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

Abstract

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.

Fig. 1. Flowchart of participating children in the TAME trial.

One child died and two children withdrew before day 15, so day 15 endpoint data were available for 122 children for most endpoints, and 118 for the primary endpoint; all these children completed their allocated intervention and standard care and are included in the per protocol analysis. A further 2 children died and one withdrew between days 15 and 28. SAM, severe acute malnutrition. Hb, haemoglobin concentration.

Fig. 2. Biopsy images from children after 14 days of treatment.

Biopsies are from children treated with a colostrum, b N-acetyl glucosamine, c teduglutide, d budesonide, and e standard care. Morphometric analysis is shown in panel f. Scale bars show 200 μm. These biopsies were selected from 22 biopsies from 25 children: 6 in the teduglutide group, 5 in the colostrum group, 5 in the budesonide group, 5 in the standard care group, and 4 in the N-acetyl glucosamine group. Individual data from morphometric analysis are shown in Fig. 3.

Fig. 3. Mucosal morphometry.

Measurements of villus height (VH) and crypt depth (CD) in 22 biopsies with satisfactory orientation obtained from children completing 14 days of treatment. a villus height (P = 0.84 by Kruskal-Wallis test across all groups). b crypt depth (P = 0.02 by Kruskal-Wallis test; by Dunn’s test P = 0.01 for colostrum and P = 0.049 for teduglutide). c, epithelial surface area.  NAG, N-acetyl glucosamine. Source Data are provided as a Source Data File (Dataset 1).