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

NCT03252093 | Terminated Phase 2 DMC FDA Drug

• 2 other identifiers: HL1310141U01HL131014-01A1
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 5

Brief Summary

Coronary Artery Bypass Graft (CABG) is a surgical procedure known to be associated with cognitive impairment. Mechanisms of cognitive impairment are complex but may include insufficient oxygenation and inflammation due to exposure to the bypass circuit. Currently there are no approved therapeutics for the prevention or treatment of cognitive impairment in these patients. A small peptide, Angiotensin-(1-7) \[Ang-(1-7)\], is known to decrease inflammation in the brain in animal models. Early studies in humans have shown it to be safe. This peptide is naturally produced by the body and has anti-inflammatory and vasodilatory effects. Investigators believe that Ang-(1-7) may be able to help lower the risk of cognitive dysfunction in patients undergoing CABG. The goal of this project is to explore effects of the experimental peptide Angiotensin-(1-7) (Ang-(1-7) in patients undergoing an elective CABG surgery to determine its safety and efficacy to prevent cognitive dysfunction in patients undergoing CABG.

Conditions

Coronary Artery Bypass Surgery; Cognitive Impairment

Outcome Measures

Primary Outcomes (1)

• Demonstrate 21 days daily administration of Ang-(1-7) in participants undergoing 1st time CABG surgery is safe and efficacious as assessed by the number of related AEs grade 3 or > and change in composite neuropsychological score up to Day 90.

  Adverse events (AEs), including serious adverse events (SAEs) will be monitored from the time of enrollment through Day 90. The number of AEs, withdrawals due to AE, and withdrawals for other reasons will be tabulated. Additional assessments include: serum blood levels of the Ang-(1-7) at Day 1, Day 3, Day 5 or Discharge and Day 21. Lastly blood pressuring monitoring pre and post treatment will occur Day 1 to discharge. Change in performance on composite scores of memory, executive functioning, language and processing speed in the treatment arm compared to placebo arm and non-surgical controls measured at 3 time points will assess the effectiveness of Ang-(1-7) in reducing postoperative cognitive impairment in CABG patients.

  Up to Day 90

Secondary Outcomes (4)

• Demonstrated change in the neuropsychological component scores assessed at baseline, Day 21 and Day 90 in the treatment and placebo arms.

  Up to Day 90

• Evidence of change in fractional anisotropy from diffusion tensor imaging on Brain MRI at baseline versus post operative Day 21 will be assessed in the treatment and placebo arms as a measure of efficacy.

  Up to Day 21

• Demonstrated change in PBR28 VT/fP, a quantitative measure of TSPO receptor density, in a composite cerebral region-of-interest (ROI) derived from brain PET imaging in the treatment and placebo arms.

  Up to Day 21

• Demonstrated associations between neuropsychogical test results, MRI findings and PBR28 binding in all participants.

  Up to Day 90

Study Arms (2)

Angiotensin-(1-7)

EXPERIMENTAL

Intervention: Drug: 200 mcg/kg/day injected subcutaneously once daily for 21 days

Drug: Angiotensin-(1-7)

Placebo for Angiotensin-(1-7)

PLACEBO COMPARATOR

Intervention: Placebo for Angiotensin-(1-7) injected subcutaneously once daily for 21 days

Drug: Placebo for Angiotensin-(1-7)

Interventions

Angiotensin-(1-7) DRUG

Subcutaneous injection of 200 mcg/kg/day

Angiotensin-(1-7)

Placebo for Angiotensin-(1-7) DRUG

Subcutaneous injection of Placebo

Placebo for Angiotensin-(1-7)

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Arizona: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Suburban Hospital: collaborator

Study Sites (5)

Banner- University Medical Center Phoenix

Phoenix, Arizona, 85006, United States

Location

University of Arizona Sarver Heart Center

Tucson, Arizona, 85724, United States

Location

Suburban Hospital

Bethesda, Maryland, 20814, United States

Location

National Institutes of Health

Bethesda, Maryland, 20892, United States

Location

INOVA Heart & Vascular Research

Falls Church, Virginia, 22042, United States

Location

MeSH Terms

Conditions

Cognitive Dysfunction

Interventions

angiotensin I (1-7)

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Study Officials

• Nancy K Sweitzer, MD, PhD

  University of Arizona

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2017
• First Posted: August 17, 2017
• Study Start: July 20, 2017
• Primary Completion: November 15, 2022
• Study Completion: November 15, 2022
• Last Updated: June 4, 2025

Record last verified: 2025-05

Locations

US (5)