Pulmonary Hypertension, Primary, 4NCT04472533
Serum Bio-markers in Pulmonary Hypertension
An observational study of Pulmonary Hypertension, Primary, 4, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by scarred blood clots in the blood vessels supplying the lungs. This in turn leads to failure of the right side of the heart. The reason why these scarred clots form is unknown. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Pulmonary Hypertension, Primary, 4
- How many people
- 377 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 4 Apr 2012to 26 Oct 2017
- Phase
- Observational
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Patients diagnosed with CTEPH, CTED and healthy control volunteers at the Royal Papworth Hospital.
Who may be able to join
- Patients able to give informed written consent
- Patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) according to international guidelines at an expert pulmonary hypertension centre
- Patients diagnosed with chronic thromboembolic disease (CTED) according to international guidelines at an expert pulmonary hypertension centre
- Age and sex matched healthy volunteers
Who cannot join
- Patients with inflammatory comorbidities
- Patients taking immunosuppressant medication
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Papworth Hospital NHS Foundation Trust
Cambridge, CB2 0AY
About this study
Official title: Role of Inflammation and Angiogenesis in Chronic Thromboembolic Pulmonary Hypertension
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by scarred blood clots in the blood vessels supplying the lungs. This in turn leads to failure of the right side of the heart. The reason why these scarred clots form is unknown. An operation to remove the scarred clots, known as pulmonary endarterectomy, is a potential cure. However, some patients have persistent obstructions within the blood vessels and heart failure even after surgery.
It is thought that abnormal levels of proteins, found in the blood stream and responsible for inflammation and the development of new blood vessels may have role in causing the disease. In this study, these proteins were measured to assess whether they provide clues as to the cause of the disease and whether they could be used for the risk stratification of patients.
Read the detailed description
Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed form of pulmonary hypertension whose pathogenesis remains to be fully elucidated. Altered endothelial homeostasis, defective angiogenesis and inflammation have been implicated. The formation of the organised occlusions is considered to arise from a failure to resolve acute pulmonary emboli. There is emerging evidence supporting the role of mediators of angiogenesis, inflammation and the coagulation cascade (and their many interactions) in CTEPH. Pulmonary endarterectomy (PEA), to remove these occlusions, may be a cure in some patients. Assessing circulating proteins associated with these processes may be not only useful for understanding disease pathogenesis but may also lead to improvements in clinical assessment.
The study was approved by the Regional Ethics Committee (Papworth Hospital Research Tissue Bank; 08/H0304/56+5). Consecutive patients undergoing PEA surgery at Royal Papworth Hospital National Health Service Foundation Trust, United Kingdom, who consented for participation in the Research Tissue Bank between February 2012 and August 2014, were recruited. A validation data set included all consecutive samples collected from CTEPH patients prior to PEA between April 2010 and Aug 2017. Patients were diagnosed in accordance with international guidelines.
Patients had serum samples collected from a peripheral vein prior to PEA. In a subset of patients, further sampling was performed at the first follow up visit to Papworth Hospital 3-6 months post-PEA. Customized human cytokine/chemokine magnetic bead assays and customized human angiogenesis/growth factor assays were used to measure levels of circulating proteins in these serum samples (interleukin [IL] 6, IL8, IL10, tumour necrosis factor [TNF] α, angiopoietin 2 [Ang2], endoglin, vascular endothelial growth factor [VEGF] a, VEGFc, VEGFd and bone morphogenetic protein 9 [BMP9]).
Levels were compared to levels from patients with chronic thromboembolic disease but no pulmonary hypertension (CTED) and healthy age and sex matched controls. In addition multivariate rank regression models were used to assess associations between levels of circulating proteins and clinical assessments carried out as part of the patients routine clinical care.
- Conditions
- Pulmonary Hypertension, Primary, 4
- Keywords
- inflammation, angiogenesis
- Medical subject headings
- Hypertension, Pulmonary, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| CTEPH | Patients diagnosed with chronic thromboembolic pulmonary hypertension | |
| CTED | Patients diagnosed with chronic thromboembolic disease but no evidence of pulmonary hypertension | |
| Control | Healthy control subjects |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assess the differences between circulating biomarkers between patients with CTEPH, CTED and controls
Assess differences in inflammatory cytokines (IL6, 8, 10, TNFa, hsCRP [all measured in pg/ml]) and markers of angiogenesis (Ang2, BMP9, Endoglin, VEGFa, VEGFc, VEGFd [all measured in pg/ml]) in patients with CTEPH compared to healthy controls
Measured: 24 hours
Secondary outcomes (11)
Assess associations, using multivariate regression modelling, between IL6 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL6 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between IL8 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL8 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between IL10 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum IL10 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between TNFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum TNFa and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between Ang2 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum Ang2 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between BMP9 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum BMP9 and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between Endoglin and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum Endoglin and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between VEGFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFa and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between VEGFc and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFc and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between VEGFd and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum VEGFd and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Assess associations, using multivariate regression modelling, between hsCRP and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Using multivariate rank regression modelling, associations between serum hsCRP and clinical assessments (pulmonary haemodynamics, functional class, six-minute walk test distance) performed in patients with CTEPH prior to pulmonary endarterectomy will be assessed. Adjustments will be made to correct for multiple testing.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2020
- Study start4 Apr 2012
- Primary completion31 Aug 2017
- Study completion26 Oct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Hypertension, Primary, 4Studies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 377 participants (actual)
Sponsor and investigators
- Lead sponsor
- Papworth Hospital NHS Foundation Trust
- Sponsor type
- Other government
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Joanna Pepke-Zaba, PhD FRCP, Principal investigator, Papworth Hospital NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04472533
- Sponsor's protocol ID
- T01502
- Status last verified
- Jul 2020
- First submitted
- 6 Jul 2020
- Last updated
- 15 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan to share individual participant data
Publications
Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29. No abstract available.
