to-use-therapeutic food (RUTF).28 Outpatient community-based 
therapeutic care reduces mortality and cross-infection rates, as well as costs, and 
increases access to treatment and recovery rates.29-31 Several clinical trials in severely 
malnourished children demonstrated successful recovery in outpatient settings with 
RUTF, reaching 100% weight-for-height.30,32 However, none of these trials have 
specifically included children with SCD and all of the malnutrition intervention studies 
have been in children under 5 years of age. Thus, we do not know the prevalence of 
refeeding syndrome in this population. Due to limitations of malnutrition, and the lack of 
recognition of the high prevalence of malnutrition in children > 5 years of age, only 
children with severe malnutrition less than 5 years of age are screened and treated for 
malnutrition in Kano, Nigeria. 
 
Preliminary Data: The 
prevalence of severe 
malnutrition in children 
with SCA in northern 
Nigeria is high when 
compared to children 
with 
SCA 
in 
high-
income 
countries. 
A 
total of 803 and 1,127 
children with SCA in the 
Nigerian and SIT cohort, 
children with SCA  from 
the USA, Canada and 
Europe screened for a 
silent strokes (n=1,127)33, 
were 
included 
in 
the 
analysis, 
respectively. 
The median age in the 
Nigerian and the SIT 
cohorts was 8.2 and 8.5 
years (range 4.9-13.8 and 5.0-13.8), respectively, and approximately half were male 
Table I : Baseline Characteristics and Nutritional Status of Pediatric Cohorts with 
SCA in Nigeria compared to High-Income Countries 
Variable 
Nigerian Cohort 
(n=803) 
SIT Cohort 
(n=1,127) 
P value# 
Age, median (range)  (years) 
8.2 (4.9-13.8)  
8.5 (5.0-
13.8)  
0.001§ 
Sex, male, % 
49.4 
51.4 
0.402 
Weight, median (kg) 
19.0  
25.9  
<0.001§ 
Height, median(cm) 
119.7  
126.8  
<0.001§ 
BMI, mean  
13.7  
16.4  
<0.001 
Hemoglobin, mean   
7.6  
8.2  
<0.001 
White Blood Count, mean  
14.7  
12.6  
<0.001 
Nutritional status- WHO-Growth 
Standard 
 
 
 
Weight Z-score, mean (SD)  
-2.5  
-0.2  
<0.001 
Height Z-score, mean (SD)  
-1.6  
-0.5  
<0.001 
BMI Z-score, mean (SD)  
-2.3  
-0.1  
<0.001 
Underweight**, %  
63.1 
33 4.4 
<0.001 
Stunting**, %  
37.6 
8.7 
<0.001 
Wasting**, %  
50.7 
3.2 
<0.001 
Severe stunting and severe 
malnutrition 
 
 
 
Severe stunting**, %  
14.1 
1.3 
<0.001 
Severe malnutrition**, % 
28.6 
0.3 
<0.001 
SCD, sickle cell disease; WHO, World Health Organization; BMI, body mass index; Hb, 
hemoglobin; WBCs, white blood cells. **Underweight; Weight-for-age Z-score < -2, 
Stunting; height-for-age z-score < -2; Wasting: weight-for-height/BMI-for-age z-score < -
2, Severe stunting; height-for-age z-score < -3, Severe malnutrition/wasting: BMI Z < -3. 
# Chi-square test for categorical variables and independent sample t-test for continuous 
variables, unless otherwise noted. P-value < 0.05 was set for statistical significance. 
§Mann-Whitney U test 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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(49.4% and 51.4%) (Table1). The Nigerian cohort had significantly higher rates of 
underweight, stunted and wasted children than the SIT cohort: All anthropometric 
variables and laboratory values in the Nigerian cohort were significantly lower when 
compared to the SIT cohort in high-income countries; mean BMI was 13.7 versus 16.9 
kg/m2 (p<0.001); children in the Nigerian cohort exhibited overall significantly poorer 
nutritional status (p<0.001) and were shorter (p<0.001). Prevalence of severe stunting 
and wasting in children with SCA in Nigeria is high: A total of 28.6% (230/803) in the 
Nigerian cohort met criteria for severe wasting and 14.1% (113/803) for severe stunting, 
which was significantly higher when compared to the age- and gender-matched pediatric 
cohort in high-income countries (0.3% (3/1,127) and 7.5% (84/1,127) respectively, 
(p<0.001). In our primary stroke prevention trial in Nigeria, children with severe 
malnutrition receiving hydroxyurea therapy had a statistically significant increase in their 
BMI when compared to those receiving hydroxyurea that were not malnourished (a 
comparative increase in BMI of 2.2, p=0.006; there is a similar comparative increase in 
BMI for age z score of 1.9, P=0.001). Taken together these studies demonstrate the 
previously undescribed challenge of severe malnutrition in older children with SCA.  
 
Innovation: For the tens of thousands of older children with SCD with severe malnutrition 
living in Nigeria and other locations in Africa, the optimal and safe strategy for treatment 
is a critical unanswered question. Despite the high prevalence of severe malnutrition in 
Nigeria and elsewhere, no specific malnutrition program is designed to screen and treat 
children with SCD. In fact, the problem is not even recognized as a treatable entity by any 
international malnutrition guideline, including the WHO guidelines. In Kano, Nigeria, all 
malnutrition philanthropic efforts and government support programs are designed 
specifically for children less than 5 years of age. Thus, even when older children with 
SCD are identified, there is no systematic approach to manage their severe malnutrition. 
To our knowledge, this would be the first severe malnutrition trial specific for 
children with SCD in Africa or elsewhere. Regardless of the results, this feasibility trial 
will provide vital evidence and experience necessary for a Phase III trial for severe 
malnutrition in SCD in Africa. 
 
 


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3. SPECIFIC AIMS 
The overall goal of this feasibility trial is to determine the acceptability of a randomized 
controlled trial (RCT) for the treatment of severe malnutrition in children with sickle cell 
disease (SCD) 5 years and greater. With an expanding pediatric population in Nigeria that 
currently exceeds 75 million, coupled with a decreasing childhood infectious disease-
related mortality, the next emerging threats to preventable childhood deaths are non-
communicable diseases. As a result of our ongoing primary stroke prevention trial 
(NCT02560935, 5R01NS094041-03) using hydroxyurea therapy in northern Nigeria, we 
unexpectedly identified severe malnutrition in children greater than 5 years of age, a 
previously unrecognized medical problem in older children. We demonstrated that 29% 
(230/803) of the cohort met criteria for severe malnutrition (BMI Z-score <-3), and 14.1% 
(113/803) were severely stunted (height-for-age Z-score <-3).34 Approximately 92% of the 
cohort of children with malnutrition was below the 5th percentile for weight of children with 
SCD living in the USA, Canada, or Europe.35 These data indicate that older children with 
SCD living in northern Nigeria are undernourished when compared to children with SCD 
in high-resource settings. Unfortunately, no international standard has been developed 
for the management of severe malnutrition in older children (greater than 5 years of age) 
irrespective of their disease status, and no standard of care has been established for the 
treatment of severe malnutrition in children with SCD at any age. A potentially unique 
attribute to treating malnutrition in children with SCD is the use of the FDA-approved anti-
metabolite, hydroxyurea, to prevent vaso-occlusive pain events in children. Preliminary 
evidence in our 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 with no specific nutritional supplement. We propose a 
randomized controlled feasibility trial in older children with SCA living in northern Nigeria. 
In preparation for a definitive phase III trial to determine if nutritional supplement 
(Plumpy’nut) and moderate fixed-dose hydroxyurea therapy is superior to 
nutritional supplement alone, we will randomly allocate 150 older children with SCA 
to each of the two arms.  To collect the necessary data for designing the phase III trial, 
we will complete the following aims:  
 
Aim 1: To assess the feasibility (rate of recruitment, retention, and adherence) of a RCT 
in a 12-week intervention period. For this aim, the primary outcome will be acceptable 
recruitment, retention, and adherence rates (to monthly medical appointments and 
nutritional and hydroxyurea therapy).  Among a pool of 700 potentially eligible children 
with SCD seen weekly at two clinical sites in the same neighborhood in northern Nigeria, 
we will recruit and randomize a total of 150 children with uncomplicated severe 
malnutrition. In the first week after starting therapy of Plumpy’nut (one sachet daily, 500 
kilocalories, for children 5 to 9 and two sachets daily for children 9 to 12 years of age), 
we will reevaluate the patient in clinic; subsequently all participants will be evaluated 
monthly and called weekly. 
 
Aim 2: To establish the safety protocol for monitoring unknown rates of complications 
associated with treating malnutrition in children with SCD.  For this aim, the primary 
outcome will be to determine the ability of a newly developed safety protocol to detect 


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refeeding syndrome and other potential complications associated with treating 
uncomplicated severe malnutrition in children with SCD on nutritional supplementation 
with and without simultaneous treatment with hydroxyurea.  We will enroll 150 children 
with severe malnutrition and 100 siblings from the same family with severe malnutrition 
and assess the safety monitoring approach that may be specific to children with SCD. 
Due to polygamy, most families, in northern Nigeria, have a large number of siblings 
making recruitment feasible.  
 
This feasibility trial will allow a more informed design of a future randomized controlled 
phase III trial to treat uncomplicated severe malnutrition in older children with SCD living in 
Africa, more specifically, Nigeria. Ultimately, if we find evidence to support our global 
hypothesis, that hydroxyurea therapy combined with nutritional supplement is superior 
than nutritional supplement alone, we will be well-positioned to implement an SCD-specific 
treatment for older children with SCD with severe malnutrition in the country with the 
greatest burden of SCD in the world and in a region where severe malnutrition is common, 
found in at least 25% of older children with SCD. With an estimated 150,000 children born 
with SCD in Nigeria each year, our strategy could be used for over 30,000 children in 
Nigeria per birth cohort with SCD and could be applicable to other children in Africa with 
SCD. 
 


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4. APPROACH 
Overview: The immediate goal of this feasibility trial is to obtain prerequisite data to guide 
the development of a definitive, NIH-funded randomized controlled phase III trial to 
determine the optimal strategy for treating severe acute malnutrition in older children with 
SCD. We will use the well-established approaches implemented for our currently funded 
3 clinical trial stroke prevention trials in children with SCD.36 
 
Design: A 12-week, open label, randomized controlled feasibility trial in children with SCD 
between 5 and 12 years of age to treat uncomplicated severe malnutrition. 
 
 Aim 1: To assess the feasibility (rate of recruitment, retention, and adherence) of 
randomized controlled trial in a 12-week intervention period.  
 
 Aim 2: To establish the safety protocol for monitoring unknown rates of 
complications associated with treating malnutrition in children with SCD. 
 
 
4.1 STUDY METHODS 
 
For these two aims, we will conduct the screening and the recruitment at the SCD 
outpatient clinic at AKTH and MMSH, 3 miles away. The Hasiya Bayero will serve as a 
referral site. During the screening phase, baseline demographic and clinical data will be 
obtained, as well as a physical exam (including edema checks, weight and height 
measurements). The average turnaround time for the laboratory investigations is 24 to 
48 hours. We will also recruit and enroll up to 100 malnourished siblings without SCD, 
but in the same age range for the comparison group. However, where this is not 
possible, non-siblings who meet the inclusion criteria for the study will be recruited for 
comparison purposes. Children with complicated acute severe malnutrition (including, 
but not limited to, poor appetite, altered mental status, fever, other signs of infection, 
bilateral edema of the extremities or respiratory distress) will be excluded and referred 
for inpatient treatment. All possible complications will be strictly monitored. For those 
research participants who develop complications (pneumonia/acute chest syndrome, re-
feeding syndrome, or sepsis, etc.), it is expected that the site Pediatrician will activate 
the standard care protocol, and such participants will be followed until resolution or 
stabilization at no cost to the parents. Such participants will continue with the trial after 
stabilization.  During the first visit, baseline demographic and clinical data will be 
obtained, as well as a physical exam (including edema checks and anthropometric 
measurements ). The anthropometric measurements will include weight, height, mid-
upper arm circumference (MUAC), skinfold thickness, and knee height. Stool 
microscopy will also be performed during the initial visit to rule out infectious etiology. 
However, Helminth in stool will not be considered an exclusion criterion for the study. 
Stool will also be collected at week 12 (visit 4) of the study, during the evaluation of 
recovery of severe acute malnutrition for future microbiome analysis. The microbiome 
analysis will be utilized to describe possible differences between participants who did 
and did not recover from severe acute malnutrition during the trial. Participants will be 


