Food as Medicine: Providing Medically Appropriate Meals to Patients After Discharge for Congestive Heart Failure Exacerbation
Phase: NA
Conditions: Heart Failure
Sponsor: University of California, San Francisco

 
 
 
 
 
 
 
 
 
 
Cardiac Recovery Through Dietary Support (CaRDS) 
 
PROTOCOL AND ANALYSIS PLAN 
 
Version 2 
 
10/10/21 
 
 
NCT: 03759925   Unique Protocol ID: 16-20742 
 
 
 
Principal Investigators: 
 
Rita Ngyen, MD 
Kartika Palar, PhD 
 
 

 
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 CaRDS Statistical Analysis Plan (May 2021) Contents  
Section 1: Administrative Information ......................................................................................... 2  
1) 
Title and trial registration .............................................................................................. 2  
2) 
Roles and responsibilities – names, affiliations, and roles of SAP contributors ............ 2  
Section 2: Introduction ............................................................................................................... 3  
3) 
Background and rationale ............................................................................................ 3  
4) 
Objectives .................................................................................................................... 3  
Section 3: Study Methods .......................................................................................................... 4  
    5)       Trial design .................................................................................................................. 4  
6) 
Randomization ............................................................................................................. 4  
7) 
Sample size ................................................................................................................. 4  
8) 
Framework ................................................................................................................... 5  
9) 
Statistical interim analyses and stopping guidance ......................................................5 
10) 
Timing of final analyses ............................................................................................... 5  
11) 
Timing of outcome assessments .................................................................................. 5  
Section 4: Statistical Principles .................................................................................................. 5 
12) 
Level of statistical significance .....................................................................................5 
13) 
Description and rationale for any adjustment for multiplicity.........................................5 
14) 
Confidence intervals .................................................................................................... 5  
15) 
Adherence and protocol deviations .............................................................................. 5 
16) 
Analysis populations ....................................................................................................6  
a.  Intent to treat ................................................................................................................ 6  
b. Adjusted intent to treat - .................................................................................................6.  
c. Per protocol: .................................................................................................................. 6  
d. 
Complete case .............................................................................................................. 6  
Section 5: Trial Population ........................................................................................................ 7   
17) 
Screening .................................................................................................................... 7  
18) 
Eligibility ...................................................................................................................... 7 
19) 
Recruitment ................................................................................................................. 8  
20) 
Withdrawal/follow-up .................................................................................................... 8  
21) 
Baseline patient characteristics .................................................................................... 9  
Section 6: Analysis ..................................................................................................................... 9  
22) 
Outcome definitions ..................................................................................................... 10  
23) 
Analysis methods ........................................................................................................12  
24) 
Missing data................................................................................................................13  
25) 
Additional analyses .....................................................................................................13  
26) 
Harms .........................................................................................................................13  
27) 
 Statistical software – ...................................................................................................14  
28) 
References ................................................................... ...............................................14.  
28) Appendix: .........................................................................................................................17  
 
 
 
 
 

 
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Section 1: Administrative Information  
1) Title and trial registration  
a. Cardiac Recovery through Dietary Support (CaRDS) Study  
b. Trial registration number: ClinicalTrials.gov: NCT03759925,   
c. UCSF Institutional Review Board number: 16-20742   
2) Roles and responsibilities – names, affiliations, and roles of SAP contributors  
a. Rita Nguyen, MD – co-Principal Investigator, for CaRDS study. San Francisco 
Department of Public Health.  
b. Kartika Palar, PhD— co-Princiap Investigator for CaRDS study. University of California, 
San Francisco.   
c. Edward A. Frongillo, Jr., PhD—Senior statistical consultant for CaRDS study. University 
of South Carolina, Columbia.   
d. Hannah Kleiner, MPH—Data manager for CarDS study. University of California, San 
Francisco.  
e. Andrea Pedroza-Tobias, PhDc – - Analyst for CaRDS study  
f. Aron O’Donnell, BS – Clinical Research Coordinator. University of California, San  
Francisco  
g. Cady Smith, BS, MDc – Clnical Research Coordinator. University of California, San 
Francisco  
 

 
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Section 2: Introduction  
3) Background and rationale [from IRB; 2016]  
Food insecurity is linked with increased cardiovascular risk, worse control of diabetes, and 
increased healthcare utilization.1,2 Food insecure seniors 1.75 more likely to report an experience 
of coronary heart disease, and 2.2 more likely to experience limitations in their activities of daily 
living.3 While lower socioeconomic status is known to correlate with increased rates of heart failure 
incidence, morbidity and mortality,4 there are no studies looking at the effects of food insecurity 
on heart failure outcomes. Prior studies5 that focused on improving disparities in heart failure 
outcomes have found that nurse-led case management services have reduced heart failure 
readmissions and improved heart failure outcomes. A few small studies have also found that 
dietitian education improves adherence to a heart failure specific diet and heart failure outcomes.6 
These studies support the hypothesis that heart failure outcomes are psychosocially mediated 
and potentially modifiable by addressing food insecurity.  
Little is known about whether the provision of nutritious food can improve health outcomes. 
Gurvey et al7 demonstrated that providing three meals per day to clients with nutritionist support 
was correlated with reduced average monthly hospitalizations by 50% compared to matched 
controls. Seligman et al. has also found decreased HgbA1c and hospitalizations in patients with 
diabetes that were connected with food bank-based provision of diabetes-appropriate foods.8,9 By 
providing patients a regular supply of healthy food, Seligman, et al. have posited that this not only 
has direct effects on the patients’ diet-sensitive health condition (like diabetes), but also enables 
patients to shift attention from concern for their next meal towards concern for their chronic health 
condition.10 Palar et al. has also demonstrated that the provision of medically appropriate foods 
can increase medication adherence, increase diabetes control, and decrease healthcare  
utilization.11  
Our preliminary findings in the Zuckerberg San Francisco General population have noted 
that of the 60% of adults admitted for heart failure that are housed, about half express 
moderate to high levels of food insecurity. The patients face many challenges 
transitioning back to the community, and challenges with medication access and life 
chaos (unpublished data) have been noted as contributory to heart failure re- admission 
rates. Since food access has been known to improve medication adherence and 
psychosocial stability,12 this suggests that our intervention may have a direct impact on 
heart failure outcomes and health care utilization.  
4) Objectives  
Aim 1: To determine the impact of medically tailored meals, groceries (“the intervention”) and 
nutritional education among patients hospitalized for heart failure exacerbation upon hospital 
discharge on heart failure clinical outcomes. We hypothesize that the intervention will lead to 
improved heart failure quality of life (primary outcome) and reduced hospitalizations and 
emergency department visits, and improved health-related quality of life (secondary outcomes) in 
the intervention arm compared to the control arm.   
Aim 2: To understand the impact of the intervention on intermediate outcomes that may be on 
the path between the intervention and improved heart failure outcomes. We hypothesize that the 