PubMed 26320113
Study at a glance
From the registry record, last updated by the sponsor on 15 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of Inflammation and Angiogenesis in Chronic Thromboembolic Pulmonary Hypertension
- ClinicalTrials.gov ID
- NCT04472533
- Acronym / sponsor ID
- T01502
- Conditions
- Pulmonary Hypertension, Primary, 4
- Keywords
- inflammation, angiogenesis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 377 participants (actual)
- Lead sponsor
- Papworth Hospital NHS Foundation TrustOther government
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 4 Apr 2012 (actual)
- Primary completion
- 31 Aug 2017 (actual)
- Study completion
- 26 Oct 2017 (actual)
- First posted
- 15 Jul 2020 (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.
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by scarred blood clots in the blood vessels supplying the lungs. This in turn leads to failure of the right side of the heart. The reason why these scarred clots form is unknown. An operation to remove the scarred clots, known as pulmonary endarterectomy, is a potential cure. However, some patients have persistent obstructions within the blood vessels and heart failure even after surgery.
It is thought that abnormal levels of proteins, found in the blood stream and responsible for inflammation and the development of new blood vessels may have role in causing the disease. In this study, these proteins were measured to assess whether they provide clues as to the cause of the disease and whether they could be used for the risk stratification of patients.
Detailed description
Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed form of pulmonary hypertension whose pathogenesis remains to be fully elucidated. Altered endothelial homeostasis, defective angiogenesis and inflammation have been implicated. The formation of the organised occlusions is considered to arise from a failure to resolve acute pulmonary emboli. There is emerging evidence supporting the role of mediators of angiogenesis, inflammation and the coagulation cascade (and their many interactions) in CTEPH. Pulmonary endarterectomy (PEA), to remove these occlusions, may be a cure in some patients. Assessing circulating proteins associated with these processes may be not only useful for understanding disease pathogenesis but may also lead to improvements in clinical assessment.
The study was approved by the Regional Ethics Committee (Papworth Hospital Research Tissue Bank; 08/H0304/56+5). Consecutive patients undergoing PEA surgery at Royal Papworth Hospital National Health Service Foundation Trust, United Kingdom, who consented for participation in the Research Tissue Bank between February 2012 and August 2014, were recruited. A validation data set included all consecutive samples collected from CTEPH patients prior to PEA between April 2010 and Aug 2017. Patients were diagnosed in accordance with international guidelines.
Patients had serum samples collected from a peripheral vein prior to PEA. In a subset of patients, further sampling was performed at the first follow up visit to Papworth Hospital 3-6 months post-PEA. Customized human cytokine/chemokine magnetic bead assays and customized human angiogenesis/growth factor assays were used to measure levels of circulating proteins in these serum samples (interleukin [IL] 6, IL8, IL10, tumour necrosis factor [TNF] α, angiopoietin 2 [Ang2], endoglin, vascular endothelial growth factor [VEGF] a, VEGFc, VEGFd and bone morphogenetic protein 9 [BMP9]).
Levels were compared to levels from patients with chronic thromboembolic disease but no pulmonary hypertension (CTED) and healthy age and sex matched controls. In addition multivariate rank regression models were used to assess associations between levels of circulating proteins and clinical assessments carried out as part of the patients routine clinical care.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| CTEPH | – | –Patients diagnosed with chronic thromboembolic pulmonary hypertension |
| CTED | – | –Patients diagnosed with chronic thromboembolic disease but no evidence of pulmonary hypertension |
| Control | – | –Healthy control subjects |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients diagnosed with CTEPH, CTED and healthy control volunteers at the Royal Papworth Hospital.
Key inclusion criteria (4 listed)
- Patients able to give informed written consent
- Patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) according to international guidelines at an expert pulmonary hypertension centre
- Patients diagnosed with chronic thromboembolic disease (CTED) according to international guidelines at an expert pulmonary hypertension centre
- Age and sex matched healthy volunteers
Key exclusion criteria (2 listed)
- Patients with inflammatory comorbidities
- Patients taking immunosuppressant medication
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Assess the differences between circulating biomarkers between patients with CTEPH, CTED and controls
Time frame: 24 hours
Assess differences in inflammatory cytokines (IL6, 8, 10, TNFa, hsCRP [all measured in pg/ml]) and markers of angiogenesis (Ang2, BMP9, Endoglin, VEGFa, VEGFc, VEGFd [all measured in pg/ml]) in patients with CTEPH compared to healthy controls
11 secondary outcomes
Assess associations, using multivariate regression modelling, between IL6 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between IL8 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between IL10 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between TNFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between Ang2 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between BMP9 and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between Endoglin and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFa and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFc and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between VEGFd and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
Assess associations, using multivariate regression modelling, between hsCRP and clinical assessments made prior to pulmonary endarterectomy in patients with CTEPH
Time frame: 24 hours
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 15 Jul 2020.
- Background: PubMed 26320113Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29. No abstract available.
- Individual participant dataSharing planned: No. No plan to share individual participant data
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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.
Joanna Pepke-Zaba, PhD FRCP principal investigator
Papworth Hospital NHS Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pulmonary Hypertension, Primary, 4, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
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 2 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 15 Jul 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 Kingdom. 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.
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?
Assess the differences between circulating biomarkers between patients with CTEPH, CTED and controls (time frame: 24 hours). 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 NCT04472533, which also lists 1 linked publication.
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 15 Jul 2020.