Pulmonary Arterial HypertensionPhase 1/2AIPAHNCT03166306
Angiogenic Imaging in Pulmonary Arterial Hypertension
A Phase 1/2 study testing PET-CT Imaging with [89Zr]-bevacizumab in people with Pulmonary Arterial Hypertension and Exercise Associated Pulmonary Arterial Hypertension, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive remodeling and obliteration of vessels of the distal pulmonary circulation. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Pulmonary Arterial Hypertension, Exercise Associated Pulmonary Arterial Hypertension
- What is being tested?
- PET-CT Imaging with [89Zr]-bevacizumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- 1 May 2018to 31 Mar 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age ≥18 years at screening;
- Documented diagnosis Group 1 PAH confirmed by resting mean pulmonary artery pressure greater than 25 mm of Hg, pulmonary vascular resistance greater than 3 Wood units, and pulmonary wedge pressure less than 12 mm of Hg measured by right heart catheterization at the time of diagnosis and before initiation of PAH specific therapy clinically stable for 60 or more days prior to enrollment, defined as no changes in medical regimen and no hospitalizations;
- Prior diagnosis of exercise-associated PAH (EPAH) confirmed by normal resting hemodynamics (mean pulmonary artery pressure < 25 mm of Hg, pulmonary artery wedge pressure < 12 mm of Hg, and pulmonary vascular resistance < 3 Wood units) measured by right heart catheterization at rest and abnormal hemodynamic response to exercise characterized by increase in mean pulmonary artery pressure > 30 mm Hg, pulmonary artery wedge pressure < 20 mm Hg, and pulmonary vascular resistance > 1 Wood unit at peak exercise and cardiac output less than 10 L/min before initiation of any PAH specific therapy. Patients need to be clinically stable for 60 or more days prior to enrollment, defined as no changes in medical regimen and no hospitalizations;
- Willingness to participate as evidenced by signing of the informed consent;
Who cannot join
- Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of <3 years;
- Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease;
- White blood cell count <2,500/uL, hematocrit < 30 percent, or platelet count < 50,000/uL;
- Elevated liver transaminase levels (AST or ALT) 20 % above upper limit of normal (ULN) or albumin 20 % below the lower limit of normal (LLN);
- Creatinine clearance < 45 mL/min as estimated with the Cockroft-Gault equation;
- Women who are pregnant or breastfeeding;
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- Men or women who plan to have children during the study period or who are unwilling to use effective forms of contraception;
- Known active cancer;
- Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers (see Exclusionary Medication List in Manual of Operations). Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions;
- Evidence of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis in the past 12 months by chest X-ray. For participants who have not had a chest X-ray during the 12 months prior to enrollment in the study, a chest X-ray will be obtained at baseline as part of the study protocol;
- New York Heart Association Class IV congestive heart failure;
- Severe asthma or COPD defined by FEV1 less than 50% predicted and FEV1/FVC less than 70% per PFTs in the past 12 months;
- Active tobacco use during the prior 10 years;
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive remodeling and obliteration of vessels of the distal pulmonary circulation. Outcomes in PAH could be improved with earlier diagnosis, and with the early deployment of therapies before irreversible changes have occurred. This study tests the sensitivity of positron emission tomography (PET)-CT scanning with [89Zr]-bevacizumab, a radioisotope-conjugated anti-VEGF antibody for detecting pulmonary vascular remodeling in PAH disease. This test could enable non-invasive diagnosis early in the course of the disease, and potentially improve outcomes in PAH,
Read the detailed description
PAH is a disease of progressive remodeling and obliteration of the distal pulmonary vasculature. The overexpression of VEGF-A in the pulmonary vasculature of patients with PAH and animal models of disease is thought to reflect a process of disordered angiogenesis that is tightly coupled to disease progression. It is hypothesized that positron emission tomography (PET)-CT scan utilizing [89Zr]-bevacizumab, a radioisotope-conjugated humanized monoclonal antibody against VEGF-A, would provide a sensitive and specific molecular imaging modality to detect pulmonary vascular remodeling activity.
