Angiogenesis in Women With Angina Pectoris Who Are Not Candidates for Revascularization (AWARE)

A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multicenter Study to Evaluate the Efficacy and Safety of Ad5FGF-4 in Female Patients With Stable Angina Pectoris Who Are Not Candidates for Revascularization

The purpose of this study is to determine whether a one-time intracoronary infusion of Ad5FGF-4 is effective in reducing the time to onset myocardial ischemia as measured by exercise treadmill testing and improving myocardial blood flow as measured by SPECT imaging. Exercise capacity, angina functional class, patient symptoms and quality of life will also be evaluated to characterize the efficacy of Ad5FGF-4. Short-term and long-term safety of Ad5FGF-4 will also be evaluated.

Study Overview

• Status: Unknown
• Conditions: Angina Pectoris
• Intervention / Treatment: Genetic: Ad5FGF-4; Genetic: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85206
      • Banner Heart Hospital
    • Tucson, Arizona, United States, 85715
      • Southwest Heart
  • California
    • Beverly Hills, California, United States, 90210
      • Access Clinical Trials
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Mission Viejo, California, United States, 92691
      • Mission Internal Medical Group
    • San Diego, California, United States, 92103
      • UCSD Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Denver Cardiology
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Cardiovascular Research Institute
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Orlando, Florida, United States, 32803
      • Florida Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • St Joseph's Research Institute
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Idaho Cardiology Associates
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Fox Valley Cardiovascular Consultants
    • Lombard, Illinois, United States, 60148
      • Midwest Heart Foundation
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Northern Indiana Research Alliance
    • Indianapolis, Indiana, United States, 46290
      • The Care Group
  • Kentucky
    • Louisville, Kentucky, United States, 40205
      • Cardiovascular Associates
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • St. Mary's Duluth Clinic
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Mid America Heart institute
    • St. Louis, Missouri, United States, 63128
      • St. Anthony's Medical Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • BryanLGH Heart Institute
    • Omaha, Nebraska, United States, 68131
      • Creighton University
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
  • New York
    • New York, New York, United States, 10021
      • Lenox Hill Heart & Vascular Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Elyria, Ohio, United States, 44035
      • North Ohio Heart Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73109
      • Oklahoma Cardiovascular Associates
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence Heart & Vascular Institute
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Heritage Cardiology Associates
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Clinic
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The Stern Cardiovascular Center
    • Nashville, Tennessee, United States, 37208
      • Meharry Medical College
  • Texas
    • Dallas, Texas, United States, 75226
      • Baylor University Medical Center at Dallas
    • San Antonio, Texas, United States, 78229
      • South Texas Cardiovascular Consultants
    • Tyler, Texas, United States, 75701
      • Cardiovascular Associates of East Texas
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center
  • Wisconsin
    • Wausau, Wisconsin, United States, 54401
      • Care Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female patients 18-75 years of age inclusive
• Stable angina classified as CCS III or IV
• Receiving treatment with at least two classes of chronic anti-anginal medication, of which two are at the maximally tolerated dose
• Left ventricular ejection fraction (LVEF) of ≥30%
• Not a candidate for, or unlikely to benefit from standard revascularization procedures as verified by an independent cardiologist or cardiothoracic surgeon (not a study investigator) at each center

• Can undergo ETT using the modified Bruce protocol and;

  1. ECG changes diagnostic of myocardial ischemia occur during the first 10 minutes of exercise
  2. Variability of the time to onset of ECG changes diagnostic of myocardial ischemia is ≤25% or within 60 seconds if the time to onset of myocardial ischemia occurs within the first 4 minutes of exercise as determined by two consecutive screening treadmill tests
• Evidence of stress induced myocardial ischemia by adenosine SPECT, defined as a reversible perfusion defect size of ≥9%
• Willing and able to comply with the study requirements including long-term follow-up
• Provided written informed consent

Exclusion Criteria:

