Clinical trial NCT05473234
Conditions: Severe Acute Malnutrition
Sponsor: University of California, San Francisco
Start date: 2022-10-06; Completion date: 2023-11-29
Enrollment: 310 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Children in this arm will receive one dose of amoxicillin. arm 2: Children in this arm will receive a 5-day course of amoxicillin (standard care).
Interventions: intervention 1: Azithromycin intervention 2: Amoxicillin
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Taimaka CMAM – SAM trial 
 
Manual of Operations and Procedures 
 
 
 
 
 
Trial registration:  NCT05473234


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TABLE OF CONTENTS 
 
ABBREVIATIONS 
3 
1. 
INTRODUCTION 
4 
1.1 
Background and Rationale 
4 
1.2 
Design Overview 
5 
1.3 
Objectives 
5 
2. 
STUDY DESIGN 
6 
2.1 
Study Setting 
6 
2.2 
Recruitment and Eligibility Criteria 
6 
2.3 
Randomization and Masking 
7 
2.4 
Interventions 
8 
2.5 
Outcomes 
8 
2.6 
Participant Timeline 
10 
2.7 
Study Team, Roles, Responsibilities 
11 
3. 
PROCEDURES 
12 
3.1 
Training 
12 
3.2 
Anthropometry 
12 
3.4 
Malaria Rapid Diagnostic Test 
16 
3.5 
Assess for bilateral pitting oedema 
18 
3.6 
Vital Status 
18 
3.7 
Clinical examination 
19 
4. 
STUDY MEDICATION 
20 
4.1 
Study Medication Description 
20 
4.2 
Dosage Information 
20 
4.3 
Medication Procurement 
20 
4.4 
Medication Quality Control 
20 
5. 
ADVERSE EVENTS 
21 
5.1 
Adverse Event Monitoring and Reporting 
21 
5.2 
Inpatient Hospitalization Transfer Information 
21 
6. 
DATA COLLECTION, MANAGEMENT, AND SECURITY 
24 
6.1 
Data Collection 
24 
6.2 
Data Management and Security 
24 
6.3 
Data Quality and Monitoring 
24 
7. 
PROTECTION OF HUMAN SUBJECTS 
25 
7.1 
Institutional Review Board Approval 
25 
7.2 
Informed Consent 
25 
8. 
DATA AND SAFETY MONITORING COMMITTEE 
26 
9. 
STATISTICAL METHODS 
27 
9.1 
Sample Size and Power 
27 
9.2 
Statistical Analysis 
27 
REFERENCES 
30 
PROTOCOL UPDATES 
31 
APPENDIX 
31 


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ABBREVIATIONS 
 
CHW: Community Health Worker 
CMAM: Community management of acute malnutrition 
DSMC: Data and Safety Monitoring Committee 
HAZ: height-for-age z-score 
IRB: Institutional Review Board 
MUAC: mid-upper arm circumference  
ODK: open data kit 
OTP: outpatient therapeutic program 
RDT: rapid diagnostic test 
RUTF: ready-to-use therapeutic food 
SAM: severe acute malnutrition 
SD: standard deviation 
SES: socio-economic status 
UCSF: University of California San Francisco  
WAZ: weight-for-age z-score 
WHO: World Health Organization 
WHZ: weight-for-height z-score


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1. INTRODUCTION 
 
1.1 
Background and Rationale 
 
Severe acute malnutrition (SAM) affects nearly 19 million children under the age of 5 
annually.1 Current World Health Organization (WHO) guidelines for treatment of SAM include 
outpatient treatment with ready-to-use therapeutic food (RUTF). Children with SAM often bear a 
large burden of infectious disease, have 9 times the risk of all-cause mortality compared to their 
well-nourished peers, and face a stronger risk of infectious mortality.2,3 Because malnutrition 
can suppress the immune system, children with SAM and co-existing infection are often 
asymptomatic. As a result, the WHO has recommended that the routine treatment of children 
with SAM include a broad-spectrum antibiotic. However, the evidence base for this 
recommendation is minimal. Two studies of amoxicillin as adjunctive therapy for SAM found 
mixed results.4,5 In Malawi, routine amoxicillin led to increased nutritional recovery and 
decreased mortality.4 In Niger, there was no effect of routine amoxicillin on either nutritional 
recovery or mortality.5 Importantly, a majority of the children included in the Malawi study had 
kwashiorkor, whereas children with kwashiorkor were excluded in Niger. A pooled analysis of 
the two studies found no benefit of amoxicillin for recovery.6 A third study of daily co-trimoxazole 
for complicated SAM additionally found no benefit for nutritional recovery or mortality.7 The role 
of antibiotics for mortality and nutritional recovery among children with uncomplicated severe 
acute malnutrition remains unclear. 
 
A recent cluster-randomized trial demonstrated that mass azithromycin distribution 
reduces all-cause mortality at the community level.8 In Niger, Tanzania, and Malawi, 
mortality was reduced by nearly 14% in communities randomized to biannual mass single-dose 
azithromycin distribution to children 1-59 months in the MORDOR trial (Macrolides Oraux pour 
Réduire les Décès avec un Oeil sur la Résistance). The largest effects were seen in Niger, with 
nearly 1 in 5 deaths averted, and in children less than 6 months of age, with approximately 25% 
reduction in mortality.  
 
Azithromycin as adjunctive therapy may offer several advantages over amoxicillin or co-
trimoxazole. First, a single dose of azithromycin has a long half-life, and thus dosing could 
occur during outpatient follow-up visits and would not rely on caregiver dosing. Second, 
amoxicillin and co-trimoxazole are much more commonly used for routine treatment in many 
regions of sub-Saharan Africa than macrolides, and baseline resistance to these antibiotic 
classes tend to be much higher.9 Adjunctive therapy with azithromycin may be preferable, given 
overall reduced exposure compared to other classes.10 Third, evidence from the MORDOR 
study in Niger indicated a substantial reduction in mortality with the use of a single dose of 
azithromycin in children without established infection. Given that children with uncomplicated 
SAM by definition do not have an established infection, the rationale for antibiotic use may be 
similar for that among children in the general population who are receiving presumptive 
treatment. As children with malnutrition are at particularly high risk of mortality, this subgroup of 
the population may stand to see greater benefits from a similar antibiotic regimen that has been 
shown to be efficacious in the general population.  
 
 
 
 
 
 
 


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1.2 
Design Overview  
 
We propose a randomized controlled trial to examine the effect of the adjunctive administration 
of azithromycin compared to amoxicillin in the treatment of children aged 6-59 months with 
uncomplicated SAM. We will randomize children presenting to nutritional programs in Gombe 
State, Nigeria to a single dose of oral azithromycin or a short course of oral amoxicillin upon 
admission into the program and follow them at each weekly clinic follow-up visit up to 8 weeks 
following admission. All enrolled children will receive non-antibiotic routine care for 
uncomplicated SAM as stated by the Nigeria guidelines, which includes ready-to-use 
therapeutic food (RUTF). Anthropometric and vital status data will be collected during follow-up. 
Weight gain and nutritional recovery over the 8-week study period will be compared by study 
arm. 
 
1.3 
Objectives 
 
SPECIFIC AIM 1: Determine the effect of azithromycin on weight gain among children 
with uncomplicated SAM. We hypothesize that children randomized to receive azithromycin 
will experience greater weight gain over an 8-week period compared to those receiving 
amoxicillin.    
 
 
SPECIFIC AIM 2: Determine the effect of azithromycin on nutritional recovery in children 
with uncomplicated SAM. We hypothesize that children randomized to receive azithromycin 
will have increased nutritional recovery 8 weeks after admission to the nutritional program 
compared to children receiving amoxicillin. 


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2. STUDY DESIGN 
 
This randomized controlled trial is designed to determine the effect of administration of 
azithromycin compared to amoxicillin as part of the treatment of uncomplicated SAM in children 
aged 6-59 months on weight gain and nutritional recovery. We 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 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.  
 
2.1 
Study Setting 
 
The trial will be conducted at outpatient therapeutic program (OTP) centers in Gombe State, 
Nigeria, which are run out of government-run primary healthcare centers (PHC) that Taimaka 
partners with for their CMAM program. Taimaka’s program uses these OTPs to run nutritional 
programs for children presenting with SAM. The PHCs are government-run, integrated health 
centers and are overseen by the Primary Healthcare Development Agency. Taimaka’s program 
links these centers to secondary facilities for referrals in the case of complications. The 
secondary facilities function as inpatient treatment centers (ITPs) and are overseen by the 
Hospital Services Management Board and the Ministry of Health.  
 
2.2 
Recruitment and Eligibility Criteria 
 
Recruitment 
 
Taimaka-employed community mobilizers (CMs) screen children for SAM at least once a month 
in the villages within the catchment areas of the program PHCs. If they are screened positive for 
moderate acute malnutrition (MAM) or SAM, they are referred to an OTP center. CMs screen for 
MAM and SAM using a tape to measure mid-upper arm circumference (MUAC). 
 
Each participating OTP center has nutrition staff (henceforth known as health agents) trained to 
enter data and conduct anthropometric measurements. All data is collected electronically on an 
ODK custom platform. The health agents at the OTP centers are trained regularly on 
malnutrition guidelines, data collection and anthropometric measurements  
 
All children presenting to the OTP centers for malnutrition will be screened, and eligibility for 
enrollment in the trial will be determined by health agents trained for the study.  
 
Eligibility criteria for enrollment sites 
 
For Phase 1, the 3 Taimaka-run OTP centers in Gombe state that will be eligible for enrollment 
are located within 1) General Hospital Deba, 2) General Hospital Bajoga, and 3) General 
Hospital Billiri. 
 


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For Phase 2, the Taimaka-run OTP centers in Gombe state will be located in PHCs in wards in 
these local government areas (LGAs): Deba, Billiri, and Funakaye (Bajoga is a town within the 
Funakaye LGA).  
 
Eligibility criteria for individuals 
 
Eligible individuals are children aged 6-59 months with SAM who present to an eligible OTP 
center during the study period and meet all of the following criteria: 
 
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  
● Either (a) no oedema or (b) Nutritional edema Grade I and II  
● Primary residence within catchment area of enrollment site 
● Available for full 8-week study 
● 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, sickle cell disease 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 
 
2.3 
Randomization and Masking 
 
Children meeting inclusion criteria will be enrolled by a local health agent after consent from 
guardian is obtained. At enrollment, children will be assigned a study identification number. 
Enrolled children will then undergo a baseline assessment. The baseline assessment includes 
data collection on demographics and socioeconomic status as well as anthropometric 
assessments. After completion of the baseline assessment, children will be randomized to 
receive either (1) a single dose of directly observed oral azithromycin plus a 5-day course of 
placebo or (2) a 5-day course of oral amoxicillin. 
 
The randomization sequence will be generated by the UCSF investigators using R (R 
Foundation for Statistical Programming, Vienna, Austria). Children will be randomized in a 1:1 


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fashion to a single dose of azithromycin with short course of placebo or a short course of oral 
amoxicillin. The randomization sequence will be linked to the study identification numbers and 
kept separately so outcomes assessors are not aware of the treatment allocation. When a child 
has been enrolled and has completed the baseline assessments, a different health agent will 
determine the allocation and will administer study medication indicated as described in Section 
4.  
 
To keep the allocation concealed, only the study nurse administering treatment will have access 
to the randomization allocations. The study nurse will treat the child in a private room without 
the outcome assessor present. For each enrolled child, the treatment administered will be 
recorded on the mobile data collection app not accessible by the outcome assessor. 
 
Given the nature of the intervention, the personnel administering treatment will not be masked 
to treatment assignment. Participants will be masked to treatment assignment, as parents of the 
children given azithromycin will receive a placebo syrup to give their child. Outcome assessors 
will be masked to treatment assignment; this will be accomplished by assigning one health 
agent to administer treatment and a separate masked health agent to perform outcome 
assessments, including anthropometry, and vital status updates.  
 
2.4 
Interventions 
 
Children will be randomized to receive a single directly observed dose of oral azithromycin plus 
placebo or a short course of oral amoxicillin. Azithromycin and the first dose of amoxicillin will be 
administered at the time of enrollment (see Section 4 for study medication details). Except for 
antibiotics, all children will receive standard outpatient treatment for uncomplicated SAM per the 
guidelines of the government of Nigeria, which includes RUTF (Plumpy’Nut, Nutriset) as follows: 
 
 
Standard treatment also includes: 
- 
Weekly appetite test, MUAC, and weight 
 
measurement 
- 
Weekly clinical examination 
- 
Weekly health and nutrition education 
- 
Weekly evaluation of RUTF consumption 
- 
Home visit if needed 
- 
Monthly height / length measurement  
 
 
 
 
 
2.5 
Outcomes 
 
Primary Outcome 
Weight gain over 8 weeks (Specific Aim 1). Weight will be measured at all follow-up time points 
and weight gain will be defined as grams per kilogram per day (g/kg/day). 
 
Secondary Outcomes 
Nutritional recovery by 8 weeks (Specific Aim 2). 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 


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days AND / OR MUAC of ≥ 125mm on 2 consecutive visits and no acute complication or edema 
for the past 7 days. The criteria chosen to define the recovery will be the same one we used to 
admit the child into the program as defined in the national guidelines: 
 
Criteria of admission 
Criteria of discharge 
MUAC < 11.5cm 
MUAC > 12.5cm (for 2 consecutive weeks) 
Sustained weight gain 
Clinically well 
Bilateral oedema 
MUAC > 12.5cm 
No oedema for 2 consecutive visits 
Clinically well 
WHZ < -3 SD 
MUAC > 12.5cm AND 
WHZ >-2 for 2 consecutive visits 
Clinically well 
 
 
● Weight gain over 12 weeks. Weight will be measured at all follow-up time points and at 
12 weeks after admission to the program. Weight gain will be defined as grams per 
kilogram per day (g/kg/day). 
● Time to recovery. Time from enrollment to nutritional recovery (defined above) will be 
calculated in days by subtracting the date of enrollment from the date of nutritional 
recovery. 
● Nonresponse at 8 weeks. Nonresponse will be documented if a child does not meet the 
criteria for nutritional recovery at 8 weeks. 
● Transfer to inpatient care. The occurrence, date, and reason for transfer from 
outpatient to inpatient treatment will be recorded. 
● Mortality by 8 weeks. Vital status will be assessed at all follow-up time points and 
mortality will be defined as death during the study period. Date of death will be recorded. 
● Mortality by 12 weeks. Vital status will be assessed at all follow-up time points and 
mortality will be defined as death during the study period. Date of death will be recorded. 
● Clinical signs of infection. At all follow-up time points, clinical signs of infection will be 
recorded, including care-giver reported experience of fever, diarrhea, vomiting, and 
respiratory infection/cough and clinical diagnoses made at by site personnel 
● Adverse events. Adverse events will be reported at all follow-up time points  
● HAZ. Height or length will be measured monthly and height-for-age z-scores will be 
calculated. 
● MUAC. Mid-upper arm circumference will be measured at all follow-up time points. 
● WAZ. Weight will be measured at all follow-up time points and weight-for-age z-scores 
will be calculated. 
● WHZ. Weight and height, assessed at all follow-up time points, will be used to calculate 
weight-for-height z-scores. 
● Malaria. Rapid diagnostic tests for malaria will be conducted at baseline and week 8 to 
determine malaria infection status. 
 
 
 


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2.6 
Participant Timeline 
 
Figure 1. Participant Timeline and Flow 
 
Children Admitted to Nutritional Program 
 
 
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  
● Either (a) no oedema or (b) Nutritional edema Grade I and II  
● Primary residence within catchment area of enrollment site 
● Available for full 8-week study 
● 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, sickle cell disease etc) 
● Allergy to macrolides/azalides 
● Insufficient appetite according to a feeding test with RUTF 
● Parent or guardian refuses to provide consent 
 
 
 
Baseline assessment: 
● Baseline questionnaire (feeding practices, household survey, maternal survey) 
● Anthropometry (height, weight, MUAC) 
● Malaria (RDT) 
 
 
 
Randomized 
 
 
 
 
Randomized to single dose azithromycin 
plus short course of placebo 
 
Randomized to a short course of oral 
amoxicillin 
 
 
 
Weekly 1-8: 
● Anthropometry (Weight, MUAC) 
● Adverse Events 
● Vital Status 


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● Clinical examination outcomes (diagnoses, treatments) 
 
Monthly: 
● Anthropometry (Height, length) 
 
Week 8: 
● Malaria RDT 
 
Week 12: 
● Anthropometry (height, weight, MUAC) 
● Vital Status 
 
 
2.7      Study Team, Roles, Responsibilities 
● Investigators (UCSF). The UCSF investigators will be responsible for the overall study 
design and implementation, data management and monitoring, data analysis, and 
dissemination of results in collaboration with Taimaka investigators. The UCSF 
investigators will design and implement trainings for study procedures and maintain 
weekly communication with local Nigerian study staff. 
● Investigators (Taimaka Project). The Taimaka investigators will be responsible for 
overall study design, implementation, data management and monitoring, data analysis, 
and dissemination of results in collaboration with UCSF investigators. The Taimaka 
investigators will oversee all local study activities, including training and regular 
supervision and monitoring of local study staff. 
● Medical Monitor. The Medical Monitor will provide clinical oversight for the enrolled 
children. Study Team Members will report serious adverse events to the Medical Monitor 
within 24 hours of occurrence, and the Medical Monitor will determine whether or not the 
event is likely to be related to the study drug. In addition, the Medical Monitor will provide 
clinical guidance for the adverse event as needed.  
● Data and Safety Monitoring Committee. The Data and Safety Monitoring Committee 
will provide independent oversight of data quality and patient safety during the course of 
the trial. See Section 8 for details. 
● Study Team Members (Taimaka project). Study Team will be responsible for 
implementation of all study procedures as described in this protocol, including 
recruitment, consent, enrollment and randomization, drug administration, and collection 
of all study data. 
o Health agent administering treatment. A health agent at each OTP center will 
be trained to determine the randomization allocation of enrolled children and to 
administer azithromycin if indicated. 
o Outcome Assessor. One health agent will be an outcome assessor for each site 
and will be trained to manage consent, enrollment, and collection of all study 
data, including outcome assessments. 
 
 
 


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3. PROCEDURES 
 
3.1 
Training 
 
All members of the OTP nutrition team will participate in multi-day training which will include a 
section on the particulars of study protocol. In addition, study nurses (study officers) who will be 
administering the treatment will receive a separate initial training. Study officers must achieve a 
score of >80% on the training quiz in order to participate in the study. Training will include a mix 
of lecture and practice. Taimaka’s OTP manager will supervise the adherence to study protocol 
by the nutrition team and the study officer and regularly check up on their understanding and 
memory of study protocols. 
 
3.2 
Anthropometry 
 
Anthropometric assessments (height or length, weight, and MUAC) will be recorded by health 
agents at baseline, weekly until recovery, week 8 and week 12. 
 
Supplies 
● Mobile data collection device & accessories 
● Height and length tapes 
● Digital scale 
● MUAC strips  
● Chucks and alcohol swabs 
● Pens and sharpie markers 
● Trash bags 
● Extra set of AA batteries (6) 
 
Anthropometry Team 
Two health agents will conduct anthropometry: 1) examiner and 2) recorder. The examiner will 
conduct the anthropometric assessments, and the recorder will enter data into the mobile 
application. 
 
Measuring Length (National operational guidelines for CMAM Nigeria) 
 
How to measure LENGTH (when lying down) If the child is less than 87cm, he/she should be 
measured lying down. 
1. One person holds the child’s head, making sure the child’s head is touching the back of 
the board. The child’s eyes should be looking straight up. 
2. The other person holds down the child’s knees, pressing the sliding wood piece against 
the child’s heels and soles of the feet. 
3. Align the child with the board 
4. Child’s arms should be lying alongside his/her body, and if necessary, the mother can 
hold the arms down 
5. The person holding the feet reads the measurement. 
 


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Measuring Height (National operational guidelines for CMAM Nigeria) 
 
How to measure HEIGHT (when standing) If the child is more than 87cm, he/she should be 
measured standing. 
1. Place the child’s feet flat and together in the centre of and against the back and base of 
the wall. 


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2. One person places their right hand just above the child’s ankles on the shins, left hand 
on the child’s knees and push against the wall. Make sure the child’s legs are straight 
and the heels and calves are against the wall 
3. Tell the child to look straight ahead making sure the child’s line of sight is level with the 
ground. 
4. The second person should place their open left hand under the child’s chin. Do not cover 
the child’s mouth or ears. Make sure the shoulders are level, the hands are at the child’s 
side, and the head, shoulder blades, and buttocks are against the wall.  
5. When the child’s position is correct, person holding the legs reads (at eye level) and call 
out the measurement to the nearest 0.1 cm. 
 
 
 
 
 
 
 
 
 


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Measuring Weight 
 
Tempered glass digital standing scales will be used to weigh infants and children to the nearest 
0.1 kg.  
 
For infants and children who cannot stand:  
1. Before weighing the child, take all his/ her clothes off 
2. Zero the scale 
3. Ask the mother to step onto the scale and record her weight in the mobile app.  
4. Place the child into her arms.  
5. Record the total weight in kg to the nearest 0.1 kg and enter into the mobile app. The 
app will calculate the weight of the child.  
6. Do not hold the scale when reading the weight 
 
For children who can stand:  
7. Before weighing the child, take all his/ her clothes off 
8. Zero the scale 
9. Ask the child to stand on the scale  
10. Make sure the child is not holding onto anything 
11. Record the weight in kg to the nearest 0.1 kg in the mobile app 
12. Do not hold the scale when reading the weight 
 
Measuring Mid-Upper Arm Circumference (National operational guidelines for CMAM 
Nigeria) 
 
The child’s MUAC will be measured three times. MUAC measurements will be taken at the 
midpoint of the left arm between the tip of the shoulder and the tip of the elbow using non-
stretch MUAC tapes.  
 
1- Find the midpoint. Ask the patient to stand, or for a small child, have the caregiver hold 
the child, with the patient’s left arm bent at a 90-degree angle. Find the bone that forms 
the tip of the shoulder (acromion process), and place the zero point of the MUAC 
measure there (it is usually the middle of the window). Extend the MUAC tape down to 
the tip of the elbow (olecranon process). Read the length in mm of this distance between 
shoulder and elbow; then divide this number in half to find the mid-point (or fold the tape 
in half between the zero and the elbow point). Mark the mid-point in pen on the patient’s 
arm. 
2- Position the patient to read the MUAC. Have the patient stand or sit with the left arm 
hanging loosely by the side of the body. Muscles should not be flexed at all. 
3- Measure the MUAC. Place the MUAC tape around the left arm at the midpoint mark. It 
should fit snugly around without constricting the arm. Read the measurement from the 
window of the tape. Take the measurement to the nearest 0.1cm. 
 


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3.4 
Malaria Rapid Diagnostic Test 
 
Malaria infection status will be assessed on all enrolled children using a rapid diagnostic test 
(RDT) at baseline. 
 
Supplies 
● Mobile data collection device & accessories 
● RDT test packet 
● Alcohol swabs 
● Gloves 
● Lancet 
● Buffer 
● Timer 
 
Conduct the Malaria RDT 
1. Check the expiry date on the test packet. If the expiry date has passed, choose another 
packet that has not yet expired. 
2. Put on the gloves. Use new gloves for each patient. 
3. Open the packet and remove: 
a. The test 
b. The capillary tube 
c. The desiccant sachet 


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4. Write the patient’s name and study ID number on the test 
5. Open the alcohol swab. Grasp the 4th finger on the patient’s left hand. Clean the finger 
with the alcohol swab. Allow the finger to dry before pricking. 
6. Open the lancet. Prick patient’s finger to get a drop of blood. 
7. Discard the lancet into an appropriate sharps receptacle immediately after pricking the 
finger. 
8. Use the capillary tube to collect the drop of blood. 
9. Use the capillary tube to put the drop of blood into the square hole on the test marked 
“A.” 
10. Discard the capillary tube into an appropriate sharps receptacle 
11. Add 6 drops of buffer into the round hole marked “B.” 
12. Wait 15 minutes after adding buffer 
13. Read test results. Do NOT read the test sooner than 15 minutes after adding the buffer. 
You may get false results 
14. How to read the test results: 
a. POSITIVE: a line near letter “C” and a line near letter “T” means the patient is 
positive for malaria. 
 
i. The test is positive even if the line near “T” is faint 
 
b. NEGATIVE: a line near letter “C” and NO LINE near letter “T” means the patient 
does NOT have malaria 
 
c. INVALID RESULT: NO LINE near letter “C” and one or no line near letter “T” 
means the test is INVALID 
 
i. Repeat the test using a new RDT and a new lancet if no control line 
appears 
15. Dispose of gloves, alcohol swab, desiccant sachet, and packaging 


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16. Record the test result in the mobile application. 
 
3.5 
Assess for bilateral pitting oedema 
 
Assessing for oedema will be done at enrollment to ensure eligibility and will also be assess at 
each weekly visits 
 
1. While child is sitting, grasp both feet in your hands. Apply firm thumb pressure to 
the tops of both feet for three full seconds (count 101, 102, 103). Remove the 
thumbs. 
2. If the depression from your thumbs remains on both feet, then the patient has 
bilateral pitting oedema. It may be easier to feel this depression than to see it. 
3. If tops of feet are edematous, repeat the process on the shins and hands. 
4. If the shins / hands are edematous, observe for oedema around the eyes. 
 
Oedema is nutritionally significant if it is present on both feet. However, bilateral pitting also be 
caused by medical conditions such as nephritic syndrome. Medical causes should be first ruled 
out before the diagnosis of nutritional Oedema is made. 
 
Grades of oedema 
 
Grade of oedema 
Observation 
Absent 
Absent, no oedema 
Grade + 
Mild: both feet / ankles 
Grade ++ 
Moderate: both feet + lower legs 
Grade +++ 
Severe: generalized oedema including both 
feet, legs, hands, arms and face/head 
 
 
Grade + 
 
 
Grade ++ 
 
 
Grade +++ 
 
Only children with grade + and grade ++ will be eligible to participate in the study. 
 
3.6 Vital Status 
 


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Vital status will be recorded at all follow-up visits up to 12 weeks after inclusion. Information 
about whether the child is alive, has died, or has moved will be recorded. Date of death and 
location of move will be recorded. 
 
3.7 
Clinical examination 
 
Outcomes of clinical examinations will be collected at enrollment, weekly follow-up visits, and at 
week 8. Clinical examinations will be conducted according to the standard of care in the 
management of SAM. Recorded outcomes include diagnoses made and treatments 
given/recommended. 
 
 


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4. STUDY MEDICATION 
Children enrolled in the study will be offered weight-based, directly observed, oral suspension 
azithromycin plus placebo or a short course of oral amoxicillin. We will monitor adverse events 
following treatment as described in Section 5.  
 
 
4.1 
Study Medication Description  
 
The azithromycin used in the trial will be suspension Azithromycin (Everdestiny) made by 
Everdestiny Pharmaceutical Limited.  
 
The oral amoxicillin routinely used at each OTP for treatment of uncomplicated severe acute 
malnutrition, which is suspension Amoxicillin (Emzor) by Emzor pharmaceuticals limited, will 
be used for this trial. 
 
The placebo used in this trial to mask participants in the azithromycin arm will be made by a 
local pharmacy. 
 
All medications and placebo used in the trial will be placed in generic bottles at the local 
pharmacy to blind participants to the trial arm. The study nurse and investigators will be 
unblinded to the bottles  
 
4.2 
Dosage Information 
 
Azithromycin will be administered as a single dose, in oral suspension form for children. Dosing 
will follow the WHO recommendations for treatment of active trachoma:  Single dose of 20mg/kg 
in children (up to the maximum adult dose of 1g).  
 
The placebo given to individuals in the azithromycin arm will be instructed to administer the 
placebo at a volume equivalent to the amoxicillin dose.   
 
Individuals who are allergic to macrolides/azalides will not be treated. 
 
Oral amoxicillin will be administered for 5 days. The first dose will be administered by the health 
agent, who will teach the caregiver how to administer the medication at home. The remaining 
doses will be administered by the caregiver. 
 
Amoxicillin will be administered at a dose of 40mg/kg twice per day for 5 days.  
 
4.3 
Medication Procurement 
 
Azithromycin, placebo, and amoxicillin will be purchased locally in Nigeria by the study team. 
Enrolled participants will incur no costs associated with the study medication.  
 
4.4 
Medication Quality Control 
 
Study medication will be stored at each site prior to use. The study team and site staff will 
regularly check and record the study medication expiration dates. The expiration dates on the 
medication containers will be strictly monitored and all expired study medicine will be discarded 
appropriately. The study coordinator will work with each health facility to ensure that they have 
appropriate stock of all study medications. 


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5. ADVERSE EVENTS 
 
5.1 
Adverse Event Monitoring and Reporting  
 
Parents or guardians of enrolled children will be instructed to report any adverse events 
experienced within the 7 days following the enrollment visit, by phone or in person. At all follow-
up visits, study staff will inquire about the child’s experience of adverse events, including if the 
child had any of the following symptoms: 
 
● Fever 
● Diarrhea 
● Vomiting 
● Abdominal pain 
● Skin rash 
● Constipation 
 
The study team will assess whether the parent or guardian sought care for the child since the 
last visit and if so, what the reason was for the health care visit and if the child was hospitalized. 
 
Serious adverse events will be defined as death, hospitalization, or any other life-threatening 
situation. Serious adverse events will be reported to the Medical Monitor within 24 hours.  
 
The health agent conducting the follow-up visit will email the Taimaka investigators if a serious 
adverse event is diagnosed, the Taimaka investigators will immediately email the Medical 
Monitor and the UCSF study team. The Medical Monitor will make a determination as to 
whether the event could be reasonably considered to be related to the study drug and will report 
the results of this determination to the study investigators, who will report to the UCSF IRB and 
the DSMC as needed. Information on all adverse events, serious and non-serious, will be 
recorded on data collection forms through the mobile application.   
 
See Appendix 5 for more information on SAE reporting.  
 
5.2 Inpatient Hospitalization Transfer Information  
 
OTP staff will screen children for conditions requiring referral to hospital care. Referrals will 
occur at multiple points, including: 
1. Enrollment 
2. All follow up visits 
 
Pathways to the ITP (Inpatient Treatment Program): 
SAM patients are referred to the ITP using a referral card, and their expenses are paid by the 
Taimaka Project.  
 
Referrals during Triage 
Triage refers to the process of identifying patients in need of urgent treatment. Triage will occur 
in the OTP waiting area and should be conducted as soon as possible after caregivers and 
children arrive. During triage, OTP staff complete two main steps:  
1. Identify children with danger signs and immediately refer them to hospital care.  
2. Check children for signs of measles and immediately isolate suspected cases.  


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Emergency Health Check: 
On arrival at the OTP waiting area, each child will be immediately assessed for danger signs, 
which are health conditions that require urgent hospital care. Danger signs include:  
1. Unconscious 
2. Lethargy, not alert  
3. Unable to move/extreme weakness 
4. Convulsions/fits/seizures 
5. Difficulty breathing  
 
For children enrolled in the trial who exhibit any of these signs, a triage assistant will assign the 
child a registration number and fill out the referral form and admissions form with basic 
information such as the name of child and caregiver, admissions number, and phone number, 
and accompany the child and caretaker to the ITP.  
 
Referrals during Anthropometric Assessment 
In some cases, conditions identified during anthropometric assessment should prompt a referral 
to the ITP. These fall into three main categories:  
1. Any child with grade 3 (+++) oedema should receive a urinalysis test strip to measure 
protein. If the result is less than 2, they should be referred to the ITP.   
2. Any child <6 months who has SAM should be referred to the ITP.  
3. At weekly visits, children showing certain signs of non-response should be referred to 
the ITP.  
 
Oedema: 
Any child with grade 3 (+++) oedema should be referred to the ITP. Additionally, OTP staff 
should request a urinalysis test for children with grade 1 (+) or grade 2 (++) oedema. This test 
will be carried out by the lab assistant. The results of this test will be used to identify non-
nutritional causes of oedema, such as kidney problems. A protein result of >2 indicates that the 
child may have non-nutrition oedema. Children with non-nutritional oedema should be advised 
to visit a hospital to check for other health problems. These steps are outlined in the table 
below.  
 
Additionally, because nutritional oedema begins in the feet and moves upward, caregivers 
should also be asked where the oedema began. If it did not begin in the feet, advise the 
caregiver to visit a hospital.  
 
SAM patients should be referred to the ITP in the event of: 
 
Criterion 
Time after 
admission into OTP 
Severe complications (defined in next lecture) 
At any visit  
Failure to gain any weight (non-edematous children) 
21 days 
Weight loss since admission to program (non-edematous children) 
14 days 
Failure to start to lose edema  
14 days 


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Edema still present  
21 days 
Weight loss of 5% of body weight (non-edematous children)  
At any visit  
Failure of appetite test  
At any visit  
Failure to start to gain weight satisfactorily after loss of edema 
(kwashiorkor) or from day 14 (marasmus) onwards. Satisfactory is 
determined as ‘at least 5 g/kg of body weight per day.’ 
At any visit  
Failure to gain weight (rule out RUTF sharing, selling, other 
noncompliance, etc.) (non-oedematous children)  
Any 14 day interval 
Weight loss for two successive visits  
At any visit  
No MUAC gain for two consecutive weeks 
At any visit 
 
 
 
 
 
 
 


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6. DATA COLLECTION, MANAGEMENT, AND SECURITY  
 
6.1 
Data Collection 
Data will be collected on enrolled children at baseline (time of enrollment), and follow-up weeks 
1-12. Written informed consent will be collected on paper and the study officer administering 
treatment will record treatment administration on Taimaka’s internal ap. All other data will also 
be collected electronically on mobile devices using ODK mobile application. 
 
Data from the study participants is stored in the same database as data from all of Taimaka’s 
patients. Taimaka will share the entire database with UCSF, and the UCSF study team will write 
a carefully-worded statistical programming script to only select records and data of the study 
participants.  
 
6.2 
Data Management and Security  
Electronic data will be uploaded daily to a secure, password-protected, cloud-based server 
hosted by Taimaka. All devices used for data collection will be password-protected, as will the 
mobile application itself. Paper forms will be stored in locked cabinets accessible only by 
specific study team members at each enrollment site. 
 
Study indicators and PII will be collected electronically and stored securely in Taimaka’s 
password-protected, cloud-based server. Study data will only be accessible by study team 
members and investigators in order to protect confidentiality. 
 
6.3 
Data Quality and Monitoring  
All study team members collecting data will undergo an initial training to learn how to use the 
mobile devices as well as best practices for data collection. Data collection will be monitored on 
a weekly basis by the study team. Concerns over data quality and completeness will be relayed 
to the local study team by email, and refresher trainings and/or additional supervision of data 
collection by local investigators will be planned as needed. The study team will send quarterly 
progress reports to the DSMC, including aggregate data on enrollment and follow-up status, 
weight gain, nutritional recovery, and adverse events. 
 
 
 


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7. PROTECTION OF HUMAN SUBJECTS 
 
Before any study procedures are implemented, the study team will obtain Institutional Review 
Board (IRB) approval from committees at UCSF and Nigeria. In addition, local study team 
members will approach each potential enrollment site to describe the study and obtain their 
consent to participate as a study site. At the individual level, study personnel will obtain written 
informed consent from at least one parent or guardian for all study activities. Any guardians who 
are illiterate will be provided an impartial witness to explain the consent form at the time of 
enrollment. If, at any time, a parent or guardian elects to withdraw a child from the study, they 
will be free to do so. Individuals who withdraw will be offered the same standard of care outside 
the study. 
 
7.1 
Institutional Review Board Approval 
 
University of California, San Francisco (UCSF) Committee on Human Research 
UCSF’s Committee on Human Research will annually review the study protocol for ethical 
approval. 
 
Gombe State Ministry of Health 
The study protocol will be reviewed and granted ethical approval by these 2 committees in 
Nigeria before any study activities begin. 
 
 
7.2 
Informed Consent 
Study personnel fluent in relevant local languages will approach parents or guardians of eligible 
children at the enrollment site. In a private setting, the study team member will explain the 
objectives, risks, and benefits of the study as well as detailed information about what study 
participation entails for the child and the parent or guardian. The study team member will clarify 
that participation in the study is voluntary, that participation may be stopped at any time, and 
that all collected data will be kept confidential and securely stored. The study team member will 
ensure comprehension by inviting the parent or guardian to ask questions and will provide time 
for the parent or guardian to consider participation. Any guardians who are illiterate will be 
provided with an impartial witness to explain the consent form. When providing consent, both 
the study team member and the parent or guardian will sign two copies the consent document. 
One copy will be given to the parent or guardian and the other will be kept for study reference. 
 
 
 


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8. DATA AND SAFETY MONITORING COMMITTEE 
 
The Data and Safety Monitoring Committee (DSMC) will consist of independent experts in 
biostatistics, epidemiology, child health and nutrition, and/or global public health. 
 
The DSMC will be empaneled prior to the beginning of the study. The committee will meet once 
prior to the start of the study and at the study’s conclusion. All study protocols will be subject to 
review and approval by Institutional Review Boards at UCSF and Nigeria, and by the DSMC.  
 
The DSMC will be notified in real time of serious adverse events (SAEs). They will notify the 
study team if they would like to receive information about SAEs in a different manner. 
Committee members will monitor any sever or unexpected trend that threatens the safety of 
study participants. The DSMC will be authorized to end the study if they deem necessary (e.g., 
safety, feasibility).  
 
The study team will send the following reports to the DSMC:  
 
● A report at 1 month post-enrollment 
● A report when 50% of the enrollment target has been reached (at 300 participants 
enrolled) 
● A study close-out report at the end of the study 
 
A study closeout meeting will be scheduled at the end of the study unless deemed unnecessary.  
 
 


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9. STATISTICAL METHODS 
 
9.1 
Sample Size and Power 
 
Specific Aim 1 We assume that inclusion of 600 children (300 randomized to each arm) will 
provide 80% power to detect a 15% increase in weight gain (g/kg/day) in children receiving 
azithromycin compared to children receiving amoxicillin at an alpha of 0.05. Assumptions for this 
calculation were based on the pattern of weight gain reported in a trial of routine amoxicillin for 
uncomplicated SAM in Burkina Faso comparing children receiving azithromycin to amoxicillin 
over time.11 We assumed an average weight gain of 2.6 g/kg/day over 8 weeks in the  
amoxicillin arm, with a standard deviation of 1.7 g/kg/day, and loss to follow-up of 10%. A 16% 
increase corresponds to a mean difference in weight gain of 0.4 g/kg/day, or an average weight 
gain of 3.0 g/kg/day in the azithromycin arm. 
 
This calculation was performed in Stata using the following command: 
 
power twomeans 2.6, sd(1.7) alpha(0.05) power(0.8) n(540) 
 
Specific Aim 2. Inclusion of 600 children (300 randomized to each arm) will provide 80% power 
to detect a 12 percentage point difference in the proportion of children achieving nutritional 
recovery in the azithromycin arm compared to the amoxicillin arm. Assumptions for this 
calculation were based on nutritional recovery reported in the amoxicillin arm of a trial of routine 
amoxicillin compared to azithromycin for uncomplicated SAM in Burkina Faso.11 We assumed 
that 36% of children in the oral amoxicillin arm would achieve nutritional recovery and a loss to 
follow-up of 10%. 
 
This calculation was performed in Stata using the following command: 
 
power twoproportions 0.36, alpha(0.05) power(0.8) n(540) 
 
 
9.2 
Statistical Analysis 
 
Baseline characteristics. Characteristics of the study population collected at baseline will be 
summarized using frequencies and percentages for categorical variables and means and 
standard deviations or medians and inter-quartile ranges for continuous variables. Baseline 
characteristics will be compared by treatment arm using Fisher’s exact test for categorical 
variables and t-tests or Wilcoxon rank-sum tests for continuous variables. 
 
Specific Aim 1. The primary analysis will compare weight gain velocity (g/kg/day) between 
groups over the 8-week follow-up period. We will estimate mean differences and 95% 
confidence intervals for the difference using a linear regression model with an indicator for study 
group. 
 
𝐸[𝑌 | 𝑋= 𝑥] = 𝛽0 + 𝛽1𝑋+ 𝑒 
Where: 
● 𝒀 = weight gain velocity from enrollment to 8 weeks  
● 𝑋 = binary indicator for treatment group (X=1 for azithromycin, X=0 for a short course of 
oral amoxicillin) 


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● 𝛽𝟏 = difference in weight gain velocity between the azithromycin group compared 
to a short course of oral amoxicillin group 
● 𝑒 ~ 𝑁 (0, 𝜎2)  
 
Sensitivity analyses will include similar linear models to assess period-specific weight gain by 
group from week 0-1, 1-2, 2-4, and 4-8. 
 