To test this hypothesis the investigators propose a Phase I/II pilot study to enroll 10 patients with known severe idiopathic or familial PAH, 10 individuals with exercise-associated PAH (EPAH), thought to be a mild and early stage of PAH, and 10 healthy volunteers with no evidence of cardiopulmonary disease. This pilot study will compare standardized uptake values (SUV) for the retention of [89Zr]-bevacizumab in the distal pulmonary vasculature in these three populations. The kinetics of equilibration and wash-out of this probe will be assessed with sequential scans at 4 and 7 days following the injection of radionuclide. In patients with PAH or EPAH, repeat scans will be performed 1 year after the initial scan to assess whether changes in clinical status correlate with [89Zr]-bevacizumab retention.
The ability of these protocols to discriminate between the lungs of healthy individuals versus patients with PAH or EPAH will be evaluated using the measure of peripheral lung tissue probe SUV, corresponding to distal pulmonary vessel uptake, normalized to the proximal aortic SUV, corresponding to the blood pool. These data will be used to define normative values for healthy controls versus PAH patients, and to generate cutoffs in signaling ratios with optimal sensitivity and specificity for disease detection. These normative ranges will be applied to the EPAH cohort to determine if this test retains sensitivity and specificity for a potentially milder, earlier form of PAH.
This study is divided into 4 Aims:
AIM 1: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging is increased in the distal pulmonary vascular bed in PAH patients compared to healthy individuals.
AIM 2: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging is increased in the distal pulmonary vascular bed in patients with exercise-associated PAH compared to healthy individuals.
AIM 3: Ascertain whether or not distal pulmonary vascular uptake of [89Zr]-bevacizumab correlates with clinical markers of PAH severity, including 6 minute walk distance, New York Heart Association functional class, right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, NT-proBNP, tricuspid annular plane systolic excursion (TAPSE) by echocardiography.
AIM 4: Ascertain whether or not changes in distal pulmonary vascular uptake of [89Zr]-bevacizumab over 1 year in patients with PAH or EPAH correlates with changes in clinical status based on clinical markers of PAH severity.
- Being tested
- PET-CT Imaging with [89Zr]-bevacizumab
- Keywords
- pulmonary vascular disease, pulmonary vascular imaging
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PET-CT Imaging with [89Zr]-bevacizumabDiagnostic test
Subjects will receive 1 millicurie of 89Zr and less than 5 mg of bevacizumab, followed by PET-CT imaging.
| Study group | Role | What they receive |
|---|---|---|
| Patients with idiopathic or familial PAH | Experimental | Ten patients with severe idiopathic or familial PAH will undergo PET-CT imaging with [89Zr]-bevacizumab. Receives: Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumab |
| Patients with exercise associated PAH | Experimental | Ten patients with exercise associated PAH (EPAH) will undergo PET-CT imaging with [89Zr]-bevacizumab. Receives: Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumab |
| Healthy volunteers | Active comparator | Ten individuals with no known cardiopulmonary disease will undergo PET-CT imaging with [89Zr]-bevacizumab. Receives: Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Distal pulmonary SUV of [89Zr]-bevacizumab
PET-CT measurement of standardized uptake values (SUV) for retention of [89Zr]-bevacizumab in peripheral lung tissues, normalized to proximal aortic retention corresponding to the blood pool.
Measured: Baseline measurement at entry into study
Secondary outcomes (1)
Change in distal pulmonary SUV of [89Zr]-bevacizumab
Change in PET-CT measurement of standardized uptake values (SUV) for retention of [89Zr]-bevacizumab in peripheral lung tissues, normalized to proximal aortic retention corresponding to the blood pool, compared over a 12 month interval.
Measured: Measurement at 12 months following initial measurement
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2017
- Study start1 May 2018
- Primary completion31 Oct 2019
- Study completion31 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pulmonary Arterial HypertensionStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe 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
- Phase 1/2
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Model description
- The investigators propose to enroll 10 patients with known severe idiopathic or familial PAH, 10 individuals with exercise-associated PAH (EPAH), felt to be a milder and early stage of PAH, and 10 healthy volunteers with no evidence of cardiopulmonary disease. Baseline PET-CT scans will be obtained 7 days after the injection of \[89Zr\]-bevacizumab. Follow- up imaging will be obtained 12 months status post enrollment.
