Clinical trial NCT04767061
Conditions: Heart Failure Heart Failure, Diastolic Heart Failure With Preserved Ejection Fraction Cardiac Failure Heart Disease
Sponsor: Weill Medical College of Cornell University
Start date: 2021-04-01; Completion date: 2023-04-28
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to understand the impact of beta-blockers on physical function in older adults with heart failure. We will achieve this objective by conducting N-of-1 trials. N-of-1 trials are personalized experiments that test different treatment options in an individual patient.

Detailed description:

Arms: arm 1: This arm will follow an ABAB sequence. "A" representing ON beta blockers and "B" representing OFF beta blockers. Subjects in this arm will continue their home dose during the initial A period, they will then crossover into Period 2, where dose reduction will begin until they are off of beta blockers. After Period 2, the subjects have the option to decide if they want to be on or off their beta blocker and proceed with the Follow-Up Phase, or continue to Period 3 if they don't feel ready to make that decision to stay on or go off their beta blocker yet. During Period 3, they will restart beta-blockers, gradually uptitrating until reaching their home dose and finally during Period 4, we will again conduct a dose reduction until off of beta blockers. arm 2: This arm will follow a BABA sequence. "A" representing ON beta blockers and "B" representing OFF of beta blockers. Subjects in this arm will have their previously prescribed beta blocker dose reduced until they are completely off of beta blockers during Period 1. They will then crossover into Period 2, where uptitration will begin until they are back on their previously prescribed dose of beta blockers. After Period 2, the subjects have the option to decide if they want to be on or off their beta blocker and proceed with the Follow-Up Phase, or continue to Period 3 if they don't feel ready to make that decision to stay on or go off their beta blocker yet. During Period 3, we will again conduct a dose reduction, until the subject is off of beta blockers and finally during Period 4, we will uptitrate them back to their home dose of beta blockers.
Interventions: intervention 1: Beta blockers
Intervention descriptions: intervention 1: The intervention is a two-arm crossover withdrawal/ reversal design (On \[A\] vs Off \[B\]) with up to 4 periods, each period lasting up to 6 weeks. During the On period (A), subjects will be on their beta blocker. During the Off period (B), their beta blockers will be down titrated and subsequently discontinued.

Subjects will be randomized into either ABAB or BABA sequences.

Protocol documents:
Prot_SAP_000.pdf: 
` 
Heart Failure with Preserved Ejection Fraction (HFpEF) Program 
 
Heart Failure with Preserved Ejection Fraction (HFpEF) and Cardiac 
Amyloidosis Program 
 
 
 
 
 
 
 
 
Sponsor Name 
New York Community Trust, National Institute on Aging 
NCT number 
NCT04767061 
Official title of study 
Pilot Deprescribing N-of-1 Trials for Beta-blockers in HFpEF 
Document date 
27 December 2022 
 
 


Protocol #12.0 
Version Date: 27Dec2022 
 
2
 
Heart Failure with Preserved Ejection Fraction (HFpEF) Program 
 
Heart Failure with Preserved Ejection Fraction (HFpEF) and Cardiac 
Amyloidosis Program 
 
Pilot Deprescribing N-of-1 Trials for Beta-blockers in HFpEF 
 
 
IRB Protocol #:                                      19-10020922 
Version Date:                                        27Dec2022  
Protocol Version:                                 12.0 
Funding Source(s):                               New York Community Trust 
                                                                 National Institute on Aging 
 
Principal Investigator: 
Parag Goyal, MD, MSc 
1305 York Avenue, 8th Floor, New York, NY 
T: 646-962-7571 
F: 646.962.1602 
Pag9051@med.cornell.edu 
 
Statistician: 
     Samprit Banerjee, PhD, MS 
 
     402 E 67th St, New York, NY  
  
 
                                                         T: 646-962-8014 
 
                                                         Sab2028@med.cornell.edu 
 
 
 


Protocol #12.0 
Version Date: 27Dec2022 
 
3
Statement of Compliance 
 
(1) [The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have completed 
Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any subject is enrolled.  Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented to 
the study.  In addition, all changes to the consent form will be IRB-approved; a determination will 
be made regarding whether a new consent needs to be obtained from subjects who provided 
consent, using a previously approved consent form.] 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional review 
boards. The contents of this document shall not be disclosed to others without written authorization from 
WCM. 
 
 
 
 
 
 
 
_________________________________________________________________ 
Institution Name 
 
 
 
 
 
 
______________________________     ______________________________     ____________________ 
Principal Investigator’s Name                 Principal Investigator’s Signature            Date 
 
 
 
 
 


Protocol #12.0 
Version Date: 27Dec2022 
 
4
List of Abbreviations 
 
6MWT 
ADL 
ADWE 
Six – Minute Walk Test 
Activities of Daily Living 
Adverse Drug Withdrawal Risk 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CPET 
CTCAE 
Cardiopulmonary Exercise Test 
Common Terminology Criteria for Adverse Events 
CTSC 
DM 
Clinical Translational Science Center  
Dose Modification 
DSMB 
Data Safety Monitoring Board 
DSMP 
ECG 
EQ5D-VAS 
Data Safety Monitoring Plan 
Electrocardiogram 
EuroQol Visual Analogue Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
HFpEF 
Heart Failure with Preserved Ejection Fraction 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
ICH 
Informed Consent Form 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
KCCQ-12 
PHI 
Kansas City Cardiomyopathy Questionnaire 12 
Protected Health Information 
PI 
Principal Investigator 
PRO 
PROMIS-SF6A 
PROMIS-29 
Patient Reported Outcomes 
Patient Reported Outcomes Measurement Information System Short Form  
Patient Reported Outcomes Measurement Information System 29 
RCT 
Randomized Clinical Trial 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SPPB 
Short Physical Performance Battery 
SOA 
Schedule of Assessments 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
Weill Cornell Medicine 


Protocol #12.0 
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 5
1. Protocol Summary 
 
Full Title: 
 
 
 
 
Pilot Deprescribing N-of-1 Trials for Beta-blockers in HFpEF    
Short Title:  
 
 
 
N-of-1 for BB in HFpEF  
Clinical Phase:  
 
 
NIH Stage 1 of Behavioral Intervention Development 
Principal Investigator:  
 
Parag Goyal, MD, MSc 
Study Description:  
 
We will determine whether N-of-1 trials, as a pragmatic, patient-centered approach to 
medication optimization that can overcome key barriers of deprescribing, can lead to 
increased subject confidence regarding the decision to continue or discontinue beta-
blockers in older adults with Heart Failure with Preserved Ejection Fraction (HFpEF).  
Sample Size: 
 
N=16 
Enrollment: 
 
This study will enroll 16 subjects.  
Study Population: 
 
Subjects will be recruited from the HFpEF Program, as well as from the Cardiology, Heart 
Failure, Geriatrics and/or Internal Medicine clinics at Weill Cornell Medicine. 
Enrollment Period: 
 
30 Months 
Study Design: 
 
This is an unblinded NIH Stage I of Behavioral Intervention Development trial, using a 
Crossover intervention model. We will enroll 16 subjects and we will conduct four rounds 
of N-of-1 trials with four subjects each. We will use a two-arm crossover titration/reversal 
design (On [A] vs. Off [B]) with up to 4 periods. Subjects will be randomized to either ABAB 
or BABA (see Figure 1 below). Each period will last up to 6 weeks, allowing for sufficient 
time for up-titration and onset of drug action, and down-titration and washout. Each 
subject will have the option to participate in less (2-3) or more periods (5-6) depending 
on whether they need additional information to make an informed decision about 
continuing or discontinuing their beta-blocker at the end of this trial. The intervention 
drug will be beta-blockers, previously prescribed to the subjects by their physician. We 
have developed a titration algorithm, where we will reduce the dose of each beta-blocker 
by 50% every week.  
Description of Sites/  
Facilities Enrolling 
Subjects: 
 
Enrollment will only be at Weill Cornell Medicine.   
 
Study Duration: 
 
Estimated Primary Completion Date of December 2022 
Subject Duration: 
 
1 Year 
Study Agent/Device Name  
Not applicable 
 
 


Protocol #12.0 
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Intervention Description: 
The intervention is a two-arm crossover withdrawal/reversal design (On [A] vs. Off [B]) 
with up to 4 periods, each period lasting up to 6 weeks. During the On period (A), subjects 
will be on their beta-blocker. During the Off period (B), their beta-blockers will be down-
titrated and subsequently discontinued; we will decrease the dose of beta-blocker by 50% 
every week regardless of which beta-blocker they are on, similar to an algorithm used in 
a prior deprescribing trial.  Subjects will be randomized to either ABAB or BABA (see Figure 
1 below). 
 
 
 
Subjects may be on any of the following beta-blockers: 
• 
Atenolol 
• 
Betaxolol 
• 
Bisoprolol 
• 
Metoprolol 
• 
Metoprolol 
Succinate 
• 
Metoprolol Tartrate 
• 
Penbutolol 
• 
Nebivolol 
• 
Propranolol 
• 
Acebutolol 
• 
Pindolol 
• 
Carvedilol 
• 
Labetalol 
• 
Nadolol 
• 
Sotalol 
• 
Nadolol 
 
Co-Primary Objectives:  
To determine the features of a feasible and pragmatic protocol for deprescribing N-of-1            
trials in patients with Heart Failure with Preserved Ejection Fraction. 
 
 
Funded by National Institute on Aging 
 
 
 
To compare physical activity between the On and Off phase via: 
- 
Step Count collected via Garmin wearable device 
Funded by the New York Community Trust 
 
 
 
 
 
To compare exercise capacity between the On and Off phase via: 
- 
Peak oxygen consumption (VO2) Cardiopulmonary Exercise Test 
Funded by the New York Community Trust 
 
 
 
 
 
To compare lower extremity function between the On and Off phase via: 
- 
Short physical performance battery (lower extremity function)  
Funded by the New York Community Trust 
 
Secondary Objective:  
To compare Patient Reported Outcomes between the On and Off phase via: 
- 
Kansas City Cardiomyopathy Questionnaire 
- 
PRO Measurement Information System including PROMIS-29, PROMIS-Sexual 
Function, PROMIS-SF 6a and EQ5D Visual Analogue Scale (VAS) 
 
 
Funded by the New York Community Trust 
 
Exploratory Objectives:  
We will explore whether N-of-1 trials can improve decision-making parameters, including 
decision conflict (measured by the Decision Conflict Scale), patient activation (measured 
by the Patient Activation Measure), Shared Decision Making (measured by the 9-item 
Shared Decision-Making Questionnaire), and attitudes toward deprescribing (measured 
by the revised patient attitudes toward deprescribing questionnaire).  
 
