Safety and Ethics in Endoscopic Studies in Children: Evidence From the BEECH Study in Zambia.

BACKGROUND: Environmental enteropathy is an example of a poorly-understood intestinal disorder affecting millions of children worldwide, characterized by malabsorption and stunting. Although there is increasing interest in non-invasive means of assessing intestinal structure and function, the potential value of intestinal biopsy for histology, immunostaining, RNA sequencing and epigenetic work means that endoscopic biopsy remains extremely valuable. We here report our experience in the BEECH (Biomarkers of Environmental Enteropathy in CHildren) study of stunting in Zambia, in the belief that it may help address the knowledge gap regarding the safety of endoscopic biopsy in vulnerable young children. METHODS: We report our experience of safety in 119 children undergoing endoscopic biopsy in the BEECH study in Lusaka Children's Hospital, Lusaka, and discuss ethical considerations in this light. RESULTS: Upper gastrointestinal endoscopy was performed on children with stunting (length-for-age z score -2 or less) not responsive to nutritional interventions. Conscious sedation was provided by anaesthetists. Of 119 children, 5 (4%) developed transient desaturation, but no serious adverse events were experienced; no clinical, demographic or anaesthetic characteristics were identified as predictive of desaturation. Two children derived clinically useful information from the endoscopy, one life-saving. Of 105 lactase tests, 59 (54%) showed hypolactasia. DISCUSSION: Children with stunting underwent endoscopy safely, and some derived clinical benefit. Safety and the possibility of clinical benefit are usually felt to be preconditions for the ethical justification for endoscopy for research in children, and we believe that these conditions were met in this study.

Malnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial.

Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6-59 months and hospitalised with SAM (using WHO definitions: WLZ <-3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum (n = 25), (ii) N-acetyl glucosamine (n = 24), (iii) subcutaneous teduglutide (n = 26), (iv) budesonide (n = 25) or (v) standard care only (n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α1-antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size -0.89 (90% CI: -1.69,-0.10) P = 0.07), while colostrum (-0.58 (-1.4, 0.23) P = 0.24), N-acetyl glucosamine (-0.20 (-1.01, 0.60) P = 0.67), and budesonide (-0.50 (-1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.