Specific Aim 2. The primary analysis will compare nutritional recovery by 8 weeks from 
baseline by arm. We will use log-binomial regression for this analysis to estimate the risk ratio. 
We will use the following model: 
 
𝑙𝑜𝑔[𝑃(𝑌= 1|𝑋1 = 𝑥1] = 𝛽0 + 𝛽1𝑋1 + 𝑒 
 
Where: 
● 𝒀 = binary indicator for nutritional recovery by 8 weeks (Y=1 for recovered, Y=0 for 
not recovered) 
● 𝑋 = binary indicator for treatment arm (X=1 for azithromycin, X=0 for a short course of 
oral amoxicillin) 
● 𝒆𝜷𝟏 = relative risk of nutritional recovery in azithromycin arm compared to a short 
course of oral amoxicillin arm 
● 𝑒 ~ 𝑁 (0, 𝜎2)  
 
If the log-binomial model fails to converge, we will use a modified Poisson model with robust 
standard errors as an alternative. 
 
Secondary outcomes. 
 
Time to event outcomes (time to recovery and time to mortality) will be assessed visually using 
Kaplan-Meier curves and compared by arm using the log-rank test. 
 
Binary outcomes will be analyzed using modified Poisson regression for rare outcomes (e.g. 
mortality) or log-binomial regression for common outcomes (e.g. malaria), using models similar 
to the one described above for Specific Aim 2. 
 
Anthropometric assessments will be analyzed using linear models as described for Specific Aim 
1, with correction for baseline values. For anthropometric assessments, z-scores will be 
calculated based on the 2006 WHO Child Growth Standards. Anthropometric z-scores will be 
analyzed as continuous variables and secondary analyses will explore categorization. 
 
All analyses will be intention-to-treat. A significance level of 0.05 for inference and 95% 
confidence intervals will be reported for all effect estimates. All analyses will be conducted using 
R (R Foundation for Statistical Computing, Vienna, Austria). For all models, model diagnostics 
will be conducted to assess appropriate fit. 
 
Missing data. 
 
If ≤10% of enrolled children is missing outcome data, complete case analyses will be 
conducted. If >10% of enrolled children are missing outcome data, inverse probability weighting 
will be used to weight complete cases by the inverse of an estimate of the probability of an 
outcome being observed as a sensitivity analysis. Weights will be constructed with the following 


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baseline characteristics chosen as factors likely to predict follow-up: SES, distance from health 
center, WHZ, and MUAC.


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REFERENCES 
 
1. 
Black RE, Victora CG, Walker SP, et al. Maternal and child undernutrition and 
overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427-
451. doi:10.1016/S0140-6736(13)60937-X 
2. 
Page AL, de Rekeneire N, Sayadi S, et al. Infections in children admitted with 
complicated severe acute malnutrition in Niger. PLoS One. 2013;8(7):e68699. 
doi:10.1371/journal.pone.0068699 
3. 
Fishman S, Caulfield LE, de Onis M, et al. Childhood and maternal underweight. In: 
Ezzati M, Lopez A, Rodgers A, Murray C, eds. Comparative Quantification of Health 
Risks Global and Regional Burden of Disease Attributable to Selected Major Risk 
Factor. Vol 1. World Health Organization; 2004:39-163. 
4. 
Trehan I, Goldbach HS, LaGrone LN, et al. Antibiotics as part of the management of 
severe acute malnutrition. Malawi Med J. 2016;28(3):123-130. 
5. 
Isanaka S, Langendorf C, Berthé F, et al. Routine Amoxicillin for Uncomplicated Severe 
Acute Malnutrition in Children. N Engl J Med. 2016;374(5):444-453. 
doi:10.1056/NEJMoa1507024 
6. 
Trehan I, Schechtman KB, Manary MJ. Amoxicillin for Severe Acute Malnutrition in 
Children. N Engl J Med. 2016;375(2):191. doi:10.1056/NEJMc1605388 
7. 
Berkley JA, Ngari M, Thitiri J, et al. Daily co-trimoxazole prophylaxis to prevent mortality 
in children with complicated severe acute malnutrition: a multicentre, double-blind, 
randomised  placebo-controlled trial. Lancet Glob Health. 2016;4(7):e464-473. 
doi:10.1016/S2214-109X(16)30096-1 
8. 
Keenan JD, Bailey RL, West SK, et al. Azithromycin to Reduce Childhood Mortality in 
Sub-Saharan Africa. N Engl J Med. 2018;378(17):1583-1592. 
doi:10.1056/NEJMoa1715474 
9. 
Rutebemberwa E, Mpeka B, Pariyo G, et al. High prevalence of antibiotic resistance in 
nasopharyngeal bacterial isolates from healthy children in rural Uganda: A cross-
sectional study. Ups J Med Sci. 2015;120(4):249-256. 
doi:10.3109/03009734.2015.1072606 
10. 
Lazzerini M, Tickell D. Antibiotics in severely malnourished children: systematic review 
of efficacy, safety and pharmacokinetics. Bull World Health Organ. 2011;89(8):594-607. 
doi:10.2471/BLT.10.084715 
11. 
O’Brien KS, Sié A, Dah C, et al. Comparing Azithromycin to Amoxicillin in the 
Management of Uncomplicated Severe Acute Malnutrition in Burkina Faso: A Pilot 
Randomized Trial. Am J Trop Med Hyg. 2022;106(3):930-938. doi:10.4269/ajtmh.21-
1023 
 
 
 


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PROTOCOL UPDATES 
 
Date 
Changes 
Oct 7 2022 
● Clarified inclusion and exclusion criteria (Section 2.2 & 2.6) 
● Clarified weight measurement (Section 3.2) 
● Clarified that illiterate guardians require impartial witness to explain 
consent (Section 7 & 7.2) 
● Added more information on DSMC roles and responsibilities (Section 8) 
● Clarified SAE report flow (Appendix 5) 
● Added referral criteria for transfer to inpatient care for SAM participants 
(Section 5) 
Nov 28 2022 
● Added Taimaka database access (Section 6.1 and 7.2) 
● Fixed grammatical errors throughout 
February 9 
2023 
● Updated Taimaka database access language per discussions with IRB 
(Section 6.1 and 7.2) 
April 19, 2023 
● Updated eligible recruitment sites information (Section 2.2) 
 
 
 
APPENDIX 
 
Appendix 1. Informed Consent Documents 
Appendix 2. Study Forms 
Appendix 3. Appetite test 
Appendix 4. Standard medical protocol for severe malnutrition 
Appendix 5. SAE Reporting flow