iNOS With Positron Emission Tomography (PET) in Cellular Inflammation. (F-NOS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Robert Gropler, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01066637
First received: February 8, 2010
Last updated: May 2, 2014
Last verified: May 2014
  Purpose

The primary purpose of this study is to measure the level of an enzyme in a patient's heart called inducible nitric oxide synthase(iNOS) using Positron Emission Tomography (PET) imaging with a radioactive tracer called 18F-NOS. These PET results will be compared to tissue results obtained during routine endomyocardial heart biopsy. The enzyme iNOS produces nitric oxide in inflammatory diseases such as acute heart transplant rejection, diabetes, Alzheimer's and cancer. Thus, PET with the radioactive tracer 18F-NOS may be a useful tool for detecting the early stages of these diseases. The safety of 18F-NOS during the study will also be assessed. All PET imaging will be performed with a CTI/Siemens Biograph 40 PET/CT scanner. Protocol was revised to add new imaging modality, Biograph mMR PET-MR scanner in order to investigate new hardware and software in order to optimize scanning procedures in order to refine image quality so that we can apply the findings to future standard clinical scans and research imaging studies. Ten additional status-post OHT patients who are scheduled for standard of care endomyocardial biopsy for allograft rejection surveillance will undergo PET/MR imaging with [18F](+/-)NOS.


Condition Intervention Phase
Heart Transplant
Drug: [18F](+/-)NOS
Phase 0

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Imaging iNOS Activity Using [18F] (+/-) NOS With Positron Emission Tomography (PET) in Cellular Inflammation.

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • To demonstrate the feasibility of imaging patients with increased levels of iNOS using [18F](+/-)NOS. [ Time Frame: 24-72 hours post [18F](+/-)NOS injection ] [ Designated as safety issue: Yes ]
    To determine its potential for use in humans, we measured 18F-NOS myocardial activity in patients after orthotopic heart transplantation (OHT) and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry. Methods: In the kinetic analysis group, 10 OHT patients underwent dynamic myocardial 18F-NOS PET/CT, followed by endomyocardial biopsy. Myocardial 18F-NOS PET was assessed using volume of distribution; standardized uptake values at 10 min; area under the myocardial moment curve (AUMC); and mean resident time at 5, 10, and 30 min after tracer injection. Tissue iNOS levels were measured by immunohistochemistry. Conclusion: Myocardial 18F-NOS activity is increased in organ rejection (a condition associated with increased iNOS levels) and correlates with tissue iNOS measurements with acceptable radiation exposure.


Secondary Outcome Measures:
  • To determine human dosimetry based on the human biodistribution of [18F](+/-)NOS in both normal adult healthy volunteers and heart transplant patients. [ Time Frame: 24-72 hours post [18F](+/-)NOS injection ] [ Designated as safety issue: Yes ]
    All subjects will receive a single intravenous administration of 7 mCi of [18F](+/-)NOS followed by dynamic PET/CT imaging


Estimated Enrollment: 50
Study Start Date: September 2009
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dosimetry Group
Patients 21 years of age or older of either sex, who are status-post heart transplant (3 women and 9 men) and normal healthy volunteers (2 women and 2 men) will be enrolled.
Drug: [18F](+/-)NOS
Other Name: 6-(1/2)(2-18F-fluoropropyl)-4-methylpyridin-2-amine
Experimental: Kinetic Analysis Group
Patients 21 years of age or older of either sex, who are status-post heart transplant (5 women and 5 men) will be enrolled.
Drug: [18F](+/-)NOS
Other Name: 6-(1/2)(2-18F-fluoropropyl)-4-methylpyridin-2-amine

Detailed Description:

Nitric oxide (NO) is an important and unique mediator of a variety of physiological and pathological processes. NO is generated from the oxidation of L-arginine to L-citrulline in a two-step process by nitric oxide synthase (NOS) enzymes. In the NOS family, there are two constitutive isozymes of NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS), and one inducible isozyme (iNOS). The three isozymes of NOS are expressed in different tissues to generate NO for specific physiological roles. nNOS generates NO as a neurotransmitter and neuromodulator, mainly in brain and peripheral nerve cells; eNOS regulates blood pressure, and blood flow primarily in vascular endothelial cells. The induction of iNOS occurs by various inflammatory stimuli (e.g., endotoxin) in activated macrophages and other types of cells and plays a crucial role in the host defense and the inflammatory processes.

