BLOCKade of Calcium Channels and Beta Adrenergic Receptors for the Treatment of Hypertension in Heart Failure With Preserved Ejection Fraction (BLOCK HFpEF) Trial
Phase: PHASE4
Conditions: Heart Failure With Preserved Ejection Fraction, Hypertension
Sponsor: University of Pennsylvania

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BLOCKade of calcium channels and beta adrenergic receptors for the treatment of hypertension 
in Heart Failure with Preserved Ejection Fraction (BLOCK HFpEF) 
 
 
Principal Investigator 
Jordana Cohen, MD, MSCE 
Renal-Electrolyte and Hypertension Division 
Center for Clinical Epidemiology 
Perelman School of Medicine, University of Pennsylvania 
(267) 588-7914 
jco@pennmedicine.upenn.edu 
 
 
Co-Investigators 
Julio Chirinos, MD, PhD 
Raymond Townsend, MD 
Jesse Chittams, MS 
Regulatory Sponsor 
University of Pennsylvania 
Funding Sponsor 
National Heart, Lung and Blood Institute (NHLBI) 
Protocol Number 
 
IRB Number 
V8 
 
833517 
 
 
Version 
2 December 2024  
 

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Protocol 
 
BLOCKade of calcium channels and beta adrenergic receptors for the treatment of hypertension 
in Heart Failure with Preserved Ejection Fraction (BLOCK HFpEF) 
 
1. Background and Specific Aims ............................................................................................................................................ 5 
2. Trial Summary ................................................................................................................................................................... 10 
3. Study Design and Population ............................................................................................................................................ 12 
3.1 Overview of the study design ..................................................................................................................................... 12 
3.2 Study sites ................................................................................................................................................................... 12 
3.3 Study population ......................................................................................................................................................... 12 
3.3.1 Inclusion Criteria .................................................................................................................................................. 12 
3.3.2 Exclusion Criteria .................................................................................................................................................. 13 
3.3.3 Criteria that will prompt discontinuation from trial participation at the four-week visit ................................... 14 
3.4 Randomized intervention ........................................................................................................................................... 14 
4. Study Visits and Procedures .............................................................................................................................................. 15 
4.1 Screening and baseline visits ...................................................................................................................................... 15 
4.1.1 Visit 0: Screening visit .......................................................................................................................................... 16 
4.1.2 Visit 1: Baseline study visit ................................................................................................................................... 17 
4.2 Randomization procedure .......................................................................................................................................... 18 
4.3 One-week (5-7 day) pre-treatment home BP assessment .......................................................................................... 18 
4.4 Intervention Phase A ................................................................................................................................................... 18 
4.4.1 Post-randomization home BP measurements ..................................................................................................... 18 
4.4.2 One-week call ....................................................................................................................................................... 19 
4.4.3 Visit 2: Intervention Phase A Endpoint Assessment ............................................................................................ 19 
4.5 One-week washout period .......................................................................................................................................... 20 
4.6 Intervention Phase B ................................................................................................................................................... 20 
4.6.1 Post-randomization home BP measurements ..................................................................................................... 20 
4.6.2 One-week call ....................................................................................................................................................... 20 
4.6.3 Visit 3: Intervention Phase B Endpoint Assessment ............................................................................................ 20 
4.7 Subject withdrawal/early termination ........................................................................................................................ 21 
4.8 Concomitant medication ............................................................................................................................................. 21 
5. Additional details regarding study measurements and data collection ........................................................................... 21 
5.1 Assessment of exercise capacity ................................................................................................................................. 21 

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5.2 Quality of life assessment ........................................................................................................................................... 22 
5.3. Measurement of late systolic load and arterial wave reflections ............................................................................. 22 
5.4 Physical Activity ........................................................................................................................................................... 22 
5.5. Assessment of the systemic vasodilatory response to exercise ................................................................................ 23 
6. Statistical considerations .................................................................................................................................................. 23 
6.1 Power calculations ...................................................................................................................................................... 23 
6.2. Data Analysis Plan ...................................................................................................................................................... 23 
6.3 Timing and Rationale for Unblinding .......................................................................................................................... 25 
7. Adverse Events .................................................................................................................................................................. 25 
7.1. Key definitions ............................................................................................................................................................ 25 
7.1.1 Adverse Event ...................................................................................................................................................... 25 
7.1.2 Suspected Adverse Reaction ................................................................................................................................ 25 
7.1.3 Serious Adverse Events (SAE) ............................................................................................................................... 25 
7.2. Classification of AE/ADEs ........................................................................................................................................... 26 
7.2.1 Classification of Adverse Events for Causal Relationship to Study Interventions ................................................ 26 
7.2.2 Classification of Adverse Events Regarding Severity Scale .................................................................................. 26 
7.2.3 Expectedness ....................................................................................................................................................... 27 
7.3 Recording and Reporting of Adverse Events ............................................................................................................... 28 
7.4 Follow-up .................................................................................................................................................................... 28 
7.5 Management of Suspected Unexpected Serious Adverse Reaction ........................................................................... 28 
7.6 Pregnancy .................................................................................................................................................................... 28 
8. Protection of Human Subjects .......................................................................................................................................... 29 
8.1 Potential benefits of the proposed research, importance of the knowledge to be gained, and risk/benefit ratio ... 29 
8.1.1 Potential benefits ................................................................................................................................................. 29 
8.1.2 Importance of the knowledge to be gained ........................................................................................................ 29 
8.1.3 Risk/benefit ratio ................................................................................................................................................. 29 
8.2 Risks to study subjects ................................................................................................................................................ 29 
8.2.1 Potential Risks of Study Interventions (Amlodipine Besylate and Metoprolol Succinate): ................................. 30 
8.2.2. Potential Risks of Study Procedures ................................................................................................................... 30 
8.2.3 Pregnancy Risks .................................................................................................................................................... 31 
8.3 Adequacy of Protection Against Risks ......................................................................................................................... 31 
8.3.1 Recruitment and Informed Consent .................................................................................................................... 31 
8.3.2 Protection Against Risks Associated with Cardiopulmonary Exercise Tests ........................................................ 32 
8.3.3 Protection Against Risks from Amlodipine .......................................................................................................... 32 

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8.3.3 Protection Against Risks from Metoprolol ........................................................................................................... 32 
8.3.4 Supine and Orthostatic Blood Pressure Measurements ...................................................................................... 32 
8.3.5 Safety Clinical Laboratory Tests ........................................................................................................................... 32 
8.3.6 Side Effect Management Plan .............................................................................................................................. 33 
8.3.7 Other Measures to Minimize Risk ........................................................................................................................ 33 
9. Study Administration, Data Handling, Record Keeping .................................................................................................... 33 
9.1 Confidentiality ............................................................................................................................................................. 33 
9.2 Subject Privacy ............................................................................................................................................................ 33 
9.3. Data Disclosure and Protection ................................................................................................................................. 34 
9.4 Data Collection and Management .............................................................................................................................. 34 
9.5 Records Retention ....................................................................................................................................................... 35 
10. Regulatory Standards ...................................................................................................................................................... 35 
10.1 Informed Consent/HIPAA Authorization ................................................................................................................... 35 
10.2 Institutional Review Board (IRB) ............................................................................................................................... 35 
10.3 Investigational New Drug (IND) Application ............................................................................................................. 35 
10.4 Auditing and Inspecting ............................................................................................................................................ 35 
11. Study Finance .................................................................................................................................................................. 35 
11.1 Funding Source .......................................................................................................................................................... 36 
11.2 Conflict of Interest .................................................................................................................................................... 36 
11.3 Subject Stipends or Payments................................................................................................................................... 36 
12. Publication and Dissemination Plan ................................................................................................................................ 36 
13. References ...................................................................................................................................................................... 37 
Appendix 1. Anticipated Study Timeline and Key Dates ....................................................................................................... 46 
Appendix 2. History of Protocol Changes ............................................................................................................................. 48 
 
 
 

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1. Background and Specific Aims 
 
Heart failure (HF) affects >5 million individuals in the US. Approximately half of individuals with HF have a 
preserved left ventricular (LV) ejection fraction (EF), termed HF with preserved EF (HFpEF). HFpEF is associated with high 
morbidity, mortality, and impaired quality of life. While there are several effective pharmacologic therapies for HF with 
reduced ejection fraction (HFrEF), none have been identified to clearly improve outcomes in HFpEF. Hypertension, which 
is present in approximately 80% of individuals with HFpEF, is the foremost modifiable risk factor for the development 
and progression of HFpEF. Current guidelines recommend β-blockers – but not calcium channel blockers (CCBs) – as first-
line antihypertensive therapy in HFpEF; this is contrary to hypertension guidelines in the general population and is based 
on limited evidence. Despite the clinical importance of hypertension in HFpEF, sparse randomized controlled trial (RCT) 
data exist evaluating the mechanistic role of common antihypertensive agents, particularly CCBs and β-blockers, in the 
management of HFpEF. We propose a novel mechanistic investigation regarding the role of dihydropyridine CCBs 
compared to β-blockers in targeting key physiologic abnormalities in HFpEF. 
HFpEF is characterized by unique physiologic abnormalities that may be differentially impacted by β-blockers 
and CCBs. HFpEF is associated with a greater blood pressure (BP) response to β-blockers than HFrEF, suggesting 
beneficial effects of β-blockers in this patient population. Excessive β-adrenergic stimulation may also be a driver of 
reduced aerobic capacity in HFpEF, which could respond favorably to β-blockade. However, in HFpEF, prolonged 
diastasis caused by the negative chronotropic effect of β-blockers may reduce cardiac output, particularly during 
exercise, contributing to impaired cardiac output reserve and aerobic limitations. β-blockers may also have effects on 
the pattern of ventricular contraction and arterial load, potentially impacting diastolic function. Similarly, CCBs may have 
beneficial effects related to vasodilation and reduction in late systolic load beyond their BP-lowering effect. However, 
CCB-induced vasodilation at rest may limit the vasodilatory reserve. Despite the high prevalence of hypertension in 
HFpEF and the important potential effects of β-blockers and CCBs on determinants of exercise capacity and quality of 
life, it is unknown which agent class has a more favorable impact in this patient population.  
Our study team has combined expertise in antihypertensive physiology and pharmacoepidemiology, HFpEF, 
arterial hemodynamic measurements, and exercise physiology. Our goal is to assess the mechanisms by which CCBs 
and β-blockers (commonly used antihypertensive agents in clinical practice), impact aerobic capacity and quality of 
life in HFpEF. We will compare the impact of a dihydropyridine CCB (amlodipine besylate 5-10mg daily) vs. a β1-selective 
β-blocker (metoprolol succinate 100-200mg daily) on densely measured home BP, physical function, quality of life, 
arterial function, chronotropic reserve, vasodilatory reserve, and LV function among 50 subjects with HFpEF in a 
randomized crossover trial design. Participants will receive 4 weeks of each intervention, with a 1-week washout period 
in-between. 
 
Specific Aim 1: To determine the effect of β-blocker therapy, compared to CCB therapy, on key clinical endpoints: 
blood pressure (BP), aerobic capacity, and quality of life. 
Hypothesis 1a: β-blocker and CCB therapy will differ in their effect on densely measured home BP. 
Hypothesis 1b: β-blocker and CCB therapy will differ in their effect on peak aerobic capacity (peak VO2). 
Hypothesis 1c: β-blocker and CCB therapy will differ in their effect on quality of life, as determined using the Kansas 
City Cardiomyopathy Questionnaire (KCCQ). 
 
Specific Aim 2: To determine the mechanisms by which β-blocker vs CCB therapy may differentially impact aerobic 
capacity and quality of life. 
Hypothesis 2a: β-blocker and CCB therapy will differ in their chronotropic effects during exercise. 
Hypothesis 2b: β-blocker and CCB therapy will differ in their impact on vasodilatory reserve.  

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Hypothesis 2c: β-blocker and CCB therapy will differ in their impact on arterial load, including resistive and pulsatile 
afterload assessed with gold-standard central pressure-flow analyses.  
Hypothesis 2d: β-blocker and CCB therapy will differ in their impact on LV systolic function (LV longitudinal strain) 
and diastolic function assessed with doppler echocardiography.  
 
Specific Aim 3: To assess if changes in BP and cardiovascular function measured in Aim 2 mediate the effect of CCB 
and β-blocker therapy on aerobic capacity and quality of life. We will perform formal explanatory analyses to assess 
which mechanistic factors have differential effects on these clinical endpoints. 
 
Our mechanism-driven approach will provide evidence-based guidance regarding the management of 
hypertension in HFpEF, enhance our understanding of the pathophysiology of HFpEF, and characterize the physiologic 
potential of these common antihypertensive agents to reduce progression and improve symptom management in this 
disease.  
 
A1. Heart failure with preserved ejection fraction (HFpEF) is a critical public health problem. Heart failure (HF) affects 
over 2% of adults in the United States (US) and is a major source of morbidity, mortality, and impaired quality of life.1-3 
Approximately 10% of adults age 75 years or older have a diagnosis of HF, and HF is the leading cause of hospitalization 
in adults age 65 years or older.4  Accordingly, HF is associated with over $21 billion in direct health care costs in the US 
annually.2 Among individuals with HF, left ventricular (LV) ejection fraction (EF) provides an important phenotypic 
distinction with regard to the pathophysiology of HF5 and response to pharmacologic therapy.6-8 Between 46 and 54% of 
individuals with HF have a preserved LVEF, termed HF with preserved EF (HFpEF).1, 3, 5  
 
The prevalence of HFpEF has increased disproportionately compared to HF with reduced EF (HFrEF). The incidence and 
prevalence of HF have risen in recent decades. With the aging of the population, the prevalence of HF is projected to 
increase by 46% between 2012 and 2030.2 In 2012, there were an estimated 915,000 new cases of HF in the US,9 
compared to 670,000 cases in 2007.10 The relative prevalence of HFpEF is increasing compared to that of HFrEF,1, 11 
strongly suggesting that the population-wide burden of HFpEF will exceed that of HFrEF in the coming decades.3 
 
HFpEF is a malignant disease associated with premature mortality, high risk of hospitalization, and poor quality of life. 
Patients with HFpEF have a similarly high incidence of HF hospitalization, mortality, and impaired quality of life as those 
with HFrEF.11, 12 Approximately half of individuals who develop HF die within 5 years of diagnosis.9 Following HF 
hospitalization, the 5-year survival in HFpEF has been demonstrated to be as low as 35-40%.1 An estimated 50% of the 
deaths in HFpEF are attributed to cardiovascular causes.3 
 
A2. There is an urgent need to identify therapies that target mechanisms of pathophysiologic progression of HFpEF. 
Multiple therapies have been identified that provide substantial clinical benefit in HFrEF. In contrast, no interventions 
currently exist that clearly reduce adverse outcomes in patients with HFpEF.7, 8 The disproportionate rise in the 
prevalence of HFpEF relative to HFrEF highlights the growing need for targeted pharmacologic therapy in HFpEF. Our 
proposal aims to evaluate the effect of commonly used and understudied antihypertensive agents on key physiologic 
abnormalities in HFpEF, including blood pressure (BP), arterial vasodilator reserve, and late systolic LV load from arterial 
wave reflections. Altering these mechanisms has the potential for both immediate-term improvements in exercise 
tolerance and long-term disease-modifying effects. Furthermore, individuals with HFpEF are often older than those with 
HFrEF,3, 11 and may benefit more from targeting factors related to disease progression, symptoms, and quality of life 
than mortality alone. Our proposal will address the potential benefit of CCBs and β-blockers in HFpEF using endpoints 
with direct clinical relevance. The study will help us to better understand specific physiologic mechanisms involved in the 
progression of HFpEF and identify potential differential benefits from these common antihypertensive agents.  
 
A3. Hypertension is the foremost modifiable risk factor for the development and progression of HFpEF. The increasing 
prevalence of HFpEF is partly attributed to rising rates of hypertension globally.11, 13 Based on data from the Framingham 

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Heart Study, individuals with a systolic BP >160 mmHg have double the lifetime risk of HF compared to those with a 
systolic BP <140 mmHg.9, 14 Correspondingly, treatment of hypertension reduces the risk of developing HF.15, 16 
Hypertension is more commonly associated with development of HFpEF than HFrEF.3, 11 Studies have shown that 80%-
90% of individuals with HFpEF have a diagnosis of hypertension.11, 17 Hypertension is a crucial target for therapeutic 
interventions in these patients due to its high burden and important pathophysiologic role in disease progression in 
HFpEF.  
 
A4. There is insufficient evidence to guide the treatment of hypertension in HFpEF. Diuretics play a central role in the 
management of symptoms related to volume overload in HFpEF. Guidelines otherwise recommend the use of β-
blockers, angiotensin converting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers (ARBs) to control blood 
pressure in patients with HFpEF, based largely on expert opinion.18, 19 Most studies evaluating the effectiveness of 
antihypertensive medications in reducing adverse outcomes in HFpEF have focused on agents that inhibit the renin-
angiotensin aldosterone system.7, 8 Overall, these studies failed to consistently demonstrate meaningful effects of 
treatment with ACE-Is or ARBs on diastolic function, quality of life, HF hospitalizations, or mortality.8, 20 Although the 
prevention of diabetic nephropathy may compel the use of ACE-Is or ARBs in HFpEF, BP control usually required 
additional antihypertensive medications. Mineralocorticoid antagonists seem to reduce the risk of HF hospitalization; 
however, mineralocorticoid antagonists are associated with high rates of hyperkalemia and do not have any consistent 
benefit with regard to exercise tolerance, quality of life, or mortality.7, 8, 20-22  
 
Sparse randomized controlled trial (RCT) data exist evaluating the role of β-blockers and CCBs in the management of 
hypertension in HFpEF.8 For the management of hypertension in the general population, dihydropyridine CCBs are 
recommended as first-line agents, while β-blockers are not recommended for first-line therapy.23 Nonetheless, β-
blockers are used more commonly than CCBs for the treatment of hypertension in HFpEF. In the Treatment of Preserved 
Cardiac Function Heart Failure with an Aldosterone 
Antagonist (TOPCAT) trial, 91% of participants had 
a diagnosis of hypertension; among these, 78% of 
were on β-blockers at baseline, while only 38% 
were on CCBs;7 these patterns of antihypertensive 
use were similar after excluding individuals with 
atrial fibrillation. β-blockers have consistently been 
demonstrated to reduce the risk of mortality in 
HFrEF.18, 19 However, few RCTs have evaluated the 
role of β-blockers for the management of 
hypertension in HFpEF, with inconclusive findings. 
Meta-analyses of data from three RCTs suggest 
that β-blockers may reduce cardiovascular 
mortality in HFpEF compared to placebo or usual 
care (hazard ratio [HR] 0.75, 95% confidence 
interval [CI] 0.60-0.9420), with no effect on HF 
hospitalization or quality of life.8, 20 These RCTs 
were limited in quality, and used definitions for 
HFpEF that are not consistent with current 
guidelines (HFpEF was defined using an LVEF 
threshold of ≥35%24 or ≥40%,25, 26 compared to the 
consensus definition of LVEF ≥50%19). To the best 
of our knowledge, no RCTs have evaluated CCBs 
for the management of hypertension in HFpEF. 
 
A5. The pathophysiologic relationship between 
hypertension and HFpEF is multifaceted, with 
Figure 1. Conceptual model: Overview of the complex 
pathophysiologic relationship between hypertension and 
HFpEF 

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several overlapping cardiac and vascular mechanisms. HFpEF is physiologically complex, with a number of contributing 
etiologies. HFpEF and hypertension are characterized by several interrelated mechanisms, including chronic activation of 
the renin-angiotensin aldosterone system27-29 and sympathetic nervous system,30 and abnormal calcium handling  
(Figure 1).31 Hypertension-mediated abnormalities in intrinsic myocardial and arterial mechanics have a major role in the 
development and progression of HFpEF.32 Pressure overload due to hypertension promotes LV hypertrophy and cardiac 
fibrosis.33 In individuals with hypertension, increased arterial stiffness, endothelial dysfunction, and renally-driven 
volume overload further drive the development and worsening of HFpEF.34-38 Targeting hypertension-mediated 
mechanisms in HFpEF has the potential to improve exercise tolerance and cardiac function, and in turn reduce the long-
term risk of adverse outcomes.  
 
A6. Several pathophysiologic factors contribute to exercise intolerance in HFpEF. Exercise intolerance is a salient 
feature of HFpEF and determines quality of life in these patients.12, 39, 40 Therefore, enhancing exercise capacity in HFpEF 
is an important objective with immediate clinical relevance. The underlying mechanisms contributing to exercise 
intolerance in HFpEF are important to consider when attempting to achieve this unmet goal. The early pathophysiologic 
paradigm of HFpEF was a failure to recruit the Frank-Starling mechanism to augment stroke volume during exercise due 
to an inadequate increase in end-diastolic volume in response to increased LV filling pressure.41 Several studies also 
reported depressed chronotropic reserve,42-46 attributed to abnormal responses to adrenergic activity.44 However, 
various studies have not demonstrated abnormal end-diastolic LV volume during exercise,42, 47 stroke volume reserve 
(i.e., increase during exercise),42-44 or chronotropic incompetence.47 Consequently, rather than resulting exclusively from 
cardiac abnormalities, HFpEF is now seen as a multifaceted disease process with a need to address not only cardiac, but 
also peripheral abnormalities.48 
 
Exercise arterial vasodilatory reserve is abnormal in HFpEF, leading to reduced O2 utilization and excessive LV 
afterload. Peak oxygen uptake (VO2) during exercise, the most widely accepted index of aerobic capacity, is consistently 
reduced in HFpEF.37, 41-44 Peripheral oxygen utilization requires adequate cardiac output during exercise in addition to 
adequate flow distribution. HFpEF is associated with endothelial dysfunction that results in reduced vasodilatory 
reserve.36, 49 Impaired vasodilatory reserve plays an important role in oxygen delivery and extraction. Vasodilatory 
responses during exercise are important for reducing LV afterload. During exercise, LV afterload must decrease to 
accommodate increases in cardiac output without excessive rise in blood pressure. In several studies, patients with 
HFpEF had blunted exercise-induced reductions in systemic vascular resistance compared to age-matched hypertensive 
subjects without HF.37, 47 This reduced vasodilatory reserve leads to an energetically-inefficient ventricular-arterial 
coupling state during exercise.37 In addition, the abnormal vasodilatory reserve has profound implications for peripheral 
oxygen delivery and utilization. The peripheral ability to redistribute flow to working muscle is a key component of the 
normal response to exercise.50 This flow distribution depends on the vasodilatory response in locomotive muscle, 
allowing it to effectively “compete” for the available cardiac output.50  
 
A7. Wave reflections and late systolic load play an important role in the pathophysiology of HFpEF. Late systolic 
pulsatile load from wave reflections, which are increased in HFpEF,51 have adverse long-term consequences on LV 
remodeling and function. Wave reflections increase the late systolic workload of the LV and profoundly impact the LV 
loading sequence (late relative to early systolic load).52-56 The pulse wave generated by the LV travels forward in arteries 
and is partially reflected at sites of impedance mismatch (i.e., bifurcations, points of change in arterial size or wall 
stiffness, predominantly in middle-sized conduit arteries).52, 53, 57 Wave reflections travel back to the heart, merging into 
a discrete reflected wave, and arrive while the LV is still ejecting blood in mid-to-late systole.53, 57  The magnitude and 
timing of wave reflections strongly predicts incident HF.34, 35, 56, 58 Hashimoto et al. demonstrated that changes in 
reflection magnitude during antihypertensive therapy are associated with regression of LV mass independent of blood 
pressure reduction.59 Our group has demonstrated that, for any given level of systolic and diastolic blood pressure, a 
greater area under the pressure curve in late systole (relative to early systole) is strongly predictive of incident HF.60 Our 
findings implicate late systolic load from arterial wave reflections as a novel strong risk factor for HF, supporting animal 
and human mechanistic findings from previous studies34, 35, 52-59, 61 and demonstrating the relevance of late systolic load 
in humans. 

