Severe Acute Malnutrition
Conditions
Brief summary
This randomized controlled trial is designed to determine the effect of administration of azithromycin compared to amoxicillin as part of the treatment of uncomplicated severe acute malnutrition (SAM) in children aged 6-59 months on weight gain and nutritional recovery. The investigators will randomize children presenting to Taimaka-run nutritional programs at health centers in Gombe State, Nigeria to a single dose of oral azithromycin or a short course of oral amoxicillin upon admission into the program. Apart from the administration of antibiotics, all children will receive standard outpatient treatment for uncomplicated SAM as specified in the guidelines of the government of Nigeria, which includes therapeutic feeding with ready-to-use therapeutic food (RUTF). Enrolled children will be followed weekly at each routine clinic follow-up visit up until nutritional recovery. All enrolled children will return for a final study visit at 8 weeks following enrollment. Anthropometric and vital status data will be collected at each follow-up visit. Weight gain and nutritional recovery over the 8-week study period will be compared by arm as a primary outcome and at 12 weeks as a secondary outcome.
Interventions
DRUGAzithromycin
Children enrolled in the trial and randomized to receive azithromycin will receive a single dose of azithromycin at 20 mg/kg up to the maximum adult dose of 1g. 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 receive amoxicillin will receive a 5-day course of amoxicillin to be given in twice-daily doses of 15 mg/kg per the Nigeria guidelines for severe acute malnutrition. The first dose will be administered at the time of enrollment, and the remaining doses will be administered by the caregiver at home. Enrolled children will also receive RUTF.
Sponsors
The Taimaka Project
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
(all must be met): * Age 6-59 months * Weight-for-height z-score (WHZ) \< -3 SD or mid-upper arm circumference (MUAC) \< 115 mm * No nutritional or nutritional edema Grade I and II * Primary residence within catchment area of enrollment site * Available for full 8-week study * Has not been admitted to a nutritional program for the treatment of severe acute malnutrition (SAM) in the 2 preceding weeks * No antibiotic use in past 7 days * No clinical complications requiring antibiotic treatment * No clinical complications requiring inpatient treatment * 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, sickle cell disease, etc) * No allergy to macrolides/azalides * Sufficient appetite according to a feeding test with ready-to-use therapeutic food (RUTF) * Appropriate written informed consent from at least one parent or guardian
Exclusion criteria
(any excludes): * Age \< 6 months or \> 59 months * WHZ ≥ -3 SD or MUAC ≥ 115 mm * Primary residence outside catchment area of enrollment site * Not available for full 8-week study * Presence of nutritional edema Grade III * Admission to a nutritional program for the treatment of SAM in the 2 preceding weeks * Antibiotic use in past 7 days * Clinical complications requiring antibiotic treatment * 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 at 8 Weeks | 8 weeks | Weight will be measured at baseline and weekly follow ups, and weight gain will be calculated at 8 weeks in g/day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Nutritional Recovery at 8 Weeks | 8 weeks | Nutritional recovery will be defined as a child having WHZ ≥ -2 on two consecutive visits and no acute complication or edema for the past 7 days AND / OR MUAC of ≥ 125mm on 2 consecutive visits and no acute complication or edema for the past 7 days. Children will be considered recovered or not recovered using these criteria Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WHZ \< -2 standard distributions below the median is defined as moderately wasted, while a WHZ \< -3 standard distributions below the median is defined as severely wasted. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Recovery | 12 weeks | Time from enrollment to nutritional recovery will be calculated in days by subtracting the date of enrollment from the date of nutritional recovery. |
| Nonresponse at 8 Weeks | 8 weeks | Number of children with nonresponse will be documented if a child does not meet the criteria for nutritional recovery at 8 weeks after enrollment. |
| Number of Participants Who Transferred to Inpatient Care | 12 weeks | The occurrence, date, and reason for transfer from outpatient to inpatient treatment will be recorded. |
| Mortality by 8 Weeks | 8 weeks | Vital status will be assessed at baseline and at weekly follow up visits for 8 weeks, and mortality will be defined as death during the study period. Date of death will be recorded. |
| Mortality by 12 Weeks | 12 weeks | Vital status will be assessed at baseline, weekly follow up visits for 8 weeks, and at 12 weeks, and mortality will be defined as death during the study period. Date of death will be recorded. |
| Weight Gain Over 12 Weeks | 12 weeks | Weight will be measured at baseline and weekly follow up visits for 8 weeks, and at 12 weeks after admission to the program. Weight gain will be defined as grams per kilogram per day (g/day). |
| Mid-upper Arm Circumference (MUAC) | 12 weeks | Mid-upper arm circumference (centimeters) will be measured at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit). |
| Weight-for-age Z-score (WAZ) | 12 weeks | Weight will be measured at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit) and weight-for-age z-scores will be calculated. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WAZ \< -2 standard distributions below the median is defined as underweight, while a WAZ \< -3 standard distributions below the median is defined as severely underweight. |
| Weight-for-height Z-score (WHZ) | 12 weeks | Weight and height, assessed at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit), will be used to calculate weight-for-height z-scores. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WHZ \< -2 standard distributions below the median is defined as moderately wasted, while a WAZ \< -3 standard distributions below the median is defined as severely wasted. |
| Malaria | 8 weeks | Rapid diagnostic tests for malaria will be conducted at baseline and week 8 to determine malaria infection status. Positivity rate will be compared between arms |
| Clinical Signs of Infection | 12 weeks | Number of participants with clinical sign of infection will be recorded At baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit, including care-giver reported experience of fever, diarrhea, vomiting, and respiratory infection/cough and clinical diagnoses made at by site personnel |
| Height-for-age Z-score (HAZ) | 12 weeks | Height or length will be measured monthly (baseline and the 4-, 8-, and 12-week follow up visits) and height-for-age z-scores will be calculated. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A HAZ \< -2 standard distributions below the median is defined as stunted, while a HAZ \< -3 standard distributions below the median is defined as severely stunted. |
Countries
Nigeria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amoxicillin Children in this arm will receive a 5-day course of amoxicillin (standard care).
