A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition : A double-blind, randomized controlled trial

RESEARCH ARTICLE A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial Robert H. J. BandsmaID 1,2,3,4,5,6,7 *, Wieger VoskuijlID 7,8,9 , Emmanuel ChimweziID 8 , Greg FeganID 10 , Andre ´Briend 11,12 , Johnstone ThitiriID 13 , Moses Ngari 13 , Laura MwalekwaID 13 , Victor BandikaID 14 , Rehema AliID 13 , Fauzat HamidID 13 , Betty OworID 13 , Neema MturiID 13 , Isabel PotaniID 8 , Benjamin Allubha 8 , Anneke C. Muller KoboldID 15 , Rosalie H. BartelsID 9 , Christian J. VerslootID 5 , Marjon Feenstra 5 , Deborah A. van den BrinkID 5 , Patrick F. van RheenenID 5 , Marko Kerac 16 , Celine BourdonID 2,7 , James A. BerkleyID 7,13,17 * 1Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Canada, 2Translational Medicine Program, Hospital for Sick Children, Toronto, Canada, 3Center for Global Child Health, Hospital for Sick Children, Toronto, Canada, 4Department of Nutrition Sciences, University of Toronto, Toronto, Canada, 5University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, the Netherlands, 6Department of Biomedical Sciences, College of Medicine, University of Malawi, Blantyre, Malawi, 7The Childhood Acute Illness and Nutrition Network (CHAIN), Nairobi, Kenya, 8Department of Paediatrics and Child Health College of Medicine, University of Malawi, Blantyre, Malawi, 9Global Child Health Group, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, the Netherlands, 10 Swansea Trials Unit, Swansea University Medical School, Swansea, United Kingdom, 11 Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark, 12 University of Tampere School of Medicine, Center for Child Health Research, Tampere, Finland, 13 KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya, 14 Department of Paediatrics, Coast General Hospital, Mombasa, Kenya, 15 University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, the Netherlands, 16 London School of Hygiene & Tropical Medicine, London, United Kingdom, 17 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom *[email protected] (RHJB); [email protected] (JAB) Abstract Background Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase. Methods and findings In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 1 / 19 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Bandsma RHJ, Voskuijl W, Chimwezi E, Fegan G, Briend A, Thitiri J, et al. (2019) A reducedcarbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial. PLoS Med 16(2): e1002747. https://doi.org/10.1371/journal. pmed.1002747 Academic Editor: Lars Åke Persson, London School of Hygiene and Tropical Medicine, UNITED KINGDOM Received: August 25, 2018 Accepted: January 18, 2019 Published: February 26, 2019 Copyright: ©2019 Bandsma 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: All data files are available at https://doi.org/10.7910/DVN/N4RISX. Funding: The study was funded by the Thrasher Research Fund to RHJB and JAB. Number 9403 (https://www.thrasherresearch.org/default.aspx). Nonfinancial support (investigational products) was provided by Nutriset (https://www.nutriset.fr/ en). The funders had no role in study design, data defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2–5 days), which was similar between randomized groups (0.23 [95% CI −0.13 to 0.60], P= 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P= 0.84). Cumulative days with diarrhea (P= 0.27), enteral (P= 0.42) or intravenous fluids (P= 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. Conclusions Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM. Trial registration ClinicalTrials.gov NCT02246296. Introduction Children with complicated severe acute malnutrition (SAM) are admitted to the hospital because they are severely ill or unable to feed sufficiently [1]. In African hospitals, their risk of inpatient death ranges between 10%–30% [2–4]. In contrast, children with SAM who are clinically stable, i.e., without signs of illness and who have an appetite (uncomplicated SAM), are usually treated in community-based programs and have a substantially lower mortality risk, ranging between <1%–7% [5–7]. In hospital settings, mortality may be reduced to some extent by adhering to World Health Organization (WHO)–recommended management [2,4,8,9], but this may