Supplementarytable 1 Fullinclusion and Exclusion Criteria 2

Readmission and mortality inmalnourished, older, hospitalized adults treated with a specializedoral nutrition supplement: a randomized clinical trial

Supplementary Material

Contents

SupplementaryTable 1 —FullInclusion and Exclusion Criteria………………….....2

SupplementaryTable 2 — Nutritional Composition of HP-HMB and PlaceboOral Supplements…...….……….……………………………..……….…..……….....……….5

SupplementaryTable 3 — Listing of All Efficacy Variables.…………….…….……....7

SupplementaryTable 4 — Assessment Measures and Statistical Models.……..….9

SupplementaryTable 5—Study Product Intake Based on Paks per Day…..….…12

SupplementaryTable 6 — Cause of Death by Primary Diagnosis for Admission..13

SupplementaryTable 7 — Study Investigators…..…..………..……………....…..…..14

SupplementaryFigure 1 — Study Product Intake (Adherence) Until First Readmission or Death………..………..…………………………………..………...... 17

SupplementaryFigure 2 — Composite and Component Endpoints at Day 30 and Day 60 Post-discharge….…………………..……………..…………………….……...18

Supplementary Table 1.Full Inclusion and Exclusion Criteria

A. Inclusion criteria

Subject, or subject’s legally acceptable representative (LAR), has voluntarily signed and dated an informed consent form, approved by an Independent Ethics Committee/Institutional Review Board and provided Health Insurance Portability and Accountability Act (or other applicable privacy regulation) authorization prior to any participation in the study.
Subject (male or female) is ≥ 65 years of age.
Subject recently (within 72 hours) admitted to hospital with a primary diagnosis of heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease.
Subject has a Subjective Global Assessment rating of B or C at screening.
Subject has anticipated length of hospital stay > 3 days and < 12 days and is expected to consume ≥ 2 Tetra Paks®of study product while in hospital
Subject is able to consume foods and beverages orally.
Subject was functionally ambulatory during the 30 days prior to admission.

B. Exclusion criteria

Subject has hypertensive crisis, not stabilized by oral medication and requires intravenous antihypertensive drips.
Subject has diagnosis of diabetes as evidenced by anti-hyperglycemic medications or HbA1c >7%.
Subject has diagnosis of current active cancer or recently (within 6 months)treated cancer other than basal cell or squamous cell carcinoma of the skin or prostate cancer.
Subject has impaired renal function (estimated glomerular filtration rate < 30 mL/min/1.73 m2).
Subject has liver failure in the opinion of the principal investigator or studyphysician, decompensated chronic liver disease (Child-Pugh Score C, test only if subject has history of hepatic disease), active hepatitis B or C receiving treatment, or hepatic encephalopathy.
Subject has active tuberculosis.
Subject has HIV with CD4 count less than 350/mm3 and on stable antiretroviral medication regimen for less than 3 months (per documentation in the medical record).
Subject has a disorder of gastrointestinal tract that, in the opinion of the principal investigator or study physician, would preclude ingestion or absorption of the study product (e.g., gastric bypass, inflammatory bowel disease, celiac disease, short bowel syndrome, acute/chronic pancreatitis, gastrointestinal bleeding or other gastrointestinal disease).
Subject has an autoimmune disorder requiring immunosuppressor treatment or a condition that is not compatible with this study in the opinion of the principal investigator or study physician.
Subject is intubated, receiving tube feeding or parenteral feeding.
Subject has severe dementia or delirium, brain metastases, eating disorder, history of significant neurological or psychiatric disorder, alcoholism, substance abuse or other conditions that may interfere with study product consumption or compliance with study protocol procedures in the opinion of the principal investigator or study physician.
Subject has any other condition or event considered exclusionary by the sponsor, principal investigator or study physician.
Subject has stated an allergy or intolerance to any of the ingredients in the study products.
Subject has a body mass index of ≥ 40 kg/m2.
Subject is a resident in a nursing home or other residential facility (subjects who are previously in short term rehabilitation facilities are eligible for the study).
Subject is a participant in another clinical study that has not been approved as a concomitant study by Abbott Nutrition.
Subject has planned surgery during the course of the study.

Supplementary Table 2.Nutritional Composition per Serving of HP-HMB and Placebo Oral Supplementsa

Nutritional component / Unit / Value
HP-HMB
(vanilla flavor) / HP-HMB
(chocolate flavor) / Placebo
Volume / mL / 237 / 237 / 237
Energy / Kcal / 350 / 350 / 48
Protein (mixture of milk protein concentrate, soy protein isolate, sodium caseinate, and whey protein concentrate) / g / 20 / 20 / —
Fat (mixture of corn oil and canola oil) / g / 11 / 11 / —
Linoleic acid / g / 3 / 3 / —
Carbohydrate / g / 44 / 45 / 12
Fructo-oligosaccharide / g / 3 / 2 / —
Sugar / g / 20 / 20 / 12
Ca-HMB (beta-hydroxy-beta-methylbutyrate) / g / 1.5 / 1.5 / —
Vitamins
Vitamin A (palmitate) / IU / 1000 / 1000 / —
Vitamin D3 / IU / 160 / 160 / —
Vitamin E / IU / 30 / 30 / —
Vitamin K1 / mcg / 20 / 20 / —
Vitamin C / mg / 60 / 60 / 10
Folic acid / mcg / 200 / 200 / —
Vitamin B1 / mg / 0.38 / 0.38 / —
Vitamin B2 / mg / 0.43 / 0.43 / —
Vitamin B6 / mg / 0.5 / 0.5 / —
Vitamin B12 / mcg / 3 / 3 / —
Niacin / mg / 5 / 5 / —
Pantothenate / mg / 2.5 / 2.5 / —
Biotin / mcg / 75 / 75 / —
L-carnitine / mg / 43 / 43 / —
Choline / mg / 83 / 83 / —
Minerals / —
Sodium / mg / 240 / 240 / —
Potassium / mg / 560 / 630 / —
Chloride / mg / 150 / 150 / —
Calcium / mg / 500 / 500 / —
Phosphorus / mg / 350 / 350 / —
Magnesium / mg / 100 / 100 / —
Iron / mg / 4.5 / 4.5 / —
Zinc / mg / 15 / 15 / —
Manganese / mg / 0.50 / 0.75 / —
Copper / mg / 0.50 / 0.75 / —
Iodine / mcg / 25 / 25 / —
Selenium / mcg / 30 / 25 / —
Chromium / mcg / 30 / 40 / —
Molybdenum / mcg / 30 / 30 / —

aSubjects were to take 2 servings per day.

HP-HMB, high-protein beta-hydroxy-beta-methylbutyrate.

Supplementary Table 3.Listing of All Efficacy Variables

Primary efficacy variable

Incidence of non-elective readmission or death at 90 days post-discharge

Secondary efficacy variables

Incidence of non-elective readmission or death at 30 and 60 days post-discharge
Length of hospitalization for initial admission
Activities of daily living, assessed using the Katz Index of Independence in Activities of Daily Living (Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the Index of ADL. Gerontologist. 1970;10:20-30)

Supportive variables

Post-discharge dietary intake measures at 30, 60 and 90 days post-discharge

–Protein intake per meal and daily total

–Energy intake per meal and daily total

Study product intake
Body weight (absolute and percent change) and BMI at hospital discharge, 30, 60 and 90 days post-discharge

Distribution of nutritional status (Subjective Global Assessment) at hospital discharge, and 30, 60 and 90 days post-discharge
Blood values at baseline, 30 and 60 days post-discharge (total protein, albumin, prealbumin, hemoglobin, hematocrit, red blood cells, white blood cells with differentials (percent and absolute values for lymphocytes, monocytes, neutrophils, eosinophils, basophils), platelet count, glucose, blood urea nitrogen, creatinine, uric acid, sodium, potassium, chloride, calcium, magnesium, phosphorus, total cholesterol, triglycerides, serum 25-hydroxyvitamin D, parathyroid hormone, and C-reactive protein)

Exploratory variables

Quality of Life at discharge and 30, 60 and 90 days post-discharge

–5-Dimension EuroQol (EQ-5D)

–36-Item Short Form Health Survey (SF-36)

Mini-Mental State Exam at discharge and 30, 60 and 90 days post-discharge
Grip strength (absolute and percent change) at discharge, 30, 60, 90 days post discharge
Care Transitions Measure® at 15 days post-discharge
Factors for health economic outcomes

–Discharge destination/service

–Post-discharge morbid events (e.g., number of falls, consequences of falls, respiratory infections, pneumonia, urinary tract infections, influenza, pressure ulcers)

–Post-discharge medical care consumption (general practitioner visits, home care, nursing care, specialist visits, urgent care visits, emergency ward visits, and rehabilitation visits)

Supplementary Table 4.Assessment Measures and Statistical Models

Subjective Global Assessment (SGA):The SGA is a widely used and practical assessment measure of malnutrition that provides classification of malnutrition based on both medical history and clinician observations and is recommended by the American Society of Parenteral and Enteral Nutrition (Mueller C, Compher C, Ellen DM. A.S.P.E.N. clinical guidelines: Nutrition screening, assessment, and intervention in adults. JPEN J Parenter Enteral Nutr. 2011;35(1):16-24). Based on defined items that capture relevant medical history (weight change, dietary changes, gastrointestinal symptoms, and functional capacity) and physical examination (fat, muscle, edema, and ascites), patients are classified into one of three categories of nutrition status: well-nourished (A), mildly to moderately malnourished (B), or severely malnourished (C).

Serum 25-hydroxyvitamin D: Blood samples were collected using Gold top SST tubes at baseline and days 30 and 60. Serum samples were aliquoted and transferred to a central laboratory (ICON Central Laboratories, Farmingdale, New York) for analyses. Serum 25-hydroxyvitamin D was measured by chemiluminescence immunoassay (CLIA) using a Diasorin LIAISON analyzer.

Logistic and Cox regression models: For the primary composite endpoint and the secondary endpoints of 30 and 60 days, confirmatory models included factors of study group, gender, study group by gender interaction, screening SGA, study group by screening SGA interaction, admission diagnosis, study group by admission diagnosis interaction, and Charlson Comorbidity Index.

Negative binomial regression: For length of stay, the model included the same factors as in the logistic regression model.

Generalized estimating equations: The models used for evaluation of Subjective Global Assessment included factors of study group, visit, study group by visit interaction, gender, screening SGA, admission diagnosis, and covariates Charlson comorbidity index, age, and baseline value.

Analysis of covariance: Models for evaluating changes from discharge at 30, 60 and 90 days for weight included factors of study group, center, gender, study group by gender interaction, screening SGA, study group by screening SGA interaction, admission diagnosis, study group by admission diagnosis interaction, and covariates of Charlson comorbidity index, age, and baseline value.

Number needed to treat (NNT): The NNT, the number of patients who would be need to be treated to prevent one death, was defined as the reciprocal of the difference in proportion of deaths in placebo and proportion of deaths in HP-HMB. The Newcombe-Wilson hybrid score method was used to estimate the 95% confidence interval for the NNT (Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods.Stat Med. 1998;17:873–90[erratum in: Stat Med. 1999;18:1293]).

Statistical package:All analyses were conducted using SAS version 9.2(SAS Institute, Cary, North Carolina, USA).

Supplementary Table 5.Study Product Intake Based on Paks per Daya

Adherence / Placebo / HP-HMB
In hospital
n / 309 / 311
Intake, Paks/day, mean (SE) / 1.45 (0.03) / 1.46 (0.03)
Percent of expected intake, mean (SE) / 72.68 (1.49) / 73.15 (1.45)
Discharge through 10 days post-discharge (or readmission/death)
n / 227 / 242
Intake, Paks/day, mean (SE) / 1.69 (0.03) / 1.65 (0.03
Percent of expected intake,mean (SE) / 84.70 (1.56) / 82.44 (1.59)
Discharge through 30 days post-discharge (or readmission/death)
n / 231 / 243
Intake, Paks/day, mean (SE) / 1.57 (0.04) / 1.54 (0.04)
Percent of expected intake,mean (SE) / 78.36 (1.86) / 76.86 (1.77)

aPatients were encouraged to take 2 Paks per day.

