Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02791906
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 2
• Duration (Months): 34
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Insufficiency, Chronic	Drug: ISMN; Dietary Supplement: Vitamin C	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Mar 1, 2019
• Actual Study Completion Date: Mar 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ISMN Only Patients receive only ISMN	Drug: ISMN
Experimental: ISMN AND Vitamin C Patients receive both ISMN and Vitamin C	Drug: ISMN; Dietary Supplement: Vitamin C

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. Aerobic Capacity [Change from Baseline at Week 24 reported]

   Variability in changes in aerobic capacity (peak oxygen consumption during maximal supine bicycle exercise test)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Julio Chirinos, MD, PhD, University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 15, 2016

More Information

Publications

None provided.

• Responsible Party: Julio A. Chirinos, Principal Investigator, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02791906
• Other Study ID Numbers: 823665
• First Posted: Jun 7, 2016
• Last Update Posted: Aug 13, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Julio A. Chirinos, Principal Investigator, University of Pennsylvania: 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
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Ascorbic Acid

Study Results

Participant Flow

Recruitment Details	Screening was performed from electronic medical records searcesh for potential study participants, followed by manual review.
Pre-assignment Detail	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).

Arm/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C
Period Title: Overall Study
STARTED	4	3
COMPLETED	2	2
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	ISMN Only	ISMN AND Vitamin C	Total
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C	Total of all reporting groups
Overall Participants	4	3	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.75 (10.65)	64 (4.36)	64.43 (7.96)
Sex: Female, Male (Count of Participants)
Female	1 25%	1 33.3%	2 28.6%
Male	3 75%	2 66.7%	5 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	4 100%	3 100%	7 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 75%	2 66.7%	5 71.4%
White	1 25%	1 33.3%	2 28.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	3 100%	7 100%

Outcome Measures

1. Primary Outcome

Title	Change in LV Mass
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C
Measure Participants	2	2
Mean (Standard Deviation) [grams]	24.95 (31.5)	-10.4 (1.26)

2. Secondary Outcome

Title	Changes in Diffuse Myocardial Fibrosis
Description	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

Outcome Measure Data

Analysis Population Description

Patients who had measurements at baseline and 24 weeks.

Arm/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C
Measure Participants	2	2
Mean (Standard Deviation) [% of myocardial tissue composed of ECV]	-0.68 (4.56)	2.12 (2.99)

3. Secondary Outcome

Title	Changes in Myocardial Systolic and Diastolic Function
Description	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

Outcome Measure Data

Analysis Population Description

patients who underwent measurements at baseline and 24 weeks

Arm/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C
Measure Participants	2	1
Mean (Standard Deviation) [Percent shortening]	-3.95 (9.67)	7.23 (0)

4. Secondary Outcome

Title	Pulse Wave Reflection Magnitude
Description	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

Outcome Measure Data

Analysis Population Description

participants with measurements available at baseline and 24 weeks

Arm/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Patients receive only ISMN ISMN	Patients receive both ISMN and Vitamin C ISMN Vitamin C
Measure Participants	2	2
Mean (Standard Deviation) [% of change in magnitude]	0.47 (6.11)	-2.28 (8.77)

5. Secondary Outcome

Title	Aerobic Capacity
Description	Variability in changes in aerobic capacity (peak oxygen consumption during maximal supine bicycle exercise test)
Time Frame	Change from Baseline at Week 24 reported

Outcome Measure Data

Analysis Population Description

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/Group Title	ISMN Only	ISMN AND Vitamin C
Arm/Group Description	Monotherapy with isosorbide mononitrate	Combination therapy with isosorbide mononitrate and vitamin C
Measure Participants	1	2
Mean (Standard Deviation) [L of O2 consumed/ minute]	0.05732 (0)	0.32813 (0.49521)

Adverse Events

Time Frame	6 months
Arm/Group Title	ISMN Only		ISMN AND Vitamin C
Arm/Group Description	Monotherapy with isosorbide mononitrate		Combination therapy with isosorbide mononitrate and vitamin C
All Cause Mortality
	ISMN Only		ISMN AND Vitamin C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/3 (0%)
Serious Adverse Events
	ISMN Only		ISMN AND Vitamin C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		1/3 (33.3%)
Infections and infestations
Urosepsis requiring hospitalization	0/4 (0%)	0	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	ISMN Only		ISMN AND Vitamin C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		3/3 (100%)
Cardiac disorders
2n degree AV block	0/4 (0%)	0	1/3 (33.3%)	1
Ankle swelling	1/4 (25%)	1	0/3 (0%)	0
Gastrointestinal disorders
Heart burn	0/4 (0%)	0	1/3 (33.3%)	1
General disorders
fatigue	0/4 (0%)	0	1/3 (33.3%)	1
dry mouth	1/4 (25%)	1	1/3 (33.3%)	1
Nausea	1/4 (25%)	1	2/3 (66.7%)	2
Headache	0/4 (0%)	0	2/3 (66.7%)	3
Balance problems	0/4 (0%)	0	1/3 (33.3%)	1
Sleep	0/4 (0%)	0	1/3 (33.3%)	1
Sweating	0/4 (0%)	0	2/3 (66.7%)	2
Nervous system disorders
Drowsiness/dizziness/lightheadedness	2/4 (50%)	3	1/3 (33.3%)	1
Renal and urinary disorders
Worsening renal AKI + Hyperkalemia	1/4 (25%)	1	0/3 (0%)	0
Hypokalemia	1/4 (25%)	1	0/3 (0%)	1
Skin and subcutaneous tissue disorders
Skin rash	3/4 (75%)	4	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.