Impact of reduced dose of ready-to-use therapeutic foods in children with uncomplicated severe acute malnutrition : A randomised non-inferiority trial in Burkina Faso

RESEARCH ARTICLE Impact of reduced dose of ready-to-use therapeutic foods in children with uncomplicated severe acute malnutrition: A randomised non-inferiority trial in Burkina Faso Suvi T. KangasID 1,2 *, Ce ´cile Salpe ´teurID 2 , Victor Nikièma 3 , Leisel Talley 4 , Christian RitzID 1 , Henrik FriisID 1 , Andre ´BriendID 1,5 , Pernille KaestelID 1 1Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark, 2Expertise and Advocacy Department, Action Against Hunger (ACF), Paris, France, 3Nutrition and Health Department, Action Against Hunger (ACF) mission, Ouagadougou, Burkina Faso, 4Centers for Disease Control and Prevention, Atlanta, United States of America, 5Center for Child Health Research, University of Tampere School of Medicine, Tampere University, Tampere, Finland *[email protected] Abstract Background Children with uncomplicated severe acute malnutrition (SAM) are treated at home with ready-to-use therapeutic foods (RUTFs). The current RUTF dose is prescribed according to the weight of the child to fulfil 100% of their nutritional needs until discharge. However, there is doubt concerning the dose, as it seems to be shared, resulting in suboptimal cost-efficiency of SAM treatment. We investigated the efficacy of a reduced RUTF dose in community-based treatment of uncomplicated SAM. Methods and findings We undertook a randomised trial testing the non-inferiority of weight gain velocity of children with SAM receiving (a) a standard RUTF dose for two weeks, followed by a reduced dose thereafter (reduced), compared with (b) a standard RUTF dose throughout the treatment (standard). A mean difference of 0.0 g/kg/day was expected, with a non-inferiority margin fixed at −0.5 g/kg/day. Linear and logistic mixed regression analyses were performed, with study site and team as random effects. Between October 2016 and July 2018, 801 children with uncomplicated SAM aged 6–59 months were enrolled from 10 community health centres in Burkina Faso. At admission, the mean age (±standard deviation [SD]) was 13.4 months (±8.7), 49% were male, and the mean weight was 6.2 kg (±1.3). The mean weight gain velocity from admission to discharge was 3.4 g/kg/day and did not differ between study arms (Δ0.0 g/kg/day; 95% CI −0.4 to 0.4; p= 0.92) confirming non-inferiority (p= 0.013). However, after two weeks, the weight gain velocity was significantly lower in the reduced dose with a mean of 2.3 g/kg/day compared with 2.7 g/kg/day in the standard dose (Δ −0.4 g/kg/day; 95% CI −0.8 to −0.02; p= 0.041). The length of stay (LoS) was not different (p= PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 1 / 19 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Kangas ST, Salpe ´teur C, Nikièma V, Talley L, Ritz C, Friis H, et al. (2019) Impact of reduced dose of ready-to-use therapeutic foods in children with uncomplicated severe acute malnutrition: A randomised non-inferiority trial in Burkina Faso. PLoS Med 16(8): e1002887. https://doi.org/ 10.1371/journal.pmed.1002887 Academic Editor: Lars Åke Persson, London School of Hygiene and Tropical Medicine, UNITED KINGDOM Received: February 28, 2019 Accepted: July 23, 2019 Published: August 27, 2019 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: The database used in the current work is available from the Zenodo data repository (https://doi.org/10.5281/zenodo. 3256555). Funding: This trial was funded by Action Against Hunger France, European Commission’s Civil Protection and Humanitarian aid Operations (grant number ECHO/-WF/BUD/2015/91065), Children’s Investment Fund Foundation (grant "CIFF03: 0.73) between groups with a median of 56 days (interquartile range [IQR] 35–91) in both arms. No differences were found between reduced and standard arm in recovery (52.7% and 55.4%; p= 0.45), referral (19.2% and 20.1%; p= 0.80), defaulter (12.2% and 8.5%; p= 0.088), non-response (12.7% and 12.5%; p= 0.95), and relapse (2.4% and 1.8%; p= 0.69) rates, respectively. However, the reduced RUTF dose had a small 0.2 mm/week (95% CI 0.04 to 0.4; p= 0.015) negative effect on height gain velocity with a mean height gain of 2.6 mm/week with reduced and 2.8 mm/week with standard RUTF dose. The impact was more pronounced in children under 12 months of age (interaction, p= 0.019) who gained 2.8 mm/ week with reduced and 3.1 mm/week with standard dose (Δ −0.4 mm/week; 95% CI −0.6 to −0.2; p<0.001). Limitations include not blinding participants to the RUTF dose received and excluding all children with negative appetite test. The results are generalisable for relatively food secure contexts with a young SAM population. Conclusions Reducing the RUTF dose provided to children with SAM after two weeks of treatment did not reduce overall weight or mid-upper arm circumference (MUAC) gain velocity nor affect recovery or lengthen treatment time. However, it led to a small but significant negative effect on linear growth, especially among the youngest. The potential effect of reducing the RUTF dose in a routine program on treatment outcomes should be evaluated before scaling up. Trial registration ISRCTN registry ISRCTN50039021. Author summary Why was this study done? • Severe acute malnutrition (SAM) affects 19 million children worldwide and is treated with ready-to-use therapeutic foods (RUTFs). • The current RUTF formulation and dosage are based on an inpatient treatment model and aim at achieving fast weight gain and recovery. • However, when used in a home-based setting, the RUTF dose prescribed is often considered too large, resulting in sharing and a suboptimal cost-efficiency of SAM treatment. • We sought to investigate the efficacy of reducing the RUTF dosage used in communitybased treatment of uncomplicated SAM. What did the researchers do and find? • We conducted a randomised controlled trial testing the non-inferiority of a reduced RUTF dose in the management of uncomplicated SAM compared with standard dose. This was called the MANGO trial. Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 2 / 19 Reinventing community based management of malnutrition"), European Commission’s Civil Protection and Humanitarian aid Operations Enhanced Response Capacity (grant number ECHO/ERC/BUD/2016/91006), and Humanitarian Innovation Fund (HIF), a programme managed by Enhancing Learning and Research for Humanitarian Assistance (ELRHA). ACF France received and managed the grants. Funding provided covered the study conception and field implementation of the study, including the salaries of STK and VN for the full length of the trial. Other authors received no specific funding for their work related to the current study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: STK was previously employed by Nutriset, a producer of RUTF; HF has received research grants from ARLA Food for Health Centre and also has research collaboration with Nutriset. Other authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous five years, and declare no other relationships or activities that could appear to have influenced the submitted work. Abbreviations: CERS, Comite ´d’e ´thique pour la recherche en sante ´; CMAM, community-based management of acute malnutrition; DGPML, Direction Ge ´ne ´rale de la Pharmacie, du Me ´dicament et des Laboratoires; HAZ, height-forage z-score; HFIAS, Household Food Insecurity Access Scale; ID, identifier; IQR, interquartile range; ITT, intention to treat; LoS, length of stay; MAM, moderate acute malnutrition; MUAC, midupper arm circumference; PP, per protocol; RUTF, ready-to-use therapeutic food; SAM, severe acute malnutrition; SD, standard deviation; WAZ, weightfor-age z-score; WHO, World Health Organization; WHZ, weight-for-height z-score. • We enrolled 801 children 6–59 months of age and randomised them individually into receiving (1) a standard dose of RUTF throughout the treatment and (2) a standard dose during the first two weeks, followed by a reduced dose from third treatment week onwards. • The trial showed non-inferior weight gain velocity from admission to discharge and similar recovery and length of stay in treatment. • However, the reduced dose also resulted in a significantly slower height gain velocity compared with the standard dose. What do these findings mean? • Our findings suggest that the reduction of the RUTF dose after the first two weeks results in similar weight gain velocity and recovery rates as with the standard dose given throughout SAM treatment. • However, the reduced RUTF dose seems to slow down the height gain velocity of children and might thus not be fully optimal for children’s healthy growth. • The reduced dose approach should be tested in a routine programmatic setting and in different food security contexts before