Evaluation of the Safety and Efficacy of Ang-(1-7) to Enhance Cognitive Function in Participants Undergoing CABG

Up to 104 participants (ages 60-80) undergoing elective CABG surgery at the Banner University
Medical Center in Tucson, AZ or at Suburban Hospital/NIH Clinical Center in Bethesda, MD,
will be enrolled in this randomized, placebo-controlled, double-blind study of
Angiotensin-(1-7). Subjects who have a pre-operative neurologic, learning or psychiatric
disorder will be excluded. In addition, a concurrent group of 20 age-matched adults will be
recruited as a neuropsychological control group and will undergo neuropsychological testing
at baseline, Day 21 and Day 90.

Participants will be asked to undergo a screening process to confirm eligibility and to rule
out depression, dementia and contraindications to MRI. Prior to randomization, baseline
measures will include neuropsychological testing, brain MRI, quality of life questionnaires,
inflammatory markers and DNA/RNA sample collection. Participants will be treated for 21 days
with a daily dose of subcutaneous Ang-(1-7) (100 mcg/kg/day) (n=60) or placebo (n=30). These
measures will then be repeated at Day 21 and Day 90. The MRI will be repeated at Day 21 only.

Pharmacokinetic measurements will be obtained prior to administration of Ang-(1-7) or placebo
and hourly for 6 hours following the first 6 doses. Delirium testing will occur on a daily
basis post surgery until discharge. Serum study drug level will be obtained at Day 21.

Lastly, subjects will be followed on a weekly basis by telephone for all 12 weeks of the
study.

1. Primary Objective: To evaluate the safety and tolerability of 21 days of subcutaneous
(s.c.) once daily administration of Ang-(1-7) in eligible participants undergoing
first-time, elective coronary artery bypass graft (CABG) surgery.

2. Secondary Objectives:

1. To determine the pharmacokinetics of 21 days of treatment with Ang-(1-7).

2. To determine if 21 days of treatment with 200 mcg/kg/day of Ang-(1-7) improves
memory function measured as a change in performance from baseline to follow up on a
composite score comprised of memory, executive functioning, language and processing
speed in Ang-(1-7) treatment group compared to placebo controls and non-surgical
controls.

3. To determine if treatment with 200 mcg/kg/day Ang-(1-7) decreases postoperative
delirium length and severity as measured with the Confusion Assessment Method (CAM)
D2 to D7 ( or discharge) after surgery as compared to treatment with placebo group.

4. To determine if 21 days of treatment with 200 mcg/kg/day Ang-(1-7) improves
participant self-reported outcomes using standardized Kansas City Cardiomyopathy
Questionnaire (KCCQ) and Instrumental Activities of Daily Living (IADL) measurement
tools.

5. To determine if 21 days treatment with 200 mcg/kg/day Ang-(1-7) results in changes
in suicidal ideation and behavior as assessed by The Columbia Suicide Severity
Rating Scale (C-SSRS).

6. To compare postoperative mortality and morbidity at 90 days in the 200 mcg/kg/day
Ang-(1-7) treatment group with the placebo group.

7. To determine if 21 days of treatment of 200 mcg/kg/day Ang-(1-7) decreases
postoperative observable changes in brain fractional anisotropy as measured by
diffuse on magnetic resonance imaging (MRI) as compared to placebo.

Inclusion Criteria:

- Adult male or female first time cardiac surgical participants

- Elective on pump coronary artery bypass grafting (CABG)

- Age 60-80

- Signed, informed consent

- Geriatric Depression Scale score less than or = 14or Beck's Depression Inventory less
than or = 20

- Score > or = 25 on the Mini-Mental State Examination (MMSE)

Exclusion Criteria:

- Recent (within 60 days) Cerebrovascular disease with neurological change

- Malignancy or pre-malignant state within 5 years not including non-melanoma skin
cancer

- History of liver dysfunction with ongoing sequelae (including but not limited to liver
enzymes > 2.5 x upper limit or normal (ULN) at screening).

- History of renal dysfunction with ongoing sequelae (including but not limited to
creatinine value > 2.5 mg/dL at screening).

- Significant Lung Disease (FEV1< 1.5 L, pO2 <70 on room air, pCO2 >45)

- Presence of any severe mental illness that could affect interpretation of efficacy
data, such as schizophrenia or bipolar affective disorder; any untreated or unstable
psychiatric condition including depressive disorder or anxiety disorder.

- Active substance abuse

- Less than Grade 7 education or inability to read and perform cognitive assessment.

- Significant neurological disorder affecting memory

- Uncontrolled atrial fibrillation prior to surgery

- Concurrent use of prescription medications specifically for memory enhancement
including herbal or natural supplements

- General anesthesia (defined as anesthesia requiring intubation or ventilatory support)
within 3 months prior to randomization.

- Cardiopulmonary bypass or thoracotomy within 2 years prior to randomization.

- Chronic obstructive pulmonary disease (COPD) requiring oxygen therapy.

- Participants on immunosuppressive drugs, such as azathioprine, chemotherapeutic
agents, mycophenolate, monoclonal antibodies, or more than 20 mg/day prednisone,
within the previous 3 months

- Receipt of any investigational agent or device within 30 days of screening

- MRI contraindication not limited to abnormally high weight or height to fit in scanner
(Bore 70cm); Presence of device/hardware incompatible with MR imaging

- Conditions causing severe anemia

- Participant is practicing Jehovah Witness

- Sexually active males not practicing a medically acceptable method of contraception,
unless there is documented azoospermia.