 
Funded by National Institute on Aging 
 
 


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Primary Endpoints: 
 
The features of a feasible and pragmatic protocol for deprescribing N-of-1 trials as 
measured by qualitative interviews. 
 
 
Funded by the National Institute on Aging 
 
 
 
All of the below endpoints are being funded by the New York Community Trust. 
The change in physical activity when on beta-blocker versus when off beta-blocker, as 
measured by step count on a wearable activity monitoring device. 
The change in lower extremity function when on beta-blocker versus when off beta-
blocker, as measured by Short Physical Performance Battery 
The change in exercise capacity when on beta-blocker versus when off beta-blocker, as 
measured by peak oxygen consumption (VO2) during cardiopulmonary exercise test 
(CPET) 
 
Secondary Endpoints:  
All of the below endpoints are being funded by the New York Community Trust. 
 
 
The change in patient-reported quality of life when on beta-blocker versus when off beta-
blocker, as measured by Patient Reported Outcome Measurement System-29 (PROMIS-
29) 
 
 
The change in patient-reported sexual function when on beta-blocker versus when off 
beta-blocker, as measured by Patient-Reported Outcome Measurement Information 
System-Sexual Function (PROMIS-Sexual Function) 
 
 
The change in patient-reported cognitive function when on beta-blocker versus when off 
beta-blocker, as measured by Patient-Reported Outcome Measurement Information 
System-Short Form 6a (PROMIS SF-6a) 
 
 
The change in patient-reported health status when on beta-blocker versus when off beta-
blocker, as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ-12) 
 
 
The change in patient-reported health when on beta-blocker versus when off beta-
blocker, as measured by the EuroQol-5d Visual Analogue Scale (EQ-5D VAS) 
 
 
 
 
 
Exploratory Endpoints:  
The impact of N-of-1 trials on decision conflict as measured by the Decision Conflict 
 
Scale. 
The impact of N-of-1 trials on patient activation as measured by the Patient Activation 
Measure. 
 
 
The impact of N-of-1 trials on Shared Decision Making as measured by the 9-Item Shared 
Decision-Making Questionnaire. 
 
 
The impact of N-of-1 trials on attitudes toward deprescribing as measured by the Revised 
Patient Attitudes toward Deprescribing Questionnaire. 
 
 
 
 
 
  
 
 
 
 
 
 


Protocol #12.0 
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 8 
 
1.1 
Schema 
 
Figure 1. Study Design of a subject with 4 six-week periods  
 
Informed 
Consent 
Period 1 (6 Weeks) 
W2 
W3 
W4 
W5 
W6 
ON Arm 
Maintain baseline dose 
Full Dose 
Taper/decrease dose 
Off 
Period 2 (6 Weeks) 
W2 
W3 
W4 
W5 
W6 
Period 3 (6 Weeks) 
W1 
W2 
W3 
W4 
W5 
W6 
Re-initiate and Titrate 
Full Dose 
W1 
W2 
W3 
W4 
W5 
W6 
Re-initiate and Titrate 
Full Dose 
Taper/decrease dose 
Off 
Taper/decrease dose 
Off 
Taper/decrease dose 
Off 
Purple: Arm 1 
Blue: Arm 2 
OFF Arm 
ON Arm 
OFF Arm 
ON Arm 
OFF Arm 
ON Arm 
OFF Arm 
Period 4 (6 Weeks) 
Re-initiate and Titrate 
Full Dose 
W1 
W1 


Protocol #12.0 
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 8
1.2 
Study Objectives 
 
1.2.1  Co-Primary Objectives  
 
• 
To determine the features of a feasible and pragmatic protocol for deprescribing N-of-1            
trials in patients with Heart Failure with Preserved Ejection Fraction. (Funded by the 
National Institute on Aging) 
• 
The change in physical activity when on beta-blocker versus when off beta-blocker, as 
measured by step count on a wearable activity monitoring device. (Funded by the New 
York Community Trust) 
• 
The change in lower extremity function when on beta-blocker versus when off beta-
blocker, as measured by Short Physical Performance Battery. (Funded by the New York 
Community Trust) 
• 
The change in exercise capacity when on beta-blocker versus when off beta-blocker, as 
measured by peak oxygen consumption (VO2) during cardiopulmonary exercise test 
(CPET). (Funded by the New York Community Trust) 
 
1.2.2  Secondary Objectives 
 
• 
The change in patient-reported quality of life 
when on beta-blocker versus when off beta-
blocker, as measured by Patient Reported 
Outcome Measurement System-29 (PROMIS-
29) (Funded by the New York Community Trust) 
• 
The change in patient-reported sexual function 
when on beta-blocker versus when off beta-
blocker, as measured by Patient-Reported 
Outcome Measurement Information System-
Sexual Function (PROMIS-Sexual Function) 
(Funded by the New York Community Trust) 
• 
The change in patient-reported cognitive 
function when on beta-blocker versus when off 
beta-blocker, as measured by Patient-Reported 
Outcome Measurement Information System-
Short Form 6a (PROMIS SF-6a) (Funded by the New York Community Trust) 
• 
The change in patient-reported health status when on beta-blocker versus when off beta-
blocker, as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ-12) (Funded 
by the New York Community Trust) 
• 
The change in patient-reported health when on beta-blocker versus when off beta-
blocker, as measured by the EuroQol-5d Visual Analogue Scale (EQ-5D VAS) (Funded by 
the New York Community Trust) 
 
 
 
 
 
 
Table 1: PRO Administration Details (50 items in total) 
 Instrument 
# of 
Items 
Domain 
  
 KCCQ-12 
12 
HF-specific health 
status 
  
 PROMIS-29 
4 
Fatigue 
  
 
4 
Depression 
  
 
4 
Anxiety 
  
 
4 
Sleep 
  
 
4 
Physical function 
  
 
4 
Social Role 
  
 
5 
Pain 
interference/intensity 
  
 PROMIS (SF-
6a) 
6 
Cognitive function 
  
 PROMIS- 
Sexual 
Function 
2 
Sexual Function 
 
EQ-5D Visual 
Analogue 
Scale 
1 
Quality of Life 
 


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1.2.3  Exploratory Objectives 
 
• 
To examine whether N-of-1 trials can improve decision parameters, patient activation, 
and attitudes toward deprescribing. 
o Decision Conflict Scale (DCS) 
o Patient Activation Measure (PAM) 
o 9-Item Shared Decision-Making Questionnaire  
o revised Patient Attitudes Toward Deprescribing (rPATD) 
 
 
 


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2. Background 
 
2.1 Disease 
 
Heart Failure with Preserved Ejection Fraction (HFpEF) affects >3 million people across the US and is 
a prototypical geriatric syndrome—it disproportionately affects older adults (mean age ~76 years); 
age-related changes to the cardiovascular system and common age-related comorbid conditions are 
implicated in its pathogenesis; and multiple comorbid conditions and polypharmacy are nearly 
universal. While beta-blockers are the most commonly used medication for HFpEF (~80% in a recent 
Randomized Controlled Trial), there is substantial uncertainty regarding their benefits in HFpEF. 
Although the benefits of beta-blockers in Heart Failure with reduced ejection fraction are well-
documented, Randomized Clinical Trials (RCTs) of beta-blockers in HFpEF have been neutral to date, 
failing to consistently improve or worsen long-term outcomes including mortality and hospitalization 
rates; and short-term effects on patient-reported outcomes like function and quality of life are not 
well-described, with a signal of harm in some.  
 
2.2 Rationale 
 
High medication burden among older adults with multiple chronic conditions including those with 
heart failure is a growing problem in the United States that can negatively impact the health and 
wellbeing of older adults. Deprescribing (or medication discontinuation) has emerged as a strategy to 
improve outcomes in older adults with multiple chronic conditions and high medication burden but is 
underutilized. With this project, we will refine an innovative pragmatic subject-centered approach (N-
of-1 trials) to medication optimization in older adults, thereby improving the health and wellbeing of 
older adults with multiple chronic conditions. 
 
In Dr. Goyal’s clinical experience as Director of the HFpEF Program for the Aging, he has found that 
some patients feel better with beta-blockers while others feel worse. This idea is supported by 
opposing pathophysiologic mechanisms highlighted in the literature—on the one hand, beta-blockers 
can slow down heart rate, improve left ventricular filling, and thus improve cardiac output and overall 
functioning. On the other hand, beta-blockers can exacerbate chronotropic incompetence, worsen 
cardiac output, and reduce exercise tolerance. Beta-blockers are also a common cause of adverse 
drug reactions and can worsen function in some older adults. There is no readily discernable way to 
determine which patients will feel better and which will feel worse. Although the benefits of beta-
blockers in HF with reduced ejection fraction are well documented, RCTs of beta-blockers in HFpEF 
have been neutral to date, failing to consistently improve or worsen long-term outcomes including 
mortality and hospitalization rate. Thus, beta-blocker use in HFpEF is a well-suited and clinically 
relevant model for developing a subject-centered approach to medication optimization. 
 
N-of-1 trials offer a potentially transformative approach to deprescribing. Unlike traditional 
population-based clinical trials, N-of-1 trials are conducted within a single subject, using multiple 
crossover design experiments to compare different treatments. 
  
 
 


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2.3  Risk/Benefit Assessment  
 
The risks and benefits of N-of-1 trials relate directly to the risks of initiation and discontinuation of 
beta-blockers. 
 
