Safety Study of Pyridostigmine in Heart Failure (APP-HF)

July 27, 2017 updated by: NYU Langone Health

Augmentation of Parasympathetic Signaling With Pyridostigmine in Heart Failure

Heart failure, a common heart disease affecting nearly 6 million Americans, is associated with high rates of hospitalization and death. Abnormalities in the autonomic nervous system are thought to play an important role in the progression of heart failure. This proposal aims to determine whether novel application of pyridostigmine, a drug currently approved by the FDA only for the treatment of neuromuscular disease, can improve autonomic nervous system function in heart failure patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Autonomic dysregulation of the cardiovascular system, characterized by heightened sympathetic activity and withdrawal of parasympathetic activity promotes progression of heart failure. Pharmacological blockade of sympathetic overactivity is associated with reduced mortality risk, but there are few data on pharmacologic augmentation of parasympathetic withdrawal. Acetylcholinesterase inhibitors augment parasympathetic neurotransmission by blocking the enzymatic breakdown of acetylcholine at cholinergic receptor sites. Pyridostigmine is a short-acting, reversible acetylcholinesterase inhibitor approved by the FDA for the treatment of myasthenia gravis. Investigators propose a Phase II prospective randomized, double-blind trial to compare 12 weeks of treatment with ascending doses of pyridostigmine (15, 30, and 60 mg every 8 hours) vs. matching placebo in 60 patients with symptomatic chronic heart failure associated with left ventricular systolic dysfunction.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10016
        • New York University Langone Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 21-75 years
  • Symptomatic NYHA Class II-III heart failure >6 months
  • Left ventricular ejection fraction <35%
  • Previous implantation of implantable cardiovertor defibrillator or pacemaker
  • Guideline-recommended heart failure treatment for > 3 months
  • Able and willing to provide written informed consent

Exclusion Criteria:

  • Contraindications to cholinergic stimulation
  • Heart failure primarily attributable to genetic, valvular, infiltrative diseases
  • Persistent atrial fibrillation
  • Sick sinus syndrome
  • Pacemaker dependency during exercise
  • Severe chronotropic incompetence with peak exercise heart rate < 100 min-1
  • Severe exercise intolerance (unable to complete first stage of Bruce Protocol)
  • Coronary or cerebral atherothrombotic events within the past year
  • Hospitalization of emergency room visit for heart failure within last 3 months
  • ICD shock in last 6 months
  • Diabetes mellitus with peripheral neuropathy
  • Autonomic or peripheral neuropathy of any cause
  • Systolic blood pressure <90 or >160 mmHg
  • Resting heart rate <60 or >100 min-1
  • Serum sodium < 132 mmol/L
  • Serum creatinine >2.5 mg/dl
  • Liver function tests >3 times upper limit of normal
  • Severe anemia (Hemoglobin <10 gm/dl)
  • FEV1.0 < 60% of predicted or FEV1.0/FVC ratio <70%
  • PR interval >240 msec or second or third degree heart block on electrocardiogram
  • Exercise limited primarily by angina or non-cardiac co-morbid condition
  • Pregnant or breast-feeding women
  • Current treatment with medications known to interact with pyridostigmine
  • Known intolerance of oral preparations containing bromides
  • Any condition (e.g., psychiatric illness or active substance abuse) or situation that, in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's ability to adhere with study procedures.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pyridostigmine Bromide
Forced titration protocol 15-60 mg every 8 hours as tolerated
Drug: Pyridostigmine Bromide
15, 30, and 60 mg tabs, 1 tab every 8 hours for 10 weeks. Forced titration protocol increases dose at 2 week intervals from 15 to 30 to 60 mg as tolerated. Continue maximally tolerated dose for 4 weeks and then downtitrate at weekly intervals (60 to 30 to 15) and then discontinue.
Other Names:
  • Mestinon
Placebo Comparator: Placebo
Matching placebo forced titration 15-60 mg as tolerated
Drug: Pyridostigmine Bromide
15, 30, and 60 mg tabs, 1 tab every 8 hours for 10 weeks. Forced titration protocol increases dose at 2 week intervals from 15 to 30 to 60 mg as tolerated. Continue maximally tolerated dose for 4 weeks and then downtitrate at weekly intervals (60 to 30 to 15) and then discontinue.
Other Names:
  • Mestinon

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Baseline Heart Rate Recovery
Time Frame: Baseline
Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute)
Baseline
Post Exercise Heart Rate Recovery
Time Frame: 12 weeks
Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NYU Langone Health

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)
Nathan Kline Institute for Psychiatric Research
Oklahoma State University

Investigators

  • Principal Investigator: Stuart D Katz, MD, NYU Langone Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2011

Primary Completion (Actual)

July 1, 2015

Study Completion (Actual)

July 1, 2015

Study Registration Dates

First Submitted

August 10, 2011

First Submitted That Met QC Criteria

August 11, 2011

First Posted (Estimate)

August 12, 2011

Study Record Updates

Last Update Posted (Actual)

July 31, 2017

Last Update Submitted That Met QC Criteria

July 27, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10-02167 (Other Identifier: NYU IRB)
  • 1R01HL103988 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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