Malnutrition, Child Clinical Trial
— AMOUROfficial title:
Azithromycin as Adjunctive Treatment for Uncomplicated Severe Acute Malnutrition: the AMOUR Trial
Amoxicillin is recommended by the World Health Organization (WHO) as adjunctive therapy for the treatment of uncomplicated severe acute malnutrition (SAM). Because children with uncomplicated SAM may have asymptomatic infection due to immune suppression, presumptive treatment with a broad-spectrum antibiotic may be beneficial by clearing any existing infection and improving outcomes. Two randomized placebo-controlled randomized trials have evaluated amoxicillin for uncomplicated SAM and have found conflicting results. These results may indicate either that antibiotics are not helpful for the management of uncomplicated SAM, or that a better antibiotic is needed. Recently, the investigators demonstrated that biannual mass azithromycin distribution as a single oral dose reduces all-cause child mortality in sub-Saharan Africa. Children with uncomplicated SAM, who have an elevated risk of mortality relative to their well-nourished peers, may particularly benefit from presumptive azithromycin treatment. Our pilot data demonstrated feasibility in rapid enrollment of children with uncomplicated SAM in our study area, and showed no significant difference between azithromycin and amoxicillin, demonstrating equipoise for a full-scale trial. Here, the investigators propose an individually randomized trial in which children will be randomized to a) azithromycin, b) amoxicillin, or c) placebo, and evaluated for differences in weight gain, nutritional recovery, and the gut microbiome. The results of this study will strengthen the evidence base for policy related to the use of antibiotics as part of the management of uncomplicated SAM, including additional evidence of amoxicillin versus placebo as well as evaluation of an antibiotic class that has not been considered for uncomplicated SAM, which may lead to changes in guidelines for treatment.
Status | Not yet recruiting |
Enrollment | 7000 |
Est. completion date | July 2028 |
Est. primary completion date | September 2027 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 6 Months to 59 Months |
Eligibility | Children with uncomplicated SAM per Burkina Faso's national guidelines who present to an eligible enrollment site during the study period and meet all of the eligibility criteria below will be considered for enrollment: Inclusion criteria: - Age 6-59 months - WHZ<-3 SD or MUAC<115 mm - Primary residence within a catchment area of an enrollment site - Available for full 8-week study (primary endpoint) - Not admitted to a nutritional program for SAM treatment in the previous 2 weeks - No edema - No antibiotic use in the past 7 days - No clinical complications requiring antibiotic or 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, etc) - No known allergies to macrolides/azalides or amoxicillin/penicillin - Sufficient appetite according to a feeding test with RUTF - Written informed consent from at least one parent or guardian Exclusion criteria: - Age less than 6 month or more than 59 months - WHZ>-3 SD or MUAC>115 mm - Primary residence is not within a catchment area of an enrollment site - Not Available for full 8-week study (primary endpoint) - Admitted to a nutritional program for SAM treatment in the previous 2 weeks - Edema - Antibiotic use in the past 7 days - Clinical complications requiring antibiotic or 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) - Known allergies to macrolides/azalides or amoxicillin/penicillin - No Sufficient appetite according to a feeding test with RUTF - No Written informed consent from at least one parent or guardian - Per Burkinabé guidelines, children any of the following conditions will not be eligible for the trial and will be referred to an inpatient facility: MUAC <115 mm with complications; MUAC <115 mm plus edema; bipedal pitting edema; anorexia or no appetite for RUTF; diarrhea and dehydration; unable to ingest anything without vomiting; severe pneumonia; open cutaneous lesions; hypothermia (35*C); fever (38.5*C); paleness suggesting severe anemia; hypoglycemia; very weak, lethargic, or unconscious; convulsions; signs of vitamin A deficiency; or a condition requiring IV infusion or an NG tube. |
Country | Name | City | State |
---|---|---|---|
Burkina Faso | Centre de recherche en Santé de nouna | Nouna | Kossi |
Lead Sponsor | Collaborator |
---|---|
University of California, San Francisco | Centre de Recherche en Sante de Nouna, Burkina Faso |
Burkina Faso,
