Safety Study of Pyridostigmine in Heart Failure

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

33 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-10-31

Study Completion Date

2015-07-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Heart Failure

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Pyridostigmine Bromide

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

Group Type EXPERIMENTAL

Pyridostigmine Bromide

Intervention Type DRUG

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.

Placebo

Matching placebo forced titration 15-60 mg as tolerated

Group Type PLACEBO_COMPARATOR

Pyridostigmine Bromide

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type DRUG

Other Intervention Names

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Mestinon

Eligibility Criteria

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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.

Minimum Eligible Age

21 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No