Heart FailurePhase 1NCT00696410
The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy
A Phase 1 study testing Zinc Acetate in people with Heart Failure and Cardiomyopathies, run by University of Michigan at 1 site in United States.
Trial 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]. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Heart Failure, Cardiomyopathies
- What is being tested?
- Zinc Acetate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 48 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2008to Jun 2011
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
- Other exclusion criteria include the presence of a life-threatening illness with a projected survival ≤6 months;
- recurrent ventricular arrhythmias; end-stage renal failure;
- ongoing infection;
- inability to follow-up;
- collagen vascular disease (lupus, sarcoid);
Show all 10Show fewer
- enrollment in another investigational study;
- unstable or symptomatic peripheral artery disease;
- prior or active Zn supplementation;
- or ongoing alcohol abuse.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Michigan Health System
Ann Arbor, Michigan, 48109
About this study
Official title: Pilot Study to Assess the Impact of Zinc Supplementation on Left Ventricular Remodeling, Function, and Oxidative Stress in Nonischemic Cardiomyopathy
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.
Read the detailed description
Altered regulation of the transition-metal copper (Cu) may lead to an overproduction of reactive oxygen species (ROS) with subsequent development of a nonischemic cardiomyopathy (NISCM). Myocardial Cu levels are elevated in NISCM, and Cu levels are highest in the "diabetic cardiomyopathy." In humans, zinc (Zn) is an essential component of proteins critical for regulating myocardial cytoskeleton turnover and cellular proliferation. Zn also serves as an antioxidant and indirect regulator of redox-active Cu. By upregulating the chelator metallothionein, Zn reduces the levels of free Cu implicated in oxidative myocardial damage.
Transgenic over-expression of the antioxidant metallothionein has been shown to reduce ROS-induced myocardial damage. In diabetic cardiomyopathy, Cu chelation improves left ventricular (LV) diastolic relaxation abnormalities. However, it is unknown if Zn supplementation could alter the progression of LV systolic dysfunction through Cu depletion and ROS reduction. The aim of this pilot study is to assess the impact of a novel intervention, Zn supplementation, on myocardial remodeling by examining changes in serum levels of the types I (PINP) and III (PIIINP) collagen N-terminal propeptides. The primary study hypothesis is that Zn supplementation will have a favorable impact on the pathophysiology of NISCM by either repleting a Zn deficiency/insufficiency or by reducing myocardial damage and adverse remodeling in the setting of redox-active Cu excess.
Stable outpatients (n=40) with chronic NISCM (ejection fraction ≤40%) will receive daily oral Zn-acetate (50 mg po tid) for 10 months. Serum PINP, PIIINP, and markers of inflammation (CRP, sedimentation rate, myeloperoxidase) and oxidative stress (8-isoprostane, superoxide dismutase) will be obtained at baseline and following 10 months of Zn supplementation. Changes in collagen turnover will then be correlated with changes noted in LV systolic and diastolic function by echocardiography. Finally, we will examine for a differential treatment effect of Zn therapy in a diabetic subset (n=20) with NISCM compared with the nondiabetics.
- Conditions
- Heart Failure, Cardiomyopathies
- Being tested
- Zinc Acetate
- Keywords
- Heart Failure, Cardiomyopathy, Remodeling, Antioxidant, Zinc, Copper
- Medical subject headings
- Heart Failure, Cardiomyopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zinc AcetateDrug
Also called Galzin (zinc acetata, Teva Pharmaceuticals)
Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels ~10-12.
