Pilot Deprescribing Trials for Beta-blockers in Cardiac Amyloidosis

Sponsor

Weill Medical College of Cornell University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05019027

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this study, the investigators will test the feasibility of N-of-1 trials for deprescribing beta-blockers in patients with Cardiac Amyloidosis. To achieve this objective, 16 N-of-1 trials (on vs. off) will be conducted and subsequently interview participants to better understand feasibility and pragmatism. Each subject can participate in a total of up to 4 periods lasting between 2-6 weeks each based on each patients' health profile. The N-of-1 trials will be iteratively refined in real-time based on feedback.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Amyloidosis Heart Diseases	Drug: Beta blocker	Phase 4

Detailed Description

This is an unblinded NIH Stage I of Behavioral Intervention Development trial, using a Crossover Intervention model. The study team will enroll 16 subjects using a two-arm crossover titration/reversal design (On [A] vs. Off [B]) with up to 4 periods. Subjects will begin the study in the OFF (B) period. They will follow a pre-determined sequence: off beta-blocker, on beta-blocker, off beta-blocker, on beta-blocker. Each period will last up to 6 weeks, allowing for sufficient time for up-titration of beta-blocker and onset of drug action, and down-titration and washout. Each subject will have the option to participate in up to 4 periods, depending on whether they need additional information to make an informed decision about continuing or discontinuing their beta-blocker at the end of the trial. The intervention drug will be beta-blockers, previously prescribed to the subjects by their physician. The study team has developed a titration algorithm, where the participant's dose of each beta-blocker will be reduced by 50% every week.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Pilot Deprescribing N-of-1 Trials for Beta-blockers in Cardiac Amyloidosis

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Off On Off On Sequence This arm will follow an Off On Off On sequence. This is the only arm in the study. Subjects will begin in the Off phase (Period 1), downtitrating 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 1, Subjects will have the opportunity to crossover into Period 2, where they will begin the On phase. Subjects will restart their beta-blocker by starting a low dose and then doubling this dose every week until reaching their original dose. They will then have the opportunity to continue to Period 3 (Off phase) and Period 4 (On phase).	Drug: Beta blocker The intervention is a single-arm crossover withdrawal/reversal design (On vs Off) with up to 4 total periods, each period lasting between 2-6 weeks. During the On period, subjects will be on their beta blocker. During the Off period, their beta blockers will be down titrated and subsequently discontinued. Other Names: atenolol betaxolol bisoprolol metoprolol nebivolol nadolol propranolol acebutolol penbutolol pindolol carvedilol labetalol sotalol metoprolol succinate metoprolol tartrate

Arm

Intervention/Treatment

Other: Off On Off On Sequence

This arm will follow an Off On Off On sequence. This is the only arm in the study. Subjects will begin in the Off phase (Period 1), downtitrating 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 1, Subjects will have the opportunity to crossover into Period 2, where they will begin the On phase. Subjects will restart their beta-blocker by starting a low dose and then doubling this dose every week until reaching their original dose. They will then have the opportunity to continue to Period 3 (Off phase) and Period 4 (On phase).

Drug: Beta blocker

The intervention is a single-arm crossover withdrawal/reversal design (On vs Off) with up to 4 total periods, each period lasting between 2-6 weeks. During the On period, subjects will be on their beta blocker. During the Off period, their beta blockers will be down titrated and subsequently discontinued. Other Names: atenolol betaxolol bisoprolol metoprolol nebivolol nadolol propranolol acebutolol penbutolol pindolol carvedilol labetalol sotalol metoprolol succinate metoprolol tartrate

Outcome Measures

Primary Outcome Measures

Change in exercise capacity when on beta-blocker and off-beta blocker, as measured by peak oxygen consumption (VO2) during cardiopulmonary exercise test (CPET) [End of intervention Period 1 (Weeks 2, 3, 4, 5, or 6) and Period 2 (Weeks 8, 9, 10, 11, or 12)]
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.
Change in lower extremity function when on beta-blocker and off beta-blocker, as measured by a Short Physical Performance Battery [Baseline; End of intervention Period 1 (Weeks 2, 3, 4, 5, or 6), Period 2 (Weeks 8, 9, 10, 11, or 12), Period 3 (Weeks 14, 15, 16,17, or 18), and Period 4 (Weeks 20, 21, 22, 23, or 24)]
To understand the changes in lower extremity function between the On and Off phase via a Short physical performance battery test (lower extremity function). The Short Physical Performance Battery assesses gait speed, core strength when rising from a chair without using upper extremities, and balance while standing without a cane or walker. Total score range from 0 to 12, with higher scores indicating better physical performance.

Secondary Outcome Measures

Change in patient-reported quality of life when on beta-blocker, as measured by the Patient-Reported Outcome Measurement Information System-29 (PROMIS-29) [Baseline; Weekly over 24 weeks; Month 6, Month 9, Month 12]
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.
Change in patient-reported sexual function when on beta-blocker versus when off beta-blocker, as measured by Patient-Reported Outcome Measurement Information System-Sexual Function (PROMIS-Sexual Function) [Baseline; End of intervention Period 1 (Weeks 2, 3, 4, 5, or 6), Period 2 (Weeks 8, 9, 10, 11, or 12), Period 3 (Weeks 14, 15, 16,17, or 18), and Period 4 (Weeks 20, 21, 22, 23, or 24); Month 6, Month 9, Month 12]
Patient-Reported Outcome Measurement Information System-Sexual Function (PROMIS-Sexual Function) measures self-reported sexual function and satisfaction. Questions are ranked on a 6-point Likert scale, with higher scores indicating poorer sexual function and satisfaction.
Change in patient-reported cognitive function when on beta-blocker versus when off beta-blocker, as measured by Patient-Reported Outcome Measurement Information System-Short Form 6a (PROMIS SF-6a) [Baseline; Weekly over 24 weeks; Month 6, Month 9, Month 12]
Patient-Reported Outcome Measurement Information System-Short Form 6a (PROMIS SF-6a) is a survey of patient-perceived cognitive deficits. Questions are ranked on a 5-point Likert scale, with higher scores indicating poorer cognitive function.
Change in patient-reported health status when on beta-blocker versus when off beta-blocker, as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ-12) [Baseline; Biweekly over 24 weeks; Month 6, Month 9, Month 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.
Change in patient-reported health when on beta-blocker versus when off beta-blocker, as measured by the EuroQol-5D Visual Analogue System (EQ-5D VAS) [Baseline; End of intervention Period 1 (Weeks 2, 3, 4, 5, or 6) Period 2 (Weeks 8, 9, 10, 11, or 12), Period 3 (Weeks 14, 15, 16,17, or 18), and Period 4 (Weeks 20, 21, 22, 23, or 24)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

Alternate causes of HFpEF Syndrome:
Severe aortic stenosis and mitral stenosis
Constrictive pericarditis
High Output HF
Other compelling indication beta-blocker
Hypertrophic cardiomyopathy
Angina symptoms
Acute coronary syndrome, myocardial infraction or coronary artery bypass surgery in prior 3 years
Atrial arrhythmia with hospitalization for rapid ventricular response, prior 1 year
Sinus tachycardia >100 bpm, atrial arrhythmia with ventricular rate >90 beats per minute, systolic blood pressure >160 mmHg
Clinical instability (N-of-1 trials are appropriate for stable conditions only)
Decompensated heart failure
Hospitalized in past 30 days
Medication changes or procedures in prior 14 days that could confound observations, per PI discretion
Estimated life expectancy <6 months
Moderate-severe dementia or psychiatric disorder precluding informed consent
Any condition that, in Principal Investigator's opinion, makes the patient unsuitable for study participation