Patients With Post Orthotopic Heart Transplantation StatusEarly Phase 1F-NOSNCT01066637
iNOS With Positron Emission Tomography (PET) in Cellular Inflammation.
A Early Phase 1 study testing [18F](+/-)NOS in people with Patients With Post Orthotopic Heart Transplantation Status, run by Washington University School of Medicine at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 21 years and olderHealthy volunteers can take part
- Conditions the study is for
- Patients With Post Orthotopic Heart Transplantation Status
- What is being tested?
- [18F](+/-)NOS
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2009to Jun 2012
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
- Able to give informed consent.
- 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.
Who cannot join
- 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.
- Unable to tolerate 60-90 mins of PET imaging or is claustrophobic.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: Imaging iNOS Activity Using [18F] (+/-) NOS With Positron Emission Tomography (PET) in Cellular Inflammation.
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.
Read the 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.
- Being tested
- [18F](+/-)NOS
- Keywords
- Heart transplant patients
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
[18F](+/-)NOSDrug
Also called 6-(1/2)(2-18F-fluoropropyl)-4-methylpyridin-2-amine
Injection of radiotracer [18F](+/-)NOS for PET imaging and kinetic data analysis
| Study group | Role | What they receive |
|---|---|---|
| Dosimetry Group | Experimental | To determine its potential for use in humans, we measured 18F-NOS myocardial activity in patients after orthotopic heart transplantation (OHT) (3 women and 9 men) and normal healthy volunteers (2 women and 2 men), and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry. Receives: Drug: [18F](+/-)NOS |
| Kinetic Analysis Group | Experimental | Measurement of myocardial levels of enzyme nitric oxide synthase(iNOS) using PET and 18F-NOS in post heart transplant patients (5 women and 5 men) undergoing endomyocardial biopsy as part of their normal post-transplant evaluation. Kinetic data of the tracer will be compared with the heart tissue measurements of iNOS measured by immunohistochemistry. Receives: Drug: [18F](+/-)NOS |
What is being measured
The primary outcome is the main question the study is designed to answer.
To Measure Free Fatty Acid by Imaging Patients With Increased Levels of iNOS Using [18F](+/-)NOS.
Measured: 24-72 hours post [18F](+/-)NOS injection
Secondary outcomes (1)
To Determine Human Dosimetry in Both Normal Adult Healthy Volunteers and Heart Transplant Patients.
All subjects will receive a single intravenous administration of 7 mCi of [18F](+/-)NOS followed by dynamic PET/CT imaging
Measured: 24-72 hours post [18F](+/-)NOS injection
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Feb 2010 (estimated)
- Study startSep 2009
- Primary completionJun 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Patients With Post Orthotopic Heart Transplantation StatusStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Robert J Gropler, MD, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01066637
- Sponsor's protocol ID
- 09-0986
- Other IDs
- 201106273
- Acronym
- F-NOS
- Status last verified
- Jul 2020
- First submitted
- 8 Feb 2010
- Last updated
- 7 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem. 1993 Jun 15;268(17):12231-4. No abstract available.
PubMed 7685338Kaneki M, Shimizu N, Yamada D, Chang K. Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox Signal. 2007 Mar;9(3):319-29. doi: 10.1089/ars.2006.1464.
PubMed 17184170Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001 Aug 1;357(Pt 3):593-615. doi: 10.1042/0264-6021:3570593.
PubMed 11463332Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 2005 Jun;57(2):217-52. doi: 10.1124/pr.57.2.1.
PubMed 15914468
Study at a glance
From the registry record, last updated by the sponsor on 7 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Imaging iNOS Activity Using [18F] (+/-) NOS With Positron Emission Tomography (PET) in Cellular Inflammation.
- ClinicalTrials.gov ID
- NCT01066637
- Acronym / sponsor ID
- F-NOS / 09-0986
- Keywords
- Heart transplant patients
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Study start
- Sep 2009 (actual)
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 10 Feb 2010 (estimated)
- Results
- Posted 7 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dosimetry Group | Experimental | Drug: [18F](+/-)NOSTo determine its potential for use in humans, we measured 18F-NOS myocardial activity in patients after orthotopic heart transplantation (OHT) (3 women and 9 men) and normal healthy volunteers (2 women and 2 men), and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry. |
| Kinetic Analysis Group | Experimental | Drug: [18F](+/-)NOSMeasurement of myocardial levels of enzyme nitric oxide synthase(iNOS) using PET and 18F-NOS in post heart transplant patients (5 women and 5 men) undergoing endomyocardial biopsy as part of their normal post-transplant evaluation. Kinetic data of the tracer will be compared with the heart tissue measurements of iNOS measured by immunohistochemistry. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
- Able to give informed consent.
- 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.
Key exclusion criteria (3 listed)
- 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.
- Unable to tolerate 60-90 mins of PET imaging or is claustrophobic.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| [18F](+/-)NOSAlso: 6-(1/2)(2-18F-fluoropropyl)-4-methylpyridin-2-amineInjection of radiotracer [18F](+/-)NOS for PET imaging and kinetic data analysis | Drug | Dosimetry Group, Kinetic Analysis Group |
Primary outcome
To Measure Free Fatty Acid by Imaging Patients With Increased Levels of iNOS Using [18F](+/-)NOS.
Time frame: 24-72 hours post [18F](+/-)NOS injection
1 secondary outcome
To Determine Human Dosimetry in Both Normal Adult Healthy Volunteers and Heart Transplant Patients.
Time frame: 24-72 hours post [18F](+/-)NOS injection
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 7685338Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem. 1993 Jun 15;268(17):12231-4. No abstract available.
- Background: PubMed 17184170Kaneki M, Shimizu N, Yamada D, Chang K. Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox Signal. 2007 Mar;9(3):319-29. doi: 10.1089/ars.2006.1464.
- Results publication: PubMed 11463332Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001 Aug 1;357(Pt 3):593-615. doi: 10.1042/0264-6021:3570593.
- Results publication: PubMed 15914468Mollace V, Muscoli C, Masini E, Cuzzocrea S, Salvemini D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 2005 Jun;57(2):217-52. doi: 10.1124/pr.57.2.1.
- Individual participant dataSharing planned: Undecided
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert J Gropler, MD principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing [18F](+/-)NOS in people with Patients With Post Orthotopic Heart Transplantation Status, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To Measure Free Fatty Acid by Imaging Patients With Increased Levels of iNOS Using [18F](+/-)NOS. (time frame: 24-72 hours post [18F](+/-)NOS injection). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01066637, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2020.