not address the full spectrum of infections and metabolic abnormalities of these seriously ill children [10–12]. In the 2013 Lancet Maternal and Child Nutrition series, improving management of SAM was identified as having the greatest likely impact on child mortality amongst nutritional interventions [13]. Current guidelines for the nutritional management of SAM in the hospital define 3 phases of treatment [14]: 1) the “stabilization phase,” during which children are fed a liquid diet (standard F75 [F75]) with a relatively low-protein (approximately 9 g/l) and relatively low-energy Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 2 / 19 collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: ALT, alanine aminotransferase; ATP, adenosine tri-phosphate; df, degrees of freedom; DSMC, Data and Safety Monitoring Committee; F75, standard F75; FDR, false discovery rate; HAZ, height-for-age z scores; IRR, incidence-rate ratio; MCT, medium-chain triglyceride; mF75, modified F75; MUAC, midupper arm circumference; RUTF, ready-to-use therapeutic food; SAM, severe acute malnutrition; TSC, Trial Steering Committee; WAZ, weight-forage z scores; WHO, World Health Organization; WHZ, weight-for-height z scores. content (75 kcal/100 ml). F75 was designed to meet the estimated nutritional requirements to restore physiological and metabolic functions and to prevent refeeding syndrome while medical conditions stabilize. No weight gain is expected during this phase of treatment; 2) the “transition phase,” during which higher protein and energy through either F100 formula or readyto-use therapeutic foods (RUTFs) are started with supplemental F75 formula; and 3) the “rehabilitation phase,” with an increased daily intake of F100 or RUTFs in order to achieve catch-up growth. Once a child has stabilized and tolerates RUTFs, WHO guidelines recommend discharge from hospital care, with continuation of the rehabilitation phase continued in the community [14,15]. The original F75 formulation was designed based on what was known about the pathophysiology of SAM at that time, before separation of treatment of complicated and uncomplicated SAM [16]. Today’s inpatient children with complicated SAM have a very different clinical profile from uncomplicated SAM treated in the community. Around 65% of calories in the F75 formula is derived from carbohydrates (maltodextrin, lactose, and sucrose). Once ingested, disaccharides such as lactose or sucrose are hydrolyzed into monosaccharides by disaccharidases found at the tip of small intestinal villi. Released monosaccharides such as glucose and galactose are then transported across the apical membrane through Na + -dependent glucose transporters, whereas fructose is taken up through a facilitative fructose transporter [17]. However, evidence suggests that children with SAM have impaired absorption of monoand disaccharides, regardless of the presence of gastroenteritis [18,19]. Limited histological evidence also shows intestinal villous atrophy [18], which is consistent with clinical signs suggestive of carbohydrate malabsorption [20]. Thus, we hypothesized that revising the current F75 into a modified, lactose-free, and reduced-carbohydrate F75 formulation could reduce osmotic diarrhea and thereby lower the number of days to complete the first phase of treatment. Early deterioration in children with SAM may also be related to refeeding syndrome, comprising severe metabolic derangements driven by insulin excretion after a sudden shift from a catabolic to an anabolic state [21]. Refeeding syndrome is characterized by hypophosphatemia, hypokalemia, and hypomagnesemia, which may impair cardiac, pulmonary, and neurological function and can result in (sudden) death. As protein synthesis is stimulated in anabolism, increased production of adenosine triphosphate (ATP) leads to a higher cellular demand for phosphate [21]. Furthermore, pancreatic insulin secretion induces the cellular uptake of glucose and electrolytes, including phosphate and potassium, and hypophosphatemia is common during nutritional rehabilitation of malnourished children and is associated with mortality [22–24]. We also hypothesized that a reduction in carbohydrate content of the modified F75 formula could lower the risk of refeeding syndrome. Together, reformulated F75 could plausibly improve early clinical outcomes among hospitalized children with SAM. We conducted a randomized, double-blind controlled trial evaluating a modified F75 formula with substantially reduced carbohydrate content and without lactose versus the currently recommended formulation of F75 among hospitalized children with SAM in Kenya and Malawi. Methods Study design and participants The study was a randomized, double-blind controlled trial conducted at two Kenyan hospitals (Kilifi County Hospital and Coast General Hospital, Mombasa) and one Malawian hospital (Queen Elizabeth Central Hospital, Blantyre). All children admitted to these study hospitals were screened for complicated SAM. The study was discussed in detail with parents or carers of potential participants in their local language, and written informed consent was sought. In Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 3 / 19 patients for which re-establishing feeding was urgent, initial verbal assent was sought and followed up with written consent after treatment initiation. Inclusion criteria were • age 6 months to 13 years; • SAM defined as mid-upper arm circumference (MUAC) <11.5 cm or weight-for-height Z score <−3 if younger than 5 years of age, BMI Z score <−3 if older than 5 years, or edematous malnutrition at any age; • being admitted to the hospital because of medical complications or failing an appetite test, as defined by WHO guidelines [16]; • weight-for-length/height or BMI, weight-for-age, and length/height-for-age Z scores were calculated using WHO 2006 and 2007 references. Exclusion criteria were • lack of informed consent, • known allergy to milk products Investigational product We compared F75 to the modified F75 (mF75) formulation (Table 1). Osmolarity was 298 mOsm/L and 232 mOsm/L for F75 and mF75, respectively. The formulations were isocaloric, and the reduced energy from carbohydrates was compensated by increased mediumchain triglycerides (MCTs), while protein and micronutrient composition were unaltered. Both formulations were manufactured by Nutriset (Nutriset, Malaunay, France) and dispensed by trained staff according to WHO recommendations: 95 kcal/kg per day, divided into 8 feeds per 24 hours. Randomization and masking Sequential study numbers were computer generated using Stata Statistical Software: Release 12 (College Station, TX: StataCorp LP) with random block sizes for each site prior to the trial. An independent statistician was responsible for computerized sequence generation. Children were allocated study numbers sequentially at each site using sealed numbered envelopes. Group allocation was blinded to participants and all trial personnel, including trial Table 1. Formulations of F75 and mF75. % Energy Quantity: g/1,000 ml Macronutrients F75 mF75 F75 mF75 Protein 5.3% 5.3% 9.9 9.9 Lipid 31.5% 51.7% 26.3 43.1 Carbohydrate 63.2% 43.0% 118.5 80.6 Total 100% 100% 154.7 133.6 Carbohydrate composition Lactose 9.9% 0% 18.6 0 Sucrose 3.6% 3.6% 6.8 6.8 Maltodextrin 50% 39% 93.2 73.9 Abbreviations: F75, standard F75; mF75, modified F75. https://doi.org/10.1371/journal.pmed.1002747.t001 Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 4 / 19 coordinators and the principal investigator. The study products were identical in appearance and packaged in color-coded sachets. Procedures Children were managed in the hospital as per Malawian or Kenyan national guidelines, both of which are based on WHO recommendations [15,16]. HIV testing by rapid antibody test was offered to all participants according to national guidelines, with appropriate counseling, follow-up tests, and referrals offered depending on results. Children were examined daily, and clinical status was recorded on a standardized proforma during ward rounds. If a child deteriorated after stabilization, they were returned to the stabilization phase and received F75 or mF75 as originally allocated. Blood and fecal samples were collected at admission and after 3 days of hospitalization. The clinical team was blinded for the allocated formula and decided whether a child was fit for discharge based on criteria such as being in rehabilitation phase, clinical condition, ability to finish RUTF, and appetite level. RUTF, nutritional counseling, and follow-up in a nutrition clinic were provided