| Study group | Role | What they receive |
|---|---|---|
| CHF patients Given Zinc Acetate | Experimental | Patients with CHF received zinc acetate 50 mg po TID. This is a pre-post study Receives: Drug: Zinc Acetate |
| Healthy controls | No intervention | Health controls; no zinc acetate administered. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Change from baseline in serum isoprostane 10 months after Zn Acetate in patients with systolic heart failure and compared with a single measure in healthy subjects
Measured: Baseline (time 0) and 10 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jun 2008 (estimated)
- Study startJun 2008
- Primary completionJun 2011
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by University of MichiganThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 48 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Responsible party
- Principal investigator, Jennifer Cowger , MD, MS, University of Michigan
- Investigators
- Keith D Aaronson, MD, MS, Principal investigator, University of MichiganJennifer A Cowger, MD, MS, Study chair, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00696410
- Sponsor's protocol ID
- HUM0001911
- Other IDs
- NIHT32-HL007853
- Status last verified
- Oct 2017
- First submitted
- 9 Jun 2008
- Last updated
- 6 Nov 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study to Assess the Impact of Zinc Supplementation on Left Ventricular Remodeling, Function, and Oxidative Stress in Nonischemic Cardiomyopathy
- ClinicalTrials.gov ID
- NCT00696410
- Acronym / sponsor ID
- HUM0001911
- Conditions
- Heart Failure, Cardiomyopathies
- Keywords
- Heart Failure, Cardiomyopathy, Remodeling, Antioxidant, Zinc, Copper
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 48 participants (actual)
- Lead sponsor
- University of MichiganUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Study start
- Jun 2008
- Primary completion
- Jun 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 12 Jun 2008 (estimated)
- Results
- Posted 4 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Altered regulation of the transition-metal copper (Cu) may lead to an overproduction of reactive oxygen species (ROS) with subsequent development of a nonischemic cardiomyopathy (NISCM). Myocardial Cu levels are elevated in NISCM, and Cu levels are highest in the "diabetic cardiomyopathy." In humans, zinc (Zn) is an essential component of proteins critical for regulating myocardial cytoskeleton turnover and cellular proliferation. Zn also serves as an antioxidant and indirect regulator of redox-active Cu. By upregulating the chelator metallothionein, Zn reduces the levels of free Cu implicated in oxidative myocardial damage.
Transgenic over-expression of the antioxidant metallothionein has been shown to reduce ROS-induced myocardial damage. In diabetic cardiomyopathy, Cu chelation improves left ventricular (LV) diastolic relaxation abnormalities. However, it is unknown if Zn supplementation could alter the progression of LV systolic dysfunction through Cu depletion and ROS reduction. The aim of this pilot study is to assess the impact of a novel intervention, Zn supplementation, on myocardial remodeling by examining changes in serum levels of the types I (PINP) and III (PIIINP) collagen N-terminal propeptides. The primary study hypothesis is that Zn supplementation will have a favorable impact on the pathophysiology of NISCM by either repleting a Zn deficiency/insufficiency or by reducing myocardial damage and adverse remodeling in the setting of redox-active Cu excess.
Stable outpatients (n=40) with chronic NISCM (ejection fraction ≤40%) will receive daily oral Zn-acetate (50 mg po tid) for 10 months. Serum PINP, PIIINP, and markers of inflammation (CRP, sedimentation rate, myeloperoxidase) and oxidative stress (8-isoprostane, superoxide dismutase) will be obtained at baseline and following 10 months of Zn supplementation. Changes in collagen turnover will then be correlated with changes noted in LV systolic and diastolic function by echocardiography. Finally, we will examine for a differential treatment effect of Zn therapy in a diabetic subset (n=20) with NISCM compared with the nondiabetics.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| CHF patients Given Zinc Acetate | Experimental | Drug: Zinc AcetatePatients with CHF received zinc acetate 50 mg po TID. This is a pre-post study |
| Healthy controls | No intervention | –Health controls; no zinc acetate administered. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (10 listed)
- 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.
- Other exclusion criteria include the presence of a life-threatening illness with a projected survival ≤6 months;
- recurrent ventricular arrhythmias; end-stage renal failure;
- ongoing infection;
- inability to follow-up;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zinc AcetateAlso: Galzin (zinc acetata, Teva Pharmaceuticals)Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels ~10-12. | Drug | CHF patients Given Zinc Acetate |
Primary outcome
Change From Baseline in Markers of Cardiac Collagen Turnover (PINP) in Patients With Systolic Heart Failure and Compared With Healthy Controls.
Time frame: Baseline (time 0) and after 10 months of Zinc Acetate.
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.
1 secondary outcome
Change From Baseline in Serum Isoprostane in Patients With Systolic Heart Failure
Time frame: Baseline (time 0) and 10 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Heart Failure
RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Not yet recruitingPhase 2
A Study of Bimagrumab in Participants With HFpEF
Heart Failure, Diastolic, Diastolic Heart Failure
Recruiting
Evaluation of a French Hospital Discharge Therapeutic Education Program by Nurses for Heart Failure Patient (EduSor)
Heart Failure
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Keith D Aaronson, MD, MS principal investigator
University of Michigan
Jennifer A Cowger, MD, MS study chair
University of Michigan
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Zinc Acetate in people with Heart Failure and Cardiomyopathies, run by University of Michigan at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Markers of Cardiac Collagen Turnover (PINP) in Patients With Systolic Heart Failure and Compared With Healthy Controls. (time frame: Baseline (time 0) and after 10 months of Zinc Acetate.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2017.