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All of these pathophysiologic mechanisms may be impacted differentially by CCBs vs. β-blockers in HFpEF. Despite the 
high clinical importance of this issue and common use of these drugs in HFpEF, no evidence is available comparing the 
effect of these agents on BP, exercise capacity, and quality of life in this population. Furthermore, no mechanistic data 
are available regarding the effects of these agents on the various determinants of exercise impairment in HFpEF.  
 
A8. The understudied role of β-blockers and dihydropyridine CCBs in HFpEF. Although β-blockers are recommended as 
first-line antihypertensive therapy in HFpEF18, 19 there is inconsistent evidence regarding their potential role in disease 
progression and symptom management.62-65 While two RCTs showed mortality benefit from β-blocker use in HFpEF,26, 65 
the Swedish Doppler Echocardiographic Study demonstrated worsening of heart failure symptoms with randomized 
treatment with carvedilol compared to placebo.64 β-blockers are highly beneficial in HFrEF because they reduce 
sympathetic activity, myocardial oxygen demand, and cardiac remodeling.66 There are no clear data regarding whether 
chronic sympathetic nervous system activation, which plays a major role in the progression of systolic dysfunction in 
HFrEF, has a similar role in HFpEF. Some evidence suggests that increased adrenergic activity may have adverse effects 
on exercise capacity in HFpEF.67 For example, there is in vivo evidence that β-adrenergic receptor stimulation provokes 
systolic and diastolic dysfunction in HFpEF.30 Individuals with HFpEF seem to have a greater BP response to β-blockers 
than individuals with HFrEF.63 However, the hemodynamic effects of heart rate lowering (i.e. with the use of β-blockade) 
have not been evaluated in HFpEF.68 Prolonged diastasis (“stand still” without active filling) caused by slowing the heart 
rate with a β-blocker may limit cardiac output reserve during exercise, which is an important component of oxygen 
consumption for any given peripheral oxygen extraction,69 thus worsening exercise tolerance.64 Given inconsistent 
evidence on the clinical effects of β-blockers in HFpEF, there is great need to better understand their mechanistic 
effects. 
 
The vasodilating effects of CCBs may reduce LV afterload and improve aerobic capacity in HFpEF. Dihydropyridine CCBs 
are recommended as first-line therapy for hypertension in the general population23 due to widely demonstrated 
effectiveness in reducing BP and cardiovascular risk, along with a favorable side effect profile.70-72 Observational 
evidence suggests no mortality benefit from treatment with CCBs in HFpEF.73 However, there are no existing trials 
evaluating the potential role of CCBs in HFpEF. While CCBs are generally well-tolerated in individuals with HFrEF, they do 
not improve aerobic capacity, LV function, or mortality risk.74-76 Nonetheless, in the general population, CCBs have 
beneficial effects related to vasodilation and arterial function beyond their BP-lowering effect.77, 78 These vasodilatory 
properties may reduce LV afterload and improve O2 utilization in HFpEF. Additionally, HFpEF is characterized by impaired 
systolic and diastolic reserve, attributed to elevated end-systolic and diastolic volume resulting in limited stroke volume 
response during exercise. This maladaptive response to exercise is likely in part due to abnormal calcium handling.31 In 
animal models, cardiac calcium handling in HFpEF is different than in HFrEF. In contrast to reduced cardiomyocyte 
calcium availability in HFrEF,79 Curl et al.’s Hypertrophic Heart Rat model of HFpEF exhibits high calcium availability.80 
These findings suggest that CCBs may improve systolic and diastolic reserve, which could improve exercise tolerance in 
HFpEF.  
 
In summary, multiple physiologic considerations suggest potentially beneficial and deleterious effects of β-blockers 
and CCBs in HFpEF. Despite the common use of these agents, studies comparing their mechanistic and clinically 
relevant effects are lacking. There is a compelling need for a randomized trial to fill this important knowledge gap. 
 
 

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2. Trial Summary 
 
Trial Title/Acronym 
BLOCKade of calcium channels and beta adrenergic receptors for the treatment 
of hypertension in Heart Failure with Preserved Ejection Fraction (BLOCK HFpEF) 
 
Funding Opportunity Announcement 
PAR-18-406 
 
Proposed Funding Agency 
National Heart, Lung, and Blood Institute, National Institutes of Health 
 
Number of Subjects 
50 
 
Study Site 
University of Pennsylvania 
 
Randomized Intervention 
Amlodipine besylate 5mg to 10mg daily for approximately four weeks versus 
metoprolol succinate 100mg to 200mg daily for approximately four weeks 
 
Primary Aim 
To compare the BP-lowering effect of amlodipine besylate and metoprolol 
succinate therapy by home BP monitoring in HFpEF 
 
Secondary Aims 
1.  To compare the effect of amlodipine besylate and metoprolol succinate 
therapy on aerobic capacity 
 
2.  To compare the effect of amlodipine besylate and metoprolol succinate 
therapy on quality of life 
 
3.  To compare the effect of amlodipine besylate versus metoprolol succinate 
therapy on LV diastolic function and arterial load 
 
Exploratory Aims 
1.  To assess if amlodipine besylate and metoprolol succinate have differential 
effects in men versus women, African Americans versus non-African 
Americans, and diabetic versus non-diabetic subjects 
 
2.  To compare the effect of amlodipine besylate versus metoprolol succinate 
therapy on: 
 
 
A) Non-dipping measured using home BP monitoring (novel) 
 
 
B) BP variability using home BP monitoring 
 
 
C) Ventilatory threshold and VO2 kinetics 
 
Primary Endpoint 
Difference in mean home systolic BP after four weeks of amlodipine besylate 
versus metoprolol succinate 
 
Secondary Endpoints 
1. Difference in mean office systolic BP 
 
2.  Difference in mean home diastolic and office diastolic BP 
 
2. Difference in mean home pulse pressure and office pulse pressure 
 
3.  Total work performed and peak oxygen uptake (VO2) during a symptom-
limited maximal effort exercise test 
 
4. Quality of life score, assessed using the Kansas City Cardiomyopathy 
Questionnaire 

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5. Measures of LV diastolic function, including E/e’ and brain natriuretic peptide 
 
6. Measures of arterial load, including arterial wave reflection, central systolic 
blood pressure, augmentation index, pulse pressure amplification, and 
forward and backward wave amplitudes 
 
 

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3. Study Design and Population 
 
3.1 Overview of the study design 
 
1) This is a randomized double-blind crossover trial in which fifty (50) subjects with HFpEF will be assigned to 
treatment with: 
A) Amlodipine besylate 5mg to 10mg by mouth daily for approximately four weeks; 
B) Metoprolol succinate 100mg to 200mg by mouth daily for approximately four weeks. 
2) The order of the interventions (AB-BA design) will be randomized, with an approximately one-week washout 
period separating each intervention. 
3) The crossover design will expose each subject to both treatments, reducing inter-subject variability and 
maximizing statistical power to evaluate the comparative effectiveness of amlodipine versus metoprolol in 
this patient population. 
4) The drugs will be prepared at the Investigational Drug Pharmacy at the University of Pennsylvania and 
dispensed by an investigational drug pharmacist, blinded to both the subjects and investigators. 
 
3.2 Study sites 
 
The study will take place at the Hospital of the University of Pennsylvania; participants will be recruited from cardiology, 
primary care, and renal clinics affiliated with the University of Pennsylvania and the surrounding community (PCAM, 
Penn Presbyterian, and 3701 Market St). 
 
3.3 Study population 
 
We will enroll fifty (50) subjects during the study. Eligibility will be determined by the PIs according to the following 
criteria. 
 
3.3.1 Inclusion Criteria 
 
1) Adults age 18-90 years 
2) Diagnosis of hypertension defined by at least two of the following: 
A) ICD-9 (401.0-404.91) or ICD-10 (I10-I13) codes signifying hypertension 
B) Treatment with antihypertensive medication other than a loop diuretic for at least two months 
C) History of previous blood pressure readings ≥130/80 mmHg at two separate office visits 
3) Stable antihypertensive therapy; defined as no changes in antihypertensive medications in the preceding 30 
days 
4) A diagnosis of heart failure in the medical chart or per the investigators’ clinical judgement based on a clinical 
picture consistent with heart failure (e.g., dyspnea on exertion, paroxysmal nocturnal dyspnea, and/or edema in 
the setting of echocardiographic or hemodynamic measurements consistent with heart failure; or probability of 
HFpEF ≥90% according to the H2FpEF score81 or clinical presentation highly suggestive of HFpEF without a more 
likely clinically apparent cause for symptoms, as determined by the HFpEF screening working group that includes 
several cardiologists) 
5) LV ejection fraction >50% 
6) Elevated filling pressures defined by at least one of the following criteria: 
A) Mitral E/e’ ratio (lateral or septal) >8 with low e’ velocity (septal e’ <7 cm/s or lateral e’ <10 cm/s) and at 
least one of the following: 

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a. Enlarged left atrium (LA volume index >34 ml/m2) 
b. Chronic loop diuretic use for management of symptoms 
c. Elevated natriuretic peptides (BNP levels >100 ng/L or NT-proBNP levels >300 ng/L) 
B) Mitral E/e’ ratio (lateral or septal) >14 
C) Previously elevated invasively determined filling pressures based on one of the following criteria: 
a. Resting LVEDP >16 mmHg 
b. Mean PCWP >12 mmHg 
c. PCWP or LVEDP ≥25 mmHg with exercise 
D) Previous acutely decompensated heart failure requiring IV diuretics 
 
3.3.2 Exclusion Criteria 
 
1) Systolic BP meeting any of the following criteria: 
A) Current office systolic BP <100 mmHg 
B) Current office systolic BP 100-119 mmHg if not receiving treatment with an antihypertensive agent or if 
holding antihypertensive medication prior to randomization would be clinically contraindicated, as per 
the investigator’s clinical judgement 
C) Current office systolic BP ≥180 mmHg if not receiving treatment with a CCB or β-blocker, or ≥160 mmHg 
if already receiving a CCB and/or β-blocker prior to the pre-randomization wash-out period 
D) Orthostatic hypotension defined as >20 mmHg decline in office systolic BP 3-5 minutes following the 
transition from sitting to standing position 
2) Resting heart rate <50 or >100 bpm 
3) Contraindication to withholding CCB or β-blocker therapy (e.g. use of non-dihydropyridine CCB [diltiazem or 
verapamil] or β-blocker for rate control for atrial fibrillation) as per the investigator’s clinical judgement 
4) Children, fetuses, neonates, prisoners, and pregnant women (women of childbearing age will undergo a 
pregnancy test during the screening visit) are not included in this research study. 
5) Inability/unwillingness to exercise 
6) Any the following echocardiographic findings: 
A) LV ejection fraction <45% on any prior echocardiogram, unless it was in the setting of uncontrolled atrial 
fibrillation/flutter or other arrhythmia, as per investigator judgment 
B) Hypertrophic, infiltrative, or inflammatory cardiomyopathy 
C) Clinically significant pericardial disease, as per investigator judgment 
D) Greater than moderate left-sided valvular disease, any degree of mitral stenosis 
E) Severe right-sided valvular disease 
F) Severe right ventricular dysfunction 
7) Active coronary artery disease, defined as any of the following: 
A) Acute coronary syndrome or coronary intervention in the past 2 months 
B) Ischemia on stress testing without either subsequent revascularization or a subsequent angiogram 
demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator 
judgement 
8) Clinically significant lung disease, defined as any of the following: 
A) Chronic Obstructive Pulmonary Disease meeting GOLD criteria stage III or greater 
B) Treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease 
C) The use of daytime supplemental oxygen 
9) Primary pulmonary arteriopathy 
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11) Any medical condition that, under the investigator’s discretion, will interfere with safe completion of the study 
or validity of the endpoint assessments 
12) Known history of an allergy or clinically significant sensitivity (as determined by the investigator) to either 
amlodipine besylate or metoprolol succinate 
 
3.3.3 Criteria that will prompt discontinuation from trial participation at the four-week visit 
 
1) New onset coronary artery disease defined as any of the following: 
A) New onset angina 
B) Acute coronary syndrome or coronary intervention for unstable coronary artery disease after 
enrollment 
C) New onset ischemia on a clinically indicated stress test after initial enrollment 
2) New clinically indicated treatment with a CCB or β-blocker that cannot be withheld as per the investigator’s 
judgement 
3) Any new medical condition that, under the investigator’s discretion, will interfere with safe completion of the 
study or the validity of the endpoint assessments 
 
Subjects who meet the following criteria will not be immediately discontinued, but will be scheduled for an ad-hoc 
additional visit for reassessment of values prior to initiation of the crossover drug: 
 
1) Office systolic BP <90 mmHg 
2) Symptomatic bradycardia (resting heart rate <50 bpm), or asymptomatic resting heart rate <45 bpm 
3) Resting heart rate >110 bpm 
 
If these criteria persist during the ad-hoc visit, the subject will be discontinued from the study. 
 