 
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intervention will improve food security, diet quality, depressive symptoms and medication 
adherence.   
Aim 3: Conduct a process evaluation to understand participant experiences in the CaRDS 
intervention, including experiences of improvement (or lack of improvement) in food security and 
health over the course of the intervention, how participants utilized the food support, barriers and 
facilitators to participating in the intervention, and feedback about the intervention to inform future 
implementation and scale-up.   
Section 3: Study Methods  
5) Trial design  
We conducted a pilot randomized controlled trial (RCT) of an intervention providing five months of 
medically tailored meals (tapering down the amount of food each month), paired with nutrition 
education, to patients upon discharge from a safety-net hospital due to congestive heart failure 
(CHF) exacerbation. Participants were randomized to the intervention (n=106) versus control 
(n=86) using a parallel design.   The goal was to test for feasibility and determine the preliminary 
impact of the intervention on heart-failure quality-of-life (primary outcome), and on in hospital 
readmission and emergency department visits (secondary outcomes).  We also set out to determine 
the impact of this intervention on intermediate outcomes important to the health of our population 
(food security, diet, mental health and medication adherence), which may be on the path from the 
intervention towards improved heart failure health outcomes. The control arm continued with usual 
care during the study period and then received the five-month meal program starting the sixth month 
after discharge from the hospital. Participants were followed with full surveys at baseline, 1 month 
and 5 months; brief versions of the survey were administered at 2- and 3-months. In addition, we 
collected medical record data on healthcare utilization outcomes. Alongside the trial, a qualitative 
study and process evaluation was conducted, which included in-depth interviews with study 
participants and survey items added to the end-line survey to translate lessons learned to guide a 
possible scale-up of the intervention.  
6) Randomization   
Initially, 148 participants were randomized in a 1:1 allocation to the intervention (n=75) and control 
arms (n=73), stratified by food security (zero affirmative answers vs. at least one affirmative 
answers on the USDA 12-question food security screener) and healthcare utilization (<3 vs. >=3 
hospital admissions at ZSFGH), based on a computer-generated assignment. However, early 
withdrawals were observed, which was higher in the intervention (n=27) than in the control arm 
(n=3). Therefore, the randomization of the last 44 participants were allocated in a 2:1 ratio for 
intervention (n=31) relative to control (n=13) arms to compensate for early withdrawals and have 
the final study arms balanced.  
7) Sample size   
Estimates from the literature were used to calculate the sample size needed for this study for the 
outcomes of changes from month 0 to month 5 in our primary outcome, heart failure quality-oflife. 
We assumed that the standard deviations (SD) seen in the current study would be similar to that 
in a similar study conducted in an urban setting in the United States.13 Sample size calculation 
were based assuming 80% power for a two-sided test at alpha of 0.05, and SD of 20.0.  With the 
outcome of change in heart failure quality of life score from baseline to 5 months, considering as 
a minimum clinical difference of 10 points in the heart failure quality of life score, the sample size 

 
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needed was 63 individuals in each arm.  We assumed a retention in the current study of 80%, 
thus the sample size needed at recruitment was at least 158 (n=79 in each arm)  
8) Framework   
The superiority hypothesis testing framework will be used, testing whether exposure to the 
intervention results in better outcomes than exposure to the control standard of care. 
Comparisons will be presented as differences between arms in changes in outcomes from 
baseline to 1 month to capture changes in acute heart failure symptoms and 30-day readmission; 
and from baseline to 5 months of follow-up to capture longer term and potentially sustained 
benefits.  
9) Statistical interim analyses and stopping guidance  
a. Information in interim analyses specifying what interim analyses will be carried out 
and listing time points   
i. None planned    
b. Any planned adjustment of the significance level due to interim analysis  i. No   
c. Details of guidelines for stopping the trial early   
i. None   
  
10) Timing of final analyses  
Final analyses will begin in Fall 2021 upon completion of all field data collection in Fall 2020 and 
completion of all medical record data collection (Summer 2021).   
11) Timing of outcome assessments   
Research staff administered full surveys to both arms at baseline, 1 month, and 5 months. 
Additional brief surveys were collected at months 2 and 3.  Medical record data were collected 
continuously in both arms from 3 months prior to baseline until 9 months after baseline.    
Section 4: Statistical Principles   
12) Level of statistical significance    
95% confidence intervals and exact p-values (or p<0.001) will be reported.  
13) Description and rationale for any adjustment for multiplicity and, if so, detailing how 
the type I error is to be controlled.   
The primary outcomes were established in the protocol, and thus no adjustments will be made for 
multiplicity.  
14) Confidence intervals   
95% confidence intervals will be reported alongside exact p-values.  
15) Adherence and protocol deviations  
a. Definition of exposure to the intervention and how this is assessed including extent of 
exposure:  
i. Receipt of medically tailored food support AND  
ii. Receipt of nutrition counseling and/or education   
b. Description of how adherence to the intervention will be presented.  