2.3.1 
Known Potential Risks 
 
All subjects: 
i) Risks associated with down-titration/discontinuation of beta-blocker: Adverse drug 
withdrawal events including tachycardia, worsened hypertension, palpitations, 
diaphoresis, shortness of breath, heart failure exacerbation, angina, myocardial 
infarction, cerebrovascular accident, arrhythmia, hospitalization, and death (shown to 
occur with abrupt cessation of beta-blocker)  
ii) Risks associated with beta-blocker use (and re-initiation/up-titration):  Adverse drug 
events or adverse drug reactions including bradycardia, heart block, hypotension, 
dizziness, fatigue, depression, confusion, heart failure exacerbation, cerebrovascular 
accident, hospitalization, and death  
iii) Risks associated with wearing the Garmin wearable device:  Local skin irritation, wrist 
pain  
iv) Risks associated with subject interviews: Emotional distress related to answering 
interview questions, and breach of confidentiality 
v) Risks associated with Cardiopulmonary Exercise Test and Short Physical Performance 
Battery: musculoskeletal injury, arrhythmias, acute coronary syndrome, hemodynamic 
instability, cardiovascular collapse, death. 
vi) Risks associated with Short physical performance battery: falling, musculoskeletal 
injury. 
vii) Risks associated with the 6-minute walk test: fatigue, dizziness. 
viii) Risks associated with blood draws: pain or bruising, dizziness, infection at the site of 
the blood draw 
 
2.3.2 
Known Potential Benefits  
 
For some, continuing beta-blockers may be beneficial: Beta-blockers slow down heart 
rate, improve left ventricular filling and thus improve cardiac output and overall 
functioning. They can function as anti-hypertensive and may suppress arrhythmias.  
 
For others, stopping beta-blockers may be beneficial: Beta-blockers can exacerbate 
chronotropic incompetence, worsen cardiac output, and reduce exercise tolerance. Beta-
blockers are also a common cause of adverse drug reactions and can worsen function in 
some older adults. Beta-blockers can also contribute to undesirable symptoms like fatigue 
and sexual dysfunction. 
 
Subjects may specifically benefit from this study by gaining insight on the individual-level 
short-term effects of beta-blockers. This information could then help subjects determine 
whether they wish to continue or discontinue beta blockers, potentially contributing to 
increased decision confidence and subject activation, and possibly improving quality of 
life. 
 
 


Protocol #12.0 
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2.3.3 
Assessment of Potential Risks and Benefits 
 
Rationale to exposing subjects to risk 
1.) Exposure to beta-blocker: Subjects are already on beta-blocker at the time of 
recruitment; thus, being on beta-blocker does not explicitly add additional risk beyond 
usual clinical care 
2.) Down-titration/discontinuation: Subjects will have their beta-blocker dose decreased 
and/or discontinued. There is limited data to support the benefits of beta-blocker in 
HFpEF, despite its frequent use. Moreover, beta-blocker use poses several harms in older 
adults including bradycardia, heart block, hypotension, dizziness, fatigue, depression, 
confusion, heart failure exacerbation, cerebrovascular accident, hospitalization and 
death. Accordingly, down-titration/discontinuation of beta-blocker may actually be safer 
than continuing beta-blocker, at least in some.   
 
To mitigate the risks of down-titration/discontinuation, we will incorporate the following: 
1.) remote monitoring protocol that includes assessments of resting heart rate and blood 
pressure  
2.) telephone calls made by the research team to the subject on the day before a dose 
modification is planned, to instruct about the next day’s dose change; the day a dose 
modification is planned, to confirm the dose change was made and the assess health 
status; and the day following dose modification, to reassess health status, where we will 
ascertain whether the subject is experiencing any withdrawal effects such as chest pain, 
tachycardia, palpitations, diaphoresis, and shortness of breath, as well as any adverse 
events, such as hospitalizations and/or adverse cardiovascular events, including HF 
exacerbation, myocardial infarction, arrhythmia, cerebrovascular accident and death; 
based off of subject feedback, telephone calls may be eliminated during the last 2 weeks 
of each period  
3.) We will also provide a 24 hour/7 day per week hotline for subjects to call if they 
develop any concerning symptoms. Importantly, we will exclude subjects with other 
indications for beta-blocker use to maximize safety. For example, individuals with 
hypertrophic cardiomyopathy will be excluded, since beta-blockers have a clear benefit 
in this condition (and are a Class I indication). 
 
We hypothesize that there will be benefits to dose reduction (down-titration/ 
discontinuation). Beta-blockers can exacerbate chronotropic incompetence, worsen 
cardiac output, and reduce exercise tolerance, as well as possibly worsen physical 
function, and be a major cause of adverse drug reactions. Dr. Goyal (as a board-certified 
heart failure physician and HFpEF specialist) has already observed this in his clinical 
practice—among nine subjects in whom he has discontinued beta-blockers, 8 of the 9 felt 
better.   
 
The justification of risk is that this study has the potential to lead to a paradigm shift in 
the way beta-blockers are used in HFpEF. We believe beta-blockers are overused in this 
subtype of heart failure and may be causing more harm than good in the many HFpEF 
subjects. 
 


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In addition, all inclusion and exclusion criteria were selected to ensure we exclude 
subjects with other evidence-based indications for beta-blockers. In other words, we 
excluded subjects who may be harmed if we stop beta-blockers. 
 
3. Study Design 
 
3.1 Overall Design 
 
This single site, NIH Stage I of Behavioral Intervention Development trial will extend principles of 
subject-centered care (a pillar of caring for older adults with MCC) to medication management by 
producing a broadly applicable approach (N-of-1) that can bypass the inherent limitations of 
randomized controlled trials which provide average treatment effects and limited data on the effects 
of medication for a single individual; and thereby facilitate personalized pharmacotherapy and 
therapeutic precision by determining the optimal therapy for the individual in the face of the inherent 
complexity and heterogeneity of older adults related to variability in clinical phenotype, drug 
metabolism, responsiveness to therapy, and health priorities.  
 
This study will also formalize a process that can increase subject involvement and incorporate shared 
decision making into medication management, an important priority in cardiovascular medicine. 
 
We will conduct N-of-1 trials using a two-arm crossover withdrawal/reversal design (On [A] vs Off [B]) 
with up to 4 periods. Subjects will be randomized to either Arm1/ABAB or Arm2/BABA (see Figure 1 
above). After the initial period (Period 1), each subject will crossover to the other arm and continue 
in that arm for up to 6 weeks (Period 2). This may be repeated for two more periods for a total of 4 
periods; each period will last up to 6 weeks, permitting sufficient time for up-titration and onset of 
drug action, and down-titration and washout. If the subject and the principal investigator make a final 
decision to discontinue or continue the beta-blocker at the end of a period, the end of intervention 
phase will begin at the end of that period visit. For the remainder of the protocol, we refer to “end of 
intervention” as period 4, but this can be changed based on when a final decision is made about the 
beta-blocker. The end of intervention visits can occur at any of the periods. The minimum number of 
periods will be 2 (AB or BA).  If the subject wishes to collect more data, then additional periods may 
be added in an alternating fashion (ABAB or BABA).  Accordingly, the number of periods will be an 
adaptive component of the protocol. 
 
For dose reduction, we will follow a schedule that was safe in a prior deprescribing trial—50% 
reduction every week until Off1. This reduction schedule will follow up-titrations and down-titrations 
outlined in section 7.4, but will also be adaptive based on subject clinical profiles and symptoms while 
on and off beta-blockers. 
 
Subjects randomized to Arm 1/ABAB (starting with On[A]), will continue their home dose during 
Period 1. They will then crossover to Period 2, where we will begin dose reduction. The dose will be 
reduced by 50% each week until the subject is off of beta-blockers. At the end of period 2 visit, 
subjects will be given the opportunity to decide if they would like to remain on or off their beta-
blocker, or if they would like to continue into period 3. If they chose to continue to period 3, they will 
restart beta-blocker by starting a low dose and then doubling this dose every week until reaching their 
 
 
1 Luymes CH, Poortvliet RKE, van Geloven N, de Waal MWM, Drewes YM, Blom JW, Smidt N, Assendelft WJJ, van den Hout WB, de Ruijter W, 
Numans ME. Deprescribing preventive cardiovascular medication in patients with predicted low cardiovascular disease risk in general practice - the 
ECSTATIC study: a cluster randomized non-inferiority trial. BMC Med. 2018;16(1):5. 


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14
home dose. During Period 4 (last period), we will again conduct a dose reduction, reducing each dose 
by 50% for a week, until the subject is off of beta-blockers.  
 
For patients in Arm 1, the number of periods a 
subject will complete is dependent on their 
decision about continuing or discontinuing their 
beta-blocker at their end of period 2 or end of 
period 3 visit. If a subject decides they would like 
to continue their beta-blocker after period 2, they 
will complete a period 3 to allow for safe up-
titration. End of period visits, including the end of 
intervention period, may be conducted either 
remotely or in person, based on subject 
preference and the current status of the COVID-
19 pandemic. End of period and end of 
intervention visits conducted remotely will not 
have 
the 
following 
physical 
assessments 
associated with it: Cardiopulmonary Exercise 
Test, Short Physical Performance Battery, blood draw, physical assessment, six-minute walk test, and 
an EKG. Subjects in Arm 1/ABAB who want to stop their beta-blocker can complete their end of 
intervention visit at period 2 and enter follow-up. 
 
Subjects randomized into Arm 2/BABA will start with Off[B]. Instead of abruptly stopping beta-blocker, 
these subjects will have their previously prescribed home beta-blocker dose reduced by 50% each 
week, until the subject is completely off beta-blocker. During Period 2, they will restart beta-blocker 
by starting a low dose and then doubling this dose every week until reaching their home dose. During 
Period 3, we will again conduct a dose reduction, reducing each dose by 50% for a week, until the 
subject is off of beta-blockers. Finally, they will restart beta-blocker by starting a low dose and then 
doubling this dose every week until reaching their home dose (Similar to Period 2). See Figure 1 above. 
Regarding patients in Arm 2, if a subject decides they would like to stop their beta-blocker after period 
2, they will complete a period 3 to allow for safe down-titration. End of period visits, including the end 
of intervention period, may be conducted either remotely or in person, based on subject preference 
and the current status of the COVID-19 pandemic. End of period and end of intervention visits 
conducted remotely will not have the following physical assessments associated with it: 
Cardiopulmonary Exercise Test, Short Physical Performance Battery, blood draw, physical assessment, 
six-minute walk test, and an EKG. Subjects in Arm 2/BABA who want to continue their beta-blocker 
can complete their end of intervention visit at period 2 and enter follow-up. 
 
We will incorporate an adaptive study design, where each subject will have the option to participate 
in less (2-3) or more periods (5-6) depending on whether they need additional information to make 
an informed decision about continuing or discontinuing their beta-blocker at the end of this trial.  
 
Subjects will wear a Garmin wearable device for the duration of the study to collect data on step count 
to quantify physical activity. We may collect additional data that is captured by the wearable devices, 
such as floors climbed, distance traveled and calories burned. We may eliminate the use of wearable 
devices per subject feedback.  
 
Subjects will also undergo a non-invasive cardiopulmonary exercise test (CPET) at the end of period 1 
and at the end of period 2 to assess exercise parameters including peak oxygen consumption. In 
Arm 1 
Week 1-6 
Week 7-12 Week 13-18 Week 19-24 
ON 
(A) 
OFF 
(B) 
ON 
(A) 
OFF 
(B) 
Arm 2 
Week 1-6 
Week 7-12 Week 13-18 Week 19-24 
OFF 
(B) 
ON 
(A) 
OFF 
(B) 
ON 
(A) 
Table 2. Design for Arm 1 & Arm 2 for a subject 
completing 4 six-week periods 
 


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addition, they will undergo the short physical performance battery at baseline and at the end of each 
intervention period. The study team will discuss the components of the CPET with the subjects prior 
to their end of period visits. 
 
Through a pre-existing remote monitoring program at Weill Cornell Medicine, we will provide subjects 
with a computer tablet and blood pressure cuff free-of-charge. This will allow us to collect vital sign 
data, including blood pressure and heart rate. We will encourage subjects to collect data up to 3 times 
per week.  Based on patient reports of any concerning symptomatology, we may encourage increased 
frequency of assessments at different time points of the study.  Also, based on prior experience, some 
subjects may want to collect data more frequently, which will allow. This approach was developed 
based on our preliminary data from 9 prior N-of-1 trials, where there were no serious adverse events 
and based on subject feedback (Several subjects requested reduced frequency of required vital sign 
assessment). If we encounter “Red Flags” (Table 3), we will call the subject to assess symptoms and 
determine the need for medical attention and/or study withdrawal.  
 
Table 3. Red Flags triggering phone call 
 
Upper Limit 
Lower Limit 
Blood Pressure 
>160/90 mmHg 
<100/60 mmHg 
Resting Heart Rate 
>100 bpm 
<60 bpm 
 
Remote monitoring will occur on a daily basis. Subjects will be provided with a tablet computer and 
blood pressure cuff free-of-charge. These data will be automatically uploaded to an online portal, 
which we will review weekly.  
 
Subjects will complete subject-reported outcome questionnaires on quality of life, cognitive 
function, and sexual function at regular intervals set by each of the validated instruments during the 
intervention stage via their tablet computers, over the phone, or via email.  
 
The interventions in this study will be used for either exploratory purposes or integrated with study 
visits to help subjects make decisions on whether they would like to continue or discontinue their 
beta-blocker medications. CPET and the respective results, RPM vitals (including blood pressure and 
heart rate), collected blood biomarker levels, step count analysis, and 6-minute walk test results and 
analysis will serve as exploratory measurements. Therefore, these results and values will not be 
explicitly shared with the subjects throughout the study to minimize bias. This way, subjects can base 
their decision-making on how they truly felt (measured by symptom and decision-making 
questionnaires) and their ability to make an informed decision with their provider. PROs, or subject 
reported outcomes will be included in the consenting process and study visits. These PROs include 
answers to their questionnaires and data visualizations analyzing how their answers differed 
between periods. The PROs will be explicitly discussed with the subjects to further motivate them to 
make an informed decision on how they feel. These expectations on what will be provided 
throughout the study will be clearly outlined during the consent process and baseline visit. If subjects 
specifically request to see these values, the PI and study team will consider providing these results 
for clinical purposes and per standard of care.  
 
We will also conduct brief qualitative interviews to assess the understandability and usability of 
materials at each of the following time points: 1) completion of informed consent, 2) completion of 
each period of the intervention arms, 3) completion of the full intervention phase for each subject, 
and 4) at 6, 9, and 12-month post end of intervention follow-up periods. Interviews may be 
conducted via phone call or via Zoom, based on subject preference. The study team will audio record 


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these interviews. All qualitative interviews will be transcribed by a professional transcribing service. 
Names and all other PHI that appear in the transcription will be replaced with a generic participant 
ID or redacted. Additional interviews may be conducted to elicit additional information related to 
themes previously discussed during interviews and/or feedback provided to the study team during 
the course of the study. 
 
Per subject feedback, we may eliminate the use of wearable devices or modify subject reported 
outcome questionnaires. We may also give caregivers the opportunity to share any feedback they 
may have. We will ask the subjects for permission to discuss the study with their caregivers. We will 
also ask the subjects for permission to contact and discuss the trial with their primary care provider 
or their primary cardiologist.  
 
At the conclusion of the intervention phase, and possibly at the end of each intervention period, we 
will provide subjects with visual analogies of their physical function and subject reported outcomes 
data. These data will be discussed with them to help them determine if they would like to continue 
or discontinue their beta-blockers for the foreseeable future.  
 
       3.2 Scientific Rationale for Study Design 
 
In Dr. Goyal’s clinical experience as Director of the HFpEF Program for the Aging, he has found that 
some subjects feel better with beta-blockers while others feel worse. This idea is supported by 
opposing pathophysiologic mechanisms highlighted in the literature—on the one hand, beta-blockers 
can slow down heart rate, improve left ventricular filling, and thus improve cardiac output and overall 
functioning. On the other hand, beta-blockers can exacerbate chronotropic incompetence, worsen 
cardiac output, and reduce exercise tolerance. Beta-blockers are also a common cause of adverse 
drug reactions and can worsen physical function in some older adults. There is no readily discernable 
way to determine which subjects will feel better and which will feel worse. Thus, beta-blocker use in 
HFpEF is a well-suited and clinically relevant model for developing a subject-centered approach to 
medication optimization. 
 
3.3 Justification for Dose  
 
During the initial “On” [A] period, the target dose will be the one that was prescribed by their usual 
physician at the time of study enrollment. Justification for the tapering dose is provided above 
(determined in consultation with other HFpEF experts and pharmacologists; also, this schedule was 
used in a prior deprescribing study that included beta-blockers). 
 
 
3.4 End of Study Definition 
 
A subject is considered to have completed the study upon completion of all phases of the study, 
including the last visit or the last scheduled procedure shown in the Schedule of Assessments (SoA), 
Section 6.1. The end of the study is defined as completion of the last visit or procedure shown in the 
SoA in the trial. 
 
 
 
 
 


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4. Subject Selection 
 
4.1 Study Population 
 
Subjects with a diagnosis of HFpEF, who are patients at Weill Cornell Medicine, and meet all 
inclusion and exclusion criteria, will be eligible for participation in this study.  
 
4.2 Inclusion Criteria 
 
1. Ambulatory adults age ≥65 years with HFpEF according to ACC/AHA guidelines (signs and 
symptoms of Heart failure AND ejection fraction ≥50%) 
2. Taking beta-blocker 
 
 
4.3 Exclusion Criteria  
 
1. Alternate causes of HFpEF Syndrome: 
a. Severe aortic stenosis and mitral stenosis 
b. Constrictive pericarditis 
c. High Output HF 
d. Infiltrative cardiomyopathy 
2. Other compelling indication beta-blocker 
a. Prior EF <50% 
b. Hypertrophic cardiomyopathy 
c. Angina symptoms 
d. Acute coronary syndrome, myocardial infarction or coronary artery bypass surgery in 
prior 3 years 
e. History of ventricular tachycardia 
f. Atrial arrhythmia with hospitalization for rapid ventricular response, prior 1 year 
g. Sinus tachycardia >100 bpm, atrial arrhythmia with ventricular rate >90 beats per 
minute, systolic blood pressure >160 mmHg 
3.  Clinical instability (N-of-1 trials are appropriate for stable conditions only) 
a. Decompensated heart failure 
b. Hospitalized in past 30 days 
c. Medication changes or procedures in prior 14 days that could confound 
observations/data, at PI discretion  
4. Estimated life expectancy <6 months 
5. Moderate-severe dementia or psychiatric disorder precluding informed consent 
6. Any condition that, in Principal Investigator’s opinion, makes the patient unsuitable for study 
participation 
 
4.4 Lifestyle Considerations 
 
Not applicable. 
 
 
 
 
 


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4.5 Screen Failures  
 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). We are not anticipating any 
screen failures, as only eligible subjects (based on pre-screening) will be consented.  All subjects will 
be randomized upon gaining consent (no additional screening procedures are necessary). 
 
In the instance of a screen failure, we will not re-screen the subject in the future. 
 
4.6 Strategies for Recruitment and Retention 
 
 
Subjects will be recruited primarily from the HFpEF Program at Weill Cornell Medicine. Cardiology, 
Geriatrics, and Primary Care clinics may be screened in addition if necessary. Approximately 70% of 
patients seen between July 2018-October 2019 in the HFpEF clinic would be eligible to participate. By 
2020 the HFpEF Program will see >200 unique patients, which will provide a sufficient number of 
subjects to enroll from. We plan to enroll 16 subjects. 
 
The research assistant will screen subjects scheduled in the HFpEF Program in advance of their 
appointments to identify potentially eligible subjects. The research assistant will then introduce the 
study to each eligible subject and conduct the informed consent process.  A screening and enrollment 
log will be kept by the research assistant. Subjects will receive $50 upon consenting, randomization, 
and completing the baseline assessment. All subjects will provide written informed consent and HIPAA 
notifications. 
 
We will not enroll the following vulnerable populations: 
• 
Pregnant women 
• 
Children 
• 
Those who lack capacity to consent 
• 
Employee/student volunteers 
 
Planned enrollment is estimated based on frequencies observed in the HFpEF Program at Weill Cornell 
Medicine. Frequencies in the HFpEF Program are as follows: 
• 
57% Women 
• 
62% White non-Hispanic 
• 
16% Black non-Hispanic 
• 
11% Hispanic/Latino 
 
Strategies for Retention:  There are several opportunities to engage subjects to ensure retention. 
We will contact subjects weekly to instruct them to complete standardized web-based patient-
reported outcomes questionnaires. Subjects will be asked to complete these assessments on their 
tablet computer (which we will provide free-of-charge and has internet capabilities), over the 
phone, or via email. We will also conduct routine phone calls for safety purposes (at this time, we 
can remind subjects to complete the weekly assessments if needed). For subjects who do not 
complete the assessments (we will track this electronically), we will call them daily to remind them 
and/or assist them with completing the assessments over the phone. If we are unable to contact the 


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subject over the phone, when applicable, we will attempt contact via email. To ensure pragmatism 
and enhance retention, assessments will be short and subject to change per subject feedback. Based 
off of subject feedback, we may eliminate subject phone calls on the last two weeks of each period. 
To maximize compliance and retention, subjects will receive $50 at the end of successful completion 
of each phase up to 4 total phases (baseline and the 4 treatment periods). They will receive an 
additional $50 as a compliance bonus at the end of period 4/end of study. In total, subjects will 
receive up to $300. We will define compliance as attending 100% of scheduled visits and completing 
90% of assessments during the defined time period.  
 
Subjects may receive reimbursement for unanticipated fees, per PI discretion.  
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for 
Subject Registration. 


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6. Study Procedures 
 
6.1 
Schedule of Assessments 
 
 
Baseline  
Research Intervention Phase 
Post Intervention Phase 
 
 
Daily 
Weekly 
Biweekly 
End of 
Periods 1-3 
End of 
Intervention 
Phase (Period 4) 
6 Month 
Follow-up 
9 Month 
Follow-up 
12 Month 
Follow-up 
Informed Consent 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
Medication Inventory 
 
 
 
 
 
 
Baseline Beta-Blocker Use 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
Central Blood Pressure 
 
 
 
 
 
 
Electrocardiogram 
 
 
 
 
 
 
Cardiopulmonary Exercise Test2 
 
 
 
 
 
 
 
 
Blood Draw for Troponin & NT-
proBNP3 
 
 
 
 
 
 
Blood Draw for Future Research4  
 
 
 
 
 
 
 
Six-Minute Walk Test 
 
 
 
 
 
 
Short Physical Performance Battery 
 
 
 
 
 
 
Qualitative Interview 
 
 
 
 
 
 
Typology Question 
 
 
 
 
 
 
 
Health Literacy 
 
 
 
 
 
 
 
 
Number Literacy 
 
 
 
 
 
 
 
 
Short Graph Literacy 
 
 
 
 
 
 
 
 
Data Preferences 
 
 
 
 
 
 
 
 
EQ5d-VAS 
 
 
 
 
 
 
PROMIS-29 
 
 
 
 
 
 
PROMIS-SF 6A 
 
 
 
 
 
 
PROMIS-Sexual Function 
 
 
 
 
 
 
KCCQ-12 
 
 
 
 
 
 
 
 
2 Cardiopulmonary Test to occur only at the end of Period 1 and Period 2. Cardiopulmonary test to be accompanied by a blood draw for NT-proBNP and Troponin. 
3 Blood samples will be collected for Troponin and NT-proBNP at the end of each period. In addition, on visits where the subject performs a Cardiopulmonary Test, we may 
collect blood for Troponin and NT-proBNP directly after the cardiopulmonary test. 
4 Optional component of this study. Blood will be drawn at baseline, as well as at the end of Period 1 and Period 2  


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Decision Making 
Outcomes 
Questionnaires5 
 
 
 
 
 
 
 
 
 
Dose Modification 
 
 
 
 
 
 
 
Telephone Call6 
 
 
 
 
 
 
 
 
 
Step Count Collection 
 
 
 
 
 
 
 
 
 
Remote Monitoring 
 
 
 
 
 
 
 
 
Interim Events History 
 
 
 
 
 
 
 
Assessment of Beta-
Blocker Usage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 Decision Making Parameters Questionnaire to consist of Decision Conflict Scale, Decision Conflict Subscales, Patient Activation Measures Survey, Shared Decision-Making 
Questionnaire (SDM-1-9) and Revised Patient Attitudes Towards Deprescribing (rPATD) 
6 Telephone contact to occur the day prior to, the day of, and the day following a dose modification. Telephone calls may be eliminated per subject feedback during the last two 
weeks of each period.  
Legend 
In-Office visit 
Conducted Remotely 
 
Conducted via Telephone 
 
Collected via Garmin wearable 
device 


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6.1.1 
Baseline In-Person Visit 
• 
Informed consent 
• 
Randomization 
o Eligible subjects will be randomly assigned to into Arm 1 (ABAB) or Arm 2 (BABA) with 
a 1:1 ratio using a computer-generated randomization scheme developed by the data 
manager. Arm 1 will be on an On-Off-On-Off (ABAB) drug scheme, while Arm 2 will be 
Off-On-Off-On (BABA) 
• 
Demographics 
• 
Medication Inventory 
• 
Baseline beta-blocker use 
• 
Physical Exam, including vital signs 
• 
Central blood pressure assessment via the UScom BP+ device 
o This device measures central and brachial blood pressure and blood pressure 
waveforms at the heart, as well as in the arm. 
• 
Electrocardiogram 
• 
Blood draw for Troponin & NT-proBNP 
• 
Blood draw for future research 
• 
Six-Minute Walk Test  
• 
Exercise test used to assess aerobic capacity endurance. The distance covered over 6 minutes 
is used as the outcome by which to compare changes in performance capacity. 
• 
Short Physical Performance Battery 
o Combines the results of gait speed, chair stand and balance tests as a predictive tool 
for possible disability and can aid in the monitoring of function in older people 
▪ 
Gait Speed: assesses the subject’s lower extremity function 
▪ 
Chair Rise: assesses core strength 
▪ 
Balance Test: assess the subject’s ability to stand unassisted without the use 
of a cane or walker 
• 
Qualitative interview on understandability of study purpose and design  
• 
Typology Questionnaire 
• 
Health Literacy Questions 
• 
Number Literacy Questions 
• 
Short Graph Literacy 
• 
EQ5D Visual Analogue Scale 
• 
PROMIS-29 
• 
PROMIS-SF 6A 
• 
PROMIS-Sexual Function 
• 
KCCQ-12 
• 
Decision Making Outcomes Questionnaires 
o Decision Conflict Scale 
o Decision Conflict Subscale 
o Patient Activation Measure (PAM) Survey 
o Shared Decision Making Questionnaire 
o Revised Patient Attitude Towards Deprescribing Questionnaire (rPATD)  
 
 
 
 


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6.1.2 
Treatment Phase 
 
 
6.1.2a Daily 
• 
Remote Monitoring 
o Remote monitoring will collect vital sign data, including blood pressure and 
heart rate via a free of charge remote monitoring platform already in use in 
the HFpEF Program. Data will be reviewed weekly. If we encounter “Red 
Flags”, we will call the subject to assess symptoms, and determine the need 
for medical attention and/or study withdrawal in consultation with the 
subject’s other physicians and the DSMB. 
▪ 
Red Flags are as follows: 
• 
Blood pressure >160/90 mmHg or <100/60 mmHg 
• 
Heart Rate >100 bpm or <50 bpm 
• 
Step Count 
o Daily step count will be collected via Garmin wearable devices that will be 
provided to subjects during the duration of the treatment phase of the trial. 
 
 
 
6.1.2b Weekly 
• 
Dose modification (as described in section 3.1) 
• 
Telephone Contact on the day prior to the dose modification, the day of the dose 
modification and on the day following dose modification. Telephone calls may be 
eliminated during the last 2 weeks of each period per subject feedback. 
• 
Patient Reported Outcomes (PROMIS-29, PROMIS-SF 6A) via web-based surveys 
taken at home on tablet computers provided to each subject, over the phone, or via 
email – frequency/length of surveys may be decreased per subject feedback 
• 
Interim Events History (Adverse Events/SAE) will be asked during each phone call 
 
 
 
6.1.2.c Biweekly 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ-12)  
 
6.1.2d End of Periods 
• 
Medication Inventory 
• 
Dose Modification 
• 
Physical Exam, including vital signs 
• 
Central blood pressure assessment via the UScom BP+ device, when possible 
• 
Electrocardiogram 
• 
Six Minute Walk Test 
• 
Cardiopulmonary Exercise Test (at the end of Period 1 and Period 2) 
o We may draw additional blood for Troponin & NT-proBNP directly after the 
CPET. On visits which include a CPET, the subject may have Troponin and NT-
proBNP drawn twice.  
• 
Blood Draw for Troponin & NT-proBNP 
• 
Blood draw for future research (at end of period 1 & end of period 2 only) 
• 
Short Physical Performance Battery 
• 
Qualitative interview on understandability and usability of study materials 
• 
EQ-5D VAS 
• 
PROMIS-29 
• 
PROMIS-SF 6A 
• 
PROMIS-Sexual Function 


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• 
Kansas City Cardiomyopathy Questionnaire (KCCQ-12) 
• 
Interim Events History 
 
6.1.2e End of Intervention Visit Period 
• 
Medication Inventory 
• 
Dose Modification 
• 
Physical Exam 
• 
Central blood pressure assessment via the UScom BP+ device 
• 
Electrocardiogram 
• 
Six Minute Walk Test 
• 
Short Physical Performance Battery 
• 
Qualitative interview on understandability and usability of study materials 
• 
Typology Question 
• 
EQ5D-VAS 
• 
PROMIS-29 
• 
PROMIS-SF 6A 
• 
PROMIS-Sexual Function 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ-12) 
• 
Interim Events History 
 
6.1.2f Unscheduled Visits 
 
Unscheduled visits may be performed at any time during the study. The unscheduled visits 
may occur on-site or as a telephone visit. All data recorded during unscheduled visits will 
be recorded in REDCap. Depending on the reason for the unscheduled visit, appropriate 
assessments will be performed based on the judgement of the investigator and the results 
will be recorded in the REDCap. 
 