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evaluated at monthly outpatient visits, which will include a physical examination, edema 
check and anthropometric measurements. The participants will be asked to come to the 
clinic for evaluation if the following medical complications were to occur: hypothermic or 
hyperthermic state (<35.5 or >38.0 degrees Celsius), cough, diarrhea and/or vomiting, 
signs of dehydration (dry mucus membranes, low urine output, cold hands and feet, 
sunken eyes). According to standard of care practices, all children with severe 
malnutrition will be treated with the following: a 7-day course of antibiotics 
(amoxicillin),37 and deworming treatment (albendazole). As per standard care, all 
children with SCD are routinely prescribed Folic acid, antimalarial prophylaxis 
(Proguanil) and also oral penicillin up to 10 years of age. A four-week supply of 
Plumpy’nut (RUTF specifically designed to treat acute malnutrition without 
complications) will be given to augment their pre-existing diet. Parents will receive 
ongoing face-to-face SCD-specific education about nutrition and hygiene. In response 
to an allergic reaction to the Plumpy’nut product, the participant will be removed from 
the study and will not be considered evaluable. The participant will be referred to 
standard of care procedures and an AE form pertaining to the event will be filled out and 
submitted.  
 
To assess adherence, our research team will make weekly phone calls in between the 
monthly clinic visits and ask about number of empty sachets and adherence to 
hydroxyurea (missed doses in last week).  During the monthly clinic visits, the family will 
be asked to bring back the empty Plumpy’nut sachets (92 g).  One or two sachets a day 
of Plumpy’nut will provide a nutritional supplement to home foods (one sachet for children 
5 to 9, and two sachets for children 9 to 12 years of age). A 24-hour dietary history using 
a USDA multi-pass interview method will be obtained during the weekly phone calls and 
at the monthly clinic visits, and a Nigerian-specific food and nutrient coding database will 
be used to estimate daily overall caloric intake.38 For emphasis, the participants enrolled 
in the study will have a study visit in the middle of the first week after enrolment. This will 
be followed by weekly phone call by the study personnel to ask for any unanticipated 
problems (i.e. questions on safety and adverse events), and to reemphasize adherence 
to study medication. To improve the adherence of the study participant consuming all 
prescribed calories, there will be community visits for a certain number of enrollees who 
consents to community visits as part of the study. The community visit will include a 
research team member traveling to the study participant's community. They will meet with 
the local community to discuss the importance of the study participant consuming the 
prescribed nutrition supplement. The participants will also come for monthly study visits 
for physical examination, anthropometric measurements and laboratory evaluation. 
 
 Inclusion criteria for children with SCD: 1) laboratory diagnosis of SCA (HbSS or 
HbSB0 thalassemia); 2) informed consent from parent or legal guardian; 3) severe 
malnutrition defined as a BMI Z-score below –3; 4) age between 5 and 12 years 
(assessment can take place up until the 13th birthday), reside within a 2 hour driving 
distance from the medical center to facilitate weekly phone call in between the monthly 
clinic visits.  
 Exclusion criteria: 1) children with complicated severe acute malnutrition; 2) children 
with electrolyte disturbances (serum Na, K, Ca, PO4) at baseline; 3) children on 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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disease-modifying therapy (hydroxyurea or regular blood transfusion therapy); and 4) 
children enrolled in other studies; 5) children with diabetes and other chronic illnesses; 
and 6) children with known HIV infection; 7) children with known allergy to dairy or 
peanuts. 
 
 Inclusion and exclusion criteria for siblings without SCD, but malnourished. 
Entry criteria will be identical to participants in the trial, except they will not have SCD 
and must be between 5 and 12 years of age. Any child in the family identified as having 
severe acute malnutrition, but less than 5 years of age, and not eligible for the trial, 
will be referred to the hospital nutritional clinic for counseling and standard care 
management. 
 
 Methods for children with SCD with uncomplicated severe malnutrition: All 
children between ages 5 to 12 years of age with SCD will be screened for malnutrition 
during outpatient clinic visits along with their siblings that also attend the clinic 
appointment. Basic demographic information, SCD phenotype, and anthropometric 
measurements (weight, height and MUAC, skinfold thickness, and knee height) will 
be collected. To identify risk factors for malnutrition, additional demographic data will 
be collected at monthly outpatient clinic visits, including but not limited to parental 
education level, marital status, annual family-income, number of rooms and people 
living in the house. We will also ask the caregivers or parents of all participants to 
complete the previously validated U.S. Household Food Security Survey and children 
with SCD and malnutrition aged 12 years the Self-Administered Food Security Survey 
Module for Youth Ages 12 and Older, because there are no validated food security 
surveys in specific to  Africa. Additionally, we will pilot basic food insecurity questions 
for all subjects 5-12y with a time interval of last week/7days. These will be structured 
interview questions as a pilot. Food insecurity surveys will be performed at study 
enrollment (visit 0) and the last study visit (visit 4). We will ask the mothers to complete 
the Public Health Questionnaire-9 (PHQ-9) to assess maternal mental health. The 
mothers will be referred to their primary care physicians if their PHQ-9 score is 
suggestive of depression (score ≥9) and will be re-assessed during the following study 
visit. 
 
 Methods for siblings of children without SCD, but with uncomplicated severe 
malnutrition: A comparison group including up to 100 siblings without SCD, between 
5 and 12 years of age, will be screened for malnutrition. The siblings will be recruited 
upon study enrollment of the participant with SCD (visit 0). All sibling participants will 
be treated according to the same protocol as their sibling with SCD. If the site 
investigator believes that other siblings are likely to require nutritional supplements, 
but they are not malnourished, then at the discretion of the site investigator they may 
provide additional sachets for the siblings in the household. These sachets will be 
funded outside of the clinical trial. 
 
 Methods to assess safety: Per WHO guidelines, severe malnutrition without medical 
complications can now be effectively managed in the community, with RTUF.39 
However, given the superimposed physiologic changes associated with SCD and 


Management of severe acute malnutrition in children with sickle cell disease >5 years of age in northern Nigeria 
 
 
 
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susceptibility to bacteremia and malaria, the risks of refeeding syndrome and other 
known complications of SCD during nutritional supplementation are unclear. For this 
purpose, comparable to what we have done for our two RCTs for stroke prevention in 
Nigeria using hydroxyurea therapy, the Executive Committee will review laboratory 
values at the various predefined intervals (Table 1), with pre-defined local abnormal 
values for children with SCD. We will obtain serum Na, K, Ca, PO4 at baseline to 
screen out those with significant electrolyte derangements and repeat those measures 
at the midpoint of week 1 and refer those with significant abnormalities for inpatient 
treatment management. Electrolyte derangement during study will be considered a 
complication of the treatment. Those individuals will be managed by the site 
pediatrician until full recovery at no cost to the parents. Supplementation of amino 
acids (<0.42mmol/L) will be based on local management practices, outside of this 
research protocol.40 Per WHO guidelines, a weight increase of 5g/kg/day 
(35/g/kg/week) will be defined as adequate growth per week. If at monthly visits, 
participant does not achieve this growth rate, the family will be interviewed to assess 
challenges with caloric intake and potential another sachet will be provided. 
 
 Nutritional supplement-PlumpyNut: is a ready to use therapeutic food that is 
used in the outpatient treatment of severe acute malnutrition. It is a fortified peanut 
butter-like paste that contains essential macro and micronutrients sufficient to 
result in rapid weight gain.1 
o Composition: Vegetable fat, ground nut/peanut butter, skimmed milk 
powder, lactoserum, maltodextrin sugar, mineral and vitamin complex. It 
comes in a 92g per sachet form equivalent to 500 kcal/sachet.1  
o Benefits:  
 It provides calories and essential nutrients that restore and maintain 
body weight and health in severely malnourished children more 
effectively than F100.2 
 It does not require refrigeration nor water for preparation. This makes 
it convenient for use in low-resource settings 
 It can be administered at home without the need for hospitalization 
or medical supervision 
 It has a 2-year shelf-life making it convenient for low-resource 
settings 
 
 Hydroxyurea is an antimetabolite chemotherapy agent, also NAFDAC approved for 
the use of preventing acute vaso-occlusive pain and other complications in SCD. 
 
 
 


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4.2 STUDY PROCEDURES 
 Personnel – Informed consent will be obtained by the site PI or their designees 
(pediatrician or research coordinator who has the strongest relationship with the 
patient during the return clinic visit).  Screening: During routine weekly clinic SCD visits 
at AKTH and daily SCD clinic visits at MMSH, the study pediatricians will discuss the 
study with the parents of eligible children with SCD between ages 5 to 12 years old. 
As part of standard of care, physical examination including anthropometric 
measurements (weight and height) will be completed. Once the child is identified as 
having severe malnutrition (BMI Z-score below –3) they will be referred to the 
nutritional clinic for management per local standard of care protocol. Children with 
severe malnutrition who qualify and agree to participate will be invited to sign consent 
and assent for study recruitment to this study.  
 
 Randomization procedures: The unit of randomization is the individual. All study 
participants with SCD will be randomized to either of the two arms of the treatment 
groups in a ratio of 1:1. The project statistician, Mark Rodeghier, PhD, will implement 
a permuted block allocation scheme, likely based on block sizes of 2 and 4, stratified 
by gender, within clinical site. Randomization will be accessed at each site through 
Research Electronic Data Capture (REDCap). The randomization module in REDCap 
allows us to load a randomization table that will allow the research coordinator at each 
site to click a ‘randomize’ button. There will be no randomization for the study 
participants without SCD, as all of these participants will receive only Plumpy’nut. 
 
Table 2  Study Protocol Timeline 
Treatments/tests 
Week 0 
Visits 1 
Week 0  
Within 7 days (goal 
of 3 to 5) days after 
Rx 
Visit 2 
Week 4 
Visit 4 
Week 8 
Visit 5-12 
Week 12 
Visit 13 
Informed consent for study enrollment 
X 
 
 
 
 
Demographic/clinical baseline data 
X 
 
 
 
 
Physical exam; weight, height, MUAC, oedema 
check 
X 
X 
X 
X 
X 
Recall food questionnaire 
X 
X 
X 
X 
X 
U.S. Household and Youth Food Security 
Survey and Youth Food Security Questionnaire  
X 
 
 
 
X  
PHQ-9 Questionnaire (mothers) 
X 
X 
X 
X 
X 
Stool microscopy 
X 
 
 
 
X 
CBC and serum pre-albumin 
X 
X 
X 
X 
X 
Phosphate, Calcium, Magnesium, Potassium 
X 
X 
 
 
 
Test dose ready-to-use Soy Plus to establish 
no acute allergy 
X 
 
 
 
 
4 week supply of Plumpy’nut 
X 
X 
X 
X 
X 
Participants with severe uncomplicated 
malnutrition: 
- 
7-day course of amoxicillin and 
Albendazole 400mg 
 
 
X 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Parental education on nutrition 
X 
X 
 
 
 


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 Recruitment and Retention Plan: At the two participating sites, they will draw from a 
pool of potential participants of at least 600 children with SCA over 5 years of age. 
Based on current assessment in 900 children with SCA screened for our primary 
stroke prevention trial (NCT02560935, 5R01NS094041-03) we expect approximately 
29% of participants will be severely malnourished. Thus, we plan to enroll all study 
participants within 3 months from initiation of the study or sooner if the recruitment 
rate is similar to our primary stroke prevention feasibility trial of ~90%.41 To ensure 
that we start enrolling participants shortly after the receipt of funding, both clinical sites 
and the Data and Clinical Coordinating Center have IRB approval for an earlier version 
of the study and will submit an amendment to adjust for the most recent changes. To 
enhance retention, we developed strategies to reduce loss to follow-up, including clear 
written instruction for management of severe malnutrition, offset the cost of patient 
transportation during monthly follow-up visits, and weekly phone calls. We will collect 
phone numbers of both or either of the parents or alternatively a close relative or a 
neighbor. Further, we will request the names, addresses, and phone numbers of two 
family members or friends who would know how to get in touch with the participant in 
the event of a missed appointment (this information will be kept at each site and will 
not be entered into the central database).  
 