at discharge, as per standard of care at each institution. Primary and secondary outcomes The primary outcome was based on the purpose of F75, which is clinical stabilization, after which a child can progress to higher protein and energy feeds to promote catch-up growth. We therefore chose the number of days between admission and first stabilization as the primary outcome, defined as having reached the transition phase of treatment and switched to another feed type. Stabilization was based on the WHO guideline [15]: 1. absence of any WHO “danger” or emergency signs: obstructed breathing, respiratory distress, cyanosis, shock (delayed capillary refill plus fast and weak pulse plus temperature gradient), severe anemia (Hb <5 g/dl), congestive cardiac failure, impaired consciousness, convulsions, severe dehydration, profuse watery diarrhea or vomiting, hypothermia; 2. loss of edema (if present on admission), defined as improving from a severe +++ edema (severe: generalized bilateral pitting edema) to ++ edema (moderate: no upper arm or upper leg edema and no facial edema), or from ++ edema to + edema (mild: only feet/ankle edema), or none; 3. and tolerating the full prescribed volume of F75 feeds and observed to be completing the feeds. Study clinicians received additional training on the WHO guidelines as well as bedside and scenario-based training on the criteria for transition to improve standardization across sites. In order to include children who died before stabilization in the analyses, they were classified as “not stabilized.” Although there is some subjectivity in determining a child’s medical condition that is “improving,” we chose stabilization as a main outcome rather than episodes of diarrhea because 1) it is the purpose of F75; 2) once a child switches to F100 or RUTFs, earlier transition could conceivably result in an increase in diarrhea unrelated to mF75 or F75; 3) diarrhea is very difficult to quantify objectively since maternal recall is not accurate in identifying episodes or severity [25]; 4) diapers may not distinguish every stool episode, and their weight is affected by urine; and 5) refeeding syndrome may be critical to early outcomes. Prespecified secondary outcomes were the total number of days and number of days prior to stabilization with Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 5 / 19 1. diarrhea (i.e., 3 or more loose or watery stools within 24 hours), 2. receipt of rehydration fluids (ReSoMal or IV fluids), 3. signs of shock (i.e., fast and weak pulse with limb versus core temperature gradient and capillary refill time >3 seconds), 4. lower chest wall indrawing, 5. hypoxemia (i.e., fingertip SaO 2 <90% or requiring oxygen to maintain SaO 2 above 90%), 6. impaired consciousness (i.e., Blantyre coma score <4) [26], 7. symptomatic hypoglycemia (i.e., blood sugar <3.0 mmol/l, tested only on clinical indication), 8. vomiting, 9. congestive cardiac failure, 10. any antibiotics and secondor third-line antibiotics, 11. receiving F75 (initial stabilization plus any restabilization), 12. Nasogastric tube feeds or nonstandard feeds, 13. receiving breastmilk. Other prespecified secondary outcomes were 1. mortality in hospital; 2. time to discharge from hospital in days; 3. the total number of days spent in the stabilization phase, including periods when children deteriorated and returned to the stabilization phase; 4. percentage change in weight between admission and day 5; 5. serum sodium, potassium, magnesium, calcium, phosphate, and albumin at day 3 and changes between admission and day 3; 6. stool osmotic gap and pH at day 3. Laboratory analyses Blood was collected at admission and day 3, from which serum was obtained and stored at −80 ˚C. For analysis, samples were thawed overnight at 4 ˚C, vortexed, and centrifuged at 1,500 g for 3 minutes. Albumin, alanine aminotransferase (ALT), creatinine, calcium, magnesium, potassium, phosphate, sodium, and urea were batch analyzed using the P-module on a Roche Modular (Roche, Indianapolis, United States) at a single laboratory (University Medical Centre Groningen, the Netherlands). Fecal samples were collected at both time points and stored at −80 ˚C. Fecal biochemistry was batch analyzed only amongst patients with clinical diarrhea in the same laboratory. These