 
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Adherence to the intervention will be presented through a narrative summarizing the 
following points:  
i. % of weeks received any food support (out of weeks scheduled to receive food 
support)  
ii. % of food received (out of total food entitlement) (POH data) iii. % of food 
consumed (out of food received) (survey data)  
iv. % of counseling or education sessions received (out of planned sessions) The cut-
off points to decide if the patient is adherent to the intervention will be defined during the 
analysis, based on the participant's exposure to the intervention.  
  
Definition of protocol deviations for the trial. The following protocol deviation occurred during the 
study and corrective actions were developed:  
a. Minor protocol deviation: Participants for study visits were seen outside of the initial 
protocol specified visit window (+/- 1 month).  All efforts were made to reach the 
participants on time, but the participants were not available or were not able to be 
located within the window and therefore they were seen outside of the visit window.  
As a result, the standard operating procedure (SOP) was updated that addresses 
follow up and retention of participants. The SOP outlines that the research assistants 
will make calls and conduct home visits in case a participant misses his or her 
appointment date to ensure that the participants are seen with the appointment 
window period.    
b. Unable to be contacted: 16 intervention participants were randomized but were not 
able to be contacted by POH to start the intervention and were considered as early 
withdrawals. Control participants could not be excluded as “early withdrawals” 
because the next visit would be a month after the baseline. Therefore, researchers 
modified the protocol and made a phone call to the control participants, right after the 
randomization, to simulate the call that the intervention participants had by POH to be 
enrolled in the food and nutrition program. From among control participants called 
right after randomization in the modified protocol, 2 could not be reached and were 
considered early withdrawals.  
The number of participants with major and minor protocol deviations will be summarized 
by study arm.   
  
16) Analysis populations – definition of analysis populations, e.g. intention to treat, per protocol, 
complete case, safety  
a. Intent to treat - The primary analysis will be intent to treat (ITT). The ITT analysis will 
include all participants in both arms who were randomized, completed all baseline 
assessments, and who had at least one follow-up visit.  (see CONSORT).  
b. Adjusted intention to treat analysis. To adjust for early withdrawals, a propensity score for 
receiving the intervention will be developed and used to estimate the probability of each 
participant to receive the intervention. The adjusted ITT analysis will be performed 
adjusting for the propensity score and for baseline covariates that were different between 
arms.   
c. Per protocol - The per protocol analysis will include all participants in the ITT sample with 
baseline and follow-up evaluations and who adhered to the food and nutrition 
intervention. The minimal adherence will be considered as receiving at least 50% of 
weeks food and groceries, and at least 1 visit with the dietitian. This definition may be 

 
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revised depending on the distribution of adherence in the intervention participants.  See 
appendix 1 for details about the food and nutrition education intervention.   
d. Complete case— We will not conduct complete case analyses as we will attempt to use 
all available data from all participants.   
  
Section 5: Trial Population  
17) Screening Data –  
a. Participants were recruited through reviewing patient lists of hospitalizations in 
collaboration with providers in the Family Medicine and Cardiology Departments at San 
Francisco General Hospital. At provider meetings, research staff presented study details 
and eligibility guidelines.   
b. Screening was conducted in two stages, during an initial review of medical charts and at 
a visit with a participant while they were in the hospital prior to discharge. During the 
medical chart screening, potential participants were screened for congestive heart failure 
exacerbation diagnosis during their current hospital admission, age 18 years or older, 
language English or Spanish, less than 6 admissions to ZSFG in the last 12 months, no 
end stage renal disease diagnosis or known plan to initiate dialysis within 6 months, no 
severe aortic stenosis diagnosis, no mention of life expectancy less than 1 year, no 
cognitive impairment, currently housed, discharge plan for patient to discharge home, and 
currently living in San Francisco. Participants who met all criteria then proceeded to the 
in-hospital screening, which included confirming potential participants are housed and 
living in San Francisco, are not receiving more than 7 meal per week of food support, do 
not have any disqualifying allergies to commonly used foods used at POH, have a 
refrigerator and freezer to store food and are able to reheat and prepare meals and 
snacks at home, are able to eat by themselves or have assistance to eat, have cognitive 
capacity to consent to be in a research study, and are not moving in the next 6 months to 
a housing situation that does not meet study eligibility criteria.   
c. A summary will be provided indicating the number of participants screened, number of 
participants eligible, non-eligible and reason for non-eligibility, number of participants 
enrolled, number of participants eligible but not enrolled and reason, and number of 
participants randomized.   
  
18) Eligibility – summary of eligibility criteria  
  
 
  
  
Criteria for inclusion of subjects:  
1. Adults hospitalized at ZSFG with acute decompensated heart failure/congestive heart failure 
exacerbation  
2. Adults with their primary residence within San Francisco  
3. Age: >18 years old  
4. Languages: English or Spanish  
5. Housed at a location where they would be able to securely receive, store and reheat food  
 
  
  
Criteria for exclusion of subjects  
1. Patients with severe or critical aortic stenosis.  
2. Patients with six or more hospital admissions within the last twelve months  
3. Patients who are being discharged to a living facility that provides meals to residents.  

