Effect of BMPR-2 Gene Mutations on Hemodynamic Response by Iloprost Inhalation in Pulmonary Arterial Hypertension

NCT ID: NCT01054105

Last Updated: 2018-12-27

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 73 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2010-10-31
• Study Completion Date: 2018-12-25

Brief 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).

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

Keywords

Pulmonary hypertension; genes; mutation; drug therapy

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Step I: BMPR-2 gene analysis

BMPR-2 gene analysis on 100 IPAH or heritable PAH Patients

Iloprost

Intervention Type: DRUG

Iloprost inhalation, 2.5 - 5mcg, 6 times per day

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

Iloprost

Intervention Type: DRUG

Iloprost inhalation, 2.5 - 5mcg, 6 times per day

Interventions

Iloprost

Iloprost inhalation, 2.5 - 5mcg, 6 times per day

Intervention Type: DRUG

Other Intervention Names

Allowable patients from Step-I; Step-II: Illoprost and Exercise Echo

Eligibility Criteria

Inclusion Criteria

1. The patients aged from 20 to 80 years

2. 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).

3. 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.

4. The patients who are able to undergo low intensity exercise test (low dose bicycle or walking)

Exclusion Criteria

1. 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.

2. 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
• 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)

3. The patients concurrently using other pulmonary vasodilator (ex. Inhaled NO, endothelin antagonists) except PDE5 inhibitor

4. The patients with poor echo window which is unavailable to accept the echo data

5. The patients who cannot do any exercise

6. The patients who changes medication administered during ventavis treatment

7. The patients with allergic reaction to ventavis

8. The patients with other systemic disease (ex. Leukemia, MM, Sickle cell anemia, significant liver disease)

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Seoul National University Hospital

OTHER

Sponsor Role: collaborator

Seoul National University Bundang Hospital

OTHER

Sponsor Role: collaborator

The Catholic University of Korea

OTHER

Sponsor Role: collaborator

Bayer

INDUSTRY

Sponsor Role: collaborator

Gachon University Gil Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Wook-Jin Chung

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wook-Jin Chung, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Gachon University Gil Medical Center

Locations

Soonchunhyang University Bucheon Hospital

Bucheon-si, , South Korea

Gachon University Gil Hospital

Incheon, , South Korea

Seoul National University Bundang Hospital

Seongnam, , South Korea

Catholic University Seoul Saint Mary's Hospital

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Sungkyunkwan University Seoul Samsung Hospital

Seoul, , South Korea

Countries

South Korea

References

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.

Reference Type: DERIVED

PMID: 32966279 (View on PubMed)

Other Identifiers

GIRBA 2278

Identifier Type: OTHER

Identifier Source: secondary_id

WJC-IIT-1001

Identifier Type: -

Identifier Source: org_study_id