Normally, the basal level of NO in all parts of the body is very low, mainly due to the constitutive nNOS and eNOS. In contrast, once expressed, iNOS can continue to generate NO in large amounts (up to μM concentrations) for a prolonged period of time. Studies have shown that production of NO by iNOS is implicated in a variety of acute and chronic inflammatory diseases (e.g., sepsis, septic shock, organ transplant rejection, vascular dysfunction in diabetes, asthma, arthritis, multiple sclerosis, and inflammatory diseases of the gut). iNOS activity has also been found in many tumors. Because of the central role of iNOS in NO-related diseases, numerous efforts have been made to develop iNOS inhibitors as pharmaceuticals ranging from the nonselective L-arginine analogues to the selective inhibitors reported recently. Some inhibitors of iNOS have shown promising results in animal models of sepsis, lung inflammation, arthritis, and autoimmune diabetes. Therefore, the development of a radiolabeled iNOS inhibitor for probing iNOS expression in vivo using noninvasive positron emission tomography (PET) imaging will be of tremendous value to the study and treatment of NO-related diseases.

Acute allograft rejection is the major contributor to mortality in patients receiving orthotopic heart transplantation (OHT). Specifically, iNOS has been thought to be the main NOS involved in producing NO that is active in acute cardiac allograft rejection. Up-regulation of iNOS occurs in macrophage cellular infiltrates and later within the graft parenchymal cells. In human cardiac transplantation a positive correlation has shown between iNOS expression and left ventricular contractile dysfunction measured by echocardiography and Doppler techniques. We have recently developed a novel PET radiotracer, [18F](+/-)NOS, designed to measure cellular iNOS activity. This study evaluates the feasibility of the method in OHT patients undergoing surveillance endomyocardial biopsy as part of their normal post-transplant evaluation for potential allograft rejection. More specifically, it will compare the myocardial kinetics of this radiotracer measured by PET with tissue measurements of iNOS measured by immunohistochemistry.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. The OHT patients will be undergoing surveillance endomyocardial biopsy and will Patients 21 years of age or older of either sex, who are status-post OHT and normal healthy volunteers (2 women and 2 men) will be enrolled.be on standard immunosuppressive therapy and anti-hyperlipidemic, anti-hypertensive and anti-diabetic therapies as needed. "Healthy volunteer" is someone who has volunteered to be imaged and who, based on physical exam and baseline electrocardiogram, has no evidence of cardiovascular disease, is not on medication, such as steroids, that will interfere with the accuracy of measuring [18F](+/-)NOS activity and is not under the care of a physician for any active medical conditions.
  2. Able to give informed consent.
  3. Not currently pregnant or nursing: Female subjects must be either: surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post menopausal (cessation of menses for more than 1 year), or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of [18F](+/-)NOS) is negative.

Exclusion Criteria:

  1. Patients with an unstable cardiovascular (e.g., severe rejection) or other clinical condition (e.g., active severe infection) that in the opinion of the Principal Investigator or designee or Dr. Ewald precludes participation in the study.
  2. Unable to tolerate 60-90 mins of PET imaging or is claustrophobic.
  3. Normal volunteers with evidence of cardiovascular disease or other diseases based on clinical evaluation and/or blood laboratory tests, which are judged by the Principal Investigator or designee to interfere with accurate determination of the of [18F](+/-)NOS on such measures.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01066637

Contacts
Contact: Deborah Delano, RN 314-747-3876 delanod@mir.wustl.edu
Contact: Kitty Krupp, RN 314-747-0183 kruppk@mir.wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
St.Louis, Missouri, United States, 63110
Contact: Deborah Delano, RN    314-747-3876    delanod@mir.wustl.edu   
Contact: Ali A Jamal, MD    314-747-3839    jamala@mir.wustl.edu   
Principal Investigator: Robert J Gropler, MD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Robert J Gropler, MD Washington University School of Medicine
  More Information

No publications provided

Responsible Party: Robert Gropler, Professor of Radiology, Medicine and Biomedical Engineering, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01066637     History of Changes
Other Study ID Numbers: 09-0986, 201106273
Study First Received: February 8, 2010
Last Updated: May 2, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
Heart transplant patients

Additional relevant MeSH terms:
Inflammation
Pathologic Processes

ClinicalTrials.gov processed this record on August 18, 2014