 
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4. Patients who anticipate moving from their current housing situation to one that does not meet our 
inclusion criteria within six months of enrollment.  
5. Patients who are part of meal provision program that provides more than 7 meals a week to the 
patient.  
6. Patients who are unable to feed themselves and do not have adequate support to help them with 
feeding.  
7. Patients with limited physical, cognitive, or behavioral abilities that would interfere with their ability 
to follow-up with a study as determined by their ability to receive the Project Open Hand services 
and follow up with survey interviews  
8. Patients with anticipated life expectancy of less than a year.  
9. Patients who lack capacity to consent to a research study.  
10. Patients currently requiring dialysis or determined to need dialysis in the next 6 months.  
11. Patients with severe allergies to eggs, soy, wheat, nuts, seeds, seed oils, pineapple, raisins, or 
certain vegetables such as onions (allergies are considered on a case-by-case basis in 
consultation with Project Open Hand).  
  
19) Recruitment – A CONSORT flow diagram will be used to summarize the number of participants 
who were:  
a. Assessed for eligibility at screening  
i. Among people with heart failure, 2996 people were assessed for eligibility   
1. 2451 did not meet the inclusion criteria  
2. 127 Discharged before doing the baseline evaluations  
3. 226 were not interested in participating in the study ii. Eligible and 
randomized  
1. 192 were eligible and randomized  
a. 106 allocated in the intervention arm  
i. 27 were early withdrawals  
b. 86 allocated in the control arm   
i. 4 were early withdrawals  
See CONSORT diagram for detail on reasons for ineligibility  
  
20) Withdrawal/follow-up  
Reasons and details of withdrawal and lost to follow up at month 1 and 5 for both arms 
will be reported and summarized in the CONSORT flow diagram.  
a. Level of withdrawal, e.g., from intervention and/or from follow-up  
i. Participants were withdrawn from the study due to unavailability to immediately 
reach out by phone, not meeting the eligibility criteria or deceased immediately 
following the randomization.  
1. 16 (15.1%) of randomized intervention and 2 (2.3%) of randomized control 
participants were unable to be contacted by phone after the baseline 
evaluations.  
2. 6 (5.7%) participants allocated to the intervention and 2 (2.3%) participants 
allocated to the control arm were excluded because did not meet eligibility 
criteria after randomization, and 3 (2.8%) participants in the intervention 
arm were immediately re-hospitalized.   
3. 1 (0.9%) participant in the intervention arm died after being randomized. ii. 
Lost to follow up (LTFU) occurred through loss of contact with study 
participants, moving out of the study area, and death. Intervention 
participants were also considered LTFU if they withdrew consent. Among 

 
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those 
that 
were 
randomized 
and 
contacted 
immediately 
after 
randomization (n=79 in intervention arm, and n=82 in control arm):  
1. At month 1, 75 (94.9%) of intervention participants and 78 (95.1%) of 
control participants were retained from month 0.  
2. At 5 months of follow-up, 60 (75.9%) of intervention participants and 59 
(71.9%) of control participants were retained from month 0.  
b. Timing of withdrawal/LTFU data  
i. 
Intervention participants left the study prior to their first encounter with Project 
Open Hand were considered withdrawn, otherwise they were considered LTFU.    
ii. Control participants that left the study prior the first call from UCSF staff were 
considered withdrawn, otherwise they were considered LTFU.  
iii. Participants that were excluded immediately after randomization were also 
considered early withdrawals.  
c. Reasons and details of how withdrawal/LTFU data will be presented  
i. Withdrawal and LTFU data are presented in the CONSORT diagram, stratified by 
study arm and visit. These data are included to establish lack of bias in screening 
and retention between the two arms. (See appendix 2)  
  
21) Baseline patient characteristics   
We will evaluate several socio-demographic and clinical characteristics at baseline by which we will 
describe our study sample. These are outlined in Table 1 below and a shell table is provided in the 
appendix. We will stratify these characteristics by intervention and control arms and report median 
and the inter-quartile range for continuous variables with skewed data and mean and SD for 
continuous variables with normal distribution. Categorical variables will be presented as numbers and 
percentages. No significance testing will be conducted or reported at baseline per CONSORT 
guidelines.   
Table 1: Baseline characteristics of CaRDS participants  
Socio-demographic  
Age, current gender, race/ethnicity, household size, relationship status, 
educational attainment  
Economic welfare  
Household food insecurity, sources of income, food support sources  
Clinical  
Heart failure quality of life; general health-related quality of life; medication 
inventory; blood pressure   
Nutrition  
Dietary quality; food consumption patterns  
Mental Health  
Depressive symptoms  
Behavioral  
Self-reported medication adherence; alcohol use, drug use  
Healthcare utilization  Recent hospitalizations, ED visits, doctor visits  
  

 
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Section 6: Analysis  
22)  Outcome definitions   
a. Aim 1: Primary Outcomes: Heart failure quality of life: The primary outcome for Aim 1 will 
be heart failure quality of life, which was assessed using the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) at baseline, 1 month and 5 months, among all study participants. 
The Kansas City Cardiomyopathy Questionnaire is a 23-item instrument that quantifies 
physical function, symptoms (frequency, severity and recent change), social function, 
self-efficacy and knowledge, and quality of life. An overall summary score can be derived 
from the physical function, symptom (frequency and severity), social function and quality 
of life domains. A clinical summary score can be obtained from the symptom frequency 
and burden domains and the physical limitation domain. Scores are transformed to a 
range of 0-100, in which higher scores reflect better health status.  
  
