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

This study has been completed.
Sponsor:
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
ClinicalTrials.gov Identifier:
NCT01415921
First received: August 10, 2011
Last updated: July 27, 2017
Last verified: July 2017
August 10, 2011
July 27, 2017
October 2011
July 2015   (Final data collection date for primary outcome measure)
  • 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)
Post Exercise Heart Rate Recovery [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ]
Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)
Complete list of historical versions of study NCT01415921 on ClinicalTrials.gov Archive Site
Not Provided
  • Resting Heart Rate Variability [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ]
    Time- and Frequency-domain assessment of sympathovagal balance
  • Cardiovagal baroreceptor function [ Time Frame: Times 0 (pre-randomization), 8 weeks, 12 weeks ]
    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 ]
    Validated Quality of Life questionnaire
  • Cholinergic Symptom Score [ Time Frame: Every 1-2 weeks for 12 weeks ]
    Validated questionnaire on cholinergic side effects
  • Spirometry [ Time Frame: Every 1-2 weeks for 12 weeks ]
    measure of lung function
  • Electrocardiogram [ Time Frame: Every 1-2 weeks for 12 weeks ]
    12-lead EKG
Not Provided
Not Provided
 
Safety Study of Pyridostigmine in Heart Failure
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.
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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Heart Failure
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
  • Experimental: Pyridostigmine Bromide
    Forced titration protocol 15-60 mg every 8 hours as tolerated
    Intervention: Drug: Pyridostigmine Bromide
  • Placebo Comparator: Placebo
    Matching placebo forced titration 15-60 mg as tolerated
    Intervention: Drug: Pyridostigmine Bromide
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
33
July 2015
July 2015   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
21 Years to 75 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01415921
10-02167
10-02167 ( Other Identifier: NYU IRB )
1R01HL103988 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
New York University School of Medicine
New York University School of Medicine
  • Nathan Kline Institute for Psychiatric Research
  • Oklahoma State University
  • National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Stuart D Katz, MD New York University School of Medicine
New York University School of Medicine
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP