Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy

NCT00879060 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: K23HL086745-01A1
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

Hypertrophic Cardiomyopathy (HCM) is the most common genetic cardiomyopathy and remains the leading cause of sudden cardiac death in young people and an important cause of heart failure symptoms and death at any age. In HCM, pathological remodeling of the left ventricle involving myocardial fibrosis is likely a major contributor to cardiac dysfunction and also a nidus for the generation of ventricular arrhythmias. Serum markers of collagen turnover have been shown to reliably reflect the magnitude of myocardial fibrosis in a variety of cardiovascular diseases. In addition, aldosterone antagonist drugs have been shown to decrease fibrous tissue formation in the myocardium in certain pathologic cardiovascular states in which aldosterone production is increased. In HCM, aldosterone production is up-regulated and has been implicated in the formation of myocardial fibrosis. Therefore, the specific aims of this proposal are to:

1. 1.assess serum markers of collagen turnover at baseline and correlate these findings with a variety of clinical and morphologic disease parameters
2. 2.examine the effects of a 12-month treatment with the aldosterone antagonist spironolactone on magnitude of fibrosis as measured by serum markers of collagen turnover as well as changes in clinical and morphologic disease parameters.
3. 3.explore the effects of a 12-month treatment with aldosterone antagonist spironolactone on heart failure status, diastolic function, arrhythmic burden, and total LV mass and quantity of fibrosis by CMR.

Conditions

Myocardial Fibrosis; Hypertrophic Cardiomyopathy

Keywords

Fibrosis; Hypertrophic cardiomyopathy; MRI; Myocardial Fibrosis; Spironolactone

Outcome Measures

Primary Outcomes (1)

• Absolute Change in Serum Markers of Collagen Turnover (Micrograms/L) Over a One-year Follow-up Period in the Spironolactone Group Compared to Placebo.

  Specific variables of collagen turnover markers that will be evaluated include markers of collagen synthesis (PINP, PIIINP), and marker of collagen degradation (ICTP). A two-sample t-test was used to compare the differences between these collagen turnover markers at baseline and the absolute differences in change from baseline to 12 months of follow-up.

  The time points measured were at Baseline and at 12 Months (Follow-Up).

Secondary Outcomes (7)

• Measure of Functional Capacity: Peak Oxygen Consumption With Exercise

  The time points measured were at Baseline and at 12 Months (Follow-Up).

• Measure of Heart Failure Symptoms According to the New York Heart Association Functional Class

  Time points were measured at Baseline and again at 12 months (follow-up)

• Measure of Indices of Diastolic Function by Tissue Doppler Echocardiography (Septal E/e')

  The time points measured were at Baseline and at 12 Months (Follow-Up).

• Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Percentage of Left Ventricular Mass (%LV)

  The time points measured were at Baseline and at 12 Months (Follow-Up).

• Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Maximum Left Ventricular Wall Thickness (in mm)

  The time points measured were at Baseline and at 12 Months (Follow-Up).

Study Arms (2)

Spironolactone

EXPERIMENTAL

Experimental group includes individuals diagnosed with HCM between the ages of 18-55 (up to 50 for men). At time of randomization subjects randomized to experimental group will be initiated on 25mg of spironolactone. If at week 4, serum potassium is \<5.5 mmol/L and serum creatinine-baseline creatinine is \<0.5 mg/dl, the study drug will be increased to the target dose of 50mg once daily.

Drug: Spironolactone

Placebo Control

PLACEBO COMPARATOR

Placebo group includes individuals diagnosed with HCM between the ages of 18-55 (up to 50 for men). At time of randomization subjects randomized to placebo group will be initiated on an inactive placebo pill.

Drug: Placebo

Interventions

Spironolactone DRUG

spironolactone 50mg daily

Also known as: Aldactone

Spironolactone

Placebo DRUG

inactive placebo pill daily

Placebo Control

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hypertrophic cardiomyopathy
• Able to swallow pills
• No prior septal reduction therapy
• Negative serum or hCG pregnancy test

You may not qualify if:

• Unable or unwilling to perform treadmill cardiopulmonary exercise test
• Prior surgical myectomy or alcohol septal ablation
• Known or suspected infiltrative or glycogen storage disease
• Significant coronary artery disease, defined as atherosclerotic coronary artery narrowing \>70% of the luminal diameter by coronary angiography
• Severe obstructive pulmonary disease, defined as forced expiratory volume in 1 second (FEV1) \<50% of predicted.
• Prior intolerance or adverse reaction to aldosterone receptor antagonist.
• History of hyper or hypoaldosteronism
• Baseline serum potassium \>5.0 mmol/L.
• Calculated creatinine clearance \<30 ml/min using Cockcroft-Gault formula.
• Pregnant or breast feeding
• Poorly controlled systemic hypertension, defined as systolic blood pressure ≥150 mmHg or diastolic pressure ≥100 mmHg, during 2 clinic visits.
• Known conditions associated with elevated serum concentrations of PIIINP (e.g., chronic liver disease, diabetes mellitus, tumors, pulmonary fibrosis, bone and rheumatoid diseases, extensive wounds) or PINP (e.g., alcoholic liver disease, metabolic bone disease, thyroid disorders), including recent trauma (≤2 weeks) or surgery (≤6 months)
• Taking drugs known to directly influence collagen metabolism including, amiodorone, ACE or angiotensin II inhibitors, aldosterone antagonists, statins, glucocorticoids and estrogens
• Patients with ICDs/pacemakers will be recruited in the study, but will be excluded from the CMR component.

Sponsors & Collaborators

• Tufts Medical Center: lead

Study Sites (1)

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Related Publications (14)

• Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014 Jul 8;64(1):83-99. doi: 10.1016/j.jacc.2014.05.003.

  PMID: 24998133 BACKGROUND

• Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas T, Lesser JR, Gruner C, Crean AM, Rakowski H, Udelson JE, Rowin E, Lombardi M, Cecchi F, Tomberli B, Spirito P, Formisano F, Biagini E, Rapezzi C, De Cecco CN, Autore C, Cook EF, Hong SN, Gibson CM, Manning WJ, Appelbaum E, Maron MS. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation. 2014 Aug 5;130(6):484-95. doi: 10.1161/CIRCULATIONAHA.113.007094.

  PMID: 25092278 BACKGROUND

• Weng Z, Yao J, Chan RH, He J, Yang X, Zhou Y, He Y. Prognostic Value of LGE-CMR in HCM: A Meta-Analysis. JACC Cardiovasc Imaging. 2016 Dec;9(12):1392-1402. doi: 10.1016/j.jcmg.2016.02.031. Epub 2016 Jul 20.

  PMID: 27450876 BACKGROUND

• Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001 Feb 13;103(6):789-91. doi: 10.1161/01.cir.103.6.789.

  PMID: 11171784 BACKGROUND

• Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004 Mar 16;109(10):1284-91. doi: 10.1161/01.CIR.0000121426.43044.2B. Epub 2004 Mar 1.

  PMID: 14993121 BACKGROUND

• Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.

  PMID: 12668699 BACKGROUND

• Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003 Oct 14;108(15):1831-8. doi: 10.1161/01.CIR.0000091405.00772.6E. Epub 2003 Sep 29.

  PMID: 14517164 BACKGROUND

• Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004 Nov 11;351(20):2058-68. doi: 10.1056/NEJMoa042739. Epub 2004 Nov 7.

  PMID: 15531767 BACKGROUND

• Pfeffer MA, Pitt B, McKinlay SM. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Jul 10;371(2):181-2. doi: 10.1056/NEJMc1405715. No abstract available.

  PMID: 25006726 BACKGROUND

• Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Heitner JF, Lewis EF, O'Meara E, Rouleau JL, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, McKinlay SM, Pitt B. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015 Jan 6;131(1):34-42. doi: 10.1161/CIRCULATIONAHA.114.013255. Epub 2014 Nov 18.

  PMID: 25406305 BACKGROUND

• Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000 Jan;35(1):36-44. doi: 10.1016/s0735-1097(99)00492-1.

  PMID: 10636256 BACKGROUND

• Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700.

  PMID: 11094035 BACKGROUND

• Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, Diez J. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation. 2004 Sep 7;110(10):1263-8. doi: 10.1161/01.CIR.0000140973.60992.9A. Epub 2004 Aug 16.

  PMID: 15313958 BACKGROUND

• Maron MS, Chan RH, Kapur NK, Jaffe IZ, McGraw AP, Kerur R, Maron BJ, Udelson JE. Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic Cardiomyopathy. Am J Med. 2018 Jul;131(7):837-841. doi: 10.1016/j.amjmed.2018.02.025. Epub 2018 Mar 28.

  PMID: 29604289 DERIVED

MeSH Terms

Conditions

Cardiomyopathy, Hypertrophic; Fibrosis

Interventions

Spironolactone

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

Study population was small in size; duration of drug administration of 1 year too abbreviated to identify clinical/ structural changes in HCM; 50% patients asymptomatic (peak VO2 normal) limit opportunity for improvement with drug intervention

Results Point of Contact

• Title: Martin Maron, MD
• Organization: Tufts Medical Center

mmaron@tuftsmedicalcenter.org

(617) 636-8066

Study Officials

• Martin S Maron, MD

  Tufts Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2009
• First Posted: April 9, 2009
• Study Start: November 1, 2007
• Primary Completion: November 1, 2011
• Study Completion: November 1, 2012
• Last Updated: April 27, 2021
• Results First Posted: April 27, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)