For analysis of the primary outcomes, we will compare:  
i.  Change in the overall KCCQ scores from baseline to five months, by study arm.   ii. 
Change in the overall KCCQ scores from baseline to one month, by study arm.   
iii. Change in the KCCQ clinical summary score from baseline to five months, by study 
arm,   
iv. Change in the KCCQ clinical summary score from baseline to one month, by study 
arm,   
v. Change in the overall physical domain KCCQ scores from baseline to five months, 
by study arm.  vi. Change in the overall physical domain KCCQ scores from 
baseline to one month, by study arm.   
  
  
b. Aim 1: Secondary outcomes:   
i. Hospitalization and Emergency Department use: As a secondary Aim 1 outcome, 
self-reported data as well as abstracted medical record data on hospital 
readmission and Emergency Department use were collected. From the data we 
will assess the number of times participants were admitted to the hospital from 
baseline to 1 month and from baseline to five months and the cumulative 
probability of being hospitalized by study arm. The following outcomes will be 
reported:  
1. Admissions to Zuckerberg San Francisco General Hospital from baseline 
to 1 month, as determined by medical records. Number of admissions to 
Zuckerberg San Francisco General Hospital from baseline to 1 month, by 
study arm, adjusting for baseline values (-3 to 0 months).  
2. Admissions to Zuckerberg San Francisco General Hospital from baseline 
to 5 months, as determined by medical records. Number of admissions to 
Zuckerberg San Francisco General Hospital from baseline to 5 months, by 
study arm, adjusting for baseline values (-3 to 0 months).  
3. Admissions to any hospital from baseline to 1 month, as determined by 
ZSFGH medical records and self-report of admission to hospitals other 
than ZSFGH. Number of admissions to any hospital from baseline to 1 
month, by study arm, adjusting for baseline values (-3 to 0 months).  
4. Admissions to any hospital from baseline to 5 month, as determined by 
ZSFGH medical records and self-report of admission to hospitals other 

 
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than ZSFGH. Number of admissions to any hospital from baseline to 5 
months, by study arm, adjusting for baseline values (-3 to 0 months).  
a. Cumulative probability to be admitted to any hospital from baseline 
to 5 months by study arm.   
5. Emergency room utilization at Zuckerberg San Francisco General Hospital 
from baseline to 1 month, as determined by medical records. Number of 
admissions to the emergency room at Zuckerberg San Francisco General 
Hospital from baseline to 1 month, by study arm, adjusting for baseline 
values (-3 to 0 months).  
6. Emergency room utilization at Zuckerberg San Francisco General Hospital 
from baseline to 5 months, as determined by medical records. Number of 
admissions to the emergency room at Zuckerberg San Francisco General 
Hospital from baseline to 5 months, by study arm, adjusting for baseline 
values (-3 to 0 months).  
7. Emergency room utilization at any hospital from baseline to 1 month, as 
determined by ZSFGH medical records and self-report of emergency room 
utilization at hospitals other than ZSFGH. Number of admissions to any 
emergency room from baseline to 1 month, by study arm, adjusting for 
baseline values (-3 to 0 months).  
8. Emergency room utilization at any hospital from baseline to 5 month, as 
determined by ZSFGH medical records and self-report of emergency room 
utilization at hospitals other than ZSFGH. Number of admissions to any 
emergency room from baseline to 5 months, by study arm, adjusting for 
baseline values (-3 to 0 months).  
  
ii. 
Overall health-related quality of life.  Self-reported quality of life using the 4-item 
Healthy Days Core Module of the CDC's Health-Related Quality of Life survey 
which asks a general assessment of health on a 5-point Likert scale as well as 3 
questions quantifying the number of days in the past 30 days participants felt their 
health was not good.  
c. Aim 2 Outcomes. The primary intermediate outcomes are changes between baseline, 1 
month and 5 months in food security, diet quality, depressive symptoms, and medication 
adherence.  
i. Food Security: We measured food security status using the 10-item adult version of 
the USDA Household Food Security Survey Module (HFSSM) Access Scale 
(HFIAS). This scale has been validated in Spanish and English in the US and is 
the reference measure for food security in the US [citations]. The ten-item 
questionnaire covers domains of worry over, sufficiency of, and quality of food 
accessed by the participant’s household. The scores will be analyzed primarily as 
a continuous variable using a sum of all responses with a possible range of 0 to 
18 in households with children, and 0 to 10 in households without children. Higher 
scores are indicative of less food security. We will examine the following outcomes:   
1. Change in food security scores from baseline to 5 months, by study arm.   
2. Change in food security scores from baseline to 1 month, by study arm.  ii. Change in 
dietary patterns: Food consumption was collected using food frequency questionnaire that assess 
the frequency of intake of 32 food items in the prior month. A change in the consumption 
(servings/day) of food groups from baseline to one month, and from baseline to five months will be 
assessed. The food groups to evaluate are food high in: Unsaturated Fat (nuts), Saturated Fat, 
Sodium, Added sugars, Fruits, Vegetables (fresh), Vegetables (canned), Animal-based Protein, 
Plants-based Protein, Dairy, and Carbs/Starch.    