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Paul B Yu, Brigham and Women's Hospital
- Investigators
- Paul B Yu, MD PhD, Principal investigator, Brigham and Women's HospitalAaron B Waxman, MD PhD, Principal investigator, Brigham and Women's HospitalMarcelo F Di Carli, MD, Principal investigator, Brigham and Women's HospitalIvana Nikolic, MD, Study director, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03166306
- Sponsor's protocol ID
- 2017P000249
- Acronym
- AIPAH
- Status last verified
- May 2021
- First submitted
- 9 May 2017
- Last updated
- 6 May 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: There is currently no plan to make individual participant data available to other researchers, outside of the publication of datasets in peer-reviewed literature.
Study at a glance
From the registry record, last updated by the sponsor on 6 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Angiogenic Imaging in Pulmonary Arterial Hypertension
- ClinicalTrials.gov ID
- NCT03166306
- Acronym / sponsor ID
- AIPAH / 2017P000249
- Keywords
- pulmonary vascular disease, pulmonary vascular imaging
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 1 May 2018 (actual)
- Primary completion
- 31 Oct 2019 (actual)
- Study completion
- 31 Mar 2020 (actual)
- First posted
- 25 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive remodeling and obliteration of vessels of the distal pulmonary circulation. Outcomes in PAH could be improved with earlier diagnosis, and with the early deployment of therapies before irreversible changes have occurred. This study tests the sensitivity of positron emission tomography (PET)-CT scanning with [89Zr]-bevacizumab, a radioisotope-conjugated anti-VEGF antibody for detecting pulmonary vascular remodeling in PAH disease. This test could enable non-invasive diagnosis early in the course of the disease, and potentially improve outcomes in PAH,
Detailed description
PAH is a disease of progressive remodeling and obliteration of the distal pulmonary vasculature. The overexpression of VEGF-A in the pulmonary vasculature of patients with PAH and animal models of disease is thought to reflect a process of disordered angiogenesis that is tightly coupled to disease progression. It is hypothesized that positron emission tomography (PET)-CT scan utilizing [89Zr]-bevacizumab, a radioisotope-conjugated humanized monoclonal antibody against VEGF-A, would provide a sensitive and specific molecular imaging modality to detect pulmonary vascular remodeling activity.
To test this hypothesis the investigators propose a Phase I/II pilot study to enroll 10 patients with known severe idiopathic or familial PAH, 10 individuals with exercise-associated PAH (EPAH), thought to be a mild and early stage of PAH, and 10 healthy volunteers with no evidence of cardiopulmonary disease. This pilot study will compare standardized uptake values (SUV) for the retention of [89Zr]-bevacizumab in the distal pulmonary vasculature in these three populations. The kinetics of equilibration and wash-out of this probe will be assessed with sequential scans at 4 and 7 days following the injection of radionuclide. In patients with PAH or EPAH, repeat scans will be performed 1 year after the initial scan to assess whether changes in clinical status correlate with [89Zr]-bevacizumab retention.
The ability of these protocols to discriminate between the lungs of healthy individuals versus patients with PAH or EPAH will be evaluated using the measure of peripheral lung tissue probe SUV, corresponding to distal pulmonary vessel uptake, normalized to the proximal aortic SUV, corresponding to the blood pool. These data will be used to define normative values for healthy controls versus PAH patients, and to generate cutoffs in signaling ratios with optimal sensitivity and specificity for disease detection. These normative ranges will be applied to the EPAH cohort to determine if this test retains sensitivity and specificity for a potentially milder, earlier form of PAH.
This study is divided into 4 Aims:
AIM 1: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging is increased in the distal pulmonary vascular bed in PAH patients compared to healthy individuals.
AIM 2: Test the hypothesis that expression of VEGF-A discerned by [89Zr]-bevacizumab imaging is increased in the distal pulmonary vascular bed in patients with exercise-associated PAH compared to healthy individuals.
AIM 3: Ascertain whether or not distal pulmonary vascular uptake of [89Zr]-bevacizumab correlates with clinical markers of PAH severity, including 6 minute walk distance, New York Heart Association functional class, right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, NT-proBNP, tricuspid annular plane systolic excursion (TAPSE) by echocardiography.
AIM 4: Ascertain whether or not changes in distal pulmonary vascular uptake of [89Zr]-bevacizumab over 1 year in patients with PAH or EPAH correlates with changes in clinical status based on clinical markers of PAH severity.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- The investigators propose to enroll 10 patients with known severe idiopathic or familial PAH, 10 individuals with exercise-associated PAH (EPAH), felt to be a milder and early stage of PAH, and 10 healthy volunteers with no evidence of cardiopulmonary disease. Baseline PET-CT scans will be obtained 7 days after the injection of [89Zr]-bevacizumab. Follow- up imaging will be obtained 12 months status post enrollment.
| Arm | Type | Receives |
|---|---|---|
| Patients with idiopathic or familial PAH | Experimental | Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumabTen patients with severe idiopathic or familial PAH will undergo PET-CT imaging with [89Zr]-bevacizumab. |
| Patients with exercise associated PAH | Experimental | Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumabTen patients with exercise associated PAH (EPAH) will undergo PET-CT imaging with [89Zr]-bevacizumab. |
| Healthy volunteers | Active comparator | Diagnostic Test: PET-CT Imaging with [89Zr]-bevacizumabTen individuals with no known cardiopulmonary disease will undergo PET-CT imaging with [89Zr]-bevacizumab. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age ≥18 years at screening;
- Documented diagnosis Group 1 PAH confirmed by resting mean pulmonary artery pressure greater than 25 mm of Hg, pulmonary vascular resistance greater than 3 Wood units, and pulmonary wedge pressure less than 12 mm of Hg measured by right heart catheterization at the time of diagnosis and before initiation of PAH specific therapy clinically stable for 60 or more days prior to enrollment, defined as no changes in medical regimen and no hospitalizations;
- Prior diagnosis of exercise-associated PAH (EPAH) confirmed by normal resting hemodynamics (mean pulmonary artery pressure < 25 mm of Hg, pulmonary artery wedge pressure < 12 mm of Hg, and pulmonary vascular resistance < 3 Wood units) measured by right heart catheterization at rest and abnormal hemodynamic response to exercise characterized by increase in mean pulmonary artery pressure > 30 mm Hg, pulmonary artery wedge pressure < 20 mm Hg, and pulmonary vascular resistance > 1 Wood unit at peak exercise and cardiac output less than 10 L/min before initiation of any PAH specific therapy. Patients need to be clinically stable for 60 or more days prior to enrollment, defined as no changes in medical regimen and no hospitalizations;
- Willingness to participate as evidenced by signing of the informed consent;
Key exclusion criteria (13 listed)
- Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of <3 years;
- Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease;
- White blood cell count <2,500/uL, hematocrit < 30 percent, or platelet count < 50,000/uL;
- Elevated liver transaminase levels (AST or ALT) 20 % above upper limit of normal (ULN) or albumin 20 % below the lower limit of normal (LLN);
- Creatinine clearance < 45 mL/min as estimated with the Cockroft-Gault equation;
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 |
|---|---|---|
| PET-CT Imaging with [89Zr]-bevacizumabSubjects will receive 1 millicurie of 89Zr and less than 5 mg of bevacizumab, followed by PET-CT imaging. | Diagnostic test | Healthy volunteers, Patients with exercise associated PAH, Patients with idiopathic or familial PAH |
Primary outcome
Distal pulmonary SUV of [89Zr]-bevacizumab
Time frame: Baseline measurement at entry into study
PET-CT measurement of standardized uptake values (SUV) for retention of [89Zr]-bevacizumab in peripheral lung tissues, normalized to proximal aortic retention corresponding to the blood pool.
1 secondary outcome
Change in distal pulmonary SUV of [89Zr]-bevacizumab
Time frame: Measurement at 12 months following initial measurement
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 May 2021.
- Individual participant dataSharing planned: No. There is currently no plan to make individual participant data available to other researchers, outside of the publication of datasets in peer-reviewed literature.
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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.
Paul B Yu, MD PhD principal investigator
Brigham and Women's Hospital
Aaron B Waxman, MD PhD principal investigator
Brigham and Women's Hospital
Marcelo F Di Carli, MD principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PET-CT Imaging with [89Zr]-bevacizumab in people with Pulmonary Arterial Hypertension and Exercise Associated Pulmonary Arterial Hypertension, run by Brigham and Women's Hospital 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 4 inclusion and 13 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 6 May 2021. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Distal pulmonary SUV of [89Zr]-bevacizumab (time frame: Baseline measurement at entry into study). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 May 2021.