3.4 Randomized intervention 
 
The following interventions will be implemented in random order, separated by an approximately one-week washout 
period: 
 
1) Amlodipine besylate: Amlodipine besylate tablets will be purchased and placed into oral gelatin capsules with an 
inert filler (lactose monohydrate). Capsules will be prepared at the University of Pennsylvania Investigational 
Drug Service. Each capsule will contain 5mg amlodipine besylate. The dose for this trial will be 5mg daily, titrated 
up to 10mg daily for a home systolic BP ≥130 mmHg and heart rate ≥50 bpm after the first week of use. 
2) Metoprolol succinate: Metoprolol succinate tablets will be purchased and placed into identical oral gelatin 
capsules with an inert filler (lactose monohydrate). The does for this trial will be 100mg daily, titrated up to 
200mg daily for a home systolic BP ≥130 mmHg and heart rate ≥50 bpm after the first week of use. 
 
We are randomizing patients because randomization provides a much more robust study design than non-randomized 
assignment to allow for assessment of differential effectiveness across these two medications. There is also no potential 
harm in randomizing the order of administration of these medications to the subjects. We selected a crossover study 
design, with individuals serving as their own controls in a randomized, AB/BA design. Our goal was to maximize the 
statistical power with an intentionally small sample size to optimize feasibility of recruitment and implementation.82, 83 

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4. Study Visits and Procedures 
 
A letter may be sent to potential subjects or they may be contacted by phone prior to initial in-person contact. 
 
An overview of the study design is presented in Figure 1, below: 
 
Figure 1. Overview of the study design and procedures 
 
 
 
4.1 Screening and baseline visits 
 
During the baseline and screening phase, subjects will take part the following steps: 
1) Initial screening for eligibility and consent (Visit 0) 
2) Approximately two-week washout period (if appropriate) 
3) Approximately one week of pre-randomization home BP monitoring, and  
4) Baseline study visit (Visit 1) 
 

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4.1.1 Visit 0: Screening visit 
 
Screening visit procedures include the following, which are described in greater detail below: 
1) Informed consent (obtained prior to any study procedures) 
2) Eligibility assessment 
3) Urine pregnancy test (if applicable) 
4) Medical history and concomitant medications 
5) Vital signs assessment 
6) Home BP device education 
 
During the screening visit, inclusion and exclusion criteria will be reviewed to ensure subject suitability for the study. 
Written informed consent will be obtained using Institutional Review Board (IRB) approved documents. Informed 
consent will be obtained before any study procedures are performed. Subjects will be given the opportunity to have all 
questions regarding their participation answered in detail in a private setting before entering the study. 
 
Following informed consent, vital signs will be measured including orthostatic blood pressure measurement. A urine 
pregnancy test will be performed in women of childbearing age. Medical history and concomitant medications will be 
assessed to determine if a two-week pre-randomization washout period is required. 
 
Subjects will also be educated on the correct use of the home BP monitor (Omron BP8000-M HeartGuide,84 Omron 
Healthcare Co., Ltd., Kyoto, Japan or Microlife BP 3MX1-4 WatchBP Home N,85 Microlife Corporation, Taiwan, ROC). 
 
4.1.1.1 Optional approximate two-week pre-randomization washout period 
 
Discontinuation of the study drugs will be necessary prior to performing the baseline measurements because the study 
will assess for differences in the outcome measures compared to the absence of either medication, and to enable blind 
randomization. If individuals are receiving treatment with a CCB or β-blocker prior to the screening visit or if they require 
discontinuation of another antihypertensive medication to achieve a sufficient BP to tolerate the addition of a new 
antihypertensive medication (i.e. screening systolic BP 100-119 mmHg), they will enter an approximate two-week 
washout period during which they will not receive the medication. In individuals who are receiving a fixed-dose 
combination of antihypertensive medication that includes a CCB or a β-blocker, the non-CCB/non-β-blocker drug(s) in 
the fixed-dose combination will be provided separately by IDS at the start of the washout period, if appropriate based 
on the baseline blood pressure (I.e., if it does not also need to be held due to a low systolic BP). In individuals who are 
receiving a high dose β-blocker (see Table, below, for qualifying doses), we will reduce the dose by ½ of their current 
dose every other day for one week followed by withholding the medication for approximately one week.86, 87 This 
discontinuation of medication is expected to cause an increase in blood pressure by an average of 10 mmHg and no 
more than 20 mmHg.88 Given the anticipated increase in blood pressure during the washout period, we will ask 
participants to contact us immediately by phone with any home BP readings ≥180 mmHg for assessment by one of the 
investigators to determine if they require referral to the emergency department (including determination if they require 
treatment for hypertensive emergency). We will also contact participants approximately 2 days after discontinuation or 
each down-titration step of their antihypertensive to assess the last 48 hours of home BP readings via phone call. Any 
individuals with a systolic BP ≥180 mmHg will be discontinued from the study. 
 
Table. Total daily dose of β-blocker treatment qualifying for taper 
Acebutolol  
800 mg 
Betaxolol  
20 mg 
Nebivolol  
40 mg 
Bisoprolol  
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Pindolol  
60 mg 
Carvedilol  
50 mg 
Atenolol  
100 mg 
Nadolol  
120 mg 
Metoprolol succinate  
200 mg 
Metoprolol tartrate  
400 mg 
Labetalol  
800 mg 
Carteolol  
10 mg 
Penbutolol  
40 mg 
Propranolol IR  
480 mg 
Propranolol LA  
320 mg 
 
4.1.2 Visit 1: Baseline study visit 
 
In individuals who do not require a washout period, the baseline visit will occur on the same day as the screening visit. 
Baseline visit procedures include the following, which are described in greater detail below: 
1) Physical exam (including repeat vital signs assessment if washout was required) 
2) KCCQ 
3) ECG 
4) Blood (CBC, comprehensive metabolic panel, NTproBNP) and urine collection (UPr/UCr) 
5) 6-minute walk test 
6) 2D echocardiogram 
7) Arterial tonometry 
 
A physical examination will be performed, including an ECG (and repeat vital sign assessment if a washout period was 
necessary). The Kansas City Cardiomyopathy Questionnaire (KCCQ) will be administered. Blood will be collected for 
measurement of a complete blood count, comprehensive metabolic panel, and NTproBNP. Urine will be collected for 
measurement of UPr/UCr. A 6-minute walk test will also be performed during this visit. Patients who demonstrate 
significant desaturation during exercise (≤94% or a fall in SpO2 ≥5%) will be excluded from the study. 
 
Echocardiography will then be performed using a standardized protocol. Images will be obtained from the parasternal 
long axis, short axis, apical 5-, 4-, 3-, and 2-chamber, subcostal, and suprasternal views for offline analysis of myocardial 
strain. Dedicated ventricular chamber images will be obtained in the 4- and 2-chamber apical positions for 
determination of left ventricular volumes. Mitral inflow velocities, including color M-mode interrogation, will be 
assessed in the 4-chamber view. Tissue Doppler imaging will be performed at the mitral septal position, approximately 
1-cm apical to the mitral valve plane. Additional images will be obtained in the parasternal short axis at the level of the 
papillary muscles, 2-chamber, and 4-chamber apical views for assessment of myocardial strain. Pulse-wave Doppler 
interrogation of the left ventricular outflow tract (LVOT) will be performed in the apical 5-chamber view. 
 
Concurrent arterial tonometry will be performed using a high-fidelity tonometer at the carotid, femoral, and radial 
arteries, using a Sphygmocor device. Waveforms will be calibrated using the brachial artery blood pressures, obtained 
using a validated oscillometric device. Waveforms will be digitally-stored for off-line analysis. We will also measure BP 
using a BP+ device (Uscom, Sydney, Australia), which is an FDA-approved device that measures brachial and central 
blood pressure using a standard brachial blood pressure cuff. Body surface measurements will be made to determine 
distance between the suprasternal notch to the carotid, radial, and femoral arteries. 
 

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4.2 Randomization procedure 
 
To preserve blinding, the treatment order assignments and the associated study-specific patient identification number 
will be provided to each study Investigation Drug Service representative. Upon determination of subject eligibility into 
the trial, the Investigation Drug Service representative will determine the treatment group assignment, and will record 
the patient identification number for that study subject. Subjects will be randomized at their baseline visit, but will not 
initiate therapy until after the completion of the approximately one-week baseline pre-treatment home BP assessment. 
 
4.3 One-week (5-7 day) pre-treatment home BP assessment 
 
Immediately following the baseline visit and prior to initiating the drug for phase A, participants will be instructed to 
perform baseline home BP monitoring using the Omron HeartGuide or Microlife WatchBP Home N. They will receive 
instructions to strictly perform the BP measurements while sitting with their back supported, following a 5-minute rest 
period, on a bare/unclothed wrist. Subjects will be asked to obtain two measurements, approximately 1 minute apart, in 
the morning prior to taking any antihypertensive medications and again in the evening approximately 12 hours later 
during every day of the baseline home BP assessment. An overview of the timing of the home BP measurements is 
presented in Figure 2, below: 
 
Figure 2. Timing of home BP monitoring relative to study visits 
 
 
4.4 Intervention Phase A 
 
Subjects will be randomized to either amlodipine besylate or metoprolol succinate as the first drug for Phase A. The 
initial dose for amlodipine will be 5mg daily and for metoprolol will be 100mg daily, administered in the morning. We 
will provide subjects with a 5-week supply of study medication to account for potential delays in follow up. 
 
4.4.1 Post-randomization home BP measurements 
 

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Subjects will again be asked to obtain two measurements, approximately 1 minute apart, in the morning prior to taking 
the medication and again in the evening approximately 12 hours later for 5-7 days prior to the one-week call, and again 
during the 5-7 days prior to the endpoint assessment.  
 
4.4.2 One-week call 
 
Subjects will be called by telephone approximately 7 days after initiating the drug to assess their home BPs in the 48 
hours prior to the call. If their home systolic BP is ≥130 mmHg and their heart rate is ≥50 bpm, the drug dose will be 
doubled (up to 10mg daily for amlodipine and 200mg daily for metoprolol). The presence of orthostatic symptoms (i.e. 
sustained lightheadedness upon standing) will prompt an ad hoc visit to assess for orthostatic vital signs. The presence 
of symptomatic orthostatic hypotension (20 mmHg reduction in systolic blood pressure with associated symptoms such 
as dizziness) at this visit will prompt discontinuation of participants from the trial. 
 
