Renal Insufficiency, Chronic
Conditions
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
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.
Interventions
DRUGISMN
DIETARY_SUPPLEMENTVitamin C
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in LV Mass | Measured at Baseline Visit and 24 Week Visit | Variability seen in change in LV mass with ISMN administration measured with steady-state free precession cardiac MRI, outcomes reflect the change, in grams |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Diffuse Myocardial Fibrosis | Measured at Baseline Visit and 24 Week Visit | Myocardial ECV was assessed using a modified Look-Locker inversion recovery sequence to assess T1 times before and following the IV administration of gadolinium contrast in a mid-ventricular short-axis slice. Parameters for modified Look-Locker inversion recovery were: field of view=340mm2; matrix size=144×192; slice thickness=6mm; repetition time=2.4ms; echo time=1.18ms; flip angle=30 degrees, bandwidth=1000 Hz/pixel, integrated parallel acquisition techniques=2. Myocardial T1measurements were performed before and at several time points (5, 10, 15, and 20-40 min) post-gadolinium administration. Modified Look-Locker inversion recovery was performed with a 5-3-3 schema with (2 inversions, 5 echo times after inversion 1, 3 T1 recovery heartbeats, and 3 echo times after inversion 2). All T1 measurements were used to compute lambda (the myocardium-blood partition coefficient) as the slope of the myocardial 1/T1 over the blood 1/T1 change, by linear regression. |
| Changes in Myocardial Systolic and Diastolic Function | Measured at Baseline Visit and 24 visits | Variability in changes in myocardial function with ISMN administration, assessed via systolic longitudinal strain (measured with tissue tracking MRI) with adequate data for tissue tracking. Strain is the shortening during contraction, expressed as a promotion of the end-diastolic myocardial length. Shortening is indicated by a negative value. Strain is a unit-less metric and is thus expressed in %. A change with negative sign indicates more pronounced shortening of baseline compared to 6 months; a change with positive sign indicates less pronounced shortening during contraction. |
| Pulse Wave Reflection Magnitude | Measured between Baseline Visit-Week 24 | Measured by arterial tonometry and echocardiography. The data reflects estimated changes in each group utilizing all available measurements, collected at all timepoints (baseline visit and weeks 1, 2, 3, 12, and 24 visits). Numbers are estimated changes in each group utilizing available measurements. The change represents the absolute change in the ratio of backward to forward wave amplitudes, multiplied by 100. |
| Aerobic Capacity | Change from Baseline at Week 24 reported | Variability in changes in aerobic capacity (peak oxygen consumption during maximal supine bicycle exercise test) |
Countries
United States
Participant flow
Recruitment details
Screening was performed from electronic medical records searcesh for potential study participants, followed by manual review.
Pre-assignment details
After assessing subjects for eligibility via electronic health record reviews (n=529), 522 were excluded due to not meeting inclusion/exclusion criteria (n=506), not being interested in participating upon telephone interview (n=3) and various other reasons (inability to contact, inability to exercise, scheduling difficulties; n=13).
Participants by arm
| Arm | Count |
|---|---|
| ISMN Only Patients receive only ISMN
ISMN | 4 |
| ISMN AND Vitamin C Patients receive both ISMN and Vitamin C
ISMN
Vitamin C | 3 |
| Total | 7 |
Baseline characteristics
| Characteristic | ISMN Only | Total | ISMN AND Vitamin C |
|---|---|---|---|
| Age, Continuous | 64.75 years STANDARD_DEVIATION 10.65 | 64.43 years STANDARD_DEVIATION 7.96 | 64 years STANDARD_DEVIATION 4.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 4 participants | 7 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 |
| other Total, other adverse events | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 0 / 4 | 1 / 3 |
Outcome results
Primary
Change in LV Mass
Variability seen in change in LV mass with ISMN administration measured with steady-state free precession cardiac MRI, outcomes reflect the change, in grams
Time frame: Measured at Baseline Visit and 24 Week Visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ISMN Only | Change in LV Mass | 24.95 grams | Standard Deviation 31.5 |
| ISMN AND Vitamin C | Change in LV Mass | -10.4 grams | Standard Deviation 1.26 |
Secondary
Aerobic Capacity
Variability in changes in aerobic capacity (peak oxygen consumption during maximal supine bicycle exercise test)
Time frame: Change from Baseline at Week 24 reported
Population: Only 3 subjects had sufficient data to compute a change from baseline, 1 in the ISMN only arm and 2 in the ISMN + Vit C arm. Below are the results of the data that was analyzed for those subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ISMN Only | Aerobic Capacity | 0.05732 L of O2 consumed/ minute | Standard Deviation 0 |
| ISMN AND Vitamin C | Aerobic Capacity | 0.32813 L of O2 consumed/ minute | Standard Deviation 0.49521 |
Secondary
Changes in Diffuse Myocardial Fibrosis
Myocardial ECV was assessed using a modified Look-Locker inversion recovery sequence to assess T1 times before and following the IV administration of gadolinium contrast in a mid-ventricular short-axis slice. Parameters for modified Look-Locker inversion recovery were: field of view=340mm2; matrix size=144×192; slice thickness=6mm; repetition time=2.4ms; echo time=1.18ms; flip angle=30 degrees, bandwidth=1000 Hz/pixel, integrated parallel acquisition techniques=2. Myocardial T1measurements were performed before and at several time points (5, 10, 15, and 20-40 min) post-gadolinium administration. Modified Look-Locker inversion recovery was performed with a 5-3-3 schema with (2 inversions, 5 echo times after inversion 1, 3 T1 recovery heartbeats, and 3 echo times after inversion 2). All T1 measurements were used to compute lambda (the myocardium-blood partition coefficient) as the slope of the myocardial 1/T1 over the blood 1/T1 change, by linear regression.
Time frame: Measured at Baseline Visit and 24 Week Visit
Population: Patients who had measurements at baseline and 24 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ISMN Only | Changes in Diffuse Myocardial Fibrosis | -0.68 % of myocardial tissue composed of ECV | Standard Deviation 4.56 |
| ISMN AND Vitamin C | Changes in Diffuse Myocardial Fibrosis | 2.12 % of myocardial tissue composed of ECV | Standard Deviation 2.99 |
Secondary
Changes in Myocardial Systolic and Diastolic Function
Variability in changes in myocardial function with ISMN administration, assessed via systolic longitudinal strain (measured with tissue tracking MRI) with adequate data for tissue tracking. Strain is the shortening during contraction, expressed as a promotion of the end-diastolic myocardial length. Shortening is indicated by a negative value. Strain is a unit-less metric and is thus expressed in %. A change with negative sign indicates more pronounced shortening of baseline compared to 6 months; a change with positive sign indicates less pronounced shortening during contraction.
Time frame: Measured at Baseline Visit and 24 visits
Population: patients who underwent measurements at baseline and 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ISMN Only | Changes in Myocardial Systolic and Diastolic Function | -3.95 Percent shortening | Standard Deviation 9.67 |
| ISMN AND Vitamin C | Changes in Myocardial Systolic and Diastolic Function | 7.23 Percent shortening | Standard Deviation 0 |
Secondary
Pulse Wave Reflection Magnitude
Measured by arterial tonometry and echocardiography. The data reflects estimated changes in each group utilizing all available measurements, collected at all timepoints (baseline visit and weeks 1, 2, 3, 12, and 24 visits). Numbers are estimated changes in each group utilizing available measurements. The change represents the absolute change in the ratio of backward to forward wave amplitudes, multiplied by 100.
Time frame: Measured between Baseline Visit-Week 24
Population: participants with measurements available at baseline and 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ISMN Only | Pulse Wave Reflection Magnitude | 0.47 % of change in magnitude | Standard Deviation 6.11 |
| ISMN AND Vitamin C | Pulse Wave Reflection Magnitude | -2.28 % of change in magnitude | Standard Deviation 8.77 |