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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by New York University School of Medicine
Sponsor:
Collaborators:
Nathan Kline Institute for Psychiatric Research
Oklahoma State University
Information provided by (Responsible Party):
Stuart Katz, New York University School of Medicine
ClinicalTrials.gov Identifier:
NCT01415921
First received: August 10, 2011
Last updated: December 10, 2013
Last verified: December 2013
  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
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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:
  • Post Exercise Heart Rate Recovery [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
    Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)


Secondary Outcome Measures:
  • Resting Heart Rate Variability [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
    Time- and Frequency-domain assessment of sympathovagal balance

  • Cardiovagal baroreceptor function [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
    Changes in heart rate and blood pressure in response to application of neck suction/pressure

  • Kansas City Cardiomyopathy Questionnaire [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ] [ Designated as safety issue: No ]
    Validated Quality of Life questionnaire

  • Cholinergic Symptom Score [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
    Validated questionnaire on cholinergic side effects

  • Spirometry [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
    measure of lung function

  • Electrocardiogram [ Time Frame: Every 1-2 weeks for 12 weeks ] [ Designated as safety issue: Yes ]
    12-lead EKG


Estimated Enrollment: 60
Study Start Date: October 2011
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: July 2014 (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. We now 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. The clinical pharmacology of pyridostigmine will be investigated for each of the following specific aims: 1) To characterize the effects of oral pyridostigmine vs. placebo on sympathovagal balance in patients with chronic heart failure; 2) To characterize the safety and tolerability of oral pyridostigmine vs. placebo in patients with chronic heart failure; and 3) To characterize the steady state pharmacokinetic and pharmacodynamic properties of repeated oral dosing of pyridostigmine in patients with chronic heart failure. Mixed effects models will be used to determine the association between study drug assignment and physiological markers of sympathovagal balance (post-exercise heart rate recovery, heart rate variability, cardiovagal baroreceptor function, and rest/exercise blood catecholamine levels), descriptive statistics to characterize safety/tolerability measures (exercise capacity, quality of life, biomarkers of disease progression, cholinergic symptoms score), and population pharmacokinetic/pharmacodynamic modeling to characterize the relationship between study dosing, study drug blood levels, the degree of cholinesterase inhibition and the measures of sympathovagal balance and safety/tolerability. The overall goal is to further characterize the potential of pyridostigmine as a novel treatment in heart failure subjects and obtain information necessary to evaluate the feasibility/logistics of a future Phase III outcomes study in heart failure patients. The proposed studies will provide new data that are critically needed to direct the future development of this promising drug as a novel therapeutic approach for reduction of morbidity and mortality in heart failure patients.

  Eligibility

Ages Eligible for Study:   21 Years to 75 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01415921

Contacts
Contact: Stuart D Katz, MD 212-263-3946 stuart.katz@nyumc.org
Contact: Mariyaa Butnar 212-263-3136 mariya.butnar@nyumc.org

Locations
United States, New York
New York University Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Stuart Katz, MD    212-263-3946    stuart.katz@nyumc.org   
Contact: Mariya Butnar    212-263-3136    mariya.butnar@nyumc.org   
Principal Investigator: Stuart D Katz, MD         
Sub-Investigator: Horacio Kaufmann, MD         
Sub-Investigator: Lucy Norcliffe-Kaufmann, Ph.D.         
Sub-Investigator: Kenneth Berger, MD         
Sub-Investigator: Roberta Goldring, MD         
Sponsors and Collaborators
New York University School of Medicine
Nathan Kline Institute for Psychiatric Research
Oklahoma State University
Investigators
Principal Investigator: Stuart D Katz, MD New York University School of Medicine
  More Information

Publications:
Responsible Party: Stuart Katz, Principal Investigator, New York University School of Medicine
ClinicalTrials.gov Identifier: NCT01415921     History of Changes
Other Study ID Numbers: 1R01HL103988-01A1, R10-02167, 1R01HL103988
Study First Received: August 10, 2011
Last Updated: December 10, 2013
Health Authority: United States: Institutional Review Board

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
Cholinesterase Inhibitors
Pyridostigmine Bromide
Bromides
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014