Readmission and mortality in malnourished, older, hospitalized adults treated

with a specialized oral nutrition supplement: a randomized clinical trial

Supplementary Material

Contents

Supplementary Table 1 — Full Inclusion and Exclusion Criteria………………….....2

Supplementary Table 2 — Nutritional Composition of HP-HMB and Placebo Oral

Supplements…...….……….……………………………..……….…..……….....……….5

Supplementary Table 3 — Listing of All Efficacy Variables.…………….…….……....7

Supplementary Table 4 — Assessment Measures and Statistical Models.……..….9

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

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

Supplementary Table 7 — Study Investigators…..…..………..……………....…..…..14

Supplementary Figure 1 — Study Product Intake (Adherence) Until First

Readmission or Death………..………..…………………………………..……….......17

Supplementary Figure 2 — Composite and Component Endpoints at Day 30 and

Day 60 Post-discharge….…………………..……………..…………………….……...18

1

Supplementary Table 1. Full Inclusion and Exclusion Criteria

A. Inclusion criteria

1. 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.

2. Subject (male or female) is ≥ 65 years of age.

3. Subject recently (within 72 hours) admitted to hospital with a primary diagnosis of

heart failure, acute myocardial infarction, pneumonia, or chronic obstructive

pulmonary disease.

4. Subject has a Subjective Global Assessment rating of B or C at screening.

5. 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

6. Subject is able to consume foods and beverages orally.

7. Subject was functionally ambulatory during the 30 days prior to admission.

B. Exclusion criteria

1. Subject has hypertensive crisis, not stabilized by oral medication and requires

intravenous antihypertensive drips.

2. Subject has diagnosis of diabetes as evidenced by anti-hyperglycemic

medications or HbA1c >7%.

2

3. 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.

4. Subject has impaired renal function (estimated glomerular filtration rate < 30

mL/min/1.73 m2).

5. Subject has liver failure in the opinion of the principal investigator or study

physician, 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.

6. Subject has active tuberculosis.

7. 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).

8. 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).

9. 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.

10.Subject is intubated, receiving tube feeding or parenteral feeding.

3

11.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.

12.Subject has any other condition or event considered exclusionary by the sponsor,

principal investigator or study physician.

13.Subject has stated an allergy or intolerance to any of the ingredients in the study

products.

14.Subject has a body mass index of ≥ 40 kg/m2.

15.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).

16.Subject is a participant in another clinical study that has not been approved as a

concomitant study by Abbott Nutrition.

17.Subject has planned surgery during the course of the study.

4

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

Oral Supplementsa

Nutritional component Unit ValueHP-HMB(vanilla flavor)

HP-HMB(chocolate flavor)

Placebo

Volume mL 237 237 237Energy Kcal 350 350 48Protein (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 12Fructo-oligosaccharide g 3 2 —Sugar g 20 20 12Ca-HMB (beta-hydroxy-beta-methylbutyrate)

g 1.5 1.5 —

VitaminsVitamin 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 10Folic 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 —

5

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.

6

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

7

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)

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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

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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

10

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).

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

 Adherence Placebo HP-HMBIn hospital

n 309 311Intake, 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 242Intake, Paks/day, mean (SE) 1.69 (0.03) 1.65 (0.03Percent of expected intake, mean (SE) 84.70 (1.56) 82.44 (1.59)

Discharge through 30 days post-discharge (or readmission/death)

n 231 243Intake, 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.

12

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

Cause of Death Total Heart failure Acute MI Pneumonia COPDPlacebo(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 1Dementia 1 1Failure to thrive 1 1Intraventricular hemorrhage

1 1

Ischemic cardiomyopathy

1 1

Ischemic stroke 1 1Multiorgan failure 1 1Parkinson’s disease 1 1Sepsis 2 2Ventricular tachycardia

2 1 1

Unknown 8 1 3 3 1 2Total 30 15 7 5 1 1 11 6 11 3Mortality 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.

13

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; William Sargeant,

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

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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; Elizabeth

Seeholzer, MetroHealth Medical Center, Cleveland

Pennsylvania: Roddy Canosa, Physician Specialists of Northern Lancaster County

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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, Vanderbilt University Medical Center, 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; Thomas Martin,

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; William

Rodriguez, VA Caribbean Healthcare System, San Juan; Jose Vazquez-Tanus,

Research and Cardiovascular Corp., Ponce

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

death.

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

17

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

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

18