Amoxicillin: Children enrolled in the trial and randomized to receive amoxicillin will receive a 5-day course of amoxicillin to be given in twice-daily doses of 15 mg/kg per the Nigeria guidelines for severe acute malnutrition. The first dose will be administered at the time of enrollment, and the remaining doses will be administered by the caregiver at home. Enrolled children will also receive RUTF. | 151 |
| Azithromycin Children in this arm will receive one dose of amoxicillin.
Azithromycin: Children enrolled in the trial and randomized to receive azithromycin will receive a single dose of azithromycin at 20 mg/kg up to the maximum adult dose of 1g. Oral azithromycin will be administered at the time of enrollment. Enrolled children will also receive RUTF. | 159 |
| Total | 310 |
Baseline characteristics
| Characteristic | Amoxicillin | Total | Azithromycin |
|---|---|---|---|
| Age, Continuous | 15.79 month STANDARD_DEVIATION 7.8 | 16.16 month STANDARD_DEVIATION 8.3 | 16.52 month STANDARD_DEVIATION 8.7 |
| 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 | 151 Participants | 310 Participants | 159 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 Nigeria | 151 participants | 310 participants | 159 participants |
| Sex: Female, Male Female | 76 Participants | 157 Participants | 81 Participants |
| Sex: Female, Male Male | 75 Participants | 153 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 42 | 3 / 58 |
| other Total, other adverse events | 1 / 133 | 3 / 142 |
| serious Total, serious adverse events | 1 / 133 | 0 / 142 |
Outcome results
Primary
Weight Gain at 8 Weeks
Weight will be measured at baseline and weekly follow ups, and weight gain will be calculated at 8 weeks in g/day
Time frame: 8 weeks
Population: 96 children in Amoxicillin arm and 120 children in Azithromycin arm had anthropometry form collected between the 8 weeks window (42 to 70 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Weight Gain at 8 Weeks | 30.42 g/day | Standard Deviation 17.11 |
| Azithromycin | Weight Gain at 8 Weeks | 27.75 g/day | Standard Deviation 18.82 |
Secondary
Number of Participants With Nutritional Recovery at 8 Weeks
Nutritional recovery will be defined as a child having WHZ ≥ -2 on two consecutive visits and no acute complication or edema for the past 7 days AND / OR MUAC of ≥ 125mm on 2 consecutive visits and no acute complication or edema for the past 7 days. Children will be considered recovered or not recovered using these criteria Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WHZ \< -2 standard distributions below the median is defined as moderately wasted, while a WHZ \< -3 standard distributions below the median is defined as severely wasted.
Time frame: 8 weeks
Population: 96 children in Amoxicillin arm and 120 children in Azithromycin arm had anthropometry form collected between the 8 weeks window (42 to 70 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Number of Participants With Nutritional Recovery at 8 Weeks | 85 Participants |
| Azithromycin | Number of Participants With Nutritional Recovery at 8 Weeks | 105 Participants |
Other Pre-specified
Clinical Signs of Infection
Number of participants with clinical sign of infection will be recorded At baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit, including care-giver reported experience of fever, diarrhea, vomiting, and respiratory infection/cough and clinical diagnoses made at by site personnel
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Clinical Signs of Infection | 6 Participants |
| Azithromycin | Clinical Signs of Infection | 16 Participants |
Other Pre-specified
Height-for-age Z-score (HAZ)
Height or length will be measured monthly (baseline and the 4-, 8-, and 12-week follow up visits) and height-for-age z-scores will be calculated. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A HAZ \< -2 standard distributions below the median is defined as stunted, while a HAZ \< -3 standard distributions below the median is defined as severely stunted.
