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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

August 10, 2011
December 10, 2013
October 2011
July 2014   (final data collection date for primary outcome measure)
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)
Same as current
Complete list of historical versions of study NCT01415921 on ClinicalTrials.gov Archive Site
  • 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
Same as current
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. 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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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.
 
Recruiting
60
August 2014
July 2014   (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.
Both
21 Years to 75 Years
No
Contact: Stuart D Katz, MD 212-263-3946 stuart.katz@nyumc.org
Contact: Mariyaa Butnar 212-263-3136 mariya.butnar@nyumc.org
United States
 
NCT01415921
1R01HL103988-01A1, R10-02167, 1R01HL103988
Yes
Stuart Katz, 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
December 2013

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