Pulmonary Arterial HypertensionPILGRIMNCT01054105
Effect of BMPR-2 Gene Mutations on Hemodynamic Response by Iloprost Inhalation in Pulmonary Arterial Hypertension
An observational study of Pulmonary Arterial Hypertension, run by Gachon University Gil Medical Center at 6 sites in South Korea.
Trial summary
In the present study, the investigators want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients (Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II). Read more about this study
- Who is it for?
- Ages 20 to 80 years
- Conditions the study is for
- Pulmonary Arterial Hypertension
- What is being tested?
- Iloprost
- How many people
- 73 participants
- Where
- 6 sitesSouth Korea
- Study dates
- Oct 2010to 25 Dec 2018
- 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 20 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Previously diagnosed PAH
Who may be able to join
- The patients aged from 20 to 80 years
- Newly diagnosed WHO category I PAH patients: Patients who meet the following criteria within 3 months obtained by right heart catheterization (mean PAP of more than 25 mm Hg at rest and mean pulmonary arterial wedge pressure (PCWP) or left ventricular end-diastolic pressure of 15 mm Hg or less) or echocardiography (peak PAP of more than 40mmHg and mean PAP more than 30mmHg).
- Previously diagnosed PAH patients who refractory to conventional treatment except iloprost inhalation solution (Ventavis): Patients meet the echo criteria (peak PAP of more than 40mmHg and mean PAP more than 30mmHg) who have been treated with PAH medications except iloprost inhalation solution (Ventavis) after diagnosed as WHO Group 1 PAH based on prior RHC data (above criteria) but refractory to them.
- The patients who are able to undergo low intensity exercise test (low dose bicycle or walking)
Who cannot join
- The patients with other left heart disease (category II in WHO classification of pulmonary hypertension); ex. Congestive HF, cardiomyopathy, significant valvular heart disease, significant arrhythmia, suspicious elevated PCWP.
- The patients with category III,IV and V in WHO classification of pulmonary hypertension:
- Pulmonary hypertension with lung disease and/or hypoxemia
- Chronic obstructive pulmonary disease
- Interstitial lung disease
- Sleep disorder breathing
Show all 33Show fewer
- Alveolar hyperventilation disorders
- Chronic exposure to high altitude
- Developmental abnormalities
- Pulmonary hypertension due to chronic thrombotic and/or embolic disease
- Thromboembolic obstruction of the proximal pulmonary arteries
- Thromboembolic obstruction of the distal pulmonary arteries
- Non-thrombotic pulmonary embolism (e.g. tumor or parasitic)
- Miscellaneous disorders affecting the pulmonary vasculature
- Patients with contraindication to Ventavis;(Hypersensitive to Ventavis, High risk of bleeding, which can be increased by use of Ventavis (e.g. active peptic ulcer, trauma, intracranial hemorrhage)
- Severe coronary disease
- Unstable angina
- History of Acute myocardial infarction within 6 months
- Uncompensated heart failure not under close medical monitoring
- Severe arrhythmia
- Suspected pulmonary congestion
- Cerebrovascular disease within 3 months (e.g. transient ischemic attack, stoke)
- Pulmonary hypertension due to venous occlusive disease, valvular defect with dysfunction of cardiac muscle, which is independent of pulmonary hypertension)
- Pregnancy
- Women with high probability of pregnancy
- Breast feeding
- Renal failure (creatinine clearance: less than 30mL/min)
- The patients concurrently using other pulmonary vasodilator (ex. Inhaled NO, endothelin antagonists) except PDE5 inhibitor
- The patients with poor echo window which is unavailable to accept the echo data
- The patients who cannot do any exercise
- The patients who changes medication administered during ventavis treatment
- The patients with allergic reaction to ventavis
- The patients with other systemic disease (ex. Leukemia, MM, Sickle cell anemia, significant liver disease)
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
South Korea6 sites
Soonchunhyang University Bucheon Hospital
Bucheon-si
Gachon University Gil Hospital
Incheon, 405-760
Seoul National University Bundang Hospital
Seongnam
Catholic University Seoul Saint Mary's Hospital
Seoul
Seoul National University Hospital
Seoul
Sungkyunkwan University Seoul Samsung Hospital
Seoul
About this study
Official title: The Prevalence of BMPR-2 Gene Mutations in Korean Patients With Pulmonary Arterial Hypertension (PAH) and the Effects of Gene Mutations on Hemodynamic Response by Drug Therapy
In the present study, the investigators want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients (Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).
Read the detailed description
Pulmonary arterial hypertension (PAH) consists of a group of vascular abnormalities with elevated pulmonary arterial pressure and pulmonary vascular resistance. Idiopathic or familial PAH is progressive over several years and believed to be fatal without treatment. (1-2) The results of the Endothelin Antagonist tRial in mildly symptomatic PAH (EARLY) indicate that early diagnosis and treatment of PAH might improve time to clinical worsening and emphasize that PAH needs to be diagnosed and treated in the early stages. (3) Germline mutations of bone morphogenetic protein receptor (BMPR)-2, a member of the transforming growth factor (TGF)-β superfamily, have been found in familial and sporadic forms of idiopathic PAH,(4-6) and in appetite-suppressant PAH.(7) The BMPR-2 gene, on chromosome 2q33, has 13 exons. Exons 1-3 encode an extracellular domain, exon 4 encodes the transmembrane domain, exons 5-11 a serine/threonine kinase domain, and exons 12 and 13 a very large intracellular C-terminus of unknown function that appears to be unique to BMPR-2. (8) Mutations in familial PAH have been reported in all exons except for 5 and 13. (9) About 10-25% of sporadic cases of idiopathic PAH are thought to have BMPR-2 mutations (10) and rare cases of PAH associated with congenital heart disease, connective tissue disease and drug induced PAH were reported. (11-12) It is likely that genetic predispositions exist based on normal variations in genes that may influence the pulmonary circulation. However, the studies regarding prevalence of BMPR-2 gene mutations in Korean patients have not been performed.
In a previous study, family members of familial PAH patients showed an increased pulmonary artery systolic pressure (PASP) rise during exercise as assessed by echocardiography. (13-14) In other study, relatives of idiopathic/familial PAH patients displayed enhanced frequency of pulmonary hypertensive response during exercise and that this response is associated with mutations in the BMPR-2 gene. (15) These results suggest that asymptomatic gene carriers, in the absence of manifest pulmonary hypertension, might have enhanced PASP during exercise and more risk to develop resting pulmonary hypertension in the future compared with patients without gene mutations. Therefore, the treatment response by variable vasodilators (ex. calcium channel blockers, endothelin antagonist or prostacyclin analogues..) may be different based on the presence of BMPR-2 gene. In the present study, we want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients(Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).
- Conditions
- Pulmonary Arterial Hypertension
- Being tested
- Iloprost
- Keywords
- Pulmonary hypertension, genes, mutation, drug therapy
- Medical subject headings
- Pulmonary Arterial Hypertension, Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IloprostDrug
Also called Allowable patients from Step-I, Step-II: Illoprost and Exercise Echo
Iloprost inhalation, 2.5 - 5mcg, 6 times per day
| Study group | Role | What they receive |
|---|---|---|
| Step I: BMPR-2 gene analysis | BMPR-2 gene analysis on 100 IPAH or heritable PAH Patients Receives: Drug: Iloprost | |
| Step-II: Iloprost and Exercise Echo | Illoprost inhalation for 3 months \& Check-up before and after treatment; WHO functional classification Assessment of exercise capacity (6M walk test) Cardiopulmonary exercise echocardiography NT-proBNP Receives: Drug: Iloprost |
What is being measured
The primary outcome is the main question the study is designed to answer.