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Height-for-age Z-score (HAZ) | -3.77 z score | Standard Deviation 1.98 |
| Azithromycin | Height-for-age Z-score (HAZ) | -3.64 z score | Standard Deviation 1.49 |
Other Pre-specified
Malaria
Rapid diagnostic tests for malaria will be conducted at baseline and week 8 to determine malaria infection status. Positivity rate will be compared between arms
Time frame: 8 weeks
Population: 55 children in Amoxicillin arm and 66 children in Azithromycin arm had malaria test between the 8 weeks window (42 to 70 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Malaria | 9 Participants |
| Azithromycin | Malaria | 16 Participants |
Other Pre-specified
Mid-upper Arm Circumference (MUAC)
Mid-upper arm circumference (centimeters) will be measured at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit).
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Mid-upper Arm Circumference (MUAC) | 12.70 centimeters (cm) | Standard Deviation 0.7 |
| Azithromycin | Mid-upper Arm Circumference (MUAC) | 12.73 centimeters (cm) | Standard Deviation 0.52 |
Other Pre-specified
Mortality by 12 Weeks
Vital status will be assessed at baseline, weekly follow up visits for 8 weeks, and at 12 weeks, and mortality will be defined as death during the study period. Date of death will be recorded.
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Mortality by 12 Weeks | 4 Participants |
| Azithromycin | Mortality by 12 Weeks | 3 Participants |
Other Pre-specified
Mortality by 8 Weeks
Vital status will be assessed at baseline and at weekly follow up visits for 8 weeks, and mortality will be defined as death during the study period. Date of death will be recorded.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Mortality by 8 Weeks | 3 Participants |
| Azithromycin | Mortality by 8 Weeks | 2 Participants |
Other Pre-specified
Nonresponse at 8 Weeks
Number of children with nonresponse will be documented if a child does not meet the criteria for nutritional recovery at 8 weeks after enrollment.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Nonresponse at 8 Weeks | 11 Participants |
| Azithromycin | Nonresponse at 8 Weeks | 15 Participants |
Other Pre-specified
Number of Participants Who Transferred to Inpatient Care
The occurrence, date, and reason for transfer from outpatient to inpatient treatment will be recorded.
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amoxicillin | Number of Participants Who Transferred to Inpatient Care | 3 Participants |
| Azithromycin | Number of Participants Who Transferred to Inpatient Care | 4 Participants |
Other Pre-specified
Time to Recovery
Time from enrollment to nutritional recovery will be calculated in days by subtracting the date of enrollment from the date of nutritional recovery.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Time to Recovery | 21.4 days | Standard Deviation 19.2 |
| Azithromycin | Time to Recovery | 22.4 days | Standard Deviation 19.3 |
Other Pre-specified
Weight-for-age Z-score (WAZ)
Weight will be measured at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit) and weight-for-age z-scores will be calculated. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WAZ \< -2 standard distributions below the median is defined as underweight, while a WAZ \< -3 standard distributions below the median is defined as severely underweight.
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Weight-for-age Z-score (WAZ) | -2.67 z score | Standard Deviation 1.31 |
| Azithromycin | Weight-for-age Z-score (WAZ) | -2.48 z score | Standard Deviation 0.95 |
Other Pre-specified
Weight-for-height Z-score (WHZ)
Weight and height, assessed at all follow-up time points (baseline, weekly follow up visits for 8 weeks, and at the 12-week follow up visit), will be used to calculate weight-for-height z-scores. Anthropomorphic outcomes are defined according to the World Health Organization's 2006 Child Growth Standards A z-score of 0 represents the population median. The z-score will be positive if the data value lies above the mean, and it will be negative if the value lies below the median. A WHZ \< -2 standard distributions below the median is defined as moderately wasted, while a WAZ \< -3 standard distributions below the median is defined as severely wasted.
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Weight-for-height Z-score (WHZ) | -0.69 z score | Standard Deviation 1.44 |
| Azithromycin | Weight-for-height Z-score (WHZ) | -0.60 z score | Standard Deviation 1.54 |
Other Pre-specified
Weight Gain Over 12 Weeks
Weight will be measured at baseline and weekly follow up visits for 8 weeks, and at 12 weeks after admission to the program. Weight gain will be defined as grams per kilogram per day (g/day).
Time frame: 12 weeks
Population: 42 children in Amoxicillin arm and 58 children in Azithromycin arm had anthropometry form collected between the 12 weeks window (70 to 98 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amoxicillin | Weight Gain Over 12 Weeks | 22.67 g/day | Standard Deviation 13.13 |
| Azithromycin | Weight Gain Over 12 Weeks | 23.89 g/day | Standard Deviation 11.58 |