 Study follow-up visits: In addition to the safety check at mid-week of week 1, all 
participants with severe uncomplicated severe malnutrition will undergo monthly study 
and weekly phone calls to ensure monthly adherence to protocol and weekly weight 
gain. In the first week of the trial the patient will be re-evaluated in clinic to monitor for 
refeeding syndrome.  Siblings will be encouraged to visit during trial enrollment visit 
for assessment of their nutritional status, and if severely malnourished, will be asked 
to enroll if > 5 years of age or referred to the malnutrition clinic if < 5 years of age. If 
the site investigators believe that the family will share the sachets for the participant 
enrolled in the trial, they will also be provided with additional sachets per the discretion 
of the local site investigator. We will also determine adherence to Plumpy’nut therapy 
with weekly phone call and by the family bringing back the empty sachets at monthly 
study visits. We will assess the adherence to hydroxyurea, by all of the following - 
weekly phone calls for missed doses, pill count return at each visit, fetal hemoglobin 
at baseline and upon exit, MCV change from baseline and with each CBC, and 
absolute neutrophil count from baseline and each CBC.41 We will record all cases of 
hospitalizations. In cases of treatment failure (e.g. when the participants do not gain 
weight 12-weeks after enrollment or lose weight); participants will be re-consented for 
hydroxyurea therapy and Plumpy Nut (ready-to-use-therapeutic food). These 
participants will be followed for an additional 12 weeks and re-evaluated. If a 
participant is enrolled in treatment failure, then at week 24, their fetal hemoglobin will 
be evaluated. 
 
 Nutrition and Vocational Training: Unlike severe malnutrition treatment in acute caloric 
deprivation or increased energy expenditure, children with sickle cell anemia in Kano, 
Nigeria, will continue to experience insults to their nutritional status from a biological 
and socioeconomic standpoint after trial cessation. Therefore,  in addition to 
malnutrition treatment within the trial, we propose a multifaceted program42 focused 


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on empowerment through nutrition education with demonstration of readily available 
local foods and vocational education. These programs will aim to increase the agency 
of the primary caregiver to improve the nutritional status of the participant.  
Nutrition programming. The trial already contains nutritional education for the 
caregivers. However, to increase the sustainability of the weight gain of short-term 
nutrition intervention (Plumpy'Nut), it is apparent that a more intensive nutrition 
education tailored to the economic environment of the households. The participant's 
mother and a designated partner will receive education about using local foods and 
vocatio. The designated partner is an individual who has a primary role in the 
participant's nutrition, either purchasing, preparation, or allocation of the foodstuffs. 
The mother and designated partner will attend the nutrition workshops held biweekly 
for a total of 3 workshops over 6 weeks. The workshops will contain the following 
education: 
• Education regarding the specific nutritional needs of a child with sickle cell anemia 
• Individual economic education regarding the cost of purchasing foods that could 
fill nutrient gaps43,44 (affordable nutrient-dense foods) 
• Provision of one week of nutrient-dense food for the family to increase visibility and 
demonstrate the feasibility of economic nutritious food choices 
• Interactive cooking preparation and demonstration with subsequent serving size 
demonstration appropriate for the participant 
o The low bioavailability of some essential micronutrients can be substantially 
enhanced with appropriate processing and food combinations.45  
Additionally, there will be a one month check-in to assess anthropometric changes 
after the nutritional and  vocational education. 
Vocational education. We will also incorporate vocational education and general 
life skills coaching. Technical skills training and support will also be provided 
biweekly for a total of 3 workshops over 6 weeks. The training will increase the 
caregiver's occupational or entrepreneurial skills to increase the caregiver's agency. 
Ultimately, the goal is to increase employment and earnings. The programming will 
integrate both hard skills and life skills training, as the combination is thought to be 
more effective.46 General life skills support will be discussed at every clinic study 
visit even after the formal vocation programming finishes.  
 
Stipend. Due to the increased demand for study participants and their caregivers and 
designated partners, we propose increasing the stipend for each visit. Additionally, the 
designated partner will receive a stipend at each nutrition workshop. 
Follow-up. We will record the weight and height measurements of study participants 
who have exited the trial through standard of care measurements at follow-up visits in 
their respective sickle cell clinics.  
 


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 Treatment Failure: Indication for PlumpyNut and Hydroxyurea Therapy (SCD 
participants only): enrolled participant that has fulfilled all the inclusion criteria but 
still has a BMI Z score of less than -3 or is losing weight after 12 weeks of Plumpy’nut 
would still be eligible for the 4-5 sachets of RUTF (Plumpy’nut). The main difference 
is that this would translate to “standard RUTF,” where the RUTF is provided in 
sufficient quantity to meet all of the nutritional requirements of a child recovering from 
severe acute malnutrition. However, our intervention is investigating the use of RUTF 
provided to children with SAM as a supplement to the usual family diet.  
 