Subjects may experience symptoms after dose uptitration that do not prompt exclusion from the trial, as per the criteria 
noted above (for example, but not limited to, mild dizziness, fatigue). In these instances, the investigator can reduce the 
dose back to one capsule daily for the remainder of the treatment phase. 
 
If a participant reports worsening heart failure symptoms or blood pressures ≥180/100, we will perform twice weekly 
calls to obtain a symptom check and repeat blood pressure values until the participant is determined to be stable by the 
investigators. Three or more blood pressure values above this threshold or progression of symptoms will trigger a 
symptom visit and assessment for early termination from the study, per the investigators’ discretion. 
 
At approximately 3 weeks into each interventional phase, the Actigraph devices will be given to the subjects. The goal 
will be for the subjects to wear these devices during the final week of each interventional phase to look for differences 
with each therapy. The devices will be brought back by the subject at his/her next visit. 
 
4.4.3 Visit 2: Intervention Phase A Endpoint Assessment 
 
Following approximately four weeks of therapy with amlodipine or metoprolol, participants will return for endpoint 
assessments. Endpoint assessments will include the following: 
1) Collection of home BPs 
2) Physical exam 
3) Side effect and compliance assessment 
4) KCCQ 
5) ECG 
6) Blood and urine collection 
7) 2D echocardiogram 
8) Arterial tonometry 
9) Actigraphy 
10) Maximal effort supine bicycle exercise test 
11) Continuous wave near infrared spectroscopy (NIRS) to measure oxygenation of muscle tissue (optional) 
 
Physical examination with measurement of orthostatic blood pressure, pill count, side effect assessments, and KCCQ will 
be performed. A urine pregnancy test will be performed again in women of childbearing age. Subjects will then undergo 
repeat echocardiography, arterial tonometry, and blood pressure measurements (including BP+ central blood pressure 
measurements). Subjects will then perform a maximal-effort peak oxygen consumption (VO2) test using a supine bicycle 
exercise test with expired gas analysis. 
 

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4.5 One-week washout period 
 
Following the endpoint assessment, subjects will enter an approximately one-week washout period during which they 
will not receive any study medications. 
 
4.6 Intervention Phase B 
 
Following the washout period, subjects will receive either amlodipine besylate or metoprolol succinate during Phase B of 
the trial. Subjects will receive the intervention (amlodipine or metoprolol) that was not administered in Phase A, such 
that each subject will receive both study interventions in this crossover design. The one-week call and Endpoint 
Assessment Visit will be repeated, as above. We will provide subjects with a 21-day supply of study medication to 
account for potential delays in the shipment of the remainder of their medication after the one-week call. 
 
4.6.1 Post-randomization home BP measurements 
 
Subjects will again be asked to obtain two measurements, approximately 1 minute apart, in the morning prior to taking 
the medication and again in the evening approximately 12 hours later for 5-7 days prior to the one-week call, and again 
during the 5-7 days prior to the endpoint assessment.  
 
4.6.2 One-week call 
 
Subjects will again be called by telephone approximately 7 days later to assess their home BPs in the 48 hours prior to 
the call. If their home systolic BP is ≥130 mmHg and their heart rate is ≥50 bpm, the drug dose will be doubled (up to 
10mg daily for amlodipine and 200mg daily for metoprolol). The presence of orthostatic symptoms (i.e. sustained 
lightheadedness upon standing) will prompt a visit to assess for orthostatic vital signs. The presence of symptomatic 
orthostatic hypotension (20 mmHg reduction in systolic blood pressure with associated symptoms such as dizziness) will 
prompt exclusion of patients from the trial. 
 
Subjects may experience symptoms after dose uptitration that do not prompt exclusion from the trial, as per the criteria 
noted above (for example, but not limited to, mild dizziness, fatigue). In these instances, the investigator can reduce the 
dose back to one capsule daily for the remainder of the treatment phase. 
 
If a participant reports worsening heart failure symptoms or blood pressures ≥180/100, we will perform twice weekly 
calls to obtain a symptom check and repeat blood pressure values until the participant is determined to be stable by the 
investigators. Three or more blood pressure values above this threshold or progression of symptoms will trigger a 
symptom visit and assessment for early termination from the study, per the investigators’ discretion. 
 
At approximately 3 weeks into each interventional phase, the Actigraph devices will be given to the subjects. The goal 
will be for the subjects to wear these devices during the final week of each interventional phase to look for differences 
with each therapy. The devices will be brought back by the subject at his/her next visit. 
 
4.6.3 Visit 3: Intervention Phase B Endpoint Assessment 
 
Following approximately four weeks of therapy with amlodipine or metoprolol, participants will return for endpoint 
assessments. Endpoint assessments will include repeat measurements of the following: 
1) Collection of home BPs 
2) Physical exam 

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3) Side effect and compliance assessment 
4) KCCQ 
5) ECG 
6) Blood and urine collection 
7) 2D echocardiogram 
8) Arterial tonometry 
9) Actigraphy 
10) Maximal effort supine bicycle exercise test 
11) Continuous wave near infrared spectroscopy (NIRS) to measure oxygenation of muscle tissue (optional) 
 
Physical examination with measurement of orthostatic blood pressure, pill count, side effect assessments, and KCCQ will 
be performed. A urine pregnancy test will be performed again in women of childbearing age. Subjects will then undergo 
repeat echocardiography, arterial tonometry, and blood pressure measurements (including BP+ central blood pressure 
measurements). Subjects will then perform a maximal-effort peak oxygen consumption (VO2) test using a supine bicycle 
exercise test with expired gas analysis. 
 
4.7 Subject withdrawal/early termination 
 
Subjects may voluntarily withdraw from the study at any time and for any reason. Subjects may also be withdrawn at the 
investigator’s discretion. The investigator may withdraw a patient from the study due to protocol non-compliance, 
incorrect enrollment or randomization, or for any other reasons related to subject safety. The reason for study 
discontinuation will be recorded on the appropriate case report form and all such subjects will be asked to complete an 
early termination visit. 
 
During the early termination visit, we will document: 1) vital signs; 2) compliance with the medications, including pill 
count; 3) adverse effects; 4) specific reason for withdrawal. We will also collect any remaining study medications. 
 
4.8 Concomitant medication 
 
Subjects should be treated with standard of care medications for HFpEF or associated comorbidities. As per the inclusion 
criteria, subjects should be on a stable medical regimen for HFpEF prior to entry. Further adjustment of diuretics or 
blood pressure medications during the study period is discouraged and should only be performed according to new and 
clinically compelling worsening of clinical status. Subjects will be withdrawn from the study if a CCB or β-blocker is 
initiated during routine clinical care that cannot be withheld. 
5. Additional details regarding study measurements and data collection 
 
5.1 Assessment of exercise capacity 
 
We will use a supine bicycle exercise protocol in conjunction with expired gas analysis to assess oxygen consumption 
(VO2) during exercise. Subjects will perform a maximal exertion limited exercise test using a graded-exercise protocol. 
We will use a supine cycle ergometer designed for stress echocardiography (Stress Echo Ergometer 1505, Medical 
Positioning, Inc, Kansas City, MO). Subjects will undergo expired gas analysis with a Parvo Medics True One 2400 device 
(Parvo Medics, Sandy, UT), an Innocor device (Innovision Inc) or equivalent. Resistance began at 15 W for 3 minutes, 
increasing to 25 W for 3 minutes, and then increasing by 25 W every 3 minutes thereafter. Breath-by-breath information 
will be recorded. We will use custom-designed software already developed in Matlab (MathWorks, Natick, MA) at our 

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lab for offline processing and quantification of all exercise data.89 All data quantification will be blinded to treatment. 
Total work performed will be computed and exercise efficiency will be defined as (total work/total oxygen consumed). 
Sensitivity analyses will be performed excluding those individuals with a respiratory exchange ratio below a reasonable 
threshold at baseline. 
 
5.2 Quality of life assessment 
 
This will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ).90 We will administer the KCCQ to 
subjects prior to randomization and at the end of each intervention phase (4-week time point in both phases). This is a 
validated 23-item questionnaire that assess physical function, symptoms, social function, self-efficacy and knowledge, 
and quality of life. It has been used extensively in heart failure studies (http://cvoutcomes.org/pages/3214). 
 
5.3. Measurement of late systolic load and arterial wave reflections 
 
We will use a high-fidelity Millar applanation tonometer to record carotid pressure waveforms, which will be calibrated 
using brachial artery pressures. Central arterial tonometric recordings and Doppler flow velocity files will be processed 
off-line using custom-designed software written in Matlab (The Mathworks, Natick, MA) as previously described.34, 91 We 
have successfully implemented this method in multiple previous studies34, 53, 92 and have published a tutorial detailing 
our analysis methods.52, 53 After signal-averaging of pressure and flow, time alignment of carotid pressure and LV outflow 
curves will be performed to maximize concordance of the rapid systolic upstroke of pressure and flow, concordance of 
the dicrotic notch and cessation of flow, zero value of the phase angle of higher-frequency harmonics (7th to 10th) of 
input impedance, and linearity of the early systolic pressure-flow relationship.91 After computation of aortic input 
impedance, proximal aortic characteristic impedance (Zc) will be computed in the frequency domain as previously 
described.91 Pressure and flow harmonics were separated into forward and backward components using standard wave 
separation analysis.52, 53, 91 The sum of forward and backward pressure harmonics yields the forward and backward 
waves, respectively. We will assess the reflection coefficient in the first 3 harmonics. As reflection coefficient is derived 
from the ratio of two sine waves, it is a complex number with an amplitude and phase-angle, which can correspond to 
different degrees of destructive or constructive interference between forward and backward waves. Therefore, the net-
effect of reflections will be expressed as the real part of Γ, which becomes increasingly positive as pressure from wave 
reflections increases (constructive interference), and negative when destructive interference leads to a net decrease in 
pressure by wave reflections at a given harmonic.93 Since all harmonics of wave reflection contribute variably to systolic 
LV load, our primary measure of late systolic load will be the net pressure related to wave reflections during ejection in 
the time domain, which better represents the impact of reflections on LV afterload. We will first compute the product of 
flow and aortic Zc (QZc product), which represents the pressure resulting from the interaction of blood flow with aortic 
root Zc.53 The relation between QZc and measured pressure reveals the direct effect of wave reflections on the arterial 
system.94 We will therefore quantify the additional ejection-phase pressure load from wave reflections arising distal to 
the root (i.e., reflection-related pressure time integral during ejection, as the difference between measured pressure 
and the QZc product). Carotid-femoral pulse wave velocity (PWV), an index of large artery stiffness,95, 96 will also be 
measured97 using a Sphygmocor device (Atcor Medical).95 We will also measure carotid-radial PWV using the 
Sphygmocor device. 
 
5.4 Physical Activity 
 
We will measure activity level in all subjects with the Actigraph device, which has been previously validated. This device 
can be worn on the wrist, and measures acceleration each minute in the anterior-posterior, mediolateral, and vertical 
axis, and summarizes that information as a vector magnitude. The software will use this data to calculate physical 
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Actigraph device to the subjects during approximately the final week of each interventional phase. We will ask the 
subjects to put the device on and will provide informational materials to assist with device placement. We will also 
discuss device placement with the subjects at the study visits as well as over the phone as needed. Subjects will bring 
the devices to the endpoint assessment visits. Subjects will be fully oriented in the use of this device. The device may be 
removed for showering or swimming but otherwise should be worn continuously. The specific details in the use of this 
device will be provided to study subjects. We will use the average METS of activity over this time period as an estimate 
of physical activity. We will also records steps taken. 
 
