Safety Study of Pyridostigmine in Heart Failure
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 21 - 75 |
| Updated: | 4/21/2016 |
| Start Date: | October 2011 |
| End Date: | July 2016 |
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.
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.
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.
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.
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New York University Langone Medical Center NYU NYU Langone Medical Center, a world-class, patient-centered, integrated,...
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