o PlumpyNut sachets / day: In view of the fact that no standard protocol for the 
use of Plumpy nuts in children > 5years exists, we intend to dispense 4 to 5 
sachets of plumpy nuts / participant / day 
 Our justification for the prescription includes: We shall adopt the 
UNICEF/WHO guidelines (outpatient management of SAM) of achieving 
at least 150 to 200 kcal/kg/day for children weighing more than 12 kg. 
This is the maximum limit obtainable according to the UNICEF reference 
table (for outpatient management of SAM) as shown in the table below. 
This can be achieved by ingesting 4 to 5 sachets / day.47 
 Most studies conducted on HIV adult patients with SAM on nutritional 
rehabilitation used 4 sachets of plumpy nuts/patient/day. Notable 
examples are in Ethiopia (2014) 3 Kenya (2011).48 
o Monitoring/Follow up visits: This will entail a total of 12-weeks follow-up visits 
with the first visit within 1 week of initiation of Plumpy’nut (optimally within 3-5 
days) then subsequently 3 monthly visits. During each visit, a clinical history 
and examination will be taken. Edema check, MUAC, weight, height, 
temperature, respiratory rate, pulse oximetry, and blood pressure will be 
assessed and documented. Parents/legal guardians of all participants enrolled 
will be provided with infrared thermometers with different color coding, easy to 
use even for parents with low literacy level. The caregiver will be educated on 
temperature control and signs of dehydration. In addition, the caregivers will be 
given a thermometer with strict guidelines on how to assess the temperature at 
home. These are as discussed in the MOP under monitoring of patients on 
Plumpy’nut.  
o Hydroxyurea Therapy: We will constitute hydroxyurea to children with SCD 
only, routine folic acid and palludrine. Enrolled participants will receive 
amoxicillin and albendazole only once at the study initiation prior to 
commencement of Plumpy’nut. 
o Weekly Phone calls: Will be done weekly in between the bi-weekly clinic visits. 
Care givers will be asked about adherence and the number of consumed 
sachets. A 24-hour dietary recall will be done. They will be asked to bring the 
empty sachets when coming for their follow-up visits. 
TABLE: REFERENCE TABLE FOR PRESCRIPTION OF RUTF(based on 92g packets)1 
Weight in (kg) 
 
Sachets/day(200 kcal/kg/day) 
75% of prescribed amount 
(150 kcal/kg/day) 
3.5 – 3.9 
1 1/2 
1 1/4 
4.0 -4.9 
2 
1 1/2 


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5.0 – 6.9 
2 1/2 
2 1/4 
7.0 -8.4 
3 
2 1/2 
8.5-9.4 
3 1/2 
2 3/4 
9.5 -10.4 
4 
3 1/4 
10.5-11.9 
4 1/2 
3 1/2 
≥12 
5 
4 
 
 
 Steps to limit and monitor adverse events (AE) or serious adverse events (SAE): 
Monitoring for unanticipated adverse effect will be performed by querying participants 
at each follow-up visits about the occurrence of complications since the participant’s 
last follow-up contact. Data will be collected by local research staff on AEs, and on 
any abnormal findings (history, physical exam, laboratory, or imaging) of a participant 
in the study. AEs will be recorded at study visits every week using a structured form 
for detecting signs of complicated severe acute malnutrition and classified based on 
seriousness, expectedness, and relatedness by physicians not otherwise involved in 
this study. Unexpected AEs are adverse reactions that are not consistent (nature or 
severity) with the available information on outpatient treatment of malnourished 
children with or without SCD with Plumpy’nut. A pharmacovigilance structure will also 
be instituted at participating sites to monitor and identify adverse effects. 
A serious adverse event (SAE) is an event that: 
a. Results in near death or death; 
b. Life-threatening (participant at risk of death at the time of the event); 
c. 
Requires or prolongs hospitalization more than 7 days; 
d. Causes persistent or significant disability; 
e. Results in a congenital anomaly; 
f. 
Other medical events (in the opinion of the investigator) that may put the participant 
at risk or require intervention to prevent a SAE. 
 
SAEs will be scored using the Common Toxicity Criteria for Adverse Events (CTCAE) 3.0 
of the National Cancer Institute and the standard nomenclature for defining the causal 
relation between the AE and study drug (unrelated, probably not related/remote, possibly 
related, probably related, and definitely related). All SAE including death require prompt 
reporting by email communication or telephone to the Principal Investigator as well as 
BMS Worldwide Safety worldwide.safety@bsm.com) within 24 hours of becoming aware 
of the event, and to the IRB of record within the required timeframe. If pneumonia/acute 
chest syndrome, refeeding syndrome or sepsis is suspected, research personnel should 
activate the standard care protocol at site without the consent of the Coordinating Center 
and Statistical Coordinating Center.  All SAEs should be followed until resolution or 
stabilization.  All SAE reports of death in the first 6 months of the study will be reported to 
the DSMB within two weeks of occurrence.  The SAE report will include a description of 


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the event provided by the site, indication of tests, and details of hospitalization, as 
available.  All SAEs should be followed until resolution or stabilization.   
Adjudication Process by Site Investigator and Principal Investigator 
 
 
 
Adjudication Process for Primary Cause of Hospitalization: 
 
• 
IF the patient presents with neurological deficits confirmed to be a stroke or 
transient ischemic attack and acute chest syndrome, pain, fever, or other 
symptoms; 
THEN 
the 
primary 
cause 
of 
the 
hospitalization 
is 
STROKE/TRANSIENT ISCHEMIC ATTACK.   
 
• 
IF the patient presents with acute chest syndrome, pain, fever, other symptoms, 
and no indication of neurological deficits for stroke or transient ischemic attack; 
THEN the primary cause of the hospitalization is ACUTE CHEST SYNDROME. 
 
• 
IF the patient presents with pain, fever, other symptoms, and no acute chest 
syndrome or indication of neurological deficits for stroke or transient ischemic 
attack; THEN the primary cause of the hospitalization is PAIN. 
 
• 
IF the patient presents with fever and other symptoms, and no pain, acute chest 
syndrome, or indication of neurological deficits for stroke or transient ischemic 
attack; THEN the primary cause of the hospitalization is FEVER. 
 
• 
IF the patient presents with fever and other symptoms, and no pain, acute chest 
syndrome, or indication of neurological deficits for stroke or transient ischemic 
attack; THEN the primary cause of the hospitalization is FEVER. 
 
• 
IF the patient presents with other symptoms, and no fever, pain, acute chest 
syndrome, or indication of neurological deficits for stroke or transient ischemic 
attack; THEN the primary cause of the hospitalization is OTHER. The primary 
reason should be provided after adjudication along with all applicable secondary 
reasons for hospitalization. 
 


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When the primary cause of hospitalization adjudicated by site investigator/designee and 
principal investigator is CONCORDANT, no further action is needed. The final 
adjudication is the primary cause agreed upon by both parties. 
 
When the primary cause of hospitalization adjudicated by site investigator/designee and 
principal investigator is DISCORDANT, a joint review occurred to discuss the file 
collaboratively to determine the final primary cause based on the algorithm. 
 
The secondary cause(s) of hospitalization will be reviewed; however, the final 
adjudication is at the discretion of the site investigator/designee completing the 
adjudication.  For the duration of the study, participant hospitalizations are documented 
with CRF 39: Interim Hospitalization and CRF 21: Adverse Event, as applicable.  When 
available, a de-identified source document will be uploaded for review.  The adjudication 
of all parties are documented via REDCap in CRF AA3:  Principal Investigator 
Adjudication of SPRING Hospitalizations. 
 
Definitions: 
 
1) Pain: a SCA-associated pain episode requiring admission to the hospital and 
treatment with opioids. Emergency department visits were not included in this 
definition due to the variation in outpatient pain management practices and to 
capture only acute severe pain events.49 Headaches treated with opioids were also 
not included in this 
definition due to the difference in proposed pathophysiology of headaches as 
opposed to 
acute vaso-occlusive pain.50 
2) Fever: Temperature greater than or equal to 110.4°F or 38°C. 
3) Acute chest syndrome (ACS): presence of at least 2 of the following criteria, 
including positive chest signs: temperature greater than 38°C, increased 
respiratory rate of greater than the 90th percentile for age51 or >20 breaths per 
minute, positive chest pain or pulmonary auscultatory findings, increased oxygen 
requirement (SpO2drop >3% from a documented steady-state value on room air), 
and a new radio-density on chestroentgenogram.52 In the absence of abdominal 
shielding, a chest X-ray will be done as available. A diagnosis of pneumonia will 
be considered an ACS episode. All cases of acute vaso-occlusive pain and ACS 
episodes will be adjudicated with the site pediatrician, hematologists and principal 
investigator on the research team to ensure a uniform definition.53 
4) Malaria: Based on World Health Organization and local study site guidelines, a 
fever (greater than or equal to 110.4°F or 38°C) and positive light microscopy, rapid 
diagnostic test that can detect P. falciparum completed (depending on test 
availability). 
The adjudication will be completed using the algorithm and entered in REDCap for all 
participants with hospitalizations with the above indices. The adjudication process will 


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include the study principal investigator(s), site pediatrician, hematologist, data coordinator 
and any study personnel, as needed. 
 


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SAMPLE SIZE AND STATISTICAL ANALYSIS PLAN 
Sample Size and Power for Aim 1:  
We will use the data from the R21 feasibility study to better define recruitment efficiency, 
retention rate, and adherence rates to protocol. We will also assess weight gain in the 
two arms of the trial. Sample size calculations were not performed because our immediate 
goal of this study is to assess the feasibility an RCT of this nature in northern Nigeria. Due to 
budget constraints, we will recruit a total of 150 children with severe malnutrition and up 
to 100 siblings without SCD with severe malnutrition that are identified during enrollment 
of participants with SCD. 
 
Data analysis plan, data integrity, management and dissemination:  
To assess feasibility of a RCT, the primary outcome for aim 1 will be: proportion of eligible 
individuals that agree to be included, referred to as recruitment rate, the retention rate for 
the trial and the adherence rates to both the protocol and to therapy (Plumpy’nut and 
hydroxyurea). The demographic characteristics of all children will be summarized as 
mean and standard deviations for continuous variables; for categorical variables, counts 
and percentages will be used. Prevalence will be summarized by proportions. 
Anthropometric indices (BMI-for-age (BMIZ), weight-for-age (WAZ) and height-for-age 
(HAZ) Z-scores) will be calculated using WHO 2007 R Macro Package to assess growth 
and development of the children.54  
 
Weight gain will be determined by calculating the change from baseline and compared to 
children with uncomplicated severe malnutrition without SCD. Comparisons will be made 
using the Student’s t-test for continuous parameters and a chi-square test, or Fisher’s 
exact test, for categorical parameters. Adherence rate will be assessed by proportion of 
the number of empty food sachets returned during the monthly visits. If adherence rate is 
<90% and the dropout rate is >20%, then the original protocol will be re-examined and 
alternative strategies to enhance retention and adherence will be considered. To study 
what characteristics are associated with weight gain for all participants (children with and 
without SCD), we will use two regression models. The models will include the following 
covariates, age, gender, average weekly caloric intake, and hemoglobin levels. First, we 
will use a linear regression model to study the change in weight from baseline (dependent 
covariate); second, we will use a logistic regression model to study whether weight 
increased by at least 15%, or not, from baseline (dependent covariate). Additional models 
will investigate the characteristics that affect the morbidity (hospitalization for pain or any 
other reason) and mortality rates, controlling for change in weight and caloric intake. The 
relative-risk ratios for the outcomes will also be computed, and Kaplan–Meier plots of time 
to recovery of at least 15%. Significance will be set at P<0.05 for all analyses. We will 
determine the number of individuals that complete the study protocol, referred to as the 
retention rate.  The primary outcome for aim 2 will be 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). Secondary outcomes will be the percentage ± 95% CIs for 
all adverse events during study period in the SCD group and that of their non-SCD 


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siblings. Non-parametric statistics (such as the Mann-Whitney test) will be used to 
compare the number of hospitalizations between the two groups; Kaplan-Meier analysis 
or Cox regression will be used to compare the time to an adverse event. If we observe 2 
or more SAEs in either arm, the trial will be suspended and reviewed with the Data Safety 
Monitoring Board as to whether the trial should be halted. Two SAEs suggest that a 1-
sided 95% Wilson CI (unadjusted for multiple looks at the data) for the proportion of SAEs 
exceeds 1%. If the true rate of adverse events is 1%, the probability of suspending the trial 
is <2%. If the true SAE rate is 10%, the probability of suspending the trial is >60%. We 
will determine the incidence rate for all cause hospitalizations for participants with SCD 
and severe malnutrition compared to children with SCD and no malnutrition.  Reasons for 
hospitalizations during the study period for all participants will be recorded.  
 
Missing data: Inspection of the missing data patterns will be performed with an R package, 
SensMice, to perform a sensitivity analysis to evaluate the possible mechanism of data 
missing (missing at random vs. missing not-at-random).55,56 As we have in our previous 
work, to minimize missing data, we will institute online training for the data coordinator 
prior to the start of the study; and assess weekly missing data in REDCap with weekly 
feedback to site coordinators regarding missing data.  
 
 
 
 


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5. STUDY COORDINATION 
 Study Withdrawal 
Participants may decide to discontinue participation at any time during the study.  If a 
patient voluntarily requests withdrawal from the trial, we request that the site investigator 
elicit the reasoning for the withdrawal, and provide documentation in the clinic record and 
complete the respective case report form. The site must invest time in trying to meet the 
needs of the patient and their caregivers in order to make the patient’s participation a 
success. The patient’s caregiver should provide the withdrawal in writing for the clinic 
record. All voluntary withdrawals must be communicated to the Clinical Coordinating 
Center located at Vanderbilt University Medical Center by completion of the case report 
form in REDCap, and should be recorded in the participant’s study binder onsite.  
 Data Collection and Management 
Research information, including consent forms and questionnaires will be collected once 
the participant agrees to participant and has completed the consent for the study.  The 
study coordinator will collect data and maintain all consents, study assessments, and 
study data forms in a secure fashion in research charts located in a locked file room or 
locked file cabinet.  Only the study personnel will have access to the research charts and 
database, to identify any information on participants that are in the consented for the 
study. 
Each participant will be identified with a unique identifying number in REDCap. Through 
chart review of standard care procedures, the clinical information will include, but will not 
be limited to baseline measurements of CBC and hemoglobin analysis.   
The data gathered will be entered into the REDCap data system,57 with each ID having 
a unique identifier for each participant. REDCap is a secure, web-based application for 
building and managing online databases. All data will be de-identified and samples will 
only have a unique identifier that will link the unique identifier with the patient’s name.  
REDCap is a free, secure, web-based application designed to support data capture for 
research studies. The system was developed by a multi-institutional consortium initiated 
at Vanderbilt University. Data collection is customized for each study or clinical trial by 
the research team with guidance from Harvard Catalyst EDC Support Staff. REDCap is 
designed to comply with Health Insurance Portability and Accountability (HIPPA) 
regulations.  REDCap provides user-friendly web-based case report forms, real-time data 
entry validation (e.g. for data types and range checks), audit trails, and the ability to set 
up a calendar to schedule and track critical study events such as blood-draws, participant 
visits, etc. Also, designated users can assign different levels of access for each member 
of the research team. 


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REDCap and REDCap Survey (RS), as hosted by Vanderbilt, are available only to 
investigators from Vanderbilt University, but can be used by investigators at other 
institutions as long as they are part of a project/group from Vanderbilt that is utilizing 
REDCap or RS. REDCap and RS as software applications can be used at other 
institutions, when installed by and hosted at those institutions, if they are willing to sign a 
tech transfer agreement and join the REDCap Consortium. 
 Utilization of Study Data 
The results of the research study may be published, but participants’ names or identities 
will not be revealed. Records will remain confidential. In order that confidentiality can be 
maintained, the principal investigators will keep records in locked cabinets and results 
of tests will be coded to prevent association with volunteers’ names. Participant records 
will be available to the study staff and to each site’s IRB. 
The research personnel will have access to the medical records of all consented and 
screened patients for the duration of 5 years.  This includes access to their medical 
records (i.e. clinic visits, laboratory testing, dietary questionnaires, etc.)   
 
Data Safety Monitoring Board 
Members of the Data Safety Monitoring Board (DSMB) will be appointed by the Director 
of the National Institute of Child Health and Human Development (NICHD) and report to 
the Director and to the NICHD Project Officer or the PIs.  The members are selected to 
reflect a mix of appropriate clinical expertise in sickle cell disease and knowledge of the 
design, monitoring, analysis and ethical issues of clinical research to protect the 
participants’ safety during a scientifically rigorous study.  The DSMB will monitor study 
quality, safety of participants, and efficacy.  
 
The DSMB will monitor the study performance by reviewing: 
 
participant recruitment 
 
flow of forms  
 
quality control of the data 
 
adequacy of medical monitoring  
 
adverse effect reporting  
 
adherence to protocol  
 
appropriateness of protocol changes with regard to scientific integrity 
The DSMB will monitor the safety of participants by reviewing: 
 
risk of harm inherent in participating in the study  
 
adverse events (type, incidence, and severity) 


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 
effect of protocol changes on risk 
The DSMB will monitor the efficacy of the study by reviewing: 
 
data  
 
planned and/or unplanned interim analyses  
 
stopping rules, their implementation, and resulting decisions 
 
results and conclusions 
The CC and DSMB will provide information to this Committee as requested.  The DSMB 
will review study data reports, including primary end point analysis, every six months 
either in a meeting or on a conference call. The DSMB will also decide on the criteria for 
trial termination. 
 
 


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SAP_001.pdf: 
 
 
 
 
 
ID: 170577  
Management of Severe Acute Malnutrition in SCD, in 
Northern Nigeria  
NCT03634488 
 
Protocol Version: 06/01/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis  
Data was collected and managed with Research Electronic Data Capture (REDCap) hosted at 
Vanderbilt University Medical Center. We summarized continuous variables as means and 
standard deviations (sd) or as medians and interquartile ranges (IQR) for variables not normally 
distributed. Categorical variables and prevalence were reported as numbers and percentages. 
For comparisons between groups, a chi-square test or Fisher's exact test was used for 
percentages, a t-test for means, and a Mann-Whitney U test for medians.  
We used two regression models to study characteristics associated with weight gain for all 
participants with SCD. Per protocol, we used a logistic regression model to study whether 
participants achieved a BMI z-score of at least -3.0 and whether they achieved at least a 15% 
weight gain. Finally, due to the evidence that weight-for-age z-score is associated with mortality 
in children with SCA in the same age range living in northern Nigeria,1 we utilized the same 
covariates for the logistic mode for a linear regression model to study the change in weight-
forage z-score from baseline. 
 
1. 
Klein LJ, Abdullahi SU, Gambo S, et al. Underweight children older than 5 years with sickle cell 
anemia are at risk for early mortality in a low-resource seƫng. Blood Adv. 2023;7(11):2339-2346.