5.5. Assessment of the systemic vasodilatory response to exercise 
 
Blood pressure will be measured with a validated oscillometric device at rest, at each stage of exercise and after 
exercise. Cardiac output will be measured at rest and at each stage of exercise using echocardiography. Systemic 
vascular resistance (SVR) will be calculated at rest and at peak exercise as mean arterial pressure / cardiac output. 
Systemic vasodilatory reserve will be measured as the reduction in SVR during exercise, relative to SVR at rest ([rest 
SVR– peak exercise SVR] / rest SVR). Depending on equipment availability and functionality at each site, we may also 
monitor and record muscle oxygenation in the calf (lateral aspect of left gastrocnemius) and forearm (flexor digitorum 
superficialis) during exercise non-invasively using a PortaMon98 or PortaLite near-infrared spectroscopy device (Artinis 
Medical Systems; The Netherlands).99 Both the PortaMon and PortaLite are investigational devices and not currently 
approved medical devices in the U.S. This is an exploratory metric and is optional. 
6. Statistical considerations 
 
6.1 Power calculations 
 
We will randomize 50 subjects to one of 2 sequences, each of which consists of 2 periods (AB/BA design). We considered 
a mean within-subject difference in daytime systolic BP of 5 mmHg between the therapies to be the minimum clinically 
significant difference.100 A previously published double-blind crossover trial randomized subjects with a diagnosis of 
hypertension, who were otherwise healthy, to treatment with amlodipine besylate 5-10mg daily versus metoprolol 
succinate 100-200mg daily.88 The trial demonstrated a slightly greater decline in awake ambulatory BP with metoprolol 
succinate compared to amlodipine, which did not reach statistical significance. Using standard deviations from this study 
(the most conservative standard deviation was 10.6 mmHg for the mean baseline ambulatory SBP of 148 mmHg) and 
assuming a retention rate of 85% and a within-subject correlation of 0.8, we will have 90% power at an alpha of 0.05 to 
detect a within-subject difference in mean daytime systolic BP of 5 mmHg between the different therapies and to assess 
for effect modification by sex.101 Based on the preliminary findings presented using TOPCAT data, we will also have 90% 
power to detect a 5 point difference in KCCQ score between therapies, which is considered clinically significant.102 Power 
calculations were performed using PASS16.103 
 
6.2. Data Analysis Plan 
 
The primary outcome variable will be the within-subject difference in mean daytime home SBP between the two 
therapies. All secondary outcome measures are continuous variables. The predictor of interest for all aims will be the 
intervention (amlodipine vs. metoprolol), with analyses based upon the total number of subjects randomized. Initial 
descriptive estimates of all measures will be generated for study participants at each time point by treatment group. 
Statistics will include estimates of central tendency and measures of variability, and will account for presence of 
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normalizing transformations should be applied. Outliers will be assessed via visual inspection of distributions and 
checked for accuracy.  
 
Aim 1: Our primary aim will assess the effects of amlodipine versus metoprolol on home systolic BP, aerobic capacity, 
and quality of life determined by KCCQ. An initial assessment of the treatment effect will be performed using the paired 
t-test and the non-parametric Wilcoxon sign-rank test on the difference between the paired within-subject outcome 
measures across the two therapies. This will be followed by exploratory analyses using more comprehensive linear 
mixed effects model analyses104 allowing for assessments of the treatment effect on each continuous outcome of 
interest while accounting for effects of other covariates including period, sequence, and a random subject effect nested 
within sequence. For non-normal distributed outcomes, we will use non-parametric methods or consider distribution-
stabilizing transformations.  
 
Aim 2 and 3: Our secondary outcomes involve exploratory analyses investigating mechanisms of action. In addition to 
assessing the effect of our randomized intervention on each mechanistic endpoint (Aim 2) in the same manner 
described for Aim 1, exploratory structural equation modeling will be used to evaluate associations between biologic 
mechanistic pathways and the clinical outcomes (Aim 3). The modeling will be carried out in three sequential steps: 1) 
exploratory factor analysis, 2) confirmatory factor analysis, and 3) structural equation modeling. The exploratory factor 
analysis will be based on principal axis factoring to decrease the number of variables. For both theoretical and empirical 
reasons, it will be assumed that retained factors are correlated and thus an oblique rotation method will be used. 
Measured and latent variables will be examined for co-linearity, and related variables will be combined into single 
factors with individual factor loadings. To determine the number of factors, the model will be evaluated against the 
following four rules: 1) eigenvalues greater than 1.0105; 2) Glorfeld’s106 extension of parallel analysis, where a large 
number of random correlation matrices are generated  to compare the number of eigenvalues that are significant by 
chance107; 3) high internal consistency (an α ≥0.70) for unit-weighted factors,108 and 4) interpretability.109 The heaviest 
weight will be placed on the minimum average partial and parallel analysis methods, with the scree test as a visual 
adjunct.110 The next step involves incorporating the factors into a model using confirmatory factor analysis. The model 
will be tested using goodness of fit tests to assess the overall fit of the model to the data. Various models will be tested 
and compared prior to arriving at the best fitting model. And finally, the best fitting model obtained from confirmatory 
factor analysis will incorporate a structural equation model designed to examine the links between the randomized 
intervention, the mechanistic variables, and the clinical variables assessed in the trial using mediation analysis.111, 112 
 
We are comparing multiple overlapping hypotheses related to cardiac and vascular mechanisms of HFpEF progression. 
To minimize the likelihood of Type 1 errors in our analyses (i.e. to account for multiple comparisons), we will employ a 
conservative Bonferroni approach for the comparisons of interventions.113 
 
Addressing potential confounders and mediators: Randomization should balance measured and unmeasured 
confounders across study arms. However, we will measure potential confounders, including participant demographics 
and comorbidities, and compare their distributions across arms and perform adjustments if necessary. The intervention 
groups will initially be compared within each period (time-invariant covariates will only be compared for period A) using 
ANOVA or Kruskal-Wallis analyses, depending upon whether the variables are parametric, and Fisher’s Exact tests for 
categorical variables. Significant differences between groups in these variables will result in their respective adjustment 
in the modeling of the outcome. The linear mixed-effects models will incorporate adjustments for any period effect or 
crossover effect and will include data from dropouts.114, 115 The model will include subject-specific intercepts as random 
effects, and will assume independent and identically distributed random errors within-subject. Restricted maximum 
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examined (e.g., QQ plots to assess normally distributed residuals for valid Wald tests). All mixed effects models will be 
analyzed using STATA (Statacorp LP, College Station, TX). 
 
Stratified analyses and effect modification: As demonstrated in our previous work, there are important differences in 
response to therapy and outcomes of HFpEF between men and women.116 It is important to better understand 
underlying mechanisms contributing to these observed differences across sexes. Accordingly, we will perform stratified 
analyses and will assess for effect modification by sex. We expect our study cohort to reflect the gender distribution of 
HFpEF in the general population, in which approximately 60% of patients with HFpEF are women.1-3, 101 Based on the 
anticipated distribution of men and women, we will have 90% statistical power to detect a difference in within-subject 
difference in mean daytime systolic BP of 6.9 mmHg between men and women, and 80% power to detect a 6 mmHg 
difference.101 Additional pre-specified stratified analyses will include African American vs. non-African American and 
diabetes vs. no diabetes. Exploratory analyses will evaluate effect modification by clinical HFpEF phenotypes.116, 117 We 
will also assess for effect modification by chronotropic incompetence,118 which will be determined using the heart rate 
data collected at the end of stage 1 and/or first 30 seconds of stage 2 (20 or 40 watts) of exercise testing while on beta-
blocker therapy. 
 
6.3 Timing and Rationale for Unblinding 
 
Unblinding will either occur after all subjects have been randomized and completed follow-up, or if indicated because 
the subject requires evaluation at an ad-hoc visit for potential discontinuation from the study, and the investigator 
needs to be aware of the study medication (at the investigator’s discretion) 
 
7. Adverse Events 
 
7.1. Key definitions 
 
7.1.1 Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in a subject 
whether or not considered drug or biologic related. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of the pharmaceutical product. 
 
7.1.2 Suspected Adverse Reaction 
 
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable possibility that the 
drug caused the event. “Reasonable possibility” suggests there is a causal relationship between the drug 
and the adverse event. “Suspected adverse reaction” implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
7.1.3 Serious Adverse Events (SAE) 
 

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An adverse event or suspected adverse reaction is considered serious if the investigator believes any of 
the following outcomes may occur: 
• 
Death 
• 
Life-threatening AE: Places the subject at immediate risk of death at the time of the event as it 
occurred. It does not include an AE that, had it occurred in a more severe form, might have 
caused death. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• 
Inpatient hospitalization or prolongation of hospitalization. 
• 
Congenital anomaly or birth defect. 
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition above. 
 
This determination is based on the opinion of the investigator 
 
 
7.2. Classification of AE/ADEs 
 
A medically qualified investigator must assess all AEs in terms of causal relationship to intervention, 
severity, and “expectedness” using the following guidelines. 
 
7.2.1 Classification of Adverse Events for Causal Relationship to Study Interventions 
 
Not related 
There is not a reasonable causal relationship to the investigational product 
and the adverse event. 
Unlikely related 
No temporal association or the cause of the event has been identified, or the 
drug or device is unlikely to be implicated, but there is a low  
likelihood that a causal relationship exists. 
Possibly related 
There is reasonable evidence to suggest a causal relationship between the 
drug and adverse event. 
Related 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. 
 
7.2.2 Classification of Adverse Events Regarding Severity Scale 
 
1 
Mild AE: Awareness of sign, symptom, or event, but easily tolerated; no 
treatment required 
2 
Moderate AE: Discomfort enough to cause interference with usual activity and 
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3 
Severe AE: Incapacitating, limiting usual/normal activities or significantly 
affects clinical status requiring hospitalization or prolongation of 
hospitalization. 
4 
Life-threatening or disabling 
5 
Fatal AE 
 
 
7.2.3 Expectedness 
 
The expectedness of an AE/ADE or SAR shall be determined according to the specified reference 
document containing safety information (e.g., most current product label). Any AE/ADE that is not 
identified in nature, severity, or specificity in the current study reference document(s) (e.g. protocol or 
investigator’s brochure) is considered unexpected.  
 
The following AEs are expected, disease-related events in patients with HF with preserved ejection 
fraction (HFpEF) and hypertension. 
1. Unplanned hospitalization, ER visit, or clinic visit for worsening HF 
2. Arrhythmias, particularly atrial fibrillation 
3. Sudden cardiac death 
4. Acute coronary syndrome 
5. Cerebrovascular event 
6. Venous thromboembolism 
7. Lightheadedness 
8. Worsening renal function (i.e. rising creatinine) 
9. Shortness of breath at rest or during/after exercise  
10. Fatigue at rest or during/after exercise 
11. Elevated bicarbonate (from diuresis) 
12. Low or high potassium levels (0.5 meq/L above or below the expected range; due to diuretics 
and angiotensin receptor blockers or angiotensin converting enzyme inhibitors, which are widely 
used in these patients) 
13. Rising liver enzymes 
14. Rising natriuretic peptide levels 
15. Anemia (among individuals with chronic kidney disease at baseline) 
 
The following are potential expected side effects of amlodipine besylate: 
1. Dizziness or lightheadedness 
2. Fatigue 
3. Rash 
4. Leg swelling 
5. Flushing 
6. Low blood pressure 
7. Shortness of breath or wheezing 
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9. Nausea 
 
The following are potential expected side effects of metoprolol succinate: 
1. Dizziness or lightheadedness 
2. Fatigue 
3. Rash 
4. Leg swelling 
5. Low blood pressure 
6. Slow heart rate 
7. Shortness of breath or wheezing 
8. Visual changes 
 
Amlodipine and metoprolol are commonly used antihypertensive agents; adverse events are expected to be extremely 
rare given the well-described tolerability of these medications and their widespread use in routine clinical practice. 
 
7.3 Recording and Reporting of Adverse Events 
 
The investigators will continuously supervise all aspects of the trial and review the records of the study 
subjects following each visit and at the end of their participation. The investigators will be responsible for 
ensuring that all adverse events are noted, followed and reported to the IRB. 
SAEs occurring from the time of signed informed consent to the end of Phase B will be captured on a 
CIOMS form. AEs will be classified according to the guidelines/definitions specified in section 7 of the 
protocol. Any AE rated >=3 in severity and all SAEs must be reported by the investigator or qualified 
designee to the IRB. The investigator will make an immediate determination about the necessity to modify 
the protocol, include additional information in the consent form, inform previous participants, temporarily 
hold enrollment of patients, or terminate the study. 
 