HP-HMB, high-protein beta-hydroxy-beta-methylbutyrate;SE, standard error.

Supplementary Table 6.Cause of Death by Primary Diagnosis for Admission

Cause of Death / Total / Heart failure / Acute MI / Pneumonia / COPD
Placebo
(n=309) / HP-HMB(n=313) / Placebo
(n=78) / HP-HMB(n=79) / Placebo
(n=25) / HP-HMB(n=30) / Placebo
(n=100) / HP-HMB
(n =95) / Placebo
(n=105) / HP-HMB (n=109)
Cardiorespiratory failure / 8 / 6 / 1 / 2 / 3 / 3 / 4 / 1
Chronic obstructive pulmonary disease / 6 / 2 / 1 / 1 / 1 / 4 / 1
Cancer / 1 / 2 / 1 / 1 / 1
Dementia / 1 / 1
Failure to thrive / 1 / 1
Intraventricular hemorrhage / 1 / 1
Ischemic cardiomyopathy / 1 / 1
Ischemic stroke / 1 / 1
Multiorgan failure / 1 / 1
Parkinson’s disease / 1 / 1
Sepsis / 2 / 2
Ventricular tachycardia / 2 / 1 / 1
Unknown / 8 / 1 / 3 / 3 / 1 / 2
Total / 30 / 15 / 7 / 5 / 1 / 1 / 11 / 6 / 11 / 3
Mortality rate / 9.7% / 4.8% / 9.0% / 6.3% / 4.0% / 3.3% / 11.0% / 6.3% / 10.5% / 2.8%

COPD,chronic obstructive pulmonary disease; HP-HMB, high-protein beta-hydroxy-beta-methylbutyrate; MI, myocardial infarction.

Supplementary Table 7.Study Investigators

All study sites were located in the United States including the Commonwealth of Puerto Rico. The following investigators enrolled at least one patient in the study.

Alabama: Walter Haught, Heart Center Research, LLC, Huntsville; WilliamSargeant, HealthScan Research, Montgomery
Arizona: Karen Stark, Scottsdate Healthcare, Scottsdale
Arkansas: Eric Bravo, Baptist Health Center for Clinical Research, Little Rock
California: Kenneth Deck, South Orange County Surgical Medical Group, Laguna Hills;Kang Hsu, Pulmonary Consultant & Primary Physicians Medical Group, Orange; Paul Manos, eSTudy Site, Oceanside; Lyn Raible, Novo Research,Modesto; Brad Spellberg, Los Angeles Biomedical Research Institution at Harbor-UCLA Medical Center,Torrance; Steven Stoltz, UCSF Fresno, Fresno
Connecticut: Anne Kenny UConn Health Center, Farmington
Florida: Chadi Alkhalil, Watson Clinic, Lakeland; Arden Bradley, Advanced Clinical Research Group, Stuart;Thomas Buford, University of Florida, Gainesville; William David, The Cardiovascular Center, P.A., Orlando; Sohail Khan, Panama Clinical Research Associates, Panama City; Michael Koren, Jacksonville Center for Clinical Research, Jacksonville; Rafael Martinez, Pulmonary and Sleep of Tampa Bay, Brandon; Jaynier Moya, In Vivo Clinical Research, Hialeah; Gary Richmond, Broward Health-Broward General Medical Center, Ft Lauderdale; James Rivenbark, Largo Medical Center, Largo; Neerav Shah, Cardiology Partners Clinical Research Institute, Palm Beach Gardens; Jose Suarez, Regenerate Clinical Trials, Miami; Mat Vasquez, River City Clinical Research, Jacksonville; Debra Weinstein, ZASA Clinical Research, Atlantis
Georgia: Kalai Parthiban, Atlanta Institute for Medical Research, Decatur;Thomas Ziegler, Emory University Hospital, Atlanta; Dawn Smiley, Grady Memorial Hospital, Atlanta; David Subich, Columbus Regional Research Institute, Columbus
Illinois: Richard Wunderink, Northwestern University, Chicago