• Patients of childbearing potential (must be surgically sterile or post-menopausal)
• Patients for whom an immediate revascularization procedure is indicated (CABG surgery or PCI)
• Myocardial infarction within the past 3 months
• Unstable angina or hospitalization requiring intravenous anti-anginal therapy within the 14 days prior to the start of screening evaluations
• Congestive heart failure NYHA Class IV
• Electrocardiogram that precludes accurate assessment of exercise induced myocardial ischemia (e.g., left bundle branch block, Wolf-Parkinson-White syndrome, atrial fibrillation)
• Myocarditis or restrictive pericarditis
• Left main coronary stenosis ≥70% (unless the patient has a patent graft or collateral vessels supplying the left coronary circulation) or proximal stenoses ≥70% in all major coronary conduit vessels (coronary arteries and bypass grafts)
• Clinically significant aortic or mitral valvular heart disease
• Coronary ostial stenosis that precludes adequate catheter engagement in any target vessel
• Coronary artery to venous communications, which bypass the coronary capillary bed
• Untreated life-threatening ventricular arrhythmias
• CABG surgery within the past 6 months, unless those grafts are now occluded.
• Percutaneous transluminal angioplasty (PTCA) within the past 3 months, unless the dilated vessel(s) are now occluded
• Enhanced external counterpulsation (EECP) within 3 months prior to the start of screening evaluations
• Transmyocardial or percutaneous myocardial laser revascularization within the previous year
• Prior treatment with any cardiovascular gene or stem cell therapy.
• Any intercurrent illness that may interfere with their ability to perform a maximal ETT
• Any major organ disease that substantially impairs life expectancy.
• History of cancer, other than basal cell carcinoma, or patients with any laboratory or physical exam or diagnostic procedure finding suggestive of current malignancy
• Moderate to severe nonproliferative or proliferative retinopathy from any cause (ETDRS score >35), clinically significant macular edema, or previous panretinal photocoagulation therapy
• Heparin induced thrombocytopenia or history of idiopathic thrombocytopenic purpura or other medical condition causing thrombocytopenia
• SGPT level greater than 2.0 times the upper limit of the laboratory normal range
• Bilirubin level ≥2.0 mg/dL
• Serum creatinine ≥2.5 mg/dL
• Platelet count <100,000/μL
• White blood cell count <3,000/μL
• Positive test for hepatitis B or C
• Positive test for HIV
• History of colon cancer in a first degree relative (i.e., parent, sibling or offspring) unless the patient has undergone a colonoscopy in the past 36 months with negative findings
• History of breast cancer in a first degree relative
• Patient in a family with any documented hereditary cancer syndrome
• Prior anaphylaxis reaction to iodinated contrast agents
• Patients who are known to be immunosuppressed or are receiving chronic treatment with immunosuppressive drugs
• Received an investigational drug or biologic within 30 days of screening or are currently participating in an investigational drug, biologic or device trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1	Genetic: Ad5FGF-4; Adenovirus serotype-5 mediated human fibroblast growth factor-4 gene transfer
EXPERIMENTAL: 2	Genetic: Ad5FGF-4; Adenovirus serotype-5 mediated human fibroblast growth factor-4 gene transfer
PLACEBO_COMPARATOR: 3	Genetic: Placebo; Control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in time to onset of ECG changes diagnostic of myocardial ischemia during ETT	Month 6

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in reversible perfusion defect size as measured by adenosine single-photon emission computed tomography with technetium-99m sestamibi (SPECT)(principal secondary endpoint)	Month 6
Change in total exercise treadmill time	Months 3, 6 and 12
Change in time to onset ECG changes diagnostic myocardial ischemia during ETT	Months 3 and 12
Change in time to onset of angina during ETT	Months 3, 6 and 12
Change in angina frequency and nitroglycerin	Months 3 and 6
Change in patient functional status using CCS angina class	Months 3, 6 and 12
Change in rest and stress left ventricular ejection fraction assessed using gated SPECT	Month 6
Change in quality of life using the Seattle Angina Questionnaire	Months 6 and 12
Safety of Ad5FGF-4 as assessed by adverse events and clinical laboratory testing	Through month 12
Long-term safety of Ad5FGF-4 as assessed by clinically important events	Through month 60

Collaborators and Investigators

• Sponsor: Cardium Therapeutics
• Investigators: Study Director: Robert Engler, MD, Cardium Therapeutics

Publications and helpful links

General Publications

• Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R, Andrasfay T, Engler RL. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol. 2007 Sep 11;50(11):1038-46. doi: 10.1016/j.jacc.2007.06.010. Epub 2007 Aug 24.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (ACTUAL): November 1, 2009

Study Registration Dates

• First Submitted: February 21, 2007
• First Submitted That Met QC Criteria: February 21, 2007
• First Posted (ESTIMATE): February 22, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): February 13, 2013
• Last Update Submitted That Met QC Criteria: February 11, 2013
• Last Verified: November 1, 2008

More Information

Terms related to this study

• Keywords: angina; angiogenesis; growth factor; revascularization; FGF-4; myocardia ischemia
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris
• Other Study ID Numbers: CT-3-001