A Phase 2 interventional study of ISMN and Vitamin C in Renal Insufficiency, Chronic, sponsored by University of Pennsylvania. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-08-13.
Sponsored by University of Pennsylvania · Phase 2, Interventional, and Other
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.
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.
3,840 studies on the registry are indexed under Kidney Diseases; 500 are open to participants now.
This study's enrollment of 8 is below the median of 70 across 2,640 interventional studies indexed under Kidney Diseases.
Browse Kidney Diseases studies →University of Pennsylvania is the lead sponsor of 1,635 studies on the registry; 239 are open to participants now.
Of its 154 completed or terminated interventional studies of FDA-regulated products, 104 (68%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Patients receive only ISMN
Drug: ISMN
Patients receive both ISMN and Vitamin C
Drug: ISMN · Dietary Supplement: Vitamin C
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
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
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
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
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
Screening was performed from electronic medical records searcesh for potential study participants, followed by manual review.
| Milestone | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Started | 4 | 3 |
| Completed | 2 | 2 |
| Not completed | 2 | 1 |
Variability seen in change in LV mass with ISMN administration measured with steady-state free precession cardiac MRI, outcomes reflect the change, in grams
| grams | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Change in LV Mass | 24.95 ± 31.5 | -10.4 ± 1.26 |
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.
| % of myocardial tissue composed of ECV | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Changes in Diffuse Myocardial Fibrosis | -0.68 ± 4.56 | 2.12 ± 2.99 |
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.
| Percent shortening | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Changes in Myocardial Systolic and Diastolic Function | -3.95 ± 9.67 | 7.23 ± 0 |
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.
| % of change in magnitude | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Pulse Wave Reflection Magnitude | 0.47 ± 6.11 | -2.28 ± 8.77 |
Variability in changes in aerobic capacity (peak oxygen consumption during maximal supine bicycle exercise test)
| L of O2 consumed/ minute | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Aerobic Capacity | 0.05732 ± 0 | 0.32813 ± 0.49521 |
Collected over 6 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| ISMN Only | 0/4 (0%) | 0/4 (0%) | 4/4 (100%) |
| ISMN AND Vitamin C | 0/3 (0%) | 1/3 (33.3%) | 3/3 (100%) |
| Event | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Urosepsis requiring hospitalizationInfections and infestations | 0/4 | 1/3 |
| Event | ISMN Only | ISMN AND Vitamin C |
|---|---|---|
| Skin rashSkin and subcutaneous tissue disorders | 3/4 | 1/3 |
| NauseaGeneral disorders | 1/4 | 2/3 |
| HeadacheGeneral disorders | 0/4 | 2/3 |
| SweatingGeneral disorders | 0/4 | 2/3 |
| Drowsiness/dizziness/lightheadednessNervous system disorders | 2/4 | 1/3 |
| 2n degree AV blockCardiac disorders | 0/4 | 1/3 |
| fatigueGeneral disorders | 0/4 | 1/3 |
| dry mouthGeneral disorders | 1/4 | 1/3 |
| Balance problemsGeneral disorders | 0/4 | 1/3 |
| Heart burnGastrointestinal disorders | 0/4 | 1/3 |
| Age, Continuous(years) | ISMN Only | ISMN AND Vitamin C | Total |
|---|---|---|---|
| Mean | 64.75 ± 10.65 | 64 ± 4.36 | 64.43 ± 7.96 |
| Sex: Female, Male(Participants) | ISMN Only | ISMN AND Vitamin C | Total |
|---|---|---|---|
| Female | 1 | 1 | 2 |
| Male | 3 | 2 | 5 |
| Ethnicity (NIH/OMB)(Participants) | ISMN Only | ISMN AND Vitamin C | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 0 | 0 | 0 |
| Unknown or Not Reported | 4 | 3 | 7 |
| Race (NIH/OMB)(Participants) | ISMN Only | ISMN AND Vitamin C | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 2 | 5 |
| White | 1 | 1 | 2 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | ISMN Only | ISMN AND Vitamin C | Total |
|---|---|---|---|
| United States | 4 | 3 | 7 |
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