6.1.3 
Follow-up Phase 
 
Six, nine, and twelve months after the end of intervention, the study team will access the subject’s 
electronic health record to assess the following: 
• 
Interim Events History 
• 
Determine whether subjects are taking beta-blockers or not 
• 
PROMIS-29 
• 
PROMIS-SF 6A 
• 
PROMIS-Sexual Function 
The study team will conduct a phone call or Zoom meeting with the subject to review this 
information and confirm survey completion. Surveys will be sent out to the subjects the week of 
their six-, nine-, and twelve-month follow-ups via their tablet computer provided by the study 
team, through email, or over the phone. A qualitative interview will also take place at the 6, 9, 
and 12-month follow up periods. This qualitative interview will be audio recorded and transcribed 
by a professional transcribing service. We will store the audio recordings obtained from the 
interviews three years after data analysis completion. These recordings will then be erased 
permanently. 
 
Positive indications from study participants about a hospitalization or possible events at other 
institutions will be followed by collection of selected medical records. Records will include 
administrative hospital codes and copies of relevant portions of the medical record, including 


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admission and discharge notes, progress notes, laboratory studies, ECGs, radiographic studies, 
and any other diagnostic testing or procedure notes. We will obtain an appropriate consent for 
release of information prior to obtaining medical records. 
 
For patients who have expired prior to the time of first contact for consent, we will contact the 
next of kin to obtain authorization to request/receive information about the cause of death and 
hospitalizations/emergency room visits leading up to the patient’s death. In this scenario, the next 
of kin will provide verbal consent and asked to provide a release of medical information form. 
  
7. Study Intervention 
 
7.1 Study Intervention/Device Description   
 
Beta-blockers, also known as beta-adrenergic blocking agents, work by blocking the effects of 
epinephrine. Although the benefits of beta-blockers in HF with reduced ejection fraction are well 
documented, RCTs of beta-blockers in HFpEF have been neutral to date, failing to consistently improve 
or worsen long-term outcomes including mortality and hospitalization rate. Beta-blockers do not 
provide symptomatic improvement in all subjects; some may feel better while other may feel worse 
after initiating this drug class. This is supported by opposing pathophysiologic mechanisms highlighted 
in the literature—on the one hand, beta-blockers can slow down heart rate, improve left ventricular 
filling, and thus improve cardiac output and overall functioning. On the other hand, beta-blockers can 
exacerbate chronotropic incompetence, worsen cardiac output, and reduce exercise tolerance. Beta-
blockers are also a common cause of adverse drug reactions and can worsen function in some older 
adults. There is no readily discernable way to determine which patients will feel better and which will 
feel worse. 
 
All subjects will have been taking beta-blockers prescribed by their physician prior to enrollment. The 
study team will provide the subjects dosage instructions based on the down-titration/up-titration 
schedule outlined in this protocol.  
 
The study team will not provide study drug to the subjects. Subjects will continue to obtain their beta-
blockers in the same manner as prior to study enrollment. 
 
Beta-blockers may be contraindicated in the following subjects: 
 
Relative contraindications: 
• 
Asthma; COPD (use cardio-selective β blockers/β-1 selective) 
• 
Psoriasis 
• 
Symptomatic bradycardia 
• 
Sick sinus syndrome (without a pacemaker); heart block greater than first degree 
• 
Peripheral artery occlusive disease, Raynaud phenomenon 
• 
Pregnancy  
• 
Atenolol is absolutely contraindicated in pregnancy 
 
Absolute contraindications: 
• 
Allergy 
• 
Cardiogenic shock and hypotension 
• 
Pheochromocytoma 
 


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These contraindications are less relevant because these issues would have already been considered 
by their usual prescribing physicians prior to the study. To be clear, we will not be initiating a new 
prescription of beta-blocker for subjects; all subjects enrolled will have already be prescribed beta-
blocker at the time of enrollment into the study.   
 
7.2 Availability 
 
Subjects will have been prescribed beta-blockers by their physician. Subjects will thus continue to 
obtain their beta-blockers in this manner. When modifications are made to the dosage, the study 
team will advise if their tablet or pill may be halved. In instances where the pill cannot be halved, the 
study team will prescribe a new dosage, which will be sent to the subject’s pharmacy. 
 
7.3 Acquisition and Accountability  
 
 
 
Prescriptions for beta-blocker may be provided by prescribers in the HFpEF Program as needed. 
 
7.4 Dosing and Administration 
 
We have created a down-titration schedule, where we will reduce the dose of each beta-blocker by 
50% every week, a schedule used in a prior deprescribing study of antihypertensives, that included 
beta-blockers. This schedule accounts for a sufficient number of half-lives to ensure drug clearance 
and accounts for changes in receptor density and related adrenergic hypersensitivity linked to 
withdrawal symptoms and ADWEs observed after abrupt beta-blocker cessation. Re-initiation/up-
titration will be done in reverse order. Subjects will never go on a dosage higher than their usual home 
dose. All drugs will be administered orally. To assist subjects with dose reduction, each subject will 
receive pill cutters. 
 
 
 
7.4.1 
Dosing Delays/Dose Modifications 
 
We do not anticipate any dosing delays or dose modifications outside of the aforementioned 
down-titration and up-titration schedule. However, dosing changes and other adaptations to the 
dosing schedule will be up to the discretion of the PI if clinical findings arise.  
 
7.5 General Medication Inventory and Supportive Care Guidelines 
 
All concomitant medications will be recorded and/or updated on subject medication log throughout 
the course of the study. 
Table 4: Examples of drug down-titration schedule for selected β-blockers 
Examples 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5+6 
Metoprolol 200mg daily 
100mg daily 
50mg daily 
25mg daily 
12.5mg daily 
Off 
Carvedilol 50mg BID 
25mg BID 
12.5mg BID 
6.25mg BID 
3.25mg BID 
Off 
Bisoprolol 10mg daily 
5mg daily 
2.5mg daily 
Off 
Off 
Off 
Atenolol 100mg daily 
50mg daily 
25mg daily 
12.5mg daily 
Off 
Off 
Betaxolol 20mg daily 
10mg daily 
5mg daily 
2.5mg daily 
Off 
Off 
Nebivolol 40mg daily 
20mg daily 
10mg daily 
5mg daily 
Off 
Off 
Nadolol 320mg daily 
160mg daily 
80mg daily 
40mg daily 
Off 
Off 
Propranolol 40mg BID 
20mg BID 
10mg BID 
5mg BID 
Off 
Off 
Acebutolol 600mg BID 
300mg BID 
150mg BID 
75mg BID 
Off 
Off 
Penbutolol 80mg daily 
40mg daily 
20mg daily 
10mg daily 
Off 
Off 
Pindolol 30mg BID 
15mg BID 
7.5mg BID 
Off 
Off 
Off 
Labetalol 1200mg BID 
600mg BID 
300mg BID 
150mg BID 
Off 
Off 


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7.6 Duration of Therapy and Criteria for Removal from Study 
 
We do not anticipate treatment delays. In the setting of a treatment delay due to an adverse event, 
continued study participation will depend on: 
o 
Disease progression 
o 
Intervening illness that prevents further administration of treatment, 
o 
Unacceptable adverse event(s), 
o 
Subject decision to withdraw from the study, 
o General or specific changes in the subject’s condition render the subject ineligible for further 
treatment in the judgment of the investigator. 
 
7.7 Duration of Follow Up 
 
Six, nine, and twelve months after the end of intervention we will access the electronic health record 
to assess vital status, hospitalizations, emergency department visits and whether or not the subject is 
taking a beta-blocker. 
 
7.8 Measures to Minimize Bias: Randomization and Blinding  
 
This study will not be blinded. The study team will conduct randomization using a WCM-approved 
randomization tool. 
 
7.9 Study Intervention/Follow-up Compliance 
 
Study team will ensure the protocol is followed as written. Protocol can be modified per subject 
feedback. 
 
Remote monitoring will occur on a daily basis. Subjects will be provided with a tablet computer and 
blood pressure cuff free-of-charge. These data will be automatically uploaded to an online portal, 
which we will review weekly. 
 
Telephone calls will occur on a weekly basis, during each call we will request information regarding 
drug compliance. Telephone calls may be eliminated during the last 2 weeks of each period. If unable 
to contact the subject via telephone, we will attempt through email. 
 
For subjects that are potentially lost to follow-up, we will make at least four attempts to contact them, 
in a 4-week time frame, via telephone and/or email. We will also inquire about their status from their 
physician, as well as through their electronic health records. 
 
A subject will be considered lost to follow-up if we are unable to contact them after 4 attempts in 4 
weeks. 
 
7.10 Blood for Future Research 
 
Subjects will be given the opportunity to participate in a voluntary component of the study, where we 
will draw blood samples for future research. Subjects will be informed of risks, benefits and 
alternatives. Up to 30 ml of blood will be obtained. For subjects who have a blood specimen that is 
insufficient in volume, a repeat blood draw may be performed at their next visit.  


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Blood draws for future research will follow similar processing and storage procedures as outlined in a 
companion WCM-approved IRB (Protocol 19-05020216 – Next Generation Sequencing & Molecular 
Characterization of Cardiovascular Diseases) that supports the HFpEF/Cardiovascular biobank.  
 
Subjects who consent to this additional component will have an additional 2 tubes of blood drawn at 
the baseline visit, as well as at the end of period 1 and end of period 2. 
 
8. Study Intervention Discontinuation and Subject Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
If consented subjects are intolerant or unwilling to proceed with dose modification, we will continue 
to follow them through the course of the study (if subject is willing). Remaining study procedures will 
be completed as indicated by the study protocol. If a clinically significant finding is identified 
(including, but not limited to changes from baseline) after enrollment, the investigator will determine 
if any change in subject management is needed. Any new clinically relevant finding will be reported 
as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Concomitant Medications 
• 
Decision making outcomes questionnaire 
• 
Short Physical Performance Battery 
• 
Adverse Events/SAE 
 
8.2 Subject Discontinuation/Withdrawal from the Study 
 
Subjects are free to withdraw from participation in the study at any time if they wish. 
An investigator may discontinue or withdraw a subject from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the subject (this will be 
decided on conjunction with their own physician and/or the DSMB). 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the subject meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
• 
Subject lost to follow-up after several attempts to contact subject to schedule study visit. 
 
