The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy

NCT00696410 | Completed Phase 1 Results DMC

• 2 other identifiers: HUM0001911NIHT32-HL007853
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure affects over 5.3 million Americans and, while other cardiovascular diseases have enjoyed a reduction in mortality rates over the last decade, the mortality from heart failure continues to rise\[1\]. Thus, identifying novel therapies that can reduce heart failure development and/or progression are warranted. Unifying to most cardiomyopathic processes is an impaired handling of reactive oxygen species (ROS)\[2-4\]. Reactive oxygen species are generated as byproducts of inflammation and oxidative stress that occur in the setting of normal myocardial aerobic metabolism. Metallothionein, glutathione reductase, and superoxide dismutase are major antioxidants in the myocardium that help combat oxidative stress and prevent myocardial damage. In certain clinical settings, including cardiac ischemia, diabetes, and heavy metal excess (copper, iron), myocardial oxidative stress levels are greatly increased. When pro-oxidant levels exceed myocardial antioxidant capabilities, ROS-induced membrane, protein, and DNA inactivation can lead to the development of cardiac dysfunction. One means of preventing the development or progression of cardiomyopathy is to reduce oxidative stress through up-regulation of intramyocardial antioxidants. Murine studies of cardiomyopathy have shown that oral administration of zinc acetate may succeed as an indirect myocardial anti-oxidant because zinc sufficiently up-regulates the intramyocardial production of superoxide dismutase (a zinc-dependant anti-oxidant enzyme) and metallothionein (a "super antioxidant") \[5-8\]. Zinc also directly reduces prooxidant Cu levels by reducing gastrointestinal zinc absorption. However, to date, no studies have examined the impact of zinc acetate supplementation in subjects with cardiomyopathy and systolic failure on antioxidant capacity and remodeling. The hypothesis of this pilot study is that administration of oral zinc acetate to humans with cardiomyopathy will lead to an up-regulation of myocardial anti-oxidant capabilities,leading to a favorable reduction in oxidative stress. This study will provide preliminary data to support a randomized, placebo-controlled trial of zinc therapy in heart failure as a means of improving or preventing the progression of systolic dysfunction in subjects with mild-moderate heart failure.

Conditions

Heart Failure; Cardiomyopathies

Keywords

Heart Failure; Cardiomyopathy; Remodeling; Antioxidant; Zinc; Copper

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Markers of Cardiac Collagen Turnover (PINP) in Patients With Systolic Heart Failure and Compared With Healthy Controls.

  The intervention group (patients with systolic heart failure) was given Zinc Acetate 50 mg po three times daily for 10 months. The change from baseline in markers of cardiac collagen turnover (PINP) in patients with systolic heart failure after 10 months of zinc acetate was measured and compared with a single measure from healthy controls.

  Baseline (time 0) and after 10 months of Zinc Acetate.

Secondary Outcomes (1)

• Change From Baseline in Serum Isoprostane in Patients With Systolic Heart Failure

  Baseline (time 0) and 10 months

Other Outcomes (3)

• Change in PIIINP From Baseline After 10 Months of Zinc Acetate in Systolic Heart Failure and Compared With a Single Measure in Healthy Controls

  Baseline (time 0) and 10 months

• Change From Baseline in Serum Superoxide Dismutase

  Baseline (time 0) and 10 months

• Change From Baseline in Serum Measures of of Myeloperoxidase (MPO) After 10 Months of Zinc Acetate Treatment

  Baseline (time 0) and 10 months

Study Arms (2)

CHF patients Given Zinc Acetate

EXPERIMENTAL

Patients with CHF received zinc acetate 50 mg po TID. This is a pre-post study

Drug: Zinc Acetate

Healthy controls

NO INTERVENTION

Health controls; no zinc acetate administered.

Interventions

Zinc Acetate DRUG

Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels \~10-12.

Also known as: Galzin (zinc acetata, Teva Pharmaceuticals)

CHF patients Given Zinc Acetate

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects (n=40) ≥21 years of age with chronic (≥1 year duration) nonischemic cardiomyopathy (NISCM), New York Heart Association (NYHA) functional class II-III symptoms on stable medical therapy (≥3 months of stable doses of β-blocker, angiotensin inhibitor or receptor blocker, and aldosterone inhibitor \[if appropriate\] therapies) with a documented left ventricular (LV) ejection fraction ≤40% and evidence of LV dilation will be eligible for study participation.
• The diagnosis of a nonischemic etiology for the cardiomyopathy must be supported by coronary angiography, stress echocardiography, or nuclear scintigraphy.
• To allow for a comparison of treatment effect in diabetic versus nondiabetic NISCM, half (n=20) of the subjects enrolled will be diabetic

You may not qualify if:

• Subjects with HF that is deemed to be ischemic, congenital, valvular, or infiltrative in etiology, or chemotherapy/toxin-induced will not be eligible for enrollment.
• recurrent ventricular arrhythmias; end-stage renal failure;
• ongoing infection;
• inability to follow-up;
• collagen vascular disease (lupus, sarcoid);
• enrollment in another investigational study;
• unstable or symptomatic peripheral artery disease;
• prior or active Zn supplementation;
• or ongoing alcohol abuse.

Sponsors & Collaborators

• University of Michigan: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Heart Failure; Cardiomyopathies

Interventions

Zinc Acetate

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Acetic Acid; Acetates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Limitations and Caveats

Zinc acetate was poorly tolerated by some patients. Patients often commented on GI upset (nausea) and reflux symptoms at follow-up encounter. The myeloperoxidase assay demonstrated marked variability and test validity/quality is in question.

Results Point of Contact

• Title: Jennifer Cowger, MD, Assistant Professor
• Organization: University of Michigan

jennmatt@med.umich.edu

734 936-5265

Study Officials

• Keith D Aaronson, MD, MS

  University of Michigan

  PRINCIPAL INVESTIGATOR

• Jennifer A Cowger, MD, MS

  University of Michigan

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, study Coinvestigator

Study Record Dates

• First Submitted: June 9, 2008
• First Posted: June 12, 2008
• Study Start: June 1, 2008
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: November 6, 2017
• Results First Posted: October 4, 2017

Record last verified: 2017-10

Locations

US (1)