Iowa: Kimberly Staffey, University of Iowa Hospitals and Clinics, Iowa City
Kentucky: Samuel Adams, Kentucky Heart Foundation, Lexington; Donald Gregory, Research Concierge, LLC, Hartford; Firas Koura, Kentucky Lung Clinic, Hazard

Louisiana: Pat Bass, Louisiana State University Health Science Center, Shreveport
Maine: Joan Pellegrini, Eastern Maine Medical Center, Bangor; Robert Weiss, Maine Research Associates, Auburn
Maryland: Jurga Adomaityte, Johns Hopkins University Hospital, Baltimore;John Wang, MedStar Health Research Institute - MedStar Union Memorial Hospital, Baltimore
Massachusetts: Howard Smithline, Baystate Medical Center, Springfield
Michigan: Thomas Blok, Bronson Healthcare Group, Kalamazoo;Phillip Green, eStudySite, La Mesa, Kalamazoo; Samer Kazziha, Crittenton Hospital Medical Center, Rochester Hills; Matthew Sims, William Beaumont Hospital, Royal Oak
Minnesota: Carmelo Panetta, HealthEast St Joseph's Hospital, St. Paul
Mississippi: David Headley, Port Gibson
Missouri: Farhaan Ahmad (Morton),St Anthony's Medical Center St. Louis

Nebraska: Jeffrey Carstens, Alegent Creighton Health Heart & Vascular Specialists, Omaha; Joan Eckerson, Creighton University, Omaha
Nevada: Heidi Kabler, eStudySite, Las Vegas; Anurag Mehta, VA Sierra Nevada Health Care System, Reno
New Jersey: Deborah Goss, Hackensack University Medical Center, Hackensack; Richard Perlman, Associated Cardiovascular Consultants of Lourdes, Voorhees
New York: John Fudyma, Erie County Medical Center, Buffalo
North Carolina: Denise Houston, Wake Forest University Health Sciences, Winston-Salem; Hossam Kandil/Laura Matarese, East Carolina University,Greenville; Christina McQuiston, Mission Hospital, Asheville; Lars Runquist, PMG Research of Charleston, Winston-Salem

Ohio: Ian Baird, Remington-Davis, Columbus; Robert Keyes, The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati; ElizabethSeeholzer, MetroHealth Medical Center, Cleveland
Pennsylvania: Roddy Canosa, Physician Specialists of Northern Lancaster County Medical Group, Ephrata;Howard Eisen, Drexel University College of Medicine, Philadelphia; Steven Guidera, Doylestown Hospital, Doylestown

South Carolina: Eric Matheson, Medical University of South Carolina, Charleston
South Dakota: Timothy Donelan, Sanford Clinic Family Medicine, Sioux Falls
Tennessee: Heidi Silver, VanderbiltUniversityMedicalCenter,Nashville

Texas: Nicolaas Deutz, Texas A&M University, College Station; Ahtaram Khan, Advanced Clinical Research Associates, Plano;Jose Perez, South Texas Cardiovascular Consultants, San Antonio
Virginia: Soheir Boshra, Carilion Medical Center Geriatrics, Roanoke; ThomasMartin, Salem VA Medical Center, Salem
Washington: Kevin Kavanaugh, Kootenai Heart Clinics, Spokane
Wisconsin: Dina Goytia-Leos, Sonterra Clinical Research, Middleton

Puerto Rico: Edgardo Cartagena, San Juan Bautista School of Medicine, Caguas; Raul Garcia-Rinaldi, Western Cardiovascular Surgery of Puerto Rico, Mayaguez; WilliamRodriguez, VA Caribbean Healthcare System, San Juan; Jose Vazquez-Tanus, Research and Cardiovascular Corp., Ponce

Supplementary Figure 1.Study product intake (adherence) until first readmission or death.

HP-HMB, high-protein beta-hydroxy-beta-methylbutyrate.

Supplementary Figure 2.Composite and component endpoints at Day 30 and Day 60 post-discharge.

HP-HMB, high-protein beta-hydroxy-beta-methylbutyrate.