Belesova K, Gasparrini A, Sie A, Sauerborn R, Wilkinson P. Annual Crop-Yield Variation, Child Survival, and Nutrition Among Subsistence Farmers in Burkina Faso. Am J Epidemiol. 2018 Feb 1;187(2):242-250. doi: 10.1093/aje/kwx241. — View Citation
Belesova K, Gasparrini A, Sie A, Sauerborn R, Wilkinson P. Household cereal crop harvest and children's nutritional status in rural Burkina Faso. Environ Health. 2017 Jun 20;16(1):65. doi: 10.1186/s12940-017-0258-9. — View Citation
Doan T, Hinterwirth A, Arzika AM, Cotter SY, Ray KJ, O'Brien KS, Zhong L, Chow ED, Zhou Z, Cummings SL, Fry D, Oldenburg CE, Worden L, Porco TC, Keenan JD, Lietman TM. Mass Azithromycin Distribution and Community Microbiome: A Cluster-Randomized Trial. Open Forum Infect Dis. 2018 Jul 24;5(8):ofy182. doi: 10.1093/ofid/ofy182. eCollection 2018 Aug. Erratum In: Open Forum Infect Dis. 2023 Oct 06;10(10):ofad489. — View Citation
Doan T, Hinterwirth A, Worden L, Arzika AM, Maliki R, Abdou A, Kane S, Zhong L, Cummings ME, Sakar S, Chen C, Cook C, Lebas E, Chow ED, Nachamkin I, Porco TC, Keenan JD, Lietman TM. Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution. Nat Med. 2019 Sep;25(9):1370-1376. doi: 10.1038/s41591-019-0533-0. Epub 2019 Aug 12. — View Citation
Isanaka S, Langendorf C, Berthe F, Gnegne S, Li N, Ousmane N, Harouna S, Hassane H, Schaefer M, Adehossi E, Grais RF. Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children. N Engl J Med. 2016 Feb 4;374(5):444-53. doi: 10.1056/NEJMoa1507024. — View Citation
Oldenburg CE, Hinterwirth A, Sie A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, Cummings SL, Zhong L, Chen C, Sarkar S, Barnighausen T, Lietman TM, Keenan JD, Doan T. Gut Resistome After Oral Antibiotics in Preschool Children in Burkina Faso: A Randomized, Controlled Trial. Clin Infect Dis. 2020 Jan 16;70(3):525-527. doi: 10.1093/cid/ciz455. Erratum In: Clin Infect Dis. 2024 Jan 25;78(1):231. — View Citation
Oldenburg CE, Sie A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, Barnighausen T, Ray KJ, Zhong L, Cummings S, Lebas E, Lietman TM, Keenan JD, Doan T. Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial. Open Forum Infect Dis. 2018 Nov 2;5(11):ofy289. doi: 10.1093/ofid/ofy289. eCollection 2018 Nov. Erratum In: Open Forum Infect Dis. 2023 Oct 06;10(10):ofad489. — View Citation
Sie A, Bountogo M, Nebie E, Ouattara M, Coulibaly B, Bagagnan C, Zabre P, Lebas E, Brogdon J, Godwin WW, Lin Y, Porco T, Doan T, Lietman TM, Oldenburg CE; NAITRE Study Group. Neonatal azithromycin administration to prevent infant mortality: study protocol for a randomised controlled trial. BMJ Open. 2019 Sep 4;9(9):e031162. doi: 10.1136/bmjopen-2019-031162. — View Citation
Sie A, Ouattara M, Bountogo M, Bagagnan C, Coulibaly B, Boudo V, Lebas E, Brogdon JM, Lin Y, Barnighausen T, Porco TC, Doan T, Lietman TM, Oldenburg CE; Etude CHAT Study Group. A double-masked placebo-controlled trial of azithromycin to prevent child mortality in Burkina Faso, West Africa: Community Health with Azithromycin Trial (CHAT) study protocol. Trials. 2019 Dec 4;20(1):675. doi: 10.1186/s13063-019-3855-9. — View Citation
Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, Manary MJ. Antibiotics as part of the management of severe acute malnutrition. N Engl J Med. 2013 Jan 31;368(5):425-35. doi: 10.1056/NEJMoa1202851. — View Citation
Trehan I, Schechtman KB, Manary MJ. Amoxicillin for Severe Acute Malnutrition in Children. N Engl J Med. 2016 Jul 14;375(2):191. doi: 10.1056/NEJMc1605388. No abstract available. — View Citation
Wuehler SE, Ouedraogo AW. Situational analysis of infant and young child nutrition policies and programmatic activities in Burkina Faso. Matern Child Nutr. 2011 Apr;7 Suppl 1(Suppl 1):35-62. doi: 10.1111/j.1740-8709.2010.00309.x. — View Citation
* Note: There are 12 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change in Weight Gain | This will be measured as weight gain in g/kg/day at 8 weeks from enrollment. | 8 weeks | |
Primary | Change in a-diversity Microbiome | The primary outcome will be a-diversity using inverse Simpson's diversity index at the 8-week study visit. | 8 weeks | |
Secondary | Time for Nutritional recovery | Nutritional recovery will be defined as per Burkinabé national guidelines: weight-for-height z score (WHZ) = -2 on two consecutive visits and no acute complication or edema for the past 7 days OR mid-upper arm circumference (MUAC)= 125mm on two consecutive visits and no acute complication or edema for the past 7 days. The criterion chosen to define recovery is the same as the one used to admit the child to the program. | 12 weeks | |
Secondary | Number of Transfer to inpatient care | Children will be transferred to inpatient care if they develop medical complications, or their condition deteriorates. | 12 weeks | |
Secondary | Mortality | Vital status will be assessed at all scheduled follow-up time points, and the child's vital status (alive, died, defaulted, unknown) will be recorded in the study's mobile application. A serious adverse event form will be filled out for any child who dies during the course of the study, and the death will be reported to the medical monitor within 24 hours of the report. This report will include additional information related to the circumstances surrounding the child's death and any diagnostics and/or care sought for the child. 12 months mortality status will be compared by arm and reported | 12 months | |
Secondary | Change in Mid-upper arm circumference (MUAC) | MUAC will be measured at all study visits. Change in MUAC over time will be assessed across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis. | 8 weeks | |
Secondary | Change in Mid-upper arm circumference (MUAC) | MUAC will be measured at all study visits. Change in MUAC over time will be assessed across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis. | 3 months | |
Secondary | Change in Mid-upper arm circumference (MUAC) | MUAC will be measured at all study visits. Change in MUAC over time will be assessed across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis. | 6 months | |
Secondary | Change in Mid-upper arm circumference (MUAC) | MUAC will be measured at all study visits. Change in MUAC over time will be assessed across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis. | 12 months | |
Secondary | Change in Weight-for-height z score (WHZ) | Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate. | 8 weeks | |
Secondary | Change in Weight-for-height z score (WHZ) | Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate. | 3 months | |
Secondary | Change in Weight-for-height z score (WHZ) | Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate. | 6 months | |
Secondary | Change in Weight-for-height z score (WHZ) | Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate. | 12 months | |
Secondary | Change in Weight-for-age Z-score (WAZ) | Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg. | 8 weeks | |
Secondary | Change in Weight-for-age Z-score (WAZ) | Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg. | 3 months | |
Secondary | Change in Weight-for-age Z-score (WAZ) | Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg. | 6 months | |
Secondary | Change in Weight-for-age Z-score (WAZ) | Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg. | 12 months | |
Secondary | Height-for-age Z-score (HAZ) | Height-for-age (HAZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate. | 12 months | |
Secondary | Number and type of clinic visits | At each study visit, caregivers will report if they sought medical care for their child for any reason since their last study visit, and if so, how many times they sought care, if the child was hospitalized, and the reason for seeking care (e.g., malaria, pneumonia, etc). different in number and type of clinic visits will be compared by arm and reported at 12 months | 12 months | |
Secondary | Malaria positivity | Azithromycin has been shown to have some activity against Plasmodium falciparum in vitro by targeting the plasmodial apicoplast. Some studies of azithromycin for trachoma and child mortality have shown a benefit of mass azithromycin distribution on malaria parasitemia. At baseline and 8 weeks, malaria positivity via rapid diagnostic test, tympanic temperature, and hemoglobin will all be measured. | 8 weeks | |
Secondary | Anemia | Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL. | baseline | |
Secondary | Anemia | Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL. | 8 weeks | |
Secondary | Anemia | Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin <11.0 g/dL. | 3 months | |
Secondary | Change in Resistome | Nonhosts read pairs will be aligned to the MEGARes reference antimicrobial database using Burrows-Wheeler alignment with default settings. To decrease false-positive ARD identification, only ARDs with a gene fraction of >80% will be identified as present in the sample and included in analyses. Each identified ARD will be classified at the class and gene level. The resistome will be evaluated at each time point by arm to evaluate the persistence of alterations to the resistome following oral antibiotics. | 12 months | |
Secondary | number of Relapse after recovery | Long-term relapse outcomes will also be assessed at 12 months by study arm by classifying children as having SAM or recovered, regardless of whether they were considered recovered previously. | 12 months |
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