 
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iii. Medication adherence. A Single-Item Rating Visual Analogue Scale (range 0-100) 
for medication adherence will estimate the percentage of medications taken in the 
past month and is reliable and valid, including in low-literacy populations. A higher 
value indicates higher adherence. The change in medication adherence 
(percentage points) from baseline to one month, and from baseline to five months 
between intervention and control arms will be reported.   
iv. Depressive symptoms.  Symptoms corresponding to the Diagnostic and Statistical 
Manual of Mental Disorders will be measured using the 9-item Patient Health 
Questionnaire (PHQ-9), a reliable and valid measure of symptom severity. The 
PHQ-9 score ranges from 0 to 27, with higher scores indicating higher levels of 
depression. The change in PHQ-9 scores from baseline to one month, and from 
baseline to five months among by study arms will be reported.   
  
d. Other outcomes.  
i. Sustained health benefits: To assess whether any improvements 
outcomes were sustained, researchers will evaluate the hospitalization 
and emergency department visits, four months after the intervention ended 
(at 9 months).   
1. Admissions to Zuckerberg San Francisco General Hospital from baseline 
to  9 months, as determined by medical records. Number of admissions to 
Zuckerberg San Francisco General Hospital from baseline to 9 months, by 
study arm, adjusting for baseline values (-3 to 0 months).  
2. Emergency room utilization at Zuckerberg San Francisco General Hospital 
from baseline to 9 months, as determined by medical records. Number of 
admissions to the emergency room at Zuckerberg San Francisco General 
Hospital from baseline to 9 months, by study arm, adjusting for baseline 
values (-3 to 0 months).  
ii. Process outcomes 24) 
23) Analysis methods:   
a. Preliminary/Descriptive analyses. Frequency tables for all variables and 
measures of central tendency and variability for continuous variables will 
characterize the sample and be stratified by randomization arm to check for non-
equivalence. If the two arms differ at baseline on any covariates, propensity 
scores approach will be used to obtain the desired marginal effect estimates 
under the counterfactual assumption of balanced arm.   
  
25) Analysis methods to be used and how the treatment effects will be presented:   
a. Aim 1, Hypothesis 1.  The intervention will lead to improved heart failure quality-of-life 
(primary outcome) and reduced acute care utilization (secondary outcomes) in the 
intervention arm compared to the control arm. Intent-to-treat analyses will assess whether 
the intervention will result in improved changes in primary and secondary outcomes with 
mixed effects models. These mixed models are equivalent to repeated measures models. 
Study arm (intervention or control), visits (baseline, month 1 and month 5), and the 
interactions between arms and visits will be the fixed effects and individuals will be 
considered as random effects.   
Alternative analyses will be done using analysis of covariance in which the 5 month (and 
1 month) outcome measures will be regressed on the corresponding baseline outcome 
measures and study arm. Analysis of covariance allows relaxing the assumption that the 

 
October, 2021  
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13  
baseline and follow-up measures have a 1:1 relationship and testing the assumption that 
the relationship between the baseline and follow-up measures are the same.  
Additional analyses will be done to check robustness if the two arms differ at baseline by 
controlling for the propensity score or the covariates that were important in the propensity 
score.   
 For primary and secondary outcomes, Box-Cox transformations will be used to correct 
for skewness if needed.    
To compare the probabilities of hospitalization and emergency room visits by study arm, 
a log-rank test will be performed, and visualized using Kaplan-Meier curves.  
  
b. Aim 2,  Hypothesis,  The intervention will improve food security, reduce healthcare 
utilization, and improve dietary behavior, that in turn will improve mental health (depressive 
symptoms), and medication adherence. Analysis for intermediate outcomes will be 
performed using mixed effects models, as described in Aim 1.   
  
c. Any planned sensitivity analyses for each outcome, where applicable: Not applicable.  
 
Any planned subgroup analyses for each outcome including how subgroups are defined: 
Additional models and statistical interactions (i.e., product terms) will be performed to 
identify characteristics of individuals who most benefitted from the intervention, such as 
biological sex, and food insecurity.   
24) Missing data  
a. The study team employed several strategies to account for and address missing data during 
the CaRDS trial period. To prevent or reduce missing data, data collection was computerized, 
and the questions were obtained through a trained interviewer. The analyst will examine 
patterns of non-response and inspect distributions of mediating and outcome variables to 
identify outlying or unusual values and assess distributional characteristics. Missing data will 
be categorized into: 1) missed individual questions, 2) missing forms, and 3) missed visits.  
b. Missed individual questions: Multiple imputation will be used to address incomplete data 
arising from missing forms. The assumption will be that incomplete data arise from a 
conditionally missing-at random mechanism (MAR. Auxiliary variables will be included to help 
meet the MAR assumption and sensitivity analyses will be conducted with weighted multiple 
imputation to assess the MAR assumption. Information on percent of questions missing and 
imputed will be reported for each variable as appropriate in study manuscripts. Missing items 
from a scale will be imputing using the other items in the scale.    
c. Missed visits: When a participant missed a visit, either home or clinic or both, this was noted 
in the study register.   
  
25)  Additional analyses – None   
26) Harms   
i. Data safety:   
The study team took several proactive strategies to insure the highest levels of data safety. 
First, data were collected on password protected tablets or laptops. Data were collected 
using REDCap and stored on a secure UCSF server. The data was stored in a separate 
folder than other study materials, and only members of the data team had access to this 
data. Lastly, any individual who requests study data was required to sign a data agreement 
which included not sharing the data as well as recommendations for data safety. No 
identifiers have or will be shared with external investigators.   
ii. Details on how adverse events are coded or categorized:  

 
October, 2021  
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14  
Deaths were reported to UCSF by email within 24 hours after the PIs learned of the 
occurrence. Other adverse events were not reported.   
Individuals were provided with information on how to contact the study staff to report 
adverse events associated with study participation.  No adverse events were reported that 
were associated with study participation.    
27) Statistical software  
The following software systems will be used in the analysis of CaRDS data: 1) Stata SE version 14 
[College Station, TX: StataCorp LP]  
  
a. References   
1 
Gundersen C, Ziliak JP. Food Insecurity And Health Outcomes. Health Aff 2015; 34: 
1830–9.  
2 
Golovaty I, Tien PC, Price JC, Sheira L, Seligman H, Weiser SD. Food Insecurity May Be 
an Independent Risk Factor Associated with Nonalcoholic Fatty Liver Disease among 
Low-Income Adults in the United States. J Nutr 2020; 150: 91–8.  
3 
Venci BJ, Lee S-Y. Functional limitation and chronic diseases are associated with food 
insecurity among U.S. adults. Ann Epidemiol 2018; 28: 182–8.  
4 
Khariton Y, Nassif ME, Thomas L, et al. Health Status Disparities by Sex, Race/Ethnicity, 
and Socioeconomic Status in Outpatients With Heart Failure. JACC Hear Fail 2018; 6: 
465–73.  
5 
Davis AM, Vinci LM, Chase AR, Huang ES. Cardiovascular Health Disparities. A 
systematic Review of Health Care interventions. Med Care Rev 2007; 64: 29s-100s.  
6 
Abshire M, Xu J, Baptiste D, et al. Nutritional Interventions in Heart Failure: A Systematic 
Review of the Literature. J Card Fail 2015; 21: 989–99.  
7 
Gurvey J, Rand K, Daugherty S, Dinger C, Schmeling J, Laverty N. Examining Health 
Care Costs Among MANNA Clients and a Comparison Group. J Prim Care Community 
Health 2013; 4: 311–7.  
8 
Seligman HK, Lyles C, Marshall MB, et al. A Pilot Food Bank Intervention Featuring 
Diabetes-Appropriate Food Improved Glycemic Control Among Clients In Three States. 
Health Aff 2015; 34: 1956–63.  
9 
Seligman HK, Smith M, Rosenmoss S, Marshall MB, Waxman E. Comprehensive 
Diabetes Self-Management Support From Food Banks: A Randomized Controlled Trial. 
Am J Public Health 2018; 108: 1227–34.  
10 
Seligman HK, Schillinger D. Hunger and socioeconomic disparities in chronic disease. N 
Engl J Med 2010; 363: 6–9.  

 
October, 2021  
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11 
Palar K, Napoles T, Hufstedler LL, et al. Comprehensive and Medically Appropriate Food 
Support Is Associated with Improved HIV and Diabetes Health. J Urban Heal 2017; 94: 
87–99.  
12 
Weiser SD, Sheira LA, Palar K, et al. Mechanisms from Food Insecurity to Worse HIV 
Treatment Outcomes in US Women Living with HIV. AIDS Patient Care STDS 2020; 34: 
425–35.  
13 
Hummel SL, Karmally W, Gillespie BW, et al. Home-Delivered Meals Postdischarge From 
Heart Failure Hospitalization. Circ Hear Fail 2018; 11. 
DOI:10.1161/CIRCHEARTFAILURE.117.004886.  
  
 
 

 
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Signature Page  
  
Declaration    
   
I have reviewed and agree to the Statistical Analysis Pan as presented in this document.   
 
  
 
 
       
__________________________________  
 
_March 23, 2022___   
Rita Ngyen, Principal Investigator                                                       Date   
 
 
October 4, 2021 
 
   
_____________ _____   
 
Kartika Palar, Principal Investigator    
   
   
Date    
  
   
October 3, 2021 
_______________________________                                          ____________ ______   
 
Edward A. Frongillo, Senior Statistician    
   
   
   
Date      
   
  
 
 
 
   
_______________________________   

 
October, 2021  
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29) Appendix:   
Appendix 1: Description of the intervention components  
i. Medically tailored meals and groceries:   
The five-month intervention followed a tapered model: participants received 100% daily nutrition 
during the first and second months following discharge from the hospital, 66% daily nutrition 
during the third month, and 33% daily nutrition during the fourth and fifth months. The intervention 
was designed to provide easy-to-prepare food during the first 30 days post-discharge and to 
gradually incorporate items requiring more preparation over the course of the study period. All 
food was delivered directly to participants’ homes, unless they requested pick-up instead. The 
tapered medically-tailored meal (MTM) plan is summarized in Figure A1.1 and described below:  
a. Month 1 (30 days, twice weekly deliveries): participants received two frozen medically 
tailored meals per day and supplies for daily breakfasts, including items such as milk, oats, 
cereal, yogurt, and fruit.  
b. Month 2 (30 days, twice weekly deliveries): participants received one frozen medically 
tailored meal per day; supplies for daily breakfasts, as described above; and groceries 
equivalent to one meal per day. Each grocery bag contained 2 protein choices, ½ dozen 
eggs, 2 dairy choices, 6 raw produce options, 2 bean options, and 3 grain options.  
c. Month 3 (30 days, one weekly delivery): participants received one frozen medically 
tailored meal per day and groceries equivalent to one meal per day, as described above.  
d. Month 4 (30 days, one weekly delivery): participants made the choice to receive either 
one frozen medically-tailored meal per day or groceries equivalent to one meal per day, 
as described above.  
e. Month 5 (30 days, one weekly delivery): participants received groceries equivalent to one 
meal per day, as described above.  
  