Cardiopulmonary exercise test parameters
Measured: after 3 months active follow-up
Secondary outcomes (5)
Major cardiovascular Events (cardiovascular mortality, all cause mortality, hospitalization)
cardiovascular mortality, all cause mortality, hospitalization
Measured: After 2 years follow-up
Six-minutes walking test
min
Measured: After 3 months active follow-up
WHO/NYHA class
WHO/NYHA class
Measured: After 3 months active follow-up
Echo parameters
various echo parameters
Measured: After 3 months active follow-up
NT-proBNP
NT-proBNP
Measured: After 3 months active follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2010 (estimated)
- Study startOct 2010
- Primary completion25 Dec 2018
- Study completion25 Dec 2018
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 Arterial HypertensionStudies 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
- Case-control
- Time perspective
- Prospective
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gachon University Gil Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Seoul National University Hospital, Seoul National University Bundang Hospital, The Catholic University of Korea, Bayer
- Responsible party
- Principal investigator, Wook-Jin Chung, Gachon University Gil Medical Center
- Investigators
- Wook-Jin Chung, MD,PhD, Principal investigator, Gachon University Gil Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01054105
- Sponsor's protocol ID
- WJC-IIT-1001
- Other IDs
- GIRBA 2278
- Acronym
- PILGRIM
- Status last verified
- Dec 2018
- First submitted
- 21 Jan 2010
- Last updated
- 27 Dec 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
Jang AY, Kim BG, Kwon S, Seo J, Kim HK, Chang HJ, Chang SA, Cho GY, Rhee SJ, Jung HO, Kim KH, Seo HS, Kim KH, Shin J, Lee JS, Kim M, Lee YJ, Chung WJ. Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: The PILGRIM explorative cohort. PLoS One. 2020 Sep 23;15(9):e0238698. doi: 10.1371/journal.pone.0238698. eCollection 2020.
PubMed 32966279
Study at a glance
From the registry record, last updated by the sponsor on 27 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Prevalence of BMPR-2 Gene Mutations in Korean Patients With Pulmonary Arterial Hypertension (PAH) and the Effects of Gene Mutations on Hemodynamic Response by Drug Therapy
- ClinicalTrials.gov ID
- NCT01054105
- Acronym / sponsor ID
- PILGRIM / WJC-IIT-1001
- Conditions
- Pulmonary Arterial Hypertension
- Keywords
- Pulmonary hypertension, genes, mutation, drug therapy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- Gachon University Gil Medical CenterUniversity, hospital or other
- Collaborators
- Seoul National University Hospital, Seoul National University Bundang Hospital, The Catholic University of Korea, Bayer
- Study start
- Oct 2010
- Primary completion
- 25 Dec 2018 (actual)
- Study completion
- 25 Dec 2018 (actual)
- First posted
- 22 Jan 2010 (estimated)
- 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.
In the present study, the investigators want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients (Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).
Detailed description
Pulmonary arterial hypertension (PAH) consists of a group of vascular abnormalities with elevated pulmonary arterial pressure and pulmonary vascular resistance. Idiopathic or familial PAH is progressive over several years and believed to be fatal without treatment. (1-2) The results of the Endothelin Antagonist tRial in mildly symptomatic PAH (EARLY) indicate that early diagnosis and treatment of PAH might improve time to clinical worsening and emphasize that PAH needs to be diagnosed and treated in the early stages. (3) Germline mutations of bone morphogenetic protein receptor (BMPR)-2, a member of the transforming growth factor (TGF)-β superfamily, have been found in familial and sporadic forms of idiopathic PAH,(4-6) and in appetite-suppressant PAH.(7) The BMPR-2 gene, on chromosome 2q33, has 13 exons. Exons 1-3 encode an extracellular domain, exon 4 encodes the transmembrane domain, exons 5-11 a serine/threonine kinase domain, and exons 12 and 13 a very large intracellular C-terminus of unknown function that appears to be unique to BMPR-2. (8) Mutations in familial PAH have been reported in all exons except for 5 and 13. (9) About 10-25% of sporadic cases of idiopathic PAH are thought to have BMPR-2 mutations (10) and rare cases of PAH associated with congenital heart disease, connective tissue disease and drug induced PAH were reported. (11-12) It is likely that genetic predispositions exist based on normal variations in genes that may influence the pulmonary circulation. However, the studies regarding prevalence of BMPR-2 gene mutations in Korean patients have not been performed.
In a previous study, family members of familial PAH patients showed an increased pulmonary artery systolic pressure (PASP) rise during exercise as assessed by echocardiography. (13-14) In other study, relatives of idiopathic/familial PAH patients displayed enhanced frequency of pulmonary hypertensive response during exercise and that this response is associated with mutations in the BMPR-2 gene. (15) These results suggest that asymptomatic gene carriers, in the absence of manifest pulmonary hypertension, might have enhanced PASP during exercise and more risk to develop resting pulmonary hypertension in the future compared with patients without gene mutations. Therefore, the treatment response by variable vasodilators (ex. calcium channel blockers, endothelin antagonist or prostacyclin analogues..) may be different based on the presence of BMPR-2 gene. In the present study, we want to investigate the prevalence of BMPR-2 gene mutations in the Korean PAH patients(Step-I) and to test that the PAH patients treated with iloprost inhalation solution (Ventavis®) would show hemodynamic response, especially assessed by exercise echocardiography (Step-II).
