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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01415921
First Posted: August 12, 2011
Last Update Posted: July 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Nathan Kline Institute for Psychiatric Research
Oklahoma State University
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
New York University School of Medicine
  Purpose
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.

Condition Intervention Phase
Heart Failure Drug: Pyridostigmine Bromide Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Augmentation of Parasympathetic Signaling With Pyridostigmine in Heart Failure

Resource links provided by NLM:


Further study details as provided by New York University School of Medicine:

Primary Outcome Measures:
  • Baseline Heart Rate Recovery [ Time Frame: Baseline ]
    Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute)

  • Post Exercise Heart Rate Recovery [ Time Frame: 12 weeks ]
    Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)


Enrollment: 33
Study Start Date: October 2011
Study Completion Date: July 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Mestinon

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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01415921


Locations
United States, New York
New York University Langone Medical Center
New York, New York, United States, 10016
Sponsors and Collaborators
New York University School of Medicine
Nathan Kline Institute for Psychiatric Research
Oklahoma State University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Stuart D Katz, MD New York University School of Medicine
  More Information

Publications:
Responsible Party: New York University School of Medicine
ClinicalTrials.gov Identifier: NCT01415921     History of Changes
Other Study ID Numbers: 10-02167
10-02167 ( Other Identifier: NYU IRB )
1R01HL103988 ( U.S. NIH Grant/Contract )
First Submitted: August 10, 2011
First Posted: August 12, 2011
Results First Submitted: May 20, 2016
Results First Posted: October 25, 2016
Last Update Posted: July 31, 2017
Last Verified: July 2017

Keywords provided by New York University School of Medicine:
heart failure
autonomic function
sympathovagal balance
cholinesterase inhibitors
pharmacology

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Bromides
Pyridostigmine Bromide
Anticonvulsants
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs