Uncomplicated Severe Acute Malnutrition
Conditions
Brief summary
This pilot study is a randomized controlled trial designed to test the effect of the administration of adjunctive azithromycin in conjunction with standard outpatient treatment for uncomplicated severe acute malnutrition (SAM) in children aged 6-59 months. Children presenting to nutritional programs in Burkina Faso who meet eligibility criteria will be randomized to a single dose of oral azithromycin or a 7-day course of amoxicillin (standard of care) upon admission into the program. All enrolled children will receive ready-to-use therapeutic foods (RUTF). Enrolled children will be followed at each weekly clinic follow-up visit up to 8 weeks following admission. Data on anthropometric indicators, vital status, and adverse events will be collected during follow-up. Nutritional recovery over the 8-week study period will be compared by arm.
Interventions
DRUGAzithromycin
Children enrolled in the trial and randomized to azithromycin will receive a single directly observed dose of oral azithromycin at 20 mg/kg up to the maximum adult dose of 1 g. Oral azithromycin will be administered at the time of enrollment. Enrolled children will also receive RUTF.
DRUGAmoxicillin
Children enrolled in the trial and randomized to azithromycin will receive a 7-day course of oral amoxcillin given in twice-daily doses of 50-100 mg/kg, per the Burkina Faso guidelines for the management of severe acute malnutrition. The first dose will be administered at the time of enrollment and the remaining dose will be administered by the caregiver at home. Enrolled children will also receive RUTF.
Sponsors
Centre de Recherche en Sante de Nouna, Burkina Faso
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 59 Months
Healthy volunteers
No
Inclusion criteria
* Age 6-59 months * WHZ \<-3 SD or MUAC \<115 mm * No nutritional edema * Able and willing to participate in full 8-week study * Has not been admitted to a nutritional program for the treatment of SAM in the 3 preceeding months * No antibiotic use in past 7 days * No clinical complications requiring inpatient treatment (except for routine admission for children \<6 months) * No congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of SAM treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc) * No allergy to macrolides/azalides * Sufficient appetite according to a feeding test with ready-to-use therapeutic food (RUTF) * Appropriate consent from at least one parent or guardian
Exclusion criteria
* Age \<6 months or \>59 months * WHZ ≥-3 SD or MUAC ≥115 mm * Nutritional edema * Not able or willing to participate in full 8-week study * Admission to a nutritional program for the treatment of SAM in the 3 preceeding months * Antibiotic use in past 7 days * Clinical complications requiring inpatient treatment * Congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of SAM treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc) * Allergy to macrolides/azalides * Insufficient appetite according to a feeding test with ready-to-use therapeutic food (RUTF) * Parent or guardian refuses to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weight Gain | 8 weeks | Weight will be measured at all follow-up time points and weight gain will be calculated at 8 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nutritional Recovery - Secondary Definition | 8 weeks | Summarize the cumulative proportion recovered by arm. Children are considered recovered if they had mean upper arm circumference \> 12.5 or weight-for-height/length \> -2 for 2 consecutive measurements. Additionally, it includes children who had had mean upper arm circumference \>12.5 or weight-for-height/length \> -2 on their final measurement, regardless of whether they met these criteria on the previous visit. |
| Malaria | 8 weeks | Rapid diagnostic tests for malaria will be conducted at baseline and week 8 to determine malaria infection status. |
| Mortality | 8 weeks | Vital status will be assessed at all follow-up time points and mortality will be defined as death during the study period. |
| Length/Height-for-age Z-score (LAZ/HAZ) | 8 weeks | Height or length will be measured at all follow-up time points and height-for-age z-scores will be calculated. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Stunted is length/height-for-age below the -2 z-score line. Severely stunted is below the -3 z-score line |
| Nutritional Recovery - Primary Definition | 8 weeks | Nutritional recovery is defined as, depending on admission criteria: weight-for-height/length is equal to or more than -2 Z-score and the child have had no oedema for at least 2 weeks, or the mid-upper-arm circumference is equal to or more than 125 mm and the child have had no oedema for at least 2 weeks. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Stunted is length/height-for-age below the -2 z-score line. Severely stunted is below the -3 z-score line |
| Weight-for-Age Z-scores (WAZ) | 8 weeks | Weight will be measured at all follow-up time points and weight-for-age z-scores will be calculated. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Underweight is weight-for-age below the -2 z-score line. Severely underweight is below the -3 z-score line. |
