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

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pyridostigmine Bromide
Sponsored by
NYU Langone Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring heart failure, autonomic function, sympathovagal balance, cholinesterase inhibitors, pharmacology

Eligibility Criteria

21 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • New York University Langone Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Pyridostigmine Bromide

Placebo

Arm Description

Forced titration protocol 15-60 mg every 8 hours as tolerated

Matching placebo forced titration 15-60 mg as tolerated

Outcomes

Primary Outcome Measures

Baseline Heart Rate Recovery
Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute)
Post Exercise Heart Rate Recovery
Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)

Secondary Outcome Measures

Full Information

First Posted
August 10, 2011
Last Updated
July 27, 2017
Sponsor
NYU Langone Health
Collaborators
Nathan Kline Institute for Psychiatric Research, Oklahoma State University, National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01415921
Brief Title
Safety Study of Pyridostigmine in Heart Failure
Acronym
APP-HF
Official Title
Augmentation of Parasympathetic Signaling With Pyridostigmine in Heart Failure
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NYU Langone Health
Collaborators
Nathan Kline Institute for Psychiatric Research, Oklahoma State University, National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
heart failure, autonomic function, sympathovagal balance, cholinesterase inhibitors, pharmacology

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pyridostigmine Bromide
Arm Type
Experimental
Arm Description
Forced titration protocol 15-60 mg every 8 hours as tolerated
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo forced titration 15-60 mg as tolerated
Intervention Type
Drug
Intervention Name(s)
Pyridostigmine Bromide
Other Intervention Name(s)
Mestinon
Intervention Description
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.
Primary Outcome Measure Information:
Title
Baseline Heart Rate Recovery
Description
Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute)
Time Frame
Baseline
Title
Post Exercise Heart Rate Recovery
Description
Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stuart D Katz, MD
Organizational Affiliation
NYU Langone Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
New York University Langone Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
12860856
Citation
Androne AS, Hryniewicz K, Goldsmith R, Arwady A, Katz SD. Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure. Heart. 2003 Aug;89(8):854-8. doi: 10.1136/heart.89.8.854.
Results Reference
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Safety Study of Pyridostigmine in Heart Failure

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