Figure A1.1 - Visual Overview of Tapered MTM Intervention  
Month 1  
Month 2  
Month 3  
Month 4  
Month 5  
  
Daily breakfast 
supplies  
  
  
14 frozen 
meals/wk  
  
Daily breakfast 
supplies  
  
Groceries   
(7 meals/wk)  
  
  
Groceries   
(7 meals/wk)  
   
7 frozen 
meals/wk   
  
  
  
   
Groceries   
(7 meals/wk) 
OR  
  
  
7 frozen 
meals/wk   
  
  
  
  
Groceries   
(7 meals/wk)  

 
October, 2021  
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18  
7 frozen 
meals/wk   
ii. Nutrition education: Participants in the intervention arm received monthly nutrition education and 
counseling with a Registered Dietician (RD). These sessions occurred at a location of participants' 
choosing (presumably home) for the initial and fifth encounters and over the phone for sessions during 
the second, third, and fourth months of the study period. During their assessments, RDs collected the 
following information: three-day food log, weight as reported by participant, quality of life questions, 
heart failure symptom control questions, and utilization of food resources. The five-month curriculum 
for RD visits is summarized below in Table A1.1.  
  
Table A1.1 - Overview of RD Nutrition Education Visits   
  
  
Visit #1  
Visit #2  
Visit #3  
Visit #4  
Visit #5  
Time point:  
Within 14 
days post- 
discharge 
from hospital  
Between 30- 
60 days 
postdischarge 
Between 60- 
90 days 
postdischarge   
Between 90- 
120 days 
postdischarge  
Between  
120-150 days 
postdischarge 
Location:  
Participant’s 
Home   
(or phone if 
preferred/ 
during  
COVID-19)  
Phone  
Phone  
Phone  
Participant’s 
Home   
(or phone if 
preferred/ 
during  
COVID-19)  
Visit Goals:  Instruct on 
how to keep 
a food log 
Review food 
plan for 
phases 1, 2, 
and 3 Select 
preferences 
for delivered 
grocery 
shop 
Review  
nutrition 
for 
heart failure  
Check 
homework: 
review food 
log  
DASH Diet  
Meal pattern 
Instruct on  
fluid 
restriction + 
teach volume 
concepts 
Food  
Referral  
Chart  
Follow up on 
food referral 
access- did 
they connect? 
Low Sodium  
diet and label 
reading  
Navigate Eat 
Fresh 
(if 
internet 
access)  or 
page 60, 61,  
62 Recipe 
reading and 
use Provide 
written 
instruction 
for cooking 
and recipes  
Shopping  
Skills 
Meal 
planning 
Cooking  
skills  

 
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19  
Materials/  
Recipes  
Covered:  
Introduce 
education 
materials to 
be used 
over next 
visits: - 
Tenderloin  
Cooking  
School Book 
- Folder with 
handouts  
Kitchen  
Basics- page  
10  
Spice Not  
Salt- page 34 
Souped-up 
soup- page 13  
ToasterRoasted 
Vegetables- 
page 41  
Tuna salad 
with pears- 
page 36 Red 
Beans &  
Rice- page  
37  
Southwest 
based 
potatoes- 
page 44  
Homework:  3 day food 
log  
Try one new 
recipe from 
cookbook  
Try one new 
recipe from 
cookbook  
Try one new 
recipe from 
cookbook  
  
  
  

June 10, 2020 
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18 
CaRDS RCT – CONSORT Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility (n=2996)  
Excluded (n=2804) 
¨   Not meeting inclusion criteria (n=2451) 
¨   Discharged (n=127) 
¨   Not interested (n=226) 
1-Month Visit 
¨ 75 retained at 1-month 
¨ 64 participants completed 1-
month visit 
¨ 4 lost to follow up 
Allocated to intervention (n=106) 
¨ 27 early withdrawals 
¨ 79 (75%) participants enrolled  
 
1-Month Visit 
¨ 78 retained at 1-month 
¨ 62 participants completed 1-
month visit 
¨ 4 lost to follow up 
Allocated to control (n=86) 
¨ 4 early withdrawals 
¨ 82 (97%) participants enrolled 
 
Allocation 
Follow-Up 
Randomized (n= 192) 
Enrollment 
Reasons for early withdrawal 
¨ 16 unable to be contacted 
¨ 3 discharged to a facility 
¨ 3 immediately re-hospitalized 
¨ 1 unhoused 
¨ 1 diagnosed with severe subaortic 
stenosis 
¨ 1 insufficient cognitive capacity 
¨ 1 withdrew consent 
¨ 1 died immediately after 
randomized 
Reasons for early withdrawal 
¨ 2 unable to be contacted 
¨ 1 discharged to a facility 
¨ 1 unhoused 
Reason lost to follow up after 
baseline 
¨ 4 died 
 
5-Month Visit 
¨ 60 participants completed 5-
month visit 
¨ 1 participant stopped receiving 
intervention after 1 month, 
completed 5-month visit 
¨ 15 lost to follow up 
 
5-Month Visit 
¨ 59 participants completed 5-
month visit 
¨ 19 lost to follow up 
Reason lost to follow up after 1-
month visit 
¨ 4 died 
¨ 1 moved 
¨ 10 LTFU 
 
Reason lost to follow up after 1-
month visit 
¨ 2 died 
¨ 1 moved 
¨ 16 LTFU 
 
Reason lost to follow up after 
baseline 
¨ 2 requested to stop receiving the 
intervention and then were LTFU 
¨ 2 were LTFU