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Effect of Isosorbide Mononitrate on Hypertension to Improve Left Ventricular Hypertrophy, Fibrosis and Myocardial Function (ISMN)

Primary Purpose

Hypertension

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Isosorbide Mononitrate, sustained release
Placebo capsule
Sponsored by
Corporal Michael J. Crescenz VA Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertension focused on measuring Hypertension, Isosorbide Mononitrate, Myocardial fibrosis

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Systolic blood pressure >140 mmHg, diastolic blood pressure > 90 mmHg.
  • An elevated left ventricular mass index (defined as >60 g/m1.7 in women and 80 g/m1.7 in men) OR LV posterior wall thickness >1.4 cm documented in a clinically indicated echocardiographic examination or magnetic resonance imaging scan within the previous 12 months.
  • Stable medical therapy as defined by: (1)No addition or removal of ACE inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers for 30 days. (2)No change in dosage of ACE, angiotensin-receptor blocker, beta-blockers or calcium-channel blockers s of more than 100% for 30 days.
  • Current therapy with an ACE inhibitor, hydralazine or a statin, all of which have been shown to reduce nitrate tolerance.

Exclusion Criteria:

  • Rhythm other than sinus rhythm (i.e., atrial fibrillation).
  • Non-cardiac condition limiting life expectancy to less than one year, per physician judgment.
  • Current or anticipated future need for nitrate therapy.
  • Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation).
  • Hypertrophic cardiomyopathy.
  • Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
  • Pericardial disease.
  • Primary pulmonary arteriopathy.
  • Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent.
  • Resting heart rate (HR) > 100 bpm.
  • A reduced LV ejection fraction (EF<50%).
  • Known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal).
  • Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
  • Allergy to isosorbide mononitrate.
  • Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension.
  • Therapy with rosiglitazone, since this combination is not recommended based on epidemiologic data suggesting that it may increase the risk of myocardial ischemia.
  • Current pregnancy or a positive urine pregnancy test. Women who become pregnant during the study will be discontinued from the trial.
  • Contraindications to a cardiac MRI: (i) Central nervous system aneurysm clips; (ii) Implanted neural stimulators; (iii) Implanted cardiac pacemaker or defibrillator; (iv) Cochlear implant; (v) Ocular foreign body (e.g. metal shavings); (vi) Other implanted medical devices: (e.g. drug infusion ports); (vii) Insulin pump; (viii) Metal shrapnel or bullet; (ix) Claustrophobia; (x) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (xi) Unwillingness of the patient to undergo a cardiac MRI. All patients with metallic implants will be individually evaluated prior to MRI.

Sites / Locations

  • Philadelphia VA Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Isosorbide Mononitrate, sustained release

Placebo capsule

Arm Description

One tablet containing 60 mg (Titration Stage 1) OR 120 mg (Titration Stage 2) of sustained-release ISMN administered at 8 AM.

One capsule of placebo administered once daily at 8 AM

Outcomes

Primary Outcome Measures

Change in left ventricular mass

Secondary Outcome Measures

Change in extracellular volume fraction
Change in peak myocardial systolic longitudinal strain measured by MRI
Change in peak early diastolic intraventricular pressure gradient measured by MRI
Change in late systolic hypertension derived from pulse wave analysis

Full Information

First Posted
October 9, 2013
Last Updated
August 9, 2016
Sponsor
Corporal Michael J. Crescenz VA Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01961453
Brief Title
Effect of Isosorbide Mononitrate on Hypertension to Improve Left Ventricular Hypertrophy, Fibrosis and Myocardial Function
Acronym
ISMN
Official Title
Targeting Wave Reflections to Improve Left Ventricular Hypertrophy, Fibrosis and Myocardial Function in Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
October 2014
Overall Recruitment Status
Withdrawn
Why Stopped
Funding
Study Start Date
August 2013 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Corporal Michael J. Crescenz VA Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this research study is to test whether treatment with isosorbide mononitrate will improve left ventricular hypertrophy ("thickening") which puts people at risk for developing heart failure. Once it develops, heart failure is a very serious condition and thus it is important to find ways to prevent it from happening. The investigators have reasons to believe that dilating the blood vessels with this specific medication will improve the thickening of the heart, which increases the risk of heart failure.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension
Keywords
Hypertension, Isosorbide Mononitrate, Myocardial fibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Isosorbide Mononitrate, sustained release
Arm Type
Active Comparator
Arm Description
One tablet containing 60 mg (Titration Stage 1) OR 120 mg (Titration Stage 2) of sustained-release ISMN administered at 8 AM.
Arm Title
Placebo capsule
Arm Type
Placebo Comparator
Arm Description
One capsule of placebo administered once daily at 8 AM
Intervention Type
Drug
Intervention Name(s)
Isosorbide Mononitrate, sustained release
Intervention Description
60 mg if Titration Stage 1 OR 120 mg if Titration Stage 2
Intervention Type
Drug
Intervention Name(s)
Placebo capsule
Intervention Description
One capsule of placebo administered once daily at 8 am.
Primary Outcome Measure Information:
Title
Change in left ventricular mass
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Change in extracellular volume fraction
Time Frame
24 weeks
Title
Change in peak myocardial systolic longitudinal strain measured by MRI
Time Frame
24 weeks
Title
Change in peak early diastolic intraventricular pressure gradient measured by MRI
Time Frame
24 weeks
Title
Change in late systolic hypertension derived from pulse wave analysis
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
89 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Systolic blood pressure >140 mmHg, diastolic blood pressure > 90 mmHg. An elevated left ventricular mass index (defined as >60 g/m1.7 in women and 80 g/m1.7 in men) OR LV posterior wall thickness >1.4 cm documented in a clinically indicated echocardiographic examination or magnetic resonance imaging scan within the previous 12 months. Stable medical therapy as defined by: (1)No addition or removal of ACE inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers for 30 days. (2)No change in dosage of ACE, angiotensin-receptor blocker, beta-blockers or calcium-channel blockers s of more than 100% for 30 days. Current therapy with an ACE inhibitor, hydralazine or a statin, all of which have been shown to reduce nitrate tolerance. Exclusion Criteria: Rhythm other than sinus rhythm (i.e., atrial fibrillation). Non-cardiac condition limiting life expectancy to less than one year, per physician judgment. Current or anticipated future need for nitrate therapy. Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation). Hypertrophic cardiomyopathy. Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid). Pericardial disease. Primary pulmonary arteriopathy. Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent. Resting heart rate (HR) > 100 bpm. A reduced LV ejection fraction (EF<50%). Known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal). Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization. Allergy to isosorbide mononitrate. Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension. Therapy with rosiglitazone, since this combination is not recommended based on epidemiologic data suggesting that it may increase the risk of myocardial ischemia. Current pregnancy or a positive urine pregnancy test. Women who become pregnant during the study will be discontinued from the trial. Contraindications to a cardiac MRI: (i) Central nervous system aneurysm clips; (ii) Implanted neural stimulators; (iii) Implanted cardiac pacemaker or defibrillator; (iv) Cochlear implant; (v) Ocular foreign body (e.g. metal shavings); (vi) Other implanted medical devices: (e.g. drug infusion ports); (vii) Insulin pump; (viii) Metal shrapnel or bullet; (ix) Claustrophobia; (x) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (xi) Unwillingness of the patient to undergo a cardiac MRI. All patients with metallic implants will be individually evaluated prior to MRI.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Julio A Chirinos, MD, PhD
Organizational Affiliation
Philadelphia VA Medical Center & University of Pennsylvania
Official's Role
Principal Investigator
Facility Information:
Facility Name
Philadelphia VA Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
14705758
Citation
Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003 Dec 15;68(12):2393-8.
Results Reference
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PubMed Identifier
21240870
Citation
Li H, Wang SX. Improvement of hypertension and LVH in maintenance hemodialysis patients treated with sustained-release isosorbide mononitrate. J Nephrol. 2011 Mar-Apr;24(2):236-45. doi: 10.5301/jn.2011.6252.
Results Reference
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Effect of Isosorbide Mononitrate on Hypertension to Improve Left Ventricular Hypertrophy, Fibrosis and Myocardial Function

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