The investigator or qualified designee will enter the required information regarding the AE into the 
appropriate module of the eCRF. All study procedures and cumulative adverse events are subject to full 
IRB review at least yearly. 
 
7.4 Follow-up 
 
The investigators will record follow-up safety information according to the same process used for 
reporting the initial event as described above. The investigators will follow all safety events until 
resolution, stabilization, or the event is otherwise explained. 
 
7.5 Management of Suspected Unexpected Serious Adverse Reaction 
 
The investigators will assess all SAEs and evaluate for “unexpectedness” and relationship to study drug. 
The investigators are required to complete a report for any event identified as serious, study drug related 
and unexpected, using the CIOMS format. A copy of the report will be kept in the Regulatory Binder 
 
7.6 Pregnancy 
 

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Pregnancy is a contraindication to enrollment in the study. Pregnancy occurring during the study period, although not 
considered an SAE, must be reported. The pregnancy will be recorded on the appropriate note to file. The drug will be 
discontinued immediately and subject terminated from the trial, but the pregnancy will be followed until final outcome. 
Although the study drugs are not known to be unsafe in pregnancy, risk for the fetus has not been ruled out (Pregnancy 
Category C), and any associated AEs or SAEs that occur to the mother or fetus/child will be recorded in the AE or SAE 
case report form. 
 
8. Protection of Human Subjects 
 
8.1 Potential benefits of the proposed research, importance of the knowledge to be gained, and 
risk/benefit ratio 
 
8.1.1 Potential benefits 
 
There are no anticipated direct benefits to the subjects as a result of their participation in this study nor will this be 
implied when obtaining consent. However, if our hypothesis is correct, subjects receiving amlodipine may experience 
improvements in their functional class and quality of life, although this will not be implied in any way during informed 
consent or enrollment. 
 
8.1.2 Importance of the knowledge to be gained 
 
If our hypothesis is correct, this study may identify an effective specific intervention to treat hypertension and peripheral 
mechanistic abnormalities in HFpEF patients. Furthermore, if improving these factors leads to an enhanced exercise 
capacity in this patient population, this would lead to a new standard of care in the field and a better understanding of 
the mechanisms that lead or contribute to HFpEF. 
 
8.1.3 Risk/benefit ratio 
 
The results of this study may ultimately lead to an effective treatment of hypertension in HFpEF. Since there is minimal 
risk, with potential benefits to medical knowledge and society, the risk / benefit ratio is acceptable. 
 
8.2 Risks to study subjects 
 
This study will involve recruitment of fifty (50) human subjects, each exposed to both antihypertensive medications 
(amlodipine besylate and metoprolol succinate, in a cross-over design), and therefore individuals will be studied as their 
own controls. All subjects will be adults able to give informed consent. 
 
For the trial, we will aim to achieve adequate representation of women and African Americans. Children will not be 
enrolled. Participants will be recruited from the Hospital of the University of Pennsylvania and associated outpatient 
clinics. The planned gender and ethnic distribution will be facilitated by the diverse clinical population in the enrolling 
medical center. 
 

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The study involves various tests (arterial tonometry, echocardiography, exercise testing) and the administration of 
randomized therapies (amlodipine besylate versus metoprolol succinate).   
 
8.2.1 Potential Risks of Study Interventions (Amlodipine Besylate and Metoprolol Succinate): 
 
8.2.1.1 Amlodipine besylate 
 
The main potential risks of amlodipine administration are related to its potential effect on blood pressure. Many studies 
have demonstrated a reduction in blood pressure in both hypertensive and normal subjects following amlodipine 
administration. Therefore, we will not start the interventions in individuals below the blood pressure threshold, and we 
will implement exclusion criteria and safety blood pressure checks throughout the conduct of the study to ensure 
subject safety. Common side effects are listed in section 7.2. 
 
8.2.1.1 Metoprolol succinate 
 
The main potential risks of metoprolol administration are related to its potential effect on 1) blood pressure and 2) heart 
rate. Many studies have demonstrated a reduction in blood pressure and heart rate in both hypertensive and normal 
subjects following amlodipine administration. Therefore, we will not start the interventions in individuals below the 
blood pressure and heart rate threshold, and we will implement exclusion criteria and safety blood pressure and heart 
rate checks throughout the conduct of the study to ensure subject safety. Individuals are not eligible for this study if 
they are on medications that slow their heart rate (including β-blockers such as carvedilol, bisoprolol, and propranolol 
and calcium channel blockers such as verapamil and diltiazem), and have a contraindication to stopping these 
medications during the pre-randomization washout period. Common side effects are listed in section 7.2. 
 
8.2.2. Potential Risks of Study Procedures 
 
Potential risks are associated with the study tests, the study interventions, and potential breach of confidentiality. 
 
8.2.2.1 Cardiopulmonary stress test 
 
This test is used extensively for research purposes with minimal risk to subjects. The most significant risks of the test are 
dysrhythmias or other cardiovascular complications, which are extremely rare. These procedures will be performed by 
qualified personnel according to established American Heart Association Guidelines.119, 120 Non-revascularized 
myocardial ischemia, which may increase the risk of complications during exercise testing, is an exclusion criterion for 
the study. 
 
Subjects may feel uncomfortable as a result of pushing themselves during the maximal effort exercise test. Subjects will 
likely feel short of breath and fatigued as a result of the exercise test. Various other complaints, such as nausea, 
lightheadedness, and other aches and pains are also possible as a result of the maximal effort exercise study. Although 
exercise testing may result in exhaustion, rarely do people develop abnormal heart rate or heart complications during 
exercise tests. The risk of this happening is the same as if the participant would exert themselves during stressful 
situations or during exercise elsewhere. 
 

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We will perform ECG, heart rate, and blood pressures monitoring during our exercise test. In addition to the blood 
pressure (generally increases) and heart rate (generally increases) changes during exercise, we will also monitor arterial 
saturation. This will be done non-invasively using a pulse oximeter. Of note, oxygen levels can decrease with exercise, 
even in individuals without significant cardiopulmonary disease.121, 122 If the arterial saturation falls to below 88% 
(“severe exercise induced hypoxemia”122), we will alert the patient’s primary care provider as this may prompt 
consideration for additional or alternative causes for arterial hypoxemia. 
 
8.2.2.2 Venipuncture and IV placement 
 
According to the 2010 WHO guidelines on phlebotomy, major risks associated with blood donations include hematoma 
at the site of venipuncture in 23%, and vasovagal reactions and fainting in 1%. The placement of an intravenous catheter 
would be anticipated to increase the risk of hematoma and discomfort slightly. Given that the catheter will be in place 
for a short-period of time, infection is an unlikely complication.  
 
8.2.2.3 Arterial tonometry, central blood pressure measurement, and echocardiography 
 
Tonometry and assessments of oscillometric arterial pressure waveforms are noninvasive procedures and do not have 
any known risks. Minor discomfort may occur when the tonometer is placed against the neck, arm, and groin. 
 
The PortaMon and PortaLite (near infrared spectroscopy, or NIRS) devices have no known risks.99 They are non-invasive 
devices applied on top of the skin to measure the oxygenation of underlying tissue. 
 
During various procedures (echocardiography, arterial tonometry), we will use adhesive electrodes attached to the 
participant’s skin to record the electrical signal from the heart. These may occasionally cause skin itching and irritation. 
 
8.2.3 Pregnancy Risks 
 
We will not be enrolling subjects who are pregnant or lactating in this study. Amlodipine and metoprolol are not 
absolutely contraindicated in pregnancy and breast-feeding, however risk to the fetus has not been ruled out (Pregnancy 
Category C). Additionally, the blood pressure thresholds in this study differ from the goal blood pressures during 
pregnancy, and the study may result in changes in blood pressure and heart rate that could be dangerous to a 
developing fetus. A pregnancy test will be given to women of child-bearing potential prior to enrollment in the study and 
administration of the supplement. The pregnancy test will be repeated at Visit 2 (prior to initiation of the second 
treatment period). If a woman is enrolled of child-bearing potential, we will ask that they use a medically accepted 
method of birth control (such as an IUD, birth control combination pill, patch, ring, progestin-only pills, Depo Provera 
Shot, Implanon, complete abstinence, or condoms) while they participate in the study. As subjects with HFpEF are 
generally older (>55 years old) we do not anticipate this concern to occur with our study population. 
 
8.3 Adequacy of Protection Against Risks 
 
8.3.1 Recruitment and Informed Consent 
 
Written informed consent will be obtained from the subjects by the investigators prior to entry into the research study. 
This will be performed in accordance with the guidelines and under the supervision of the University of Pennsylvania 

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Institutional Review Board. The study procedures and interventions and the associated risks will be explained to the 
subjects during the informed consent process. Only IRB-approved consent forms and related materials will be used. 
 
8.3.2 Protection Against Risks Associated with Cardiopulmonary Exercise Tests 
 
These tests will be performed by qualified personnel according to established American Heart Association Guidelines,119 
under ECG monitoring. Personnel with adequate cardiopulmonary resuscitation training and resuscitation equipment 
(crash cart) will be available during these tests. Similarly, these tests will be performed in a hospital setting where a full 
code team can be deployed immediately should complications occur. 
 
8.3.3 Protection Against Risks from Amlodipine 
 
Subjects will be thoroughly advised regarding the potential risks of the study medication and precautions needed during 
its administration. As noted in the exclusion criteria, due to the anticipated blood pressure-lowering effect of the 
medication, individuals will be excluded if their office systolic blood pressure is 1) <100 mmHg, 2) <120 mmHg if holding 
antihypertensive medication prior to randomization would be clinically contraindicated, or 3) significant for >20 mmHg 
decline 3-5 minutes following the transition from sitting to standing. 
 
8.3.3 Protection Against Risks from Metoprolol 
 
Subjects will be thoroughly advised regarding the potential risks of the study medication and precautions needed during 
its administration. As noted in the exclusion criteria, due to the anticipated blood pressure-lowering effect of the 
medication, individuals will be excluded if their office systolic blood pressure is 1) <100 mmHg, 2) <120 mmHg if holding 
antihypertensive medication prior to randomization would be clinically contraindicated, or 3) significant for >20 mmHg 
decline 3-5 minutes following the transition from sitting to standing. They will also be excluded if their resting heart rate 
is <50, or if they are on a medication that slows their heart rate (including β-blockers such as carvedilol, bisoprolol, and 
propranolol and calcium channel blockers such as verapamil and diltiazem) with a contraindication to stopping these 
medications prior to randomization. 
 
8.3.4 Supine and Orthostatic Blood Pressure Measurements 
 
Supine vital signs will be measured at the screening visit. The subject will rest in a supine position for a minimum of 3 
minutes prior to obtaining vital sign measurements. The subject will then assume a standing position for 3-5 minutes. 
Vital signs (BP and pulse rate) will then be measured while the subject is standing. A reduction in systolic blood pressure 
>20 mmHg will be considered an exclusion criterion for the study. Blood pressure measurements will be performed at 
home by the participants throughout the study, and will be repeated after approximately four weeks of randomized 
therapy. Measurements will also be prompted by reports by study subjects of 1) systolic blood pressure <90 mmHg at 
home, 2) heart rate <50 bpm at home, and 3) orthostatic symptoms at any point during the trial. The presence of 
symptomatic orthostatic hypotension (20 mmHg reduction in systolic blood pressure with associated symptom such as 
dizziness) will prompt exclusion of patients from the trial. 
 