samples were thawed overnight at 4 ˚C and weighed, diluted 3.5 times with distilled water, homogenized (Precellys 24 Homogenizer, Bertin, Rockeville, USA), and centrifuged at 16,100 g/rcf for 5 minutes. Fecal water was extracted, and osmolality was measured by freezing point depression (Osmo Station OM-6050, Arkray, Tokyo, Japan). In addition, sodium, potassium, and chloride were analyzed using the ISE900-module on Cobas Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 6 / 19 8000 (Roche, Indianapolis, USA). pH was determined using a standard pH meter. The stool osmotic gap was calculated by the equation 290 −2×(stool Na + stool K). Statistical analyses A statistical analysis plan was reviewed and approved by an independent Data and Safety Monitoring Committee (DSMC) before the treatment allocation was unmasked, and the research database was locked. The DSMC oversaw the trial and reported to the Trial Steering Committee (TSC). An interim unblinded analysis was conducted by the DSMC during the trial after 50% of participants were recruited. A recommendation to the sponsor to discontinue recruitment, in all patients or in selected subgroups, would be made by the TSC on advice from the DSMC if the data provide proof beyond reasonable doubt that one of the treatment arms is better in terms of the primary outcome or safety guided by the Haybittle–Peto criteria. The Haybittle–Peto boundary states that if an interim analysis shows a probability of less than 0.001 that the treatments are different, then the trial should be stopped early. For the primary endpoint of time to first stabilization, we regarded it as essential to include children who died before stabilization in the analysis. Therefore, the time to stabilization of children who died was entered as “999,” ensuring that they ranked bottom in the rank sum test and were included in the longest quartile of the IQR. An intention-to-treat analysis was conducted including all available data, including from children given the wrong formula at one or more feeds (primary endpoint evaluable) and children who withdrew or absconded, i.e., left the hospital without notifying the medical team or were transferred prior to stabilization (primary endpoint nonevaluable). We calculated the median (IQR) time to stabilization in the 2 randomized groups and compared their distributions using a Wilcoxon rank sum test and incidence rate ratio using Cox regression. We also conducted prespecified subgroup analyses to assess effect modification by site, HIV antibody status, edema status, and age using likelihood ratio tests. In addition, using the cmprsk R-package, we conducted competitive risk analysis to compare the cumulative incidence functions of the mutually exclusive risks of either dying prior to stabilization or achieving stabilization. Differences in these incidence functions indicate whether the cumulative probability of either dying before stabilization or achieving stabilization differs between groups as treatment progresses. For secondary outcomes, we compared the number of days with prespecified clinical features between allocated groups using regression with a zero-inflated negative binomial distribution, since many children had no days with these problems. To compare the distributions of continuous variables, we used Student ttest or Wilcoxon’s rank sum test if the variables were skewed. We compared categorical variables between randomized groups using χ 2 or Fisher’s exact tests. Trends in proportions across ordered groups were assessed by a nonparametric test for trend. HIV test results were analyzed with “not done” as a separate category, as some children who died before testing or whose parents refused testing may have been more likely to have HIV infection or exposure. Blood and stool biochemical variables between intervention arms were compared while adjusting for site, whereas models comparing admission and day 3 included a random intercept for patients. All statistical analyses were done using either Stata version 13.0 (StataCorp 2013, Stata Statistical Software: Release 13; College Station, TX: StataCorp LP) or R statistical software version 3.4.0 [27]. Sample size Based on prior trial experience [28], we estimated that 50% of children allocated to F75 would stabilize by day 5, and we calculated