Targeting Central Pulsatile Hemodynamics in Chronic Kidney Disease

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 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.

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
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 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.