A protocol for a proof-of-concept randomized control trial testing increased protein quantity and quality in ready-to-use therapeutic food in improving linear growth among 6-23-month-old children with severe wasting in Malawi

PLOS ONE STUDY PROTOCOL A protocol for a proof-of-concept randomized control trial testing increased protein quantity and quality in ready-to-use therapeutic food in improving linear growth among 6-23month-old children with severe wasting in Malawi a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Potani I, Daniel AI, Briend A, CourtneyMartin G, Berkley JA, Voskuijl W, et al. (2023) A protocol for a proof-of-concept randomized control trial testing increased protein quantity and quality in ready-to-use therapeutic food in improving linear growth among 6-23-month-old children with severe wasting in Malawi. PLoS ONE 18(8): e0287680. https://doi.org/10.1371/journal. pone.0287680 Isabel Potani1,2,3, Allison I. Daniel1,2,3,4, André Briend5,6, Glenda Courtney-Martin3, James A. Berkley7,8, Wieger Voskuijl9,10, Laura Vresk2, Celine Bourdon1, Sylvester Kathumba11, Emmie Mbale9, Robert H. J. Bandsma ID1,2,3,9* 1 Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Canada, 2 Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada, 3 Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada, 4 Independent Nutrition Consultant, Toronto, Canada, 5 Centre for Child Health Research, University of Tampere School of Medicine, Tampere, Finland, 6 Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark, 7 Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom, 8 Clinical Research Department, Kenya Medical Research Institute–Wellcome Trust Research Programme, Kilifi, Kenya, 9 Department of Paediatrics and Child Health, Kamuzu University of Health Sciences, Blantyre, Malawi, 10 Amsterdam Universtair Medische Centra, University of Amsterdam, Amsterdam Centre for Global Child Health, Emma Children’s Hospital, Amsterdam, The Netherlands, 11 Department of Nutrition and Human Immunodeficiency Virus, Ministry of Health, Lilongwe, Malawi * Abstract Editor: Aziz ur Rahman Muhammad, University of Agriculture Faisalabad, PAKISTAN Received: February 27, 2023 Accepted: June 7, 2023 Published: August 24, 2023 Copyright: © 2023 Potani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: No datasets were generated or analyzed during the current study. Deidentified data may be made available in line with the study’s sponsor’s procedures for release. Funding: IP received funding from the Schlumberger Faculty for the future Foundation (USD40,000), https://www.slb.com/about/who-weare/schlumberger-foundation and the SickKids Introduction Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth. Aim The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6–23 months old children with severe wasting. Methods We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial. PLOS ONE | https://doi.org/10.1371/journal.pone.0287680 August 24, 2023 1 / 20 PLOS ONE Centre for Global Child Health (USD18,000), https://www.sickkids.ca/siteassets/care–services/ centres/global-child-health/catalyst-grantdocuments/catalystgrant-guidelines-2023.pdf. Both grants are for early career researchers, e.g., PhD students and did not have grant numbers. The funders did not and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. A trial protocol on improving length in children with wasting using increased protein therapeutic food Outcomes The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety. Implications These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial. Trial registration The trial has been registered on clinicaltrial.gov (NCT05737472). Introduction In 2020, an estimated 13.6 million children aged 6–59 months suffered from severe wasting [1]. Severe wasting is defined as weight-for-length z-score (WLZ) <–3 standard deviations and/or mid-upper-arm circumference (MUAC) <115 mm [2]. Most children with severe wasting can safely be treated in their communities using ready-to-use therapeutic foods (RUTFs) and oral antibiotics without requiring admission to a hospital [3]. At enrolment into nutritional support programs, most children are both severely wasted and stunted (reportedly 69%), and while wasting improves with treatment, stunting does not [4]. Furthermore, some studies suggest that up to 38% of children who are not initially stunted are at risk of becoming stunted within a year following recovery from severe wasting [4, 5]. Stunting is linear growth faltering that is defined by a length-for-age z score (LAZ) <-2 SD [6]. Stunting is associated with long-term health outcomes, including poor child neurodevelopment, lower school achievement and income from work, and an increased risk of non-communicable diseases [7– 10]. Improving protein quantity and quality intake during severe wasting treatment could improve linear and ponderal growth [11–14]. The current RUTF formulation recommended by WHO contains 10–12% energy from protein but falls short of protein quality requirements set by the Food Agricultural Organisation; with a Protein Digestibility Corrected Amino Acid Score (PDCAAS) of 0.83 that is below the � 0.90 threshold [15, 16]. PDCAAS assesses protein quality in a food by the amount of essential amino acids against a standard amino acid score while correcting for the faecal amino acid digestibility. PDCAAS was superseded by the Digestible Indispensable Amino Acid Score (DIAAS), which is considered more accurate as it measures protein or amino acid digestibility at the terminal ileum and thought to better reflect amino acid absorption [15]. Designing a treatment product with optimal protein qu (...truncated)