scale-up. Introduction Worldwide, 19 million children under 5 years of age suffer from severe acute malnutrition (SAM), contributing to over 500,000 deaths per year [1]. According to the World Health Organization (WHO) guidelines for community-based management of acute malnutrition (CMAM), children without medical complications at admission are treated as outpatients, with weekly checkup visits [2]. Treatment consists of a systematic antibiotic regimen, as well as a ready-to-use therapeutic food (RUTF), prescribed according to the weight of the child and continued until discharge [2]. RUTFs are highly fortified energy dense pastes that are designed to fulfil 100% of the nutritional needs of children during the recovery from SAM [3]. In theory, the prescribed dose should enable weight gains up to 20 g/kg/day, as observed in inpatient treatment of SAM with RUTFs [4]. However, high weight gain rates have never been observed in community settings where the average ranges between 1.0 and 5.5 g/kg/day using RUTFs [5–19], suggesting a lower intake of the therapeutic product in home-based treatment. Several studies have suspected or reported product sharing within and outside the household [8,13,20] as a reason for lower weight gain. The perceived high cost and large quantity of RUTFs administered [20–25] have sparked attempts to optimise the product formulation and use [11,26–28]. One cluster-randomised trial in Sierra Leone gradually reduced the RUTF dose of children recovering from SAM when they reached moderate acute malnutrition (MAM) criteria [28]. However, the use of different recovery criteria between intervention and control groups limits the interpretation of the results. A retrospective analysis of a CMAM program in Myanmar, where, due to RUTF shortage, the dose was reduced once children with SAM reached MAM status, showed high recovery rates (90.2%). The lack of a control group in the study limits the interpretability of data Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 3 / 19 [18]. To our knowledge, no rigorous clinical trial looking at the efficacy of reducing the RUTF dose among children with SAM has been conducted. Reducing the RUTF dose given to children treated for SAM in a cost restrained setting could enable the management of more malnourished children with the same resources. The present study aimed to test, in a non-inferiority randomised controlled design, the impact of reducing the RUTF dose, after two weeks, on the weight gain velocity of children treated for uncomplicated SAM in the community. The reduction aimed to support weight gain rates of 5 g/kg/day and simplify the distribution and use of RUTF by children with SAM to 1 or 2 daily sachets for children <7 kg and �7 kg, respectively. Methods Ethics The study was performed in accordance with the principles in the Declaration of Helsinki. The research protocol obtained ethical clearance from the national ethics committee (Comite ´ d’e ´thique pour la recherche en sante ´[CERS]) and the clinical trials board (Direction Ge ´ne ´rale de la Pharmacie, du Me ´dicament et des Laboratoires [DGPML]) of Burkina Faso. An independent Data Safety Monitoring Board composed of one paediatrician and one statistician was responsible for monitoring serious adverse events and conducted five complete data reviews during the course of the study. Caregivers provided verbal and written consent prior to enrolment and were made aware of their right to withdraw from the study at any time. Caregivers in both arms were given an instant photo of their child at the end of the treatment period and a bucket with soap at the end of the 3-month post-discharge follow-up period to compensate for the time spent on study procedures. Study design We conducted a randomised controlled clinical trial (called MANGO) comparing the efficacy of a reduced RUTF dose to a standard RUTF dose in the management of uncomplicated SAM in children 6–59 months of age in a non-inferiority design. Study setting and participants The study was conducted in the Fada N’Gourma health district located in the Eastern region of Burkina Faso. Malaria is endemic, with 69.3% of children presenting a positive rapid test [29]. HIV prevalence is 1.0% among 15–49-year-olds. In 2016, the prevalence of severe wasting (weight-for-height z-score [WHZ] <−3) and moderate wasting (WHZ between −3 and −2) was 2.4% and 8.6%, respectively [30]. There were 42 health centres in the district in 2015, all run by the Ministry of Health and supported by Action Against Hunger; 10 were chosen as study sites based on criteria on minimum SAM caseload (>7 new SAM admissions/month), accessibility, and a suitable schedule to couple study visit days with routine growth monitoring days. Between October 2016 and July 2018, study participants were selected from children presenting with SAM at the 10 participating health centres for curative and preventive activities. Study staff checked admission criteria: WHZ <−3 and/or mid-upper arm circumference (MUAC) <115 mm, positive appetite test (performed as per the national protocol [31]), no oedema or medical complications, and between 6 and 59 months of age. Exclusion criteria included having received treatment for SAM within 6 months, caregiver planning to travel or unable to comply with the weekly checkup schedule, peanut or milk allergy, or disability affecting food intake. Children with any grade of oedema or medical complications, as defined by Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 4 / 19 the Burkina national protocol for CMAM [31], at any time during the study were referred to inpatient care. Randomisation Randomisation was stratified by health centre using varying block sizes from 2 to 8. Randomisation lists were generated using the website www.randomization.com. After confirming eligibility and obtaining consent from the caregiver, children were given a unique study identifier (ID) by a team supervisor and assigned to a treatment group. Only the RUTF distributors had access to the randomisation lists, while staff involved in assessing the eligibility and study outcomes of the child were blinded to the trial arm. Participants could not be blinded to the RUTF dose received. Investigators remained blinded to treatment groups until the final analysis stage. Study visits and procedures Upon admission, the child’s caregiver was interviewed regarding household socioeconomic characteristics, care practices, and recent morbidity of the child and encouraged to adhere to weekly visits until recovery. Anthropometric measurements and a clinical examination were performed at each visit from admission to discharge. As per national SAM treatment protocol, seven key messages were delivered to caregivers in both groups, including advice to continue breastfeeding and to offer family foods in addition to RUTF if needed. Anthropometrics were measured in duplicate at each visit: weight using an electronic scale (SECA 876, SECA, Hamburg, Germany) to the nearest 100 g, height (recumbent for <24 months of age; standing for �24 months of age) using a wooden measuring board (locally made) to the nearest 1 mm, and MUAC using a non-stretchable colourless measuring tape to the nearest 1 mm. Using WHO field tables, WHZ was determined and used for admission and discharge. In later analysis, WHZ was calculated using the package ‘zscore06’ [32] in STATA 15 (StataCorp, College Station, TX). Children were followed up until recovery. Children missing their study visit were contacted either directly by telephone or via a community health worker and encouraged to return. Children referred did not return to trial after inpatient phase, as referral was considered a trial endpoint. Recovered children were followed up fortnightly for 12 weeks and relapses recorded. A supplementary feeding program accompanied the post-discharge follow-up, providing readyto-use supplementary foods when available. Treatment protocol Treatment followed the Burkina national CMAM guidelines in all aspects except the RUTF dose. Half of the children received a reduced dose from the third treatment week onwards (Table 1). Medical treatment included 7 days of amoxicillin for all children at admission (50– 100 mg/kg/day), albendazole at the second treatment visit for children �12 months (200 mg to 12–23-month-olds; 400 mg to �24-month-olds) and catch-up doses for missed routine vaccinations or vitamin A supplementation (100,000 IU to 6–11-month-olds; 200,000 IU to 12– 59-month-olds, every 6 months) at admission. Any illness, such as malaria, respiratory tract infections, or diarrhoea, diagnosed during the study was treated according to national protocol. See S2 Text for the full protocol for the study. Data collection and management Two study teams were comprised of one nurse, three measurers, one food distributor, and one supervisor per team. All team members were trained on research ethics and processes; Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 5 / 19 standard operating procedures were defined, tested, and applied. Data were collected via tablets using the Open Data Kit (ODK1 software), and continuous data monitoring and cleaning were performed by a data manager under the supervision of the principal investigator. Electronic data were password protected, and field registries were kept in a locked office. Data were de-identified prior to analysis. Outcomes The primary outcome was weight gain velocity (g/kg/day) from admission to discharge. Other outcomes included weight gain velocity after two weeks, length of stay (LoS), discharge anthropometrics, linear and MUAC growth, treatment outcome, morbidity, and relapses. Weight gain velocity from admission to discharge was calculated by dividing the weight gain (weight at discharge −weight at admission) in grams by the weight at admission in kilograms and the LoS in days. Weight gain velocity after two weeks was measured as follows: (weight at discharge −weight at visit 3 [in g]) �(weight at admission [in kg]) �(LoS −14 [in days]). Missing weights at visit 3 (60 in reduced and 58 in standard arm) were imputed using mean weekly weight gained between an earlier visit (1 or 2) and later visit (4 or 5). The length of the stay was calculated as the number of days spent from admission to either recovery, referral, nonresponse, false discharge, or last visit before defaulting, lost to follow-up, or death. Linear and MUAC growth were defined as gains in millimetres (exit measure −admission measure)/week (LoS/7). A minimum acceptable mean rate of weight gain of 3.0 g/kg/day was defined at the protocol stage as a quality cutoff for evaluating general program performance. Nutritional recovery was defined as reaching a WHZ of �−2 for those admitted with a WHZ <−3 only, or MUAC �125 mm for those admitted with a MUAC <115 mm only, or both WHZ �−2 and MUAC �125 mm for those admitted with both WHZ <−3 and MUAC <115 mm upon two consecutive visits and absence of any illness. Referrals included children referred to inpatient care as a result of medical complications, >5% weight loss within three weeks, or �100 g weight gain over four weeks in the absence of apparent illness. Nonresponse included children not reaching anthropometric discharge criteria by 16 weeks of treatment who were referred to inpatient care for further examinations. Defaulters were defined as having missed three consecutive visits, but the child was confirmed to be alive. Transfers to health centres not involved in the study were categorised as defaulters. ‘Lost to follow-up’ was defined as having missed three consecutive visits without a known status of the child. False discharges included children who were erroneously discharged as recovered or referred, but upon analysis did not meet the criteria. Relapses were recorded over 12 weeks following recovery and Table 1. RUTF dose in reduced and standard dose groups. Weight (kg) Sachets/week Percent of reduction Standard RUTF dose Reduced RUTF dose Reduced RUTF dose Admission to discharge Week 1–2 Week 3 to discharge From week 1–2 to week 3 3.0–3.4 8 8 7 13% 3.5–4.9 10 10 7 30% 5.0–6.9 15 15 7 53% 7.0–9.9 20 20 14 30% 10.0–14.9 30 30 14 53% Abbreviation: RUTF, ready-to-use therapeutic foods. https://doi.org/10.1371/journal.pmed.1002887.t001 Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 6 / 19 were defined as presenting a WHZ <−3 and/or a MUAC <115 mm, or any grade of bilateral oedema. Sample size We assumed an expected mean difference in weight gain velocity between the two groups of 0.0 g/kg/day and a standard deviation (SD) of 2.6 g/kg/day with a non-inferiority margin of 0.5 g/kg/day. Assuming a power of 80% and a 5% significance level for a one-sided test, 335 children were needed in each group to demonstrate non-inferiority. To allow for dropout, the total target sample size was 800 children. Applying a 0.22 SD difference as could be observed in the main outcome with the calculated sample would allow us to detect a difference of 12% in recovery, seven days in LoS, 0.4 mm/week in MUAC gain velocity, and 0.3 mm/week in height gain velocity. Data analysis Baseline characteristics of the study population were summarised as percentages and means (±SDs). Linear mixed models were used to compare primary and secondary outcomes of weight, linear and MUAC growth velocities, LoS, and anthropometric endpoints. Results were reported as differences of reduced dose from standard dose (reduced minus standard), with positive values meaning greater estimates among reduced dose. For programmatic outcomes, logistic mixed models were used to compare groups. Time to recovery was analysed using the Cox proportional hazards model. Study sites and research teams were included in the mixed models as random effects. Unadjusted models and models adjusted for sex, age, admission measure of weight, height, MUAC, WHZ, wealth, LoS in treatment, and month of admission were fitted. Adjustments were defined in the statistical analysis plan development stage prior to data analysis (S3 Text). Model checking was based on residual plots and normal probability plots, when applicable. All analyses were performed using STATA 15 (StataCorp). Both intention to treat (ITT) and per protocol (PP) analyses were carried out for the main outcome and key secondary outcomes. ITT analysis included all children admitted to the study for whom an endpoint observation was available. PP analysis included children without missed visits who, according to maternal recall, consumed >50% of the daily dose at all times and excluded those who had received a wrong treatment dose or had been falsely discharged. Interactions were only investigated in ITT analyses. Interactions between treatment and age group (<12 months versus �12 months), sex, MUAC category (<115 versus �115 mm), WHZ category (<−3 versus �−3), and stunting (height-for-age z-score [HAZ] <−2 versus HAZ �−2) at admission were evaluated for the main outcome of weight gain velocity and the key secondary outcomes of recovery, LoS and height gain velocity, by means of likelihood ratio tests. Only significant interaction terms led to subgroup analyses. ‘Urban’ was defined as those living �30 minutes’ return trip from the regional capital city. Low birth weight (<2,500 g) was confirmed from an official birth certificate or health card. Household Food Insecurity Access Scale (HFIAS) was constructed according to FANTA indicator guide [33]. Results From October 17, 2016, to July 20, 2018, 1,186 children were diagnosed with SAM and assessed for eligibility at 10 study sites. Of these, 802 (68%) children were eligible for the study and randomised to standard or reduced RUTF dose (Fig 1). One child was excluded after randomisation for not meeting the SAM criteria at admission. Therefore, 801 patients were included in the trial: 402 in the reduced dose and 399 in the standard dose arm. Thirteen Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 7 / 19 children defaulted or were referred immediately after admission; four and nine in reduced and standard dose arms, respectively. Three children developed oedema (two in reduced and one in standard dose arm) and were excluded from weight gain calculation. Only recovered children continued to the post-discharge follow-up, contributing to the post-discharge outcome analyses including relapse rate (Fig 1). Randomisation resulted in baseline equivalence between the reduced and standard dose arms with respect to potential confounders (Table 2). The mean age at admission was 13.4 months, 49% were boys, and the mean admission weight was 6.2 kg. At visit 3, no children were <3.5 kg, 5% were 3.5–4.9 kg, 61% were 5.0–6.9 kg, 30% were 7.0–9.9 kg, and 4% were 10.0–14.9 kg. Caregivers were, on average, 28 years of age, 76% had no formal education, and 88% were categorised as food secure. Primary outcome The mean weight gain velocity from admission to discharge was 3.4 g/kg/day in both groups in ITT analysis (Δ0.0 g/kg/day; 95% CI −0.4 to 0.4). Non-inferiority of the reduced dose could be confirmed in both ITT (inferiority rejected: p= 0.013) and PP (inferiority rejected: p= 0.019) for this main outcome (Fig 2). No differences were found in weight gain velocity in PP analysis (Δ0.2 g/kg/day; 95% CI −0.5 to 0.8), in ITT among recovered only (Δ−0.1 g/kg/ day; 95% CI −0.6 to 0.4), referrals (Δ0.5 g/kg/day; 95% CI −0.6 to 1.5), or defaulters (Δ−0.3 g/ kg/day; 95% CI −1.3 to 0.8) (Table 3). No interactions were found between treatment and sex, age, MUAC category, WHZ category, or stunting status at admission. In general, mean weight Fig 1. Patient flowchart. FU, follow-up; ITT, intention to treat; PP per protocol; RUTF, ready-to-use therapeutic food; SAM, severe acute