{ "FullStudy":{ "Rank":217825, "Study":{ "ProtocolSection":{ "IdentificationModule":{ "NCTId":"NCT01516346", "OrgStudyIdInfo":{ "OrgStudyId":"01340" }, "Organization":{ "OrgFullName":"Corporal Michael J. Crescenz VA Medical Center", "OrgClass":"FED" }, "BriefTitle":"Vasodilator Therapy for Heart Failure and Preserved Ejection Fraction", "OfficialTitle":"Effect of Organic Nitrates and Hydralazine on Wave Reflections and Left Ventricular Structure and Function in Heart Failure With Preserved Ejection Fraction" }, "StatusModule":{ "StatusVerifiedDate":"April 2018", "OverallStatus":"Completed", "ExpandedAccessInfo":{ "HasExpandedAccess":"No" }, "StartDateStruct":{ "StartDate":"January 2012" }, "PrimaryCompletionDateStruct":{ "PrimaryCompletionDate":"March 2018", "PrimaryCompletionDateType":"Actual" }, "CompletionDateStruct":{ "CompletionDate":"March 2018", "CompletionDateType":"Actual" }, "StudyFirstSubmitDate":"January 19, 2012", "StudyFirstSubmitQCDate":"January 23, 2012", "StudyFirstPostDateStruct":{ "StudyFirstPostDate":"January 24, 2012", "StudyFirstPostDateType":"Estimate" }, "LastUpdateSubmitDate":"April 3, 2018", "LastUpdatePostDateStruct":{ "LastUpdatePostDate":"April 5, 2018", "LastUpdatePostDateType":"Actual" } }, "SponsorCollaboratorsModule":{ "ResponsibleParty":{ "ResponsiblePartyType":"Principal Investigator", "ResponsiblePartyInvestigatorFullName":"Julio A.Chirinos", "ResponsiblePartyInvestigatorTitle":"Director of non-invasive imaging and Assistant Professor of Medicine", "ResponsiblePartyInvestigatorAffiliation":"Corporal Michael J. Crescenz VA Medical Center" }, "LeadSponsor":{ "LeadSponsorName":"Corporal Michael J. Crescenz VA Medical Center", "LeadSponsorClass":"FED" }, "CollaboratorList":{ "Collaborator":[ { "CollaboratorName":"University of Pennsylvania", "CollaboratorClass":"OTHER" },{ "CollaboratorName":"National Institute on Aging (NIA)", "CollaboratorClass":"NIH" } ] } }, "OversightModule":{ "OversightHasDMC":"No" }, "DescriptionModule":{ "BriefSummary":"The main objective is to test the effect of prolonged therapy (24 weeks) with isosorbide dinitrate ± hydralazine on arterial wave reflections (primary endpoint). Secondary endpoints include left ventricular (LV) mass, fibrosis and diastolic function) and exercise capacity (assessed via the 6-minute walk test) in patients with Heart Failure and Preserved Ejection Fraction (HFPEF). We will also test the hypothesis that the reduction in arterial wave reflections induced by vasoactive therapy will correlate with the improvement in exercise capacity, LV mass, fibrosis and diastolic function. Finally, we will assess whether the hemodynamic response to an acute dose of sublingual nitroglycerin (NTG) can predict the sustained changes in the reflected wave and other hemodynamic parameters in response to chronic vasodilator therapy." }, "ConditionsModule":{ "ConditionList":{ "Condition":[ "Heart Failure", "Congestive Heart Failure" ] }, "KeywordList":{ "Keyword":[ "Heart Failure", "Heart failure with preserved ejection fraction (HFpEF)", "Vasodilators", "Isosorbide dinitrate", "Hydralazine", "wave reflections", "arterial stiffness", "hemodynamics" ] } }, "DesignModule":{ "StudyType":"Interventional", "PhaseList":{ "Phase":[ "Phase 2" ] }, "DesignInfo":{ "DesignAllocation":"Randomized", "DesignInterventionModel":"Parallel Assignment", "DesignPrimaryPurpose":"Treatment", "DesignMaskingInfo":{ "DesignMasking":"Quadruple", "DesignWhoMaskedList":{ "DesignWhoMasked":[ "Participant", "Care Provider", "Investigator", "Outcomes Assessor" ] } } }, "EnrollmentInfo":{ "EnrollmentCount":"54", "EnrollmentType":"Anticipated" } }, "ArmsInterventionsModule":{ "ArmGroupList":{ "ArmGroup":[ { "ArmGroupLabel":"Isosorbide dinitrate", "ArmGroupType":"Active Comparator", "ArmGroupDescription":"Research pharmacy-formulated capsules will be given to the subjects in two bottles. For this interventional arm, one of the bottles will contain the active ingredient Isosorbide Dinitrate and the other will contain placebo capsules.\n\nDosage of Isosorbide Dinitrate will be 20mg (if Stage 1) OR 40mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Isosorbide Dinitrate" ] } },{ "ArmGroupLabel":"Isosorbide dinitrate + Hydralazine", "ArmGroupType":"Active Comparator", "ArmGroupDescription":"Research pharmacy-formulated capsules will be given to the subjects in two bottles. For this interventional arm, one of the bottles will contain the active ingredient Isosorbide Dinitrate and the other will contain the active ingredient Hydralazine.\n\nDosage of Isosorbide Dinitrate will be 20mg (if Stage 1) OR 40mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.\n\nDosage of Hydralazine will be 37.5mg (if Stage 1) OR 75mg (if Stage 2). All the subjects will be uptitrated to Stage 2 dosing, if they tolerate Stage 1 dosing. Frequency is three times daily, to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Isosorbide Dinitrate + Hydralazine" ] } },{ "ArmGroupLabel":"Placebo", "ArmGroupType":"Placebo Comparator", "ArmGroupDescription":"Research pharmacy-formulated capsules will be given to subjects in two bottles. For this interventional arm, both the bottles will contain placebo capsules.\n\nDosage will be same regardless of up-titration from Stage 1 dosing to Stage 2 dosing. Frequency is three times daily, to be taken at 8 AM, 2 PM and 8 PM. Duration is for 24 weeks.", "ArmGroupInterventionList":{ "ArmGroupInterventionName":[ "Drug: Placebo" ] } } ] }, "InterventionList":{ "Intervention":[ { "InterventionType":"Drug", "InterventionName":"Isosorbide Dinitrate", "InterventionDescription":"Enrolled subjects will be randomized in a blinded fashion to 1 isosorbide dinitrate capsule TID + 1 placebo capsule TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs. Subjects receiving isosorbide dinitrate will be given 20mg PO q8am, 2pm, and 8pm and will be titrated up to 40mg PO q8am, 2pm, and 8pm.", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Isosorbide dinitrate" ] } },{ "InterventionType":"Drug", "InterventionName":"Isosorbide Dinitrate + Hydralazine", "InterventionDescription":"Enrolled subjects will be randomized in a blinded fashion to 1 isosorbide dinitrate capsule TID + 1 hydralazine capsule TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs. Subjects receiving isosorbide dinitrate will be given 20mg PO q8am, 2pm, and 8pm and will be titrated up to 40mg PO q8am, 2pm, and 8pm. Subjects receiving hydralazine will be given 37.5mg PO q8am, 2pm, and 8pm and will be titrated up to 75mg PO q8am, 2pm, and 8pm.", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Isosorbide dinitrate + Hydralazine" ] } },{ "InterventionType":"Drug", "InterventionName":"Placebo", "InterventionDescription":"Enrolled subjects will be randomized in a blinded fashion to 2 placebo capsules TID. In addition, all subjects will receive a single in-lab dose of 0.4 mg of sublingual nitroglycerine (open label) before randomization to the blinded study drugs.", "InterventionArmGroupLabelList":{ "InterventionArmGroupLabel":[ "Placebo" ] } } ] } }, "OutcomesModule":{ "PrimaryOutcomeList":{ "PrimaryOutcome":[ { "PrimaryOutcomeMeasure":"The change in late systolic load from wave reflections between baseline and after 24 weeks of randomized therapy", "PrimaryOutcomeTimeFrame":"24 weeks" } ] }, "SecondaryOutcomeList":{ "SecondaryOutcome":[ { "SecondaryOutcomeMeasure":"The change in LV mass & collagen volume fraction measured by MRI; early mitral annular velocity, myocardial strain, 6-minute walk distance and NT-pro-BNP levels between baseline and after 24 weeks of randomized therapy", "SecondaryOutcomeTimeFrame":"24 weeks" },{ "SecondaryOutcomeMeasure":"Change in quality of life", "SecondaryOutcomeTimeFrame":"24 weeks" } ] } }, "EligibilityModule":{ "EligibilityCriteria":"Inclusion Criteria:\n\nPrevious clinical diagnosis of heart failure with current New York Heart Association Class II-IV symptoms.\nLV ejection fraction >50% on a clinically indicated echocardiogram or ventriculogram within 12 months prior to consent, in the absence of a change in cardiovascular status, as assessed by the principal investigators.\n\nMust have had at least one of the following within the 12 months prior to consent\n\nHospitalization for decompensated HF\nAcute treatment for HF with intravenous loop diuretic or hemofiltration.\nChronic treatment with a loop diuretic for control of HF symptoms.\nChronic diastolic dysfunction on echocardiography as evidenced by left atrial enlargement or at least stage II diastolic dysfunction.\nDocumentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.\n\nStable medical therapy as defined by:\n\nNo addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days.\nNo change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days.\nNo change in diuretic dose for 10 days.\n\nExclusion Criteria:\n\nRhythm other than sinus rhythm (i.e., atrial fibrillation).\nNeuromuscular, orthopedic or other non-cardiac condition that prevents patient from walking in a hallway.\nNon-cardiac condition limiting life expectancy to less than one year, per physician judgment.\nCurrent or anticipated future need for nitrate therapy.\nValve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation).\nHypertrophic cardiomyopathy.\nKnown infiltrative or inflammatory myocardial disease (amyloid, sarcoid).\nPericardial disease.\nPrimary pulmonary arteriopathy.\nHave 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.\nOther clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease.\nSystolic blood pressure < 110 mmHg or > 180 mm Hg.\nDiastolic blood pressure < 40 mmHg or > 100 mmHg.\nResting heart rate (HR) > 100 bpm.\nA history of reduced ejection fraction (EF<50%).\nSevere renal dysfunction (estimated GFR <30 ml/min/1.73m2 by modified MDRD equation) GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units), which would impede the safe administration of gadolinium for MRI studies contrast.\nHemoglobin <10 g/dL.\nPatients with known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal).\nPatients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.\nListed for cardiac transplantation.\nAllergy to isosorbide dinitrate or hydralazine.\nCurrent therapy with phosphodiesterase inhibitors, such as sildenafil, vardenafil or tadalafil, since the combination of nitrates and phosphodiesterase inhibitors can result in severe hypotension.\nWe will also exclude patients who are not suitable candidates for a cardiac MRI by virtue of having the following absolute or relative contraindications: (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.", "HealthyVolunteers":"No", "Gender":"All", "MinimumAge":"18 Years", "StdAgeList":{ "StdAge":[ "Adult", "Older Adult" ] } }, "ContactsLocationsModule":{ "OverallOfficialList":{ "OverallOfficial":[ { "OverallOfficialName":"Julio A Chirinos, MD, PhD", "OverallOfficialAffiliation":"Philadelphia VA Medical Center & University of Pennsylvania", "OverallOfficialRole":"Principal Investigator" } ] }, "LocationList":{ "Location":[ { "LocationFacility":"Philadelphia VA Medical Center", "LocationCity":"Philadelphia", "LocationState":"Pennsylvania", "LocationZip":"19104", "LocationCountry":"United States" } ] } }, "ReferencesModule":{ "ReferenceList":{ "Reference":[ { "ReferencePMID":"22081782", "ReferenceType":"background", "ReferenceCitation":"Bhuiyan T, Maurer MS. Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma. Curr Cardiovasc Risk Rep. 2011 Oct;5(5):440-449." },{ "ReferencePMID":"20733089", "ReferenceType":"background", "ReferenceCitation":"Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 1: pressure and flow measurements and basic principles of wave conduction and reflection. Hypertension. 2010 Oct;56(4):555-62. doi: 10.1161/HYPERTENSIONAHA.110.157321. Epub 2010 Aug 23. Review." },{ "ReferencePMID":"20733088", "ReferenceType":"background", "ReferenceCitation":"Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 2: arterial pressure-flow and pressure-volume relations in humans. Hypertension. 2010 Oct;56(4):563-70. doi: 10.1161/HYPERTENSIONAHA.110.157339. Epub 2010 Aug 23." },{ "ReferencePMID":"8086327", "ReferenceType":"background", "ReferenceCitation":"Endo H, Shiraishi H, Yanagisawa M. Afterload reduction by hydralazine in children with a ventricular septal defect as determined by aortic input impedance. Cardiovasc Drugs Ther. 1994 Feb;8(1):161-6." },{ "ReferencePMID":"15752371", "ReferenceType":"background", "ReferenceCitation":"Greig LD, Leslie SJ, Gibb FW, Tan S, Newby DE, Webb DJ. Comparative effects of glyceryl trinitrate and amyl nitrite on pulse wave reflection and augmentation index. Br J Clin Pharmacol. 2005 Mar;59(3):265-70." },{ "ReferencePMID":"12558614", "ReferenceType":"background", "ReferenceCitation":"Lind L, Pettersson K, Johansson K. Analysis of endothelium-dependent vasodilation by use of the radial artery pulse wave obtained by applanation tonometry. Clin Physiol Funct Imaging. 2003 Jan;23(1):50-7." },{ "ReferencePMID":"14705758", "ReferenceType":"background", "ReferenceCitation":"Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003 Dec 15;68(12):2393-8. Review." },{ "ReferencePMID":"8310551", "ReferenceType":"background", "ReferenceCitation":"Downing GJ, Maulik D, Phillips C, Kadado TR. In vivo correlation of Doppler waveform analysis with arterial input impedance parameters. Ultrasound Med Biol. 1993;19(7):549-59." },{ "ReferencePMID":"16226934", "ReferenceType":"background", "ReferenceCitation":"Elkayam U, Bitar F. Effects of nitrates and hydralazine in heart failure: clinical evidence before the african american heart failure trial. Am J Cardiol. 2005 Oct 10;96(7B):37i-43i. Epub 2005 Aug 9. Review." },{ "ReferencePMID":"12714344", "ReferenceType":"background", "ReferenceCitation":"Brooks D, Solway S, Gibbons WJ. ATS statement on six-minute walk test. Am J Respir Crit Care Med. 2003 May 1;167(9):1287." },{ "ReferencePMID":"30764699", "ReferenceType":"derived", "ReferenceCitation":"Chirinos JA, Bhattacharya P, Kumar A, Proto E, Konda P, Segers P, Akers SR, Townsend RR, Zamani P. Impact of Diabetes Mellitus on Ventricular Structure, Arterial Stiffness, and Pulsatile Hemodynamics in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2019 Feb 19;8(4):e011457. doi: 10.1161/JAHA.118.011457." },{ "ReferencePMID":"28219917", "ReferenceType":"derived", "ReferenceCitation":"Zamani P, Akers S, Soto-Calderon H, Beraun M, Koppula MR, Varakantam S, Rawat D, Shiva-Kumar P, Haines PG, Chittams J, Townsend RR, Witschey WR, Segers P, Chirinos JA. Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2017 Feb 20;6(2). pii: e004262. doi: 10.1161/JAHA.116.004262." } ] } } }, "AnnotationSection":{ "AnnotationModule":{ "UnpostedAnnotation":{ "UnpostedResponsibleParty":"Julio A.Chirinos, Director of non-invasive imaging and Assistant Professor of Medicine, Corporal Michael J. Crescenz VA Medical Center", "UnpostedEventList":{ "UnpostedEvent":[ { "UnpostedEventType":"Release", "UnpostedEventDate":"March 12, 2020" },{ "UnpostedEventType":"Reset", "UnpostedEventDate":"March 27, 2020" } ] } } } }, "DerivedSection":{ "MiscInfoModule":{ "VersionHolder":"April 22, 2020" }, "InterventionBrowseModule":{ "InterventionMeshList":{ "InterventionMesh":[ { "InterventionMeshId":"D000006830", "InterventionMeshTerm":"Hydralazine" },{ "InterventionMeshId":"D000007547", "InterventionMeshTerm":"Isosorbide" },{ "InterventionMeshId":"D000007548", "InterventionMeshTerm":"Isosorbide Dinitrate" },{ "InterventionMeshId":"C000030397", "InterventionMeshTerm":"Isosorbide-5-mononitrate" } ] }, "InterventionAncestorList":{ "InterventionAncestor":[ { "InterventionAncestorId":"D000004234", "InterventionAncestorTerm":"Diuretics, Osmotic" },{ "InterventionAncestorId":"D000004232", "InterventionAncestorTerm":"Diuretics" },{ "InterventionAncestorId":"D000045283", "InterventionAncestorTerm":"Natriuretic Agents" },{ "InterventionAncestorId":"D000045505", "InterventionAncestorTerm":"Physiological Effects of Drugs" },{ "InterventionAncestorId":"D000014665", "InterventionAncestorTerm":"Vasodilator Agents" },{ "InterventionAncestorId":"D000020030", "InterventionAncestorTerm":"Nitric Oxide Donors" },{ "InterventionAncestorId":"D000045504", "InterventionAncestorTerm":"Molecular Mechanisms of Pharmacological Action" },{ "InterventionAncestorId":"D000000959", "InterventionAncestorTerm":"Antihypertensive Agents" } ] }, "InterventionBrowseLeafList":{ "InterventionBrowseLeaf":[ { "InterventionBrowseLeafId":"M9161", "InterventionBrowseLeafName":"Isosorbide", "InterventionBrowseLeafAsFound":"Isosorbide", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M9162", "InterventionBrowseLeafName":"Isosorbide Dinitrate", "InterventionBrowseLeafAsFound":"Isosorbide Dinitrate", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M252616", "InterventionBrowseLeafName":"Isosorbide-5-mononitrate", "InterventionBrowseLeafAsFound":"Isosorbide Dinitrate", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M8471", "InterventionBrowseLeafName":"Hydralazine", "InterventionBrowseLeafAsFound":"Hydralazine", "InterventionBrowseLeafRelevance":"high" },{ "InterventionBrowseLeafId":"M5994", "InterventionBrowseLeafName":"Diuretics", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M15995", "InterventionBrowseLeafName":"Vasodilator Agents", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M11090", "InterventionBrowseLeafName":"Nitric Oxide", "InterventionBrowseLeafRelevance":"low" },{ "InterventionBrowseLeafId":"M2858", "InterventionBrowseLeafName":"Antihypertensive Agents", "InterventionBrowseLeafRelevance":"low" } ] }, "InterventionBrowseBranchList":{ "InterventionBrowseBranch":[ { "InterventionBrowseBranchAbbrev":"NaAg", "InterventionBrowseBranchName":"Natriuretic Agents" },{ "InterventionBrowseBranchAbbrev":"All", "InterventionBrowseBranchName":"All Drugs and Chemicals" },{ "InterventionBrowseBranchAbbrev":"NiOxD", "InterventionBrowseBranchName":"Nitric Oxide Donors" },{ "InterventionBrowseBranchAbbrev":"VaDiAg", "InterventionBrowseBranchName":"Vasodilator Agents" },{ "InterventionBrowseBranchAbbrev":"AnAg", "InterventionBrowseBranchName":"Antihypertensive Agents" },{ "InterventionBrowseBranchAbbrev":"Resp", "InterventionBrowseBranchName":"Respiratory System Agents" } ] } }, "ConditionBrowseModule":{ "ConditionMeshList":{ "ConditionMesh":[ { "ConditionMeshId":"D000006333", "ConditionMeshTerm":"Heart Failure" } ] }, "ConditionAncestorList":{ "ConditionAncestor":[ { "ConditionAncestorId":"D000006331", "ConditionAncestorTerm":"Heart Diseases" },{ "ConditionAncestorId":"D000002318", "ConditionAncestorTerm":"Cardiovascular Diseases" } ] }, "ConditionBrowseLeafList":{ "ConditionBrowseLeaf":[ { "ConditionBrowseLeafId":"M8004", "ConditionBrowseLeafName":"Heart Failure", "ConditionBrowseLeafAsFound":"Heart Failure", "ConditionBrowseLeafRelevance":"high" },{ "ConditionBrowseLeafId":"M8002", "ConditionBrowseLeafName":"Heart Diseases", "ConditionBrowseLeafRelevance":"low" } ] }, "ConditionBrowseBranchList":{ "ConditionBrowseBranch":[ { "ConditionBrowseBranchAbbrev":"BC14", "ConditionBrowseBranchName":"Heart and Blood Diseases" },{ "ConditionBrowseBranchAbbrev":"All", "ConditionBrowseBranchName":"All Conditions" } ] } } } } } }