| Weight-for-Height Z-score (WHZ) | 8 weeks | Weight and height, assessed at all follow-up time points, will be used to calculate weight-for-height z-scores. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Overweight is weight-for-length/height above the 2 z-score line. Severely overweight; weight-for-length/height above the 3 z-score line |
| Intestinal Microbiome | Baseline, 8 weeks | baseline and 8 week intestinal microbiome will be compared between the 2 arms alpha diversity using inverse Simpson's index and Shannon's index, expressed in effective number. The Shannon Diversity Index is a quantitative measure that reflects how many different bacterial species there are in a sample. The greater the index, the more diverse the gut microbiota. An index of 0 indicates a community that only has one species. A negative change indicates a decrease in diversity and a positive change indicates an increase in diversity. The Simpson's Diversity Index is a measure of diversity which takes into account the number of species present, as well as the relative abundance of each species. As species richness and evenness increase, so diversity increases. The value ranges between 0 and 1, where 1 represents infinite diversity and 0, no diversity. |
| Mid-Upper Arm Circumference (MUAC) | 8 weeks | Mid-upper arm circumference will be measured at all follow-up time points |
Countries
Burkina Faso
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin children in this arm will receive one dose of azithromycin
Azithromycin: Children enrolled in the trial and randomized to azithromycin will receive a single directly observed dose of oral azithromycin at 20 mg/kg up to the maximum adult dose of 1 g. Oral azithromycin will be administered at the time of enrollment. Enrolled children will also receive RUTF. | 161 |
| Amoxicillin Children in this arm will receive a 7 day course of amoxicillin (standard of care)
Amoxicillin: Children enrolled in the trial and randomized to azithromycin will receive a 7-day course of oral amoxcillin given in twice-daily doses of 50-100 mg/kg, per the Burkina Faso guidelines for the management of severe acute malnutrition. The first dose will be administered at the time of enrollment and the remaining dose will be administered by the caregiver at home. Enrolled children will also receive RUTF. | 140 |
| Total | 301 |
Baseline characteristics
| Characteristic | Azithromycin | Amoxicillin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 161 Participants | 140 Participants | 301 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 16.9 months STANDARD_DEVIATION 8.4 | 16.5 months STANDARD_DEVIATION 8.2 | 16.7 months STANDARD_DEVIATION 8.4 |
| Curently breastfeeding | 108 Participants | 104 Participants | 212 Participants |
| Exclusively breastfeeding | 10 Participants | 11 Participants | 21 Participants |
| HAZ (Height for Age Z-score) | -2.4 Z score STANDARD_DEVIATION 1.5 | -2.5 Z score STANDARD_DEVIATION 1.6 | -2.4 Z score STANDARD_DEVIATION 1.6 |
| Height | 72.2 cm STANDARD_DEVIATION 6.6 | 71.6 cm STANDARD_DEVIATION 6.6 | 71.9 cm STANDARD_DEVIATION 6.6 |
| Mother's age | 26 years STANDARD_DEVIATION 6.2 | 26.2 years STANDARD_DEVIATION 6 | 26.1 years STANDARD_DEVIATION 6.1 |
| MUAC (Middle Upper Arm Circumference) | 11.2 cm STANDARD_DEVIATION 0.4 | 11.2 cm STANDARD_DEVIATION 0.5 | 11.2 cm STANDARD_DEVIATION 0.5 |
| Number of children under 5 in the household | 2 Children STANDARD_DEVIATION 1.7 | 1.9 Children STANDARD_DEVIATION 1.5 | 1.9 Children STANDARD_DEVIATION 1.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 161 Participants | 140 Participants | 301 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Burkina Faso | 161 participants | 140 participants | 301 participants |
| Sex: Female, Male Female | 92 Participants | 77 Participants | 169 Participants |
| Sex: Female, Male Male | 69 Participants | 63 Participants | 132 Participants |
| Weight | 6.8 Kg STANDARD_DEVIATION 1.3 | 6.6 Kg STANDARD_DEVIATION 1.3 | 6.7 Kg STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 161 | 1 / 140 |
| other Total, other adverse events | 106 / 161 | 100 / 140 |
| serious Total, serious adverse events | 41 / 161 | 43 / 140 |
Outcome results
Primary
Weight Gain
Weight will be measured at all follow-up time points and weight gain will be calculated at 8 weeks
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Weight Gain | 1.8 g/kg/day | Standard Deviation 2.1 |
| Amoxicillin | Weight Gain | 2.0 g/kg/day | Standard Deviation 2.2 |
Secondary
Intestinal Microbiome
baseline and 8 week intestinal microbiome will be compared between the 2 arms alpha diversity using inverse Simpson's index and Shannon's index, expressed in effective number. The Shannon Diversity Index is a quantitative measure that reflects how many different bacterial species there are in a sample. The greater the index, the more diverse the gut microbiota. An index of 0 indicates a community that only has one species. A negative change indicates a decrease in diversity and a positive change indicates an increase in diversity. The Simpson's Diversity Index is a measure of diversity which takes into account the number of species present, as well as the relative abundance of each species. As species richness and evenness increase, so diversity increases. The value ranges between 0 and 1, where 1 represents infinite diversity and 0, no diversity.
Time frame: Baseline, 8 weeks
Population: Children who had a rectal swab collected at baseline and at 8 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azithromycin | Intestinal Microbiome | Week 8 Simpson's Index | 4.5 Index | Standard Deviation 2.8 |
| Azithromycin | Intestinal Microbiome | Baseline Simpson's Index | 4.0 Index | Standard Deviation 2.6 |
| Azithromycin | Intestinal Microbiome | Week 8 Shannon's Index | 7.5 Index | Standard Deviation 4.6 |
| Azithromycin | Intestinal Microbiome | Baseline Shannon's Index | 6.6 Index | Standard Deviation 4.4 |
| Amoxicillin | Intestinal Microbiome | Week 8 Shannon's Index | 9.1 Index | Standard Deviation 5.8 |
| Amoxicillin | Intestinal Microbiome | Week 8 Simpson's Index | 5.3 Index | Standard Deviation 2.9 |
| Amoxicillin | Intestinal Microbiome | Baseline Shannon's Index | 8.3 Index | Standard Deviation 5.6 |
| Amoxicillin | Intestinal Microbiome | Baseline Simpson's Index | 5.1 Index | Standard Deviation 3.5 |
Secondary
Length/Height-for-age Z-score (LAZ/HAZ)
Height or length will be measured at all follow-up time points and height-for-age z-scores will be calculated. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Stunted is length/height-for-age below the -2 z-score line. Severely stunted is below the -3 z-score line
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Length/Height-for-age Z-score (LAZ/HAZ) | -2.3 Z-score | Standard Deviation 1.5 |
| Amoxicillin | Length/Height-for-age Z-score (LAZ/HAZ) | -2.37 Z-score | Standard Deviation 1.5 |
Secondary
Malaria
Rapid diagnostic tests for malaria will be conducted at baseline and week 8 to determine malaria infection status.
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Malaria | 13 Participants |
| Amoxicillin | Malaria | 15 Participants |
Secondary
Mid-Upper Arm Circumference (MUAC)
Mid-upper arm circumference will be measured at all follow-up time points
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Mid-Upper Arm Circumference (MUAC) | 12.4 cm | Standard Deviation 0.8 |
| Amoxicillin | Mid-Upper Arm Circumference (MUAC) | 12.3 cm | Standard Deviation 0.8 |
Secondary
Mortality
Vital status will be assessed at all follow-up time points and mortality will be defined as death during the study period.
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Mortality | 2 Participants |
| Amoxicillin | Mortality | 1 Participants |
Secondary
Nutritional Recovery - Primary Definition
Nutritional recovery is defined as, depending on admission criteria: weight-for-height/length is equal to or more than -2 Z-score and the child have had no oedema for at least 2 weeks, or the mid-upper-arm circumference is equal to or more than 125 mm and the child have had no oedema for at least 2 weeks. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Stunted is length/height-for-age below the -2 z-score line. Severely stunted is below the -3 z-score line
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Nutritional Recovery - Primary Definition | 56 Participants |
| Amoxicillin | Nutritional Recovery - Primary Definition | 48 Participants |
Secondary
Nutritional Recovery - Secondary Definition
Summarize the cumulative proportion recovered by arm. Children are considered recovered if they had mean upper arm circumference \> 12.5 or weight-for-height/length \> -2 for 2 consecutive measurements. Additionally, it includes children who had had mean upper arm circumference \>12.5 or weight-for-height/length \> -2 on their final measurement, regardless of whether they met these criteria on the previous visit.
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Nutritional Recovery - Secondary Definition | 98 Participants |
| Amoxicillin | Nutritional Recovery - Secondary Definition | 87 Participants |
Secondary
Weight-for-Age Z-scores (WAZ)
Weight will be measured at all follow-up time points and weight-for-age z-scores will be calculated. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Underweight is weight-for-age below the -2 z-score line. Severely underweight is below the -3 z-score line.
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Weight-for-Age Z-scores (WAZ) | -2.58 Z-score | Standard Deviation 1.1 |
| Amoxicillin | Weight-for-Age Z-scores (WAZ) | -2.65 Z-score | Standard Deviation 1.1 |
Secondary
Weight-for-Height Z-score (WHZ)
Weight and height, assessed at all follow-up time points, will be used to calculate weight-for-height z-scores. A z-score of 0 represents the population mean. The z-score will be positive if the data value lies above the mean, and negative if the data value lies below the mean. Anthropometric outcomes were defined according to the 2006 World Health Organization's Child Growth Standards: Overweight is weight-for-length/height above the 2 z-score line. Severely overweight; weight-for-length/height above the 3 z-score line
Time frame: 8 weeks
Population: All children who were followed up to 8 weeks. This analysis excludes 19 children who were lost to follow-up before 8 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Weight-for-Height Z-score (WHZ) | -1.89 Z-score | Standard Deviation 1.2 |
| Amoxicillin | Weight-for-Height Z-score (WHZ) | -1.95 Z-score | Standard Deviation 1 |