the sample size required to demonstrate a 10% absolute increase in percentage stabilized at day 5 to 60% in the intervention arm (equivalent to a Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 7 / 19 hazard ratio of 1.35). With an alpha of 5% and power of 80%, the number of patients required was 381 per arm, and to allow for 10% anticipated losses, we aimed to recruit 420 per arm. Ethical considerations The trial was registered at ClinicalTrials.gov, number NCT02246296. Ethical approval was obtained from the College of Medicine Research Ethics Boards of the University of Malawi (P.03/14/1540), the KEMRI Ethical Review Committee (SCC 2799), the Oxford Tropical Research Ethics Committee (OXTREC 58–14), and the Hospital for Sick Children Research Ethics Board, Toronto (1000046559). Results Patient characteristics Between 4 December 2014 and 24 December 2015, 843 hospitalized children were enrolled, 418 were allocated to F75, and 425 were allocated to mF75 (Fig 1). The median age of participants was 16 months (IQR 10 to 25 months); 385 (46%) were female, 264 (31%) had kwashiorkor, 382 (45%) had diarrhea at admission, and 179 (21%) had a positive HIV test, with 46 (5.5%) having a declined or missed HIV test. Overall, 516 (61%) were enrolled in Kenya and 327 (39%) in Malawi. Baseline clinical and demographic characteristics were similar between randomized groups and are presented in Table 2. Of a total of 7,098 child days of hospitalization, 2,615 were prior to stabilization, and 75/843 (8.9%) children died prior to stabilization. Nine children voluntarily withdrew from the study prior to stabilization, and 6 absconded from the hospital (as defined above). Seven children were transferred to another hospital, 4 of whom because of hospital closure due to a health worker strike. Nine children (1.0%) received the wrong formula at one or more feeding times and were included in the primary analysis. Primary outcome The median time to stabilization was 3 days (IQR 2–6 days) (Fig 2,Table 3, and S1 Fig), and there was no evidence for difference in time to stabilization between randomized groups; absolute difference 0.23 (95% CI −0.13 to 0.60, P= 0.59). Prespecified subgroup analyses did not suggest effect modification by the presence of diarrhea at admission, age, edema, or site (S1 Table). There was evidence of an effect of HIV status (P <0.0001) on both time to stabilization and time to mortality but no interaction between HIV status and effect of allocated feeds (P�0.33, S2 Table). Secondary clinical outcomes There was no effect of the intervention on mortality before stabilization (P= 0.84) or during hospitalization overall (P= 0.44, Table 3). As presented in S3 Table, 117 (14%) children experienced a serious adverse event before stabilization without evidence of difference between randomized groups (P= 0.59). Diarrhea was common; of the 416 children without diarrhea at admission, 176 (38%) developed diarrhea in hospital. The number of days with diarrhea prior to stabilization and during the whole hospitalization period were similar in both groups (Table 3). There were no significant differences in the number of days with vomiting or receiving rehydration fluids (ReSoMal or IV fluids). The types of other feeds children received (nonstandard milks) and routes (nasogastric or oral) were not affected by randomized allocation, except breast milk, which was lower in the mF75 group (P= 0.04). Hypoglycemia (<3.0 mmol/l) rarely occurred, and the number of days with an episode of hypoglycemia was not Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 8 / 19 influenced by the intervention (Table 3). The number of days receiving antibiotics was also not affected by the intervention and neither was the mean (±SD) percent of weight change between admission and day 5 (3.1% ±5.8% in nonoedematous, P= 0.78; −3.4% ±7.1% in oedematous patients, P= 0.63). Although uncommonly diagnosed, the incidence of cliniciandefined congestive heart failure was lower in the mF75 group (P= 0.007). Fig 1. Numbers of children who were screened, assigned a trial group, and included in the primary analysis. Children aged 6 months to 13 years who were admitted for complicated SAM were screened for eligibility in the participating hospitals. They were enrolled after informed consent