The reason for subject discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF) in REDCap. Subjects who sign the informed consent form and are randomized but 
do not receive the study intervention may be replaced. Subjects who sign the informed consent form, 
and are randomized and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will be replaced. 
 
 
 


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8.3 Lost to Follow Up 
 
A subject will be considered lost to follow-up if we are unable to contact them after four attempts in 
4 weeks. 
 
The following actions must be taken if a subject fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the subject, reschedule the missed visit within five business 
days, counsel the subject on the importance of maintaining the assigned visit schedule, and 
ascertain if the subject wishes to and/or should continue in the study. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subjects. These contact attempts will be documented in the 
subject’s medical record or study file.  
• 
Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
9. Correlative/Special Studies  
 
Not applicable. 
 
10.  Measurement of Effect 
 
Not applicable 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, and 
efficacy data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC. It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group-based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures. REDCap is maintained on CTSC-owned servers that are backed up nightly and 
support encrypted (SSL-based) connections. Nationally, the software is developed, enhanced, and 
supported through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
 
 
11.1.2 Smart Watches, Tablet Computers and Internet Capable Devices 
 
Subjects will be provided with Garmin wearable devices. Garmin devices will function as a typical 
Garmin device. Data will be exported from the Garmin devices directly onto an ITS-tagged, WCMC-
issued computer. It will then be transferred onto our WCMC server and deleted from the 
computer. We will codify data in order for us to conduct data analysis and to share with subjects 
and their physicians. 
 


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Although the devices will be used primarily to collect step-count, we will collect all relevant health 
data the device provides, including, but not limited to calories burned, floors climbed, and 
distance traveled. 
 
Phillips internet capable tablet computers will be provided to subjects for remote monitoring. 
These devices are already in use in the HFpEF Program. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained before study initiation.  
Before initiation of the study, the protocol, the ICF, other written material given to the subjects, 
and any other relevant study documentation will be submitted to the appropriate Ethics 
Committee. Written approval of the study and all relevant study information must be obtained 
before the study center can be initiated. Any necessary extensions or renewals of IEC/IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, or other 
study documentation. The written approval of the IEC/IRB together with the approved ICF must 
be filed in the study files. The Investigator will report promptly to the IEC/IRB any new information 
that may adversely affect the safety of the subjects or the conduct of the study. The Investigator 
will submit written summaries of the study status to the IEC/IRB as required. On completion of 
the study, the IEC/IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form and will 
be signed and dated by the original protocol approving signatories. All protocol amendments will 
be submitted to the relevant institutional IEC/IRB for approval before implementation, as 
required by local regulations. The only exception will be when the amendment is necessary to 
eliminate an immediate hazard to the trial subjects. In this case, the necessary action will be taken 
first, with the relevant protocol amendment following shortly thereafter. Weill Cornell Medicine 
must approve all consent form changes prior to local IRB submission. Relevant study 
documentation will be submitted to the regulatory authorities of the participating countries, 
according to local/national requirements, for review and approval before the beginning of the 
study. On completion of the study, the regulatory authorities will be notified that the study has 
ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the ethical 
principles based on the Declaration of Helsinki, GCP, ICH guidelines and the applicable national 
and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable ethics 
committees and investigations will be undertaken by scientifically and medically qualified 
persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-GCP 
and local regulations, as applicable, from each potential subject or each subject’s legally 


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31
authorized representative prior to participating in the research study. Subjects who agree to 
participate will sign the approved informed consent form and will be provided a copy of the signed 
document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided to the 
subject must approved by IRB prior to use. The ICF will adhere to IRB/IEC requirements, applicable 
laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to http://www.clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate trial locations and trial site contact 
information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study, all documents and data 
relating to the study will be kept in an orderly manner by the Investigator in a secure study file.   
 
12. Statistical Considerations 
 
To provide statistics to the subjects when sharing key outcomes, we will compare PROs between Periods 
A (On) and Periods B (Off) using a linear or generalized linear mixed effects model that will include the 
fixed effects of beta-blocker, treatment effect (A vs B), period effect (1, 2, 3, 4 etc.) and a patient-level 
random intercept to account for within-patient repeated measurements. The period fixed effect will 
estimate the effects of down-titration/up-titration and the time-dependent treatment effect will estimate 
On vs. Off effect. We will also explore period-specific fixed effects for treatment and compare the models 
using Akaike Information Criterion. As an exploratory analysis, we will also test the pattern of activity as a 
function of time in specialized statistical models called functional data model.  
 
 Power: The study team will have 80% power to detect a within-patient difference of 1.1 standard 
deviations in the four outcomes at an α=1.67% (after controlling for Type I error inflation due to three 
outcomes). While power for these analyses will be modest, they will provide pilot data necessary for a 
future proposal to the National Institute of Health (NIH) and/or Patient-Centered Outcomes Research 
Institute (PCORI) to conduct a larger multi-center randomized controlled trial to determine whether 
discontinuation of BB in HFpEF can improve outcomes relevant to older adults including function and 
quality of life. 
 
Power: The co-primary objective is to determine features of a feasible and pragmatic protocol for 
deprescribing N-of-1 trials, which will be done through an iterative stakeholder-engaged process (C.1.2). 
The goal is not to establish safety and/or efficacy here. Thus, power calculations for this Aim are less 
relevant.  
 


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       12.1 Study Design/Endpoints 
We will collect data on physical function, patient-reported outcomes, decision parameters, patient 
activation, and attitudes toward deprescribing. 
 
12.2 Sample Size/Accrual Rate 
 
 
We plan to enroll one subject/month for 16 months. 
 
12.3 Stratification Factors  
 
Not applicable 
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Endpoints 
 
The study team will compare the On-arm to the Off-arm for the 4 main outcomes of interest—
vitals collected via remote monitoring, step-count, peak oxygenation uptake, short physical 
performance battery score, and patient-reported outcome domains. To achieve this, analysis 
will use a general linear mixed effects model, where fixed effects of BB, period effect (Period 
1 or Period 2) and carry-over effect will be included. In addition, a patient-level random 
intercept will be added to the model to account for within-patient repeated measurements. 
To control for inflation of Type I error due to testing multiple outcomes, the Holm’s stepdown 
procedure  will be used. The overall Type I error will be set at 5% and all statistical analyses 
will be two-sided. 
 
1. Vitals collected via Remote Monitoring. A general linear mixed effects model will be used, 
comparing daily pulse and blood pressure averages of the On and Off arms. The study team 
will analyze data from the timeframe during which BB is completely stopped (“Off” when 
participating in the Off-arm) and at usual dose (“Full dose” when participating in the On-arm); 
this will occur during the last 2 weeks each Period (see Figure 1). The study team will utilize a 
general analytic framework to analyze average blood pressure and pulse during each period.  
 
2. Physical activity (via step-count).  A general linear mixed effects model will be used, comparing 
daily step-count averages of the On and Off arms.  The study team will analyze data from the 
timeframe during which BB is completely stopped (“Off” when participating in the Off-arm) and 
at usual dose (“Full dose” when participating in the On-arm); this will occur during the last 2 
weeks of each Period (see Figure 1).  The study team will utilize a general analytic framework to 
analyze average daily step-count during each period. As an exploratory analysis, the study team 
will also perform analysis that will visualize and test the pattern of activity as a function of time in 
specialized statistical models called functional data model developed for this purpose. The study 
team will then test the differences in the properties of these curves between the two treatment 
groups.  
 
3. Function (via short physical performance battery).  A general linear mixed effects model will be 
used, comparing the short physical performance battery score of the On and Off arms. 


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4. Exercise capacity (via peak oxygen consumption during exercise).  A general linear mixed effects 
model will be used, comparing VO2 of the On and Off arms. 
 
5. Patient-reported outcomes (PROs).  A general linear mixed effects model will be used, comparing 
each patient-reported outcome domain (HF-specific quality of life, fatigue, depression, 
anxiety, sleep, physical function, social role, and pain) of the On and Off arms.  The study 
team will analyze data from the timeframe during which BB is completely stopped (“Off” when 
participating in the Off-arm) and at usual dose (“Full dose” when participating in the On-arm); 
this will occur during weeks 5 and 6 of each Period, or the last two weeks of the period.  (see 
Figure 1).   
 
6. Subject Qualitative Interviews. Directed content analysis methods will be used to develop 
relevant categories and themes from interview transcript data. Coding will be conducted 
through the coding platform Dedoose. Transcripts will be analyzed by two team members, 
consulting additional members to establish consensus where needed. Inter-rater reliability 
between coders will be established using a Cohen's Kappa score. 
 
To provide statistics to the subjects when sharing key outcomes, we will compare PROs between 
Periods A (On) and Periods B (Off) using a linear or generalized linear mixed effects model that 
will include the fixed effects of beta-blocker, treatment effect (A vs B), period effect (1, 2, 3, 4 
etc.) and a patient-level random intercept to account for within-patient repeated measurements. 
The period fixed effect will estimate the effects of down-titration/up-titration and the time-
dependent treatment effect will estimate On vs. off effect. We will also explore period-specific 
fixed effects for treatment and compare the models using Akaike Information Criterion.  As an 
exploratory analysis, we will also test the pattern of activity as a function of time in specialized 
statistical models called functional data model.  
 
12.5 Interim Analysis 
 
We will primarily conduct analysis and track AE/SAEs in anticipation of our DSMB meetings. We will 
also conduct analysis of the primary and secondary endpoints. The DSMB will review the study 
outcomes in an unmasked fashion (study is not blinded).  
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
Not applicable 
 
12.6.2 Evaluation of Response 
 
Not applicable. 
 
 


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13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The investigator will 
be required to provide appropriate information concerning any findings that suggest significant hazards, 
contraindications, side effects, or precautions pertinent to the safe use of the drug or device under 
investigation. Safety will be monitored by evaluation of adverse events reported by subjects or observed 
by investigators or research staff. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) 
and with any route of administration, formulation, or dose, including an overdose.  
 
 
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) 
 
Adverse events are not expected, but the following are risks are possible: 
 
i) Risks associated with down-titration/discontinuation of beta-blocker: Adverse drug 
titration events including tachycardia, worsened hypertension, palpitations, diaphoresis, 
and shortness of breath, heart failure exacerbation, angina, myocardial infarction, 
cerebrovascular accident, arrhythmia, hospitalization, and death (shown to occur with 
abrupt cessation of beta-blocker)  
ii) Risks associated with beta-blocker use (and re-initiation/up-titration):  Adverse drug 
events or adverse drug reactions including bradycardia, heart block, hypotension, 
dizziness, fatigue, depression, confusion, heart failure exacerbation, cerebrovascular 
accident, hospitalization, and death  
iii) Risks associated with wearing the Garmin wearable device:  Local skin irritation, wrist 
pain  
iv) Risks associated with subject interviews: Emotional distress related to answering 
interview questions, and breach of confidentiality 
v) Risks associated with CPETs:  musculoskeletal injury, arrhythmias, acute coronary 
syndrome, hemodynamic instability, cardiovascular collapse, death 
vi) Risks associated with Short physical performance battery: falling, musculoskeletal 
injury. 
vii) Risks associated with the 6-minute walk test: fatigue, dizziness. 
viii) Risks associated with blood draws: pain or bruising, dizziness, infection at the site of 
the blood draw 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
 
The following procedures will be used to document adverse events: 
 
A vignette will be created describing the i) date of the event, ii) the date that study personnel 
became aware of the event, iii) clinical circumstances surrounding the event including 
precipitating events, iv) action taken by study personnel including treatment, and v) outcome of 
the event.  This will be documented by PI Goyal. 


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Adverse events will be graded per Common Terminology Criteria for Adverse Events version 5.0 
criteria. Grade refers to the severity of the AE. 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL7 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL8 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
 
Relatedness of the AE: This will be determined by Dr. Goyal, by using the following: 
• Definitely Related 
• Probably Related 
• Possibly Related 
• Not Related to the Research 
 
Expectedness of the AE: This will be determined by Dr. Goyal (Yes/No): 
• 
Unexpected: Those that differ from AEs highlighted in Section 13.1.1 in nature, severity 
or frequency  
• 
Expected: Those consistent with AEs highlighted in Section 13.1.1 in nature, severity, or 
frequency 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be maintained by 
the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB and DSMB 
 
All AEs occurring on this study will be reported to the WCM IRB according to the WCM IRB policy, 
which states that expected and unexpected adverse events, grades 3-5, should be reported on 
the Adverse Event & IND Safety Reporting Cumulative Table. These AEs will be reported at 
continuing review. 
 
Adverse events which meet ALL of the following 3 conditions will be reported within 7 calendar 
days of PI awareness: 
 
1. The harm is “unexpected” when its specificity and severity are not reflected in the 
informed consent form; AND 
2. The harm is “related” or “possibly related” AND 
3. The harm that places subjects at a greater risk of harm than previously known or 
recognized  
 
 
 
7 Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
8 Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 


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WCM DSMC 
All Adverse events which meet ALL of the following 3 conditions will be reported within 7 calendar 
days of PI awareness: 
 
1. The harm is “unexpected” when its specificity and severity are not reflected in the 
informed consent form; AND 
2. The harm is “related” or “possibly related” AND 
3. The harm that places subjects at a greater risk of harm than previously known or 
recognized  
 
13.1.5 Reporting Events to Subjects 
 
Not applicable. We are not performing diagnostic studies; we do not anticipate any incidental 
findings. 
 
AEs and SAEs will not be reported directly to subjects, unless otherwise instructed to by the DSMB. 
(All AEs and SAEs will be reported to the DSMB.) 
 
 13.1.6 Events of Special Interest 
 
Not applicable. 
 
13.1.7 Reporting of Pregnancy 
 
Not applicable. 
 
13.2 Definition of SAE 
 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• 
Fatal 
• 
Life threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe 
• 
Requiring in-patient hospitalization or prolongation of existing hospitalization. 
• 
Resulting in persistent or significant disability or incapacity 
• 
Congenital anomaly or birth defect 
• 
Medically significant: refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered 
to be SAEs when, based upon medical judgement, they may jeopardize the subject, 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions above. 
 
The following reasons for hospitalization are not considered as SAES: 
• 
Hospitalization for cosmetic elective surgery, or social and/or convenience reasons 
• 
Hospitalization for pre-planned surgery or standard monitoring of a pre-existing 
disease or medical condition that did not worsen 
 


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13.2.1 Reporting of SAE to IRB & DSMC 
 
 
WCM IRB:  
All SAEs occurring in this study will be reported to the IRB according to the IRB policy. IRB policy 
states that SAEs should be reported within 7 days if the following criteria are met:  
 
• 
The SAE is unexpected and not reflected in the ICF 
• 
The SAE is related or possibly related 
• 
The SAE places subjects at a greater risk of harm than previously known or recognized 
 
At yearly continuing reviews, all AEs and SAEs grade 3-5 that are either expected or unexpected 
must be reported.  
 
WCM DSMC: 
Immediate reports for SAEs will be submitted to the DSMC within 7 calendar days of PI awareness 
if they meet all the following criteria: 
 
1. The harm is “unexpected” when its specificity and severity are not reflected in the 
informed consent form; AND 
2. The harm is “related” or “possibly related” AND 
3. The harm that places subjects at a greater risk of harm than previously known or 
recognized  
 
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-Investigator] 
 
Not applicable. 
 
 
13.3 AE/SAE Follow Up 
 
In addition to reporting all adverse events, the study team will take all appropriate measures to 
ensure that subjects will have access to necessary medical care. Any acute change in medical 
condition will be reported to the subject’s physician for follow-up care. All information about the 
study will be provided to the caring physician. As this study is not blinded, there will be no masking 
issue with regard to providing optimal medical care. All study procedures will be discontinued at 
the treating physician’s request, the subject’s request, and/or as judged appropriate by the 
principal investigator.  In the case of any emergency situation, the study physicians will institute 
any emergency aid needed and then make arrangements for transportation to the Emergency 
Department. All research subjects will have access to medical care if an adverse event occurs. The 
subject and/or the insurance carrier will be billed for this care. Subjects will not receive special 
compensation for injury solely because they are subjects in the study. All subjects are fully 
informed about this policy as part of the informed consent process.  
 
For SAEs that are determined to be “possibly related” or “related”, the subject will be assessed, 
evaluated, and treated for any potential recurrence and according to the seriousness of the 
symptoms. Based on the information gathered, it will then be determined whether the subject 
should be removed from the study or continue their participation.  
 
 


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13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study subject presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the subject is screened will be considered as 
baseline and not reported as an AE. However, if the study subject’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The study coordinator or the principal investigator will record all reportable events with start dates 
occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for 
SAEs) after the last day of study participation. At each study visit, the investigator will inquire about 
the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. The following table provides examples of actions that may be taken 
following selected adverse events. 
 
 
Adverse Event  
Typical Action 
Hospitalization 
Medical management including beta-blocker management as recommended by treating physician. If 
hospitalization unrelated to study and not contraindicated following discussion between investigators 
and hospital care team, subject will continue to follow protocol while hospitalized.  
Worse or new arrhythmia  
Emergent care if indicated including admission and necessary medications/interventions.  Subject 
withdrawal from the study. 
Cerebrovascular accident 
Emergent care if indicated including admission and necessary medications/interventions.  Subject 
withdrawal from the study. 
Myocardial infarction 
Emergent care if indicated including admission and necessary medications/interventions.  Subject 
withdrawal from the study. 
Angina 
Emergent care if indicated including admission and necessary medications/interventions.  Subject 
withdrawal from the study. 
Heart failure exacerbation 
Emergent care if indicated including admission and IV diuretics. For non-emergent issues, standard 
review and adjustment of medications.  Medical management including beta-blocker management as 
recommended by treating physician.  If exacerbation unrelated to the study and not contraindicated 
following discussion between investigators and treating physician, subject will continue to follow 
protocol. 
Shortness of breath 
Evaluation of volume status, adjustment of medications.  Medical management including beta-blocker 
management as recommended by treating physician.  If exacerbation unrelated to the study and not 
contraindicated following discussion between investigators and treating physician, subject will 
continue to follow protocol.  
Worsened hypertension 
Emergent care if indicated including admission and IV antihypertensive agents. For non-emergent 
issues, standard review and management of oral medications. If unrelated to the study and not 
contraindicated following discussion between investigators and treating physician, subject will 
continue to follow protocol. 


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14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO) 
 
[The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks 
to subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of 
the subject population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing Institutional 
Review Board (IRB). The UPIRTSO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the following 
timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DSMB within 3 days of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor within 7 
days of the investigator becoming aware of the problem.  
 
15. Data and Safety Monitoring Plan (DSMP) 
 
We plan to use the WCM DSMB for this trial, as this a resource provided to the WCM scientific community, 
and they have the necessary expertise and infrastructure to act as a DSMB for this trial. All AEs and SAEs 
will be reported to the DSMB. AEs where the harm is unexpected, the harm is “related” or “possibly 
related,” and the harm suggests that the research places subjects at greater risk of harm than previously 
known, an immediate report will be submitted within 7 calendar days of the PI awareness. We will record 
seriousness, relatedness and expectedness of the adverse event, as determined by Dr. Goyal. We will 


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report when the AE occurred, as well as when the study team became aware of the AE. We will collect 
any medical documentation pertaining to the AE. If treatment must be stopped, this determination will 
be made by Dr. Goyal with the subject. Because all subjects will have been on study drug before initiating 
the trial, and we will not exceed their home dose, we do not anticipate having to terminate study 
treatment.  
 
 
The DSMB will convene to review the study data after each cohort of 4 subjects.