malnutrition. https://doi.org/10.1371/journal.pmed.1002887.g001 Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 8 / 19 gain velocity was high at the start of the treatment and decreased rapidly (Fig 3). When entering third treatment week, 27% of children still had SAM (WHZ <−3 and/or MUAC <115 mm): 108 children in the reduced and 106 children in the standard group. Weight gain velocity after the first two weeks of treatment (in ITT) was significantly different between groups, with a mean of 2.3 g/kg/day with reduced versus 2.7 g/kg/day with standard dose (Δ−0.4 g/kg/day; 95% CI −0.8 to −0.02). Results comparing the MUAC gain velocity between reduced and standard doses mirrored the results obtained with weight gain velocity (Table 3). Adjusted analysis yielded similar results that are found in S1 Table. Secondary outcomes No differences were found in anthropometry at discharge between study arms in the unadjusted model (all p>0.2). However, when using the adjusted model (adjusting for sex, age, admission measure of weight, MUAC, WHZ and height, month of admission, LoS, and wealth index), height at discharge was significantly smaller in the reduced dose arm (Table 4). This difference in height of 0.1 cm could still be observed 3 months post-recovery, although the difference was then no longer significant (p= 0.33). Weight, MUAC, weight-for-age z-score (WAZ), WHZ, and HAZ were not different at three months post-recovery. The median LoS was 56 days (interquartile range [IQR] 35–91) in both arms. The WHZ category was an effect modifier (interaction, p= 0.028) whereby children who were admitted Table 2. Baseline characteristics of 801 children with SAM, randomised to reduced or standard RUTF dose. Characteristic nReduced RUTF Standard RUTF Age, months 801 13.3 ±8.6 13.4 ±8.9 Male, % (n) 801 49.5 (199) 49.4 (197) Weight, kg 801 6.2 ±1.2 6.2 ±1.4 Height, cm 801 69.1 ±7.4 69.1 ±8.0 MUAC, mm 801 113 ±7 113 ±7 WHZ 801 −3.1 ±0.7 −3.1 ±0.7 HAZ 801 −2.4 ±1.3 −2.4 ±1.3 WAZ 801 −3.5 ±0.8 −3.5 ±0.8 Admission criteria, % (n) 801 WHZ only 27 (107) 26 (102) MUAC only 39 (156) 38 (153) WHZ and MUAC 35 (139) 36 (144) Low birth weight, % (n) 502 23 (60) 21 (50) Urban, % (n) 801 15 (59) 14 (54) Health centre �30-minute return trip, % (n) 801 39 (155) 37 (149) Caregiver’s age 801 27.8 ±7.6 27.6 ±7.9 Mother has no formal education, % (n) 801 76 (305) 75 (301) HFIAS category, % (n) 801 Food secure 88 (353) 88 (350) Mild food insecurity 9 (35) 9 (34) Moderate or severe food insecurity 3 (14) 4 (15) Open defecation, % (n) 801 77 (311) 75 (298) All values are means ±SD unless otherwise indicated. Abbreviations: HAZ, height-for-age z-score; HFIAS, Household Food Insecurity Access Scale; MUAC, mid-upper arm circumference; RUTF, ready-to-use therapeutic food; SAM, severe acute malnutrition; SD, standard deviation; WAZ, weight-for-age z-score; WHZ, weight-for-height z-score. https://doi.org/10.1371/journal.pmed.1002887.t002 Impact of reduced RUTF on anthropometry and program outcomes of children with SAM PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002887 August 27, 2019 9 / 19 S2 Table. Results of the PP analysis of programmatic outcomes. PP, per protocol. (DOCX) S3 Table. Results of the adjusted analysis of height and HAZ gain. HAZ, height-for-age zscore. (DOCX) S1 Text. CONSORT checklist. (DOC) S2 Text. MANGO study protocol. (DOCX) S3 Text. MANGO statistical analysis plan. (DOCX) S1 Abstract. French language translation of the Abstract. (DOCX) Acknowledgments We thank Dieynaba N’Diaye, Benjamin Guesdon, and Audrey Papucci for critical feedback and proofreading of the manuscript; Mike Zangenberg, Erin Hulland, and Steven Russell for the data safety monitoring; research teams for their everyday efforts in implementing the trial; and study participants and caregivers for participating in the trial. Author Contributions Conceptualization: Ce ´cile Salpe ´teur, Henrik Friis, Andre ´Briend, Pernille Kaestel. Data curation: Suvi T. Kangas, Victor Nikièma. Formal analysis: Suvi T. Kangas, Christian Ritz, Henrik Friis, Pernille Kaestel. Funding acquisition: Ce ´cile Salpe ´teur. Investigation: Suvi T. Kangas, Pernille Kaestel. Project administration: Suvi T. Kangas, Ce ´cile Salpe ´teur, Victor Nikièma. Supervision: Ce ´cile Salpe ´teur, Christian Ritz, Henrik Friis, Pernille Kaestel. Writing – original draft: Suvi T. Kangas. Writing – review & editing: Suvi T. 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