was obtained. SAM, severe acute malnutrition. https://doi.org/10.1371/journal.pmed.1002747.g001 Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 9 / 19 Supporting information S1 CONSORT checklist. (PDF) S1 Protocol. Randomized controlled trial of a reduced-carbohydrate formulation of F75 therapeutic milk among children with SAM. SAM, severe acute malnutrition. (DOCX) S1 Table. Primary endpoint and prespecified subgroup analyses. All data are median (IQR) or geometric means (95% CI), as indicated. (DOCX) S2 Table. Competitive risk models. All data are presented as median (IQR). (DOCX) S3 Table. List of serious adverse events. (DOCX) S1 Fig. Probability of stabilization and death between the two treatment groups. Competing risk analysis simultaneously compares the estimated cumulative incidence curves of mutually exclusive events: first stabilization (solid line) or death prior to stabilization (dashed lines). Withdrawals and absconded cases were censored. Differences in cumulative incidence functions between F75 (blue line) and mF75 (black line) and all subgroup analysis models were compared using Gray’s test. Significance threshold, P<0.05. F75, standard F75; mF75, modified F75. (TIF) Acknowledgments We thank Nutriset, Rouen, France, for preparing and providing the standard and modified F75. We thank the TSC (Elizabeth Molyneux, University of Malawi, College of Medicine, Blantyre, Malawi; Ahmed Laving, University of Nairobi, Kenya; and Indi Trehan, Washington University in St. Louis, Missouri, USA) for their suggestions. We thank the Data Safety Monitoring Committee (David Brewster, National Hospital, Dili, East Timor; Charles Opondo, London School of Hygiene and Tropical Medicine, London, United Kingdom; and Michael Boele van Hensbroek, Academic Medical Center, Amsterdam, the Netherlands) for their oversight. We thank the many individuals and organizations who made this study possible, including all the children and their families who took part; the Department of Paediatrics and Child Health, Queen Elizabeth Central Hospital in Blantyre, Malawi; and the Kilifi District Hospital and Coast Provincial General Hospital in Mombasa, Kenya. We also acknowledge the hard work of our research staff in Malawi and Kenya. Author Contributions Conceptualization: Robert H. J. Bandsma, Wieger Voskuijl, Andre ´Briend, Benjamin Allubha, Patrick F. van Rheenen, Marko Kerac, James A. Berkley. Data curation: Emmanuel Chimwezi, Johnstone Thitiri, Moses Ngari, Deborah A. van den Brink, James A. Berkley. Formal analysis: Robert H. J. Bandsma, Emmanuel Chimwezi, Greg Fegan, Moses Ngari, Celine Bourdon, James A. Berkley. Funding acquisition: Robert H. J. Bandsma, James A. Berkley. Modified formulation for children with severe acute malnutrition PLOS Medicine | https://doi.org/10.1371/journal.pmed.1002747 February 26, 2019 16 / 19 Investigation: Wieger Voskuijl, Johnstone Thitiri, Laura Mwalekwa, Victor Bandika, Rehema Ali, Fauzat Hamid, Betty Owor, Neema Mturi, Isabel Potani, Benjamin Allubha, Anneke C. Muller Kobold, Rosalie H. Bartels, Christian J. Versloot, Marjon Feenstra, Deborah A. van den Brink. Methodology: Robert H. J. Bandsma, Wieger Voskuijl, Emmanuel Chimwezi, Greg Fegan, Andre ´Briend, Johnstone Thitiri, Laura Mwalekwa, Anneke C. Muller Kobold, Christian J. Versloot, Marjon Feenstra, Deborah A. van den Brink, Patrick F. van Rheenen, Marko Kerac, Celine Bourdon. Project administration: Johnstone Thitiri. Supervision: Robert H. J. Bandsma, Wieger Voskuijl, Johnstone Thitiri, Victor Bandika, Neema Mturi, Isabel Potani, Benjamin Allubha, Rosalie H. Bartels, James A. Berkley. Visualization: Robert H. J. Bandsma, Christian J. Versloot, Celine Bourdon. Writing – original draft: Robert H. J. Bandsma, Wieger Voskuijl, James A. Berkley. Writing – review & editing: Robert H. J. Bandsma, Wieger Voskuijl, Emmanuel Chimwezi, Greg Fegan, Andre ´Briend, Johnstone Thitiri, Moses Ngari, Laura Mwalekwa, Victor Bandika, Rehema Ali, Fauzat Hamid, Betty Owor, Neema Mturi, Isabel Potani, Benjamin Allubha, Anneke C. Muller Kobold, Rosalie H. Bartels, Christian J. Versloot, Marjon Feenstra, Deborah A. van den Brink, Patrick F. van Rheenen, Marko Kerac, Celine Bourdon, James A. Berkley. References 1. Trehan I, Manary MJ. 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