8.3.5 Safety Clinical Laboratory Tests 
 

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Laboratory evaluations will be collected prior to study drug initiation. Among women who are not surgically sterilized or 
post-menopausal, a urine pregnancy test will be performed at screening (prior to all baseline studies and drug initiation) 
and at the end of the first treatment phase. Complete blood count, liver enzymes, a basic metabolic panel (including 
serum creatinine for assessments of renal function) will also be performed prior to randomization and approximately 
four weeks after initiation of randomized therapy. 
 
8.3.6 Side Effect Management Plan 
 
Both intervention medications are widely used in clinical practice, and are known to have minimal side effects. However, 
a plan for management of side effects will be in place. The use of acetaminophen may be used for headaches during the 
study. Although hypotension is not expected based on stringent exclusion criteria, it should be managed as per standard 
clinical practice. We will also collect information on the frequency and type of expected and unexpected side effects 
reported by participants. We will ask participants to contact us immediately via phone if they develop any intolerable 
side effects, at which time the investigator will assess the safety of continuation with the study, if a dose reduction may 
be appropriate, or if the study drug should be discontinued and the participant should be removed from the study for 
their safety. 
 
8.3.7 Other Measures to Minimize Risk 
 
Phlebotomy, arterial tonometry, and echocardiographic examinations will only be performed by appropriately trained 
personnel as per our institutional standards. 
 
9. Study Administration, Data Handling, Record Keeping 
 
9.1 Confidentiality 
 
All information obtained as part of protocol will be maintained in locked research files. Electronic data will be stored in a 
password secured database (REDCap). This database will be available only with secure high-level password protection to 
safeguard the privacy of the participants. Any source documents for each patient involved in the protocol, other than 
the patient’s electronic medical chart, will be maintained in a centralized, secured location. Source documentation is all 
information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the study. Examples of source documents include demographic information, medical 
information, visit records and questionnaires. All information in the database will be traceable to the source documents 
in the patient’s file. Any information that is not already clinically available in the subject’s medical record will be directly 
entered into REDCap by the study team. No data containing any form of patient identifier will be provided for any 
purpose, including publication and collaborations with other investigators. 
 
9.2 Subject Privacy 
 

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Privacy of subjects will be maintained as the subject will interact with the investigators in the setting of a room 
designated for private patient care. Any written communication (e.g. questionnaires) will be kept confidential and 
private as outlined above. 
Data collected will contain PHI including: name, date of birth, and medical record number. Information about study 
subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). Those regulations require a signed subject authorization informing the subject of the 
following: 
• 
What protected health information (PHI) will be collected from subjects in this study; 
• 
Who will have access to that information and why; 
• 
Who will use or disclose that information; 
• 
The rights of a research subject to revoke their authorization for use of their PHI. 
Research data will be stored in a centralized, secure location (locked office of the PI). The consent document asks for 
specific permission to analyze genomic/proteomic data.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that 
the subject is alive) at the end of their scheduled study period. 
Research results and are kept confidential and no one will have access to research results without permission from the 
participant. 
 
9.3. Data Disclosure and Protection 
 
Data disclosed to collaborating sites will not be identifiable and will be assigned a tracking number. If research results 
are confirmed clinically this information may be made part of a participant’s medical record as the information is 
expected to alter medical management and health outcomes. Research results will not be made part of a participant’s 
medical record. 
Although a master database will be kept with the subjects’ names and research lab numbers to allow for retrospective 
correlation of results with clinical features, the subjects’ names will not be available to anyone other than the immediate 
study team and will not be used for identification of the subject in the laboratory or in reports of the research. The 
database will be kept in a secured computer and file. 
 
9.4 Data Collection and Management 
 
Before entering any data into the database, staff will be trained regarding the protocol and data entry specific to this 
protocol and database. Throughout the protocol, the Principal Investigator will regularly meet with the study staff to 
discuss any problems or concerns, as well as study enrollment. 
Information will be stored in a research file identified only by a code number. The key connecting the participants’ 
names to their code number will be stored in a separate, secure electronic folder only accessible to study investigators. 

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Information used for scientific publications will not contain any identifying information. All testing results will be 
considered confidential and will not be placed in the patients’ medical records. They will be kept in locked research files 
in a separate location. Test results that are not felt to be clinically relevant - have no proven medical management to 
reduce risk for development of disease - or are of unknown clinical significance will not be disclosed. 
 
9.5 Records Retention 
 
Research records will be retained for at least 7 years after the completion of this study. All study electronic files will be 
kept for at least 6 years after IRB acknowledgement of study termination. 
10. Regulatory Standards 
 
10.1 Informed Consent/HIPAA Authorization 
 
The site investigator, or a person designated by the site investigator, will fully inform the subject of all pertinent aspects 
of the clinical trial including the review of the informed consent form approved by the IRB. Prior to a subject's 
participation in the clinical trial, the Informed Consent Form will be signed and personally dated by the subject or by the 
subject’s legally acceptable representative. All subjects will receive a copy of the informed consent form. 
 
10.2 Institutional Review Board (IRB) 
 
The investigators will submit this protocol to the University of Pennsylvania IRB. During the study, any amendment or 
modification to the protocol will be sent to the IRB. The IRB will also be informed of any event likely to affect the safety 
of subjects or the continued conduct of the study, in particular any change in safety and all updates to the protocol will 
be sent to IRB. 
 
10.3 Investigational New Drug (IND) Application 
 
An IND exemption has been issued by the Office of Clinical Research. 
 
10.4 Auditing and Inspecting 
 
The Investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
11. Study Finance 
 

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11.1 Funding Source 
 
 The trial is supported by the National Institutes of Health, National Heart Lung and Blood Institute R01 HL153646-01 
 
11.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy of Conflicts of Interest 
Related to Research. 
11.3 Subject Stipends or Payments 
 
Subject will receive financial compensation for their participation in this study in the form of a check. We will follow the 
following reimbursement scheme: 
• 
Completion of Visit #1: $150 
• 
Completion of Visit #2: $250 
• 
Completion of Visit #3: $250 
 
The maximum total amount (if a subject completes all study visits) will be $650. Subjects will be paid for each visit that 
they complete, including completion of the corresponding home blood pressure monitoring. 
 
We recognize that travel may present a hardship for some participants who have difficulty with transportation. For these 
individuals, and until our budget prevents us from being able to do so, we may be willing to help arrange for 
transportation through the university (up to $100 per trip). 
 
12. Publication and Dissemination Plan 
 
 The analyzed results of the trial will be submitted for publication to a peer-reviewed journal within six months following 
the completion of the final trial visit. The project will be registered with clinicaltrials.gov, and the results will be 
submitted to clinicaltrials.gov no later than one year following the completion date of the project. 
 
 
 

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Appendix 1. Anticipated Study Timeline and Key Dates 
 
Study Timeline 
The anticipated time of study duration, beginning with the grant award through study completion is 5 years.  The study 
timelines and milestones are detailed below.  
 
Overall Study Timeline 
Study Timeline (start 
date 09/01/2020) 
Pre-
Funding 
Period 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Protocol, ICF, DSMB 
creation, IRB 
submission 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB approval, 
manuals, CRFs, 
database, hiring 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol/database 
training, study drug 
packaging, initiation 
mtg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report generation, 
quality control, DSMB 
approval/initial 
meeting, 
clinicaltrials.gov 
registration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Open for recruitment, 
Active enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment and 
Enrollment  
 
X 
X 
X 
X 
25% 
X 
X 
X 
50% 
X 
X 
X 
75% 
X 
X 
100% 
 
 
 
 
Follow up visits 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Database lock and 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Manuscript 
preparation and 
revision; submit 
clinicaltrials.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Key Milestones 
The dates below are deadlines by which key milestones will be completed using an R01 award start date of 9/1/2020. 
 
Year 1 milestones 
• 
Study drug received by investigational pharmacy and packaged for distribution (8/1/19) 
• 
Trial registration in ClinicalTrials.gov complete (8/1/20) 
• 
DSMB membership finalized (9/1/20) 
• 
Database testing; report generation (9/20/20) 
• 
First DSMB meeting (9/20/20) 
• 
Database set up complete (10/1/20) 
• 
Manuals and case report forms finalized (10/1/20) 
• 
GCP, protocol, and database training complete (10/1/20) 
• 
Open for enrollment (11/1/20) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (4/1/21) 

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Years 2-5 milestones 
• 
25% enrollment (12/1/21) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (10/1/21) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (4/1/22) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (10/1/22) 
• 
50% enrollment (12/1/22) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (4/1/23) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (10/1/23) 
• 
75% enrollment (12/1/23) 
• 
Protocol implementation and data monitoring; DSMB meetings every 6 months (4/1/24) 
• 
100% enrollment (9/1/24) 
• 
Final follow-up visit (11/1/24) 
• 
Final monitoring (11/15/24) 
• 
Database lock including batched laboratory analysis (12/1/24) 
• 
Submission of primary manuscript (3/1/25) 
• 
Submission of study results to ClinicalTrials.gov (9/31/25) 
 
 

BLOCK HFpEF 
 
 
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CONFIDENTIAL 
This material is property of the University of Pennsylvania 
Appendix 2. History of Protocol Changes 
 
Version 1 (June 2019) was the protocol for the 4-patient trial pilot, which was halted due to restrictions in research 
during the initial surge of the coronavirus disease 2019 pandemic in March 2020. The protocol was subsequently 
transitioned to the full 50-subject protocol and was IRB approved in June 2020 (with continuing review approved in July 
2020). The only change was the difference in sample size from 4 to 50, and power calculations from the R01 submission.  
 
Version 2 (November 2020) of the protocol was updated with the funding sponsor information, study timeline, and 
change in threshold for uptitration of study medication from 135 mmHg systolic blood pressure to 130 mmHg systolic 
blood pressure, consistent with recent hypertension guideline thresholds for blood pressure control. Version 2 was 
finalized after receiving input from all DSMB members, and before any subjects were enrolled. 
 
Version 3 (March 2022) of the protocol was updated to clarify the exclusion criteria for recovered EF to permit 
enrollment if prior reduced EF was in the setting of atrial fibrillation/flutter or other arrhythmia, as per investigator 
judgment. The analytic plan was updated to include assessment for chronotropic incompetence as an effect modifier. 
 
Version 4 (June 2022) of the protocol was updated to clarify the inclusion criteria to permit use of the H2FPEF score and 
investigator judgement for assessment of the diagnosis of HFpEF, and to expand the exclusion criteria to exclude greater 
than moderate left-sided valvular disease and mitral valve replacement. 
 
Version 5 (March 2023) of the protocol was updated to clarify the inclusion criteria for the diagnosis of heart failure, 
which typically needs to be made by the investigators’ clinical discretion based on participant signs and symptoms in 
combination with echocardiographic or hemodynamic measurements, given that the diagnosis is often missed by 
patients’ providers and the diagnostic code, accordingly, is frequently not included in the medical record.123 This version 
of the protocol also formalized the frequency of monitoring of participants who develop expected adverse events 
including worsening heart failure symptoms and elevated blood pressures to require twice weekly monitoring of 
symptoms/blood pressures by phone and the addition of a symptom visit and formal assessment for possible early 
withdrawal, if determined to be clinically appropriate by the investigators. 
 
Version 6 (August 2023) of the protocol was updated to add coverage for transportation for participants in whom 
transportation to appointments creates excessive hardship. 
 
Version 7 (February 2024) of the protocol was updated to add the scenario of fixed-dose combination antihypertensive 
medications combined with the study drugs, in which case the non-study drug component(s) of the fixed-dose 
combination will be prescribed and provided by IDS at the start of the pre-treatment washout period. The protocol 
wording was also updated to ensure that it is clear that NIRS testing is an exploratory metric that is optional based on 
device availability and functionality. 
 
Version 8 (November 2024) of the protocol was updated to remove arterial tonometry during 
exercise. It had been included in the protocol in error. The data is not required for the study, is not listed as 
part of any of the endpoint measurements described in the protocol, and this is not in any way required to 
determine systemic vasodilatory response to exercise. The change does not impact participants’ risk or 
data in any way.