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Step I: BMPR-2 gene analysis | – | Drug: IloprostBMPR-2 gene analysis on 100 IPAH or heritable PAH Patients |
| Step-II: Iloprost and Exercise Echo | – | Drug: IloprostIlloprost inhalation for 3 months \& Check-up before and after treatment; WHO functional classification Assessment of exercise capacity (6M walk test) Cardiopulmonary exercise echocardiography NT-proBNP |
Who may qualify
- Ages
- 20 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Previously diagnosed PAH
Key inclusion criteria (4 listed)
- The patients aged from 20 to 80 years
- Newly diagnosed WHO category I PAH patients: Patients who meet the following criteria within 3 months obtained by right heart catheterization (mean PAP of more than 25 mm Hg at rest and mean pulmonary arterial wedge pressure (PCWP) or left ventricular end-diastolic pressure of 15 mm Hg or less) or echocardiography (peak PAP of more than 40mmHg and mean PAP more than 30mmHg).
- Previously diagnosed PAH patients who refractory to conventional treatment except iloprost inhalation solution (Ventavis): Patients meet the echo criteria (peak PAP of more than 40mmHg and mean PAP more than 30mmHg) who have been treated with PAH medications except iloprost inhalation solution (Ventavis) after diagnosed as WHO Group 1 PAH based on prior RHC data (above criteria) but refractory to them.
- The patients who are able to undergo low intensity exercise test (low dose bicycle or walking)
Key exclusion criteria (33 listed)
- The patients with other left heart disease (category II in WHO classification of pulmonary hypertension); ex. Congestive HF, cardiomyopathy, significant valvular heart disease, significant arrhythmia, suspicious elevated PCWP.
- The patients with category III,IV and V in WHO classification of pulmonary hypertension:
- The patients concurrently using other pulmonary vasodilator (ex. Inhaled NO, endothelin antagonists) except PDE5 inhibitor
- The patients with poor echo window which is unavailable to accept the echo data
- The patients who cannot do any exercise
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 |
|---|---|---|
| IloprostAlso: Allowable patients from Step-I, Step-II: Illoprost and Exercise EchoIloprost inhalation, 2.5 - 5mcg, 6 times per day | Drug | Step I: BMPR-2 gene analysis, Step-II: Iloprost and Exercise Echo |
Primary outcome
Cardiopulmonary exercise test parameters
Time frame: after 3 months active follow-up
5 secondary outcomes
Major cardiovascular Events (cardiovascular mortality, all cause mortality, hospitalization)
Time frame: After 2 years follow-up
Six-minutes walking test
Time frame: After 3 months active follow-up
WHO/NYHA class
Time frame: After 3 months active follow-up
Echo parameters
Time frame: After 3 months active follow-up
NT-proBNP
Time frame: After 3 months active follow-up
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 27 Dec 2018.
- Derived from this study: PubMed 32966279Jang AY, Kim BG, Kwon S, Seo J, Kim HK, Chang HJ, Chang SA, Cho GY, Rhee SJ, Jung HO, Kim KH, Seo HS, Kim KH, Shin J, Lee JS, Kim M, Lee YJ, Chung WJ. Prevalence and clinical features of bone morphogenetic protein receptor type 2 mutation in Korean idiopathic pulmonary arterial hypertension patients: The PILGRIM explorative cohort. PLoS One. 2020 Sep 23;15(9):e0238698. doi: 10.1371/journal.pone.0238698. eCollection 2020.
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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.
Wook-Jin Chung, MD,PhD principal investigator
Gachon University Gil Medical Center
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pulmonary Arterial Hypertension, run by Gachon University Gil Medical Center at 6 sites in South Korea.
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 33 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 27 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in South Korea. 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?
Cardiopulmonary exercise test parameters (time frame: after 3 months active follow-up). 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 NCT01054105, 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 27 Dec 2018.