N-of-1 for Beta-Blockers in Cardiac Amyloidosis

N-of-1 Trials to Promote Deprescribing in Older Adults With Transthyretin Cardiac Amyloidosis

The study team will generate preliminary data on whether patients with cardiac amyloidosis feel better when their beta-blocker is stopped. To achieve this objective, 20 N-of-1 trials (on vs. off) will be conducted, and the study team will subsequently interview participants to better understand their outcomes. Each subject will participate in 2 periods lasting between up to 6 weeks each based on each patient's health profile. We will also engage stakeholders to understand the acceptability and feasibility of deprescribing N-of-1 trials. The N-of-1 trials will be iteratively refined in real-time based on feedback.

Study Overview

• Status: Recruiting
• Conditions: Heart Diseases; Cardiac Amyloidosis
• Intervention / Treatment: Drug: Beta blocker

Detailed Description

The intervention is an unblinded NIH Stage I of Behavioral Intervention Development trial, using a single-arm crossover withdrawal/reversal design (On [A] vs. Off [B]) with 2 periods, each period lasting up to 6 weeks, allowing for down-titration and washout. During the On (A) period, subjects will be on their beta-blocker, previously prescribed to the subjects by their physician. During the Off (B) period, their beta-blockers will be down-titrated and subsequently discontinued; we will decrease the dose of beta-blocker by 50% every week regardless of which beta-blocker they are on, similar to an algorithm used in a prior deprescribing trial.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Princess Osma, BA; Phone Number: 646-962-5910; Email: pro4001@med.cornell.edu
• Study Contact Backup: Name: Kate Zarzuela, MD; Phone Number: 646-962-5909; Email: kaz4004@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine
      • Principal Investigator: Parag Goyal, MD, MSc
      • Contact: Princess Osma, BA; Phone Number: 646-962-5910; Email: pro4001@med.cornell.edu
      • Contact: Kate Zarzuela, MD; Phone Number: 646-962-5909; Email: kaz4004@med.cornell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ambulatory adults age ≥65 years with TTR-cardiac amyloidosis (confirmed by PYP scan or biopsy)
2. Taking beta-blocker

Exclusion Criteria:

1. Other compelling indication beta-blocker

   1. Angina symptoms
   2. Acute coronary syndrome, myocardial infarction or coronary artery bypass surgery in prior 3 years
   3. Atrial arrhythmia with hospitalization for rapid ventricular response, prior 1 year
   4. Sinus tachycardia >100 bpm, atrial arrhythmia with ventricular rate >90 beats per minute, systolic blood pressure >160 mmHg

2. Clinical instability (N-of-1 trials are appropriate for stable conditions only)

   1. Decompensated heart failure
   2. Hospitalized in past 30 days
   3. Medication changes or procedures in the prior 14 days that could confound observations, per the Principal Investigator's discretion
3. Estimated life expectancy <6 months
4. Moderate-severe dementia or psychiatric disorder precluding informed consent
5. Language barrier that will preclude informed consent and ability to comprehend study procedures
6. Non-compliance or inability to complete study procedures
7. Enrollment in a clinical trial not approved for co-enrollment
8. Any condition that, in Principal Investigator or treating physician's opinion, makes the patient unsuitable for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: On-Off Sequence; This arm will follow an On-Off sequence. This is the only arm in the study. Subjects will begin in the On phase (Period 1), maintaining their beta-blocker dosage as previously prescribed to the subjects by their physician. Subjects will then continue to the Off phase (Period 2) where they will down-titrate their beta-blocker by 50% each week until they are completely off the drug for a total of two weeks. At the end of Period 2, the subjects will have their End of Intervention visit in which they will determine if they would like to continue or discontinue their beta-blockers for the foreseeable future.

Drug: Beta blocker; The intervention is a single-arm crossover withdrawal/reversal design (On vs Off) with 2 total periods, each period lasting between up to 6 weeks. During the On period, subjects will be on their beta blocker. During the Off period, their beta blockers will be down-titrated by 50% each week and will be subsequently discontinued. Other Names: acebutolol; atenolol; betaxolol; bisoprolol; carvedilol; labetalol; metoprolol succinate; metoprolol tartrate; nadolol; nebivolol; penbutolol; pindolol; propranolol; sotalol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in exercise capacity when on beta-blocker versus when off beta-blocker, as measured by peak oxygen consumption (VO2) during Cardiopulmonary Exercise Test (CPET).	To understand the changes in exercise capacity between the On and Off phase via a Peak oxygen consumption (VO2) Cardiopulmonary Exercise Test. Cardiopulmonary exercise testing (CPET) measures breath-by-breath oxygen production during symptom-limited exercise on a stationary bike or treadmill. This permits calculation of peak oxygen consumption (VO2). Percent predicted peak VO2 for body weight will also be calculated.	End of Period 1 (Week 2, 3, 4, 5, or 6) and Period 2 (Week 8, 9, 10, 11, or 12)
The change in patient-reported health status when on beta-blocker versus when off beta-blocker, as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ-12).	The Kansas City Cardiomyopathy Questionnaire (KCCQ-12) is a heart failure-specific health status survey. Questions are ranked on 5- to 7-point Likert scales, with higher scores indicating better health status.	Baseline; Bi-weekly, End of Period 1 (Week 2, 3, 4, 5, or 6), End of Period 2 (Week 8, 9, 10, 11, or 12)
The change in patient-reported quality of life when on beta-blocker versus when off beta-blocker, as measured by the EuroQol-5d Visual Analogue Scale.	The EuroQol-5D Visual Analogue System (EQ-5D VAS) indicates patient-perceived health on a vertical visual analogue scale. The scale ranges from 0, indicating poorest health, to 100, indicating best health.	Baseline; End Period 1 (Weeks 2, 3, 4, 5, or 6), End of Period 2 (Weeks 8, 9, 10, 11, or 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in patient-reported quality of life when on beta-blocker, as measured by the Patient-Reported Outcome Measurement Information System-29 (PROMIS-29)	Patient-Reported Outcome Measurement Information System-29 (PROMIS-29) is a health-related quality of life survey, with questions from 6 domains: depression, anxiety, physical function, pain interference, sleep disturbance, and ability to engage in social roles and activities. Questions are ranked on a 5-point Likert scale, with higher scores at times indicating better quality of life, and at other times indicating poorer quality of life. There is a pain rating scale ranging from 0 to 10, with higher scores indicating higher pain level. Scores are reported for each domain, as well as for pain rating.	Baseline; Weekly for up to 12 weeks; End of Period 1 (Week 2, 3, 4, 5, or 6), Period 2 (Week 8, 9, 10, 11, or 12)

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: U.S. Deprescribing Research Network
• Investigators: Principal Investigator: Parag Goyal, MD, MSc, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: August 17, 2021
• First Submitted That Met QC Criteria: August 17, 2021
• First Posted (Actual): August 24, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: heart failure; deprescribing; HFpEF; beta blocker; cardiac amyloidosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Metabolic Diseases; Proteostasis Deficiencies; Heart Diseases; Amyloidosis; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-Antagonists
• Other Study ID Numbers: 21-07023710

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes