Clinical trial NCT02791906: Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease
Official title: Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Renal Insufficiency, Chronic
Keywords: Chronic Kidney Diseases
Chronic Kidney Insufficiency
Chronic Renal Diseases
Chronic Renal Insufficiency
Kidney Insufficiency, Chronic
Cardiac Failure
Congestive Heart Failure
Heart Decompensation
Heart Failure, Congestive
Myocardial Failure
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2016-06-07
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Heart failure (HF) is an epidemic and is a major burden on the US healthcare system. The most common cardiovascular endpoint is HF. Thus, novel interventions to prevent HF in chronic kidney disease (CKD) are highly desirable. This study will assess: the variability in the response to isosorbide mononitrate (ISMN) therapy; the degree of change in central hemodynamics and cardiac endpoints through analysis of changes in left ventricle (LV) mass, diffuse myocardial fibrosis, and myocardial systolic and diastolic function.

Detailed description: This is a open label, parallel arm, randomized study of ISMN with or without vitamin C to improve exercise capacity and LV remodeling in CKD. Twenty subjects with CKD will be enrolled in this study and three different daily doses of sustained release isosorbide mononitrate (SR-ISMN) will be administered over time accompanied by a random administration of vitamin C in half of the subjects (500 mg three times daily). Before administration of SR-ISMN, baseline assessments will be performed. These include arterial tonometry, Doppler echocardiography, reflection magnitude measurements, a bicycle exercise test, activity monitoring, cardiac MRI, 24-hour blood pressure monitoring, and blood drawing. After these assessments, a dose of 30 mg of SR-ISMN will be administered daily (either with or without vitamin C) for the first week, 60 mg SR-ISMN for the second week, and 120 mg for the third week. After each week, blood pressure and central hemodynamics will be assessed. The third week visit also includes the bicycle exercise study and initiating the long term dose (60 or 120 mg) of SR-ISMN. In the long-term phase, blood pressure and hemodynamics are assessed at 12-weeks post initiation of the study medication(s). After 24 weeks we will perform the final assessment, which includes the same tests performed during the baseline assessment. Enrollment will take place at the Hospital of the University of Pennsylvania and the Penn Presbyterian Medical Center.

Eligibility criteria: Inclusion Criteria:

* Chronic kidney disease stage 3
* Elevated left ventricular mass index or LV posterior wall thickness \>1.4 cm documented in a clinically indicated echocardiographic or MRI examination within the previous 24 months or electrocardiographic LV hypertrophy
* Stable medical therapy as defined by no addition, removal or change in dosage \>100% of Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers 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:

* A clinically- indicated stress test demonstrating significant myocardial ischemia within 1 year of enrollment, not followed by coronary revascularization
* Rhythm other than sinus (i.e., atrial fibrillation)
* Non-cardiac condition limiting life expectancy to \<1 year
* Current or anticipated future need for long acting organic nitrate therapy
* Severe aortic or mitral valve disease
* Hypertrophic cardiomyopathy
* Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid)
* Pericardial disease
* Primary pulmonary arteriopathy
* History of myocardial infarction, unstable angina, percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days, or requirement for 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)
* Allergy to ISMN
* Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or tadalafil
* Therapy with rosiglitazone
* Current pregnancy or a positive urine pregnancy test; women who become pregnant during the study will be discontinued from the trial
* Therapy with warfarin
* History of kidney stones
* History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Systolic blood pressure \<110 mmHg or diastolic blood pressure \<40 mmHg;
* Contraindications to a cardiac MRI: (a) Central nervous system aneurysm clips; (b) Implanted neural stimulators; (c) Implanted cardiac pacemaker or defibrillator; (d) Cochlear implant; (e) Ocular foreign body (e.g. metal shavings); (f) Other implanted medical devices: (e.g. drug infusion ports); (g) Insulin pump; (h) Metal shrapnel or bullet; (i) Claustrophobia; (j) Extreme obesity rendering the patient unable to fit into narrow-bore scanners; (k) Unwillingness of the patient to undergo a cardiac MRI.

Primary outcomes:
measure: Change in LV Mass
timeFrame: Measured at Baseline Visit and 24 Week Visit
Secondary outcomes:
measure: Changes in Diffuse Myocardial Fibrosis
timeFrame: Measured at Baseline Visit and 24 Week Visit
measure: Changes in Myocardial Systolic and Diastolic Function
timeFrame: Measured at Baseline Visit and 24 visits
measure: Pulse Wave Reflection Magnitude
timeFrame: Measured between Baseline Visit-Week 24
measure: Aerobic Capacity
timeFrame: Change from Baseline at Week 24 reported
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Julio Chirinos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: