UMIN-CTR Clinical Trial

Public title

An Exploratory Clinical Study on the Impact of Pulmonary Circulation on Patients with Idiopathic Pulmonary Fibrosis

Acronym

An Exploratory Clinical Study on the Impact of Pulmonary Circulation on Patients with Idiopathic Pulmonary Fibrosis

Scientific Title

An Exploratory Clinical Study on the Impact of Pulmonary Circulation on Patients with Idiopathic Pulmonary Fibrosis

Scientific Title:Acronym

An Exploratory Clinical Study on the Impact of Pulmonary Circulation on Patients with Idiopathic Pulmonary Fibrosis

Region

Japan

Condition

Idiopathic Pulmonary Fibrosis

Classification by specialty

Medicine in general	Cardiology	Pneumology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To examine the relationship between pulmonary circulation parameters, including pulmonary vascular resistance (PVR) and the prognosis in patients with idiopathic pulmonary fibrosis (IPF).

Basic objectives2

Others

Basic objectives -Others

To examine the relationship between pulmonary circulation parameters, including pulmonary vascular resistance (PVR), and the activities of daily living (ADL) and exercise tolerance in patients with idiopathic pulmonary fibrosis (IPF).

Trial characteristics_1

Exploratory

Trial characteristics_2

Developmental phase

Primary outcomes

To examine the relationship between pulmonary circulation parameters, including pulmonary vascular resistance (PVR) and the prognosis in patients with idiopathic pulmonary fibrosis (IPF).

Key secondary outcomes

To examine the relationship between pulmonary circulation parameters, including pulmonary vascular resistance (PVR), and the activities of daily living (ADL) and exercise tolerance in patients with idiopathic pulmonary fibrosis (IPF).

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

YES

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Prevention

Type of intervention

Maneuver

Interventions/Control_1

Right Heart Catheter

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1) Patients with IPF enrolled under UMIN ID: UMIN000042159 who completed the two year observation period.
2) Patients aged 20 years old or older (both sexes)
3) Patients diagnosed at this hospital as having IPF (WHO functional class 2, 3 or 4) without hypoxia at rest or during 6MWT (to exclude those with decreased ADL and dyspnea in daily living associated with hypoxia and to minimize the influence of hypoxic pulmonary vasoconstriction [HPV] as a potential cause of PH associated with decreased partial pressure of oxygen in arterial blood [PaO2]) (PaO2 < 60 mmHg).
Including those whose hypoxia (PaO2 < 60 mmHg) had been corrected with long-term oxygen therapy (LTOT)
4) Patients with stable IPF who had not required any change of treatment within 3 months prior to study entry, i.e., those confirmed to have completely organized honeycomb lung (chronic IIP based on high-resolution computed tomography (CT) findings for which no effective therapy exists); and who presented to our hospital for the first time with symptoms of progressive respiratory failure and had not received any medical treatment for IPF within 3 months prior to their visit.
Excluding those whose progressive respiratory failure required no treatment for IPF itself and those who had an increased LTOT dose as a minimum requirement for progressive respiratory failure.
5) Patients with eePAP or PH requiring close clinical monitoring, diagnosed with an assumed PAWP 15 mmHg and less than 15 mmHg, mPAP < 25 mmHg, and mPAP during the Valsalva maneuver 30 mmHg and more than 30 mmHg, or mPAP at rest 25 mmHg and more than 25 mmHg.
6) Inpatients and outpatients
7) Patients who provided written informed consent to participate in this study

Key exclusion criteria

1) Patients who had received bosentan or any other drug specific for PAH (e.g., phosphodiestetrase type 5 [PDE-5] inhibitors, endothelin receptor antagonists, or prostaglandin analogs) prior to their enrollment
2) Patients with any disease that could cause right heart overload
3) Patients with hypoxia during 6MWT (PaO2 < 60 mmHg)*.
* Excluded were those whose hypoxia (PaO2 < 60 mmHg) had been corrected with LTOT (i.e., those in whom LTOT is in place to ensure PaO2 > 60 mmHg both at rest and during 6MWT, who were deemed equivalent to IPF patients receiving routine therapy in clinical practice to allow them to be monitored for changes in their condition, prognosis and functional capacity for ADL).
4) Women who were pregnant or might have been pregnant, and who were lactating
5) Other patients judged by the investigator to be ineligible for this study (e.g., those with any disease or condition other than IPF that might affect their ADL, such as arrhythmia, LV failure, pulmonary thromboembolism, connective tissue diseases, intervertebral disc herniation, as they were confirmed by history taking, physical examination, chest x-ray, echocardiography [ECG], lung perfusion scintigraphy, and measurements of various parameters conducted during the run-in period).

Target sample size

50

Name of lead principal investigator

1st name	Yosuke
Middle name
Last name	Tanaka

Organization

Nippon Medical School

Division name

Department of Respiratory Medicine

Zip code

113-8603

Address

1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan

TEL

0338222131

Email

yosuke-t@nms.ac.jp

Name of contact person

1st name	Yosuke
Middle name
Last name	Tanaka

Organization

Nippon Medical School

Division name

Department of Respiratory Medicine

Zip code

113-8603

Address

1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan

TEL

0338222131

Homepage URL

Email

yosuke-t@nms.ac.jp

Institute

Nippon Medical School

Institute

Department

Personal name

Yosuke Tanaka

Organization

Nippon Medical School

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

the medical ethics committee of Nippon Medical School

Address

1-1-5, Sendagi, Bunkyo-ku, Tokyo

Tel

0338222131

Email

yosuke-t@nms.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

日本医科大学付属病院

Date of disclosure of the study information

2024

Year

09

Month

10

Day

URL releasing protocol

Publication of results

Published

URL related to results and publications

https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-025-03837-0

Number of participants that the trial has enrolled

49

Results

Results Higher PVR was linked to poorer prognosis and restrictive decline, correlating with mMRC, 6MWD, and MET. It predicted overall survival and home-stay survival.
Conclusions PVR was significantly related to prognosis, ADL, and exercise tolerance in IPF. Even within 2 years, it predicted outcomes, suggesting value as an early prognostic marker and supporting routine monitoring.

Results date posted

2025

Year

09

Month

29

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2025

Year

08

Month

26

Day

Baseline Characteristics

Target patient population
As part of the interim analysis of an ongoing prospective study (UMIN ID: UMIN000042159), this exploratory study was conducted in patients with IPF complicated by secondary ERPE or PH classified as WHO functional class II, III, or IV. Eligible patients were those who received conventional management for lung disease without PAH-specific therapies between October 2020 and September 2022, and who completed a two-year follow-up.

Inclusion was conditional on meeting all eligibility criteria and having no exclusion criteria.

Participant flow

Grouping of patients
The classification of patients into each PH severity group is summarized in Fig. 1.

This analysis targeted patients from our ongoing study with minimal IPF activity at diagnosis, confirmed by chronic fibrosing interstitial pneumonia (f-IIP) on high-resolution CT, and included right heart catheterization (RHC) to evaluate right heart function for symptom assessment.

According to the current diagnostic criteria, exercise-induced pulmonary hypertension (exercise-PH) is diagnosed by confirming an mPAP/cardiac output (CO) slope > 3 mmHg/L/min during exercise. However, diagnosing exercise-induced PH is not straightforward. In this study, we interpreted patients with an mPAP < 25 mmHg and mPAWP <= 15 mmHg, but with an mPAP >= 30 mmHg during straining, as potentially developing pulmonary hypertension during daily life. Although these patients were not strictly classified as having exercise-induced PH, they were regarded as having exercise-induced elevation of pulmonary artery pressure (eePAP) in this study. Among them, those with an mPAP below 20 mmHg were classified into the ERPE group.

Although the current diagnostic criteria define PH as a resting mPAP > 20 mmHg, this analysis used data from an ongoing study originally designed prior to the guideline revision. In that protocol, patients were assigned to the PH group if they had a resting mPAP >= 25 mmHg, or if their resting mPAP was between 20 and 25 mmHg and mPAP >= 30 mmHg was observed during straining.

Based on these data, we classified patients as having less severe PH if they had a resting mPAP between 20 and 35 mmHg and mPAWP <= 15 mmHg, and as having severe PH if they had mPAP >= 35 mmHg with mPAWP <= 15 mmHg. This stratification reflects the structure of the original data and forms the analytical basis of the present study.

The aim of this study was to assess the extent to which PH, ranging from ERPE to mild and severe PH secondary to IPF, impacts the clinical course of IPF patients. Furthermore, this study aimed to emphasize the importance of early evaluation of conditions leading to PH and to explore the potential utility of future research on early therapeutic intervention for such conditions.

Adverse events

Of the 49 patients, 21 experienced ADL decline due to worsening conditions, including dyspnea on exertion, leading to hospitalization and permanent facility care. Among them, 16 died.
In the ERPE group, events included 1 myocardial infarction (day 577), 1 fall with fracture (day 450), 2 pneumonias (days 24, 438), 1 hepatitis (day 438), and 2 hospital transfers due to relocation (days 518, 700).
In the less severe PH group, there was 1 case of depression (day 262) and 1 cerebral infarction (day 180). Evaluation parameters were recorded until each event.

Outcome measures

Home-stay survival and overall survival
Among the 49 IPF patients included in the analysis, 21 required permanent facility care within the 2-year follow-up period (severe PH: 3, less severe PH: 11, ERPE: 7). The mean duration from enrollment to this event (home-stay survival) was 320.48 +/- 245.07 days. Stratified by group, the mean durations were 335.00 +/- 279.85 days for severe PH, 377.09 +/- 253.49 days for less severe PH, and 225.29 +/- 224.59 days for ERPE.

The estimated mean 2-year home-stay survival durations for all patients were 533.38 +/- 39.68 days overall, 398.50 +/- 138.64 days for the severe PH group, 525.20 +/- 59.17 days for the less severe PH group, and 504.77 +/- 53.09 days for the ERPE group. No significant hazard ratios were observed between the less severe and the ERPE groups in Cox proportional hazard models. Sixteen patients died during the 2-year observation period (severe PH: 3, less severe PH: 7, ERPE: 6). The mean survival time among deceased patients was 381.94 +/- 235.64 days (346.33 +/- 292.34 for severe PH, 437.57 +/- 236.63 for less severe PH, and 334.83 +/- 239.68 for ERPE). Estimated 2-year overall survival durations were 594.06 +/- 33.86 days overall, with 413.50 +/- 142.26 for severe PH, 606.58 +/- 50.27 for less severe PH, and 573.21 +/- 45.47 for ERPE. No statistically significant differences were observed among the three groups.

Findings from right heart catheterization
Given the small sample size, data from the severe PH group should be considered reference values, with no definitive conclusions. However, all indicators, including mPAP, suggested greater right heart strain in this group compared to the others. In contrast, no significant differences in CO or CI were observed between the less severe and the ERPE groups, but mPAP and PVR showed significant differences.

Additional parameters
The severe PH group results should be treated as reference due to the small sample size (four patients), limiting definitive conclusions. However, this group tended to be older, with lower height, weight, ADL, and exercise tolerance compared to the others.

No significant differences were found in the 6MWT or mMRC scale, but maximum exercise tolerance, measured by the treadmill exercise test, differed significantly between groups. Pulmonary function tests showed no significant differences in restrictive lung dysfunction indicators, but %DLco significantly differed between the ERPE group and the two PH groups.

Correlation between evaluated parameters and ADL, exercise tolerance, and prognosis
Analysis of all patients showed significant correlations between the mMRC scale and pulmonary function, including %VC (Spearman's r = -0.69, p < 0.0001) and FVC (r = -0.53, p = 0.0001). Similarly, 6MWD correlated with %VC (r = 0.64, p < 0.0001) and FVC (r = 0.56, p < 0.0001). Maximum exercise tolerance (MET) also correlated with %VC (r = 0.40, p = 0.0064) and FVC (r = 0.45, p = 0.0017). PVR showed significant correlations with mMRC (r = 0.47, p = 0.0007), 6MWD (r = -0.41, p = 0.0042), and MET (r = -0.60, p < 0.0001), with similar trends observed for mPAP.

%VC and FVC did not significantly correlate with mPAP but did correlate with PVR: %VC (r = -0.31, p = 0.031) and FVC (r = -0.34, p = 0.020). %DLco was significantly inversely correlated with PVR in the total cohort (r = -0.58, p < 0.0001), but not within subgroups (ERPE: r = -0.30, p = 0.10; less severe PH: r = -0.30, p = 0.19).

For prognostic analyses, proportional hazard analysis identified %VC (HR 0.98, p = 0.024), %DLco (HR 0.97, p = 0.0067), mean PAP (HR 1.05, p = 0.042), and PVR (HR 1.20, p = 0.032) as significant factors for home-stay survival. FVC was not significant (HR 0.80, p = 0.45).

For overall survival, %VC (HR 0.97, p = 0.027), %DLco (HR 0.97, p = 0.0062), mean PAP (HR 1.066, p = 0.025), and PVR (HR 1.28, p = 0.013) were significant, while FVC was not (HR 0.70, p = 0.31).

Plan to share IPD

N.A

IPD sharing Plan description

N.A

Recruitment status

Completed

Date of protocol fixation

2020

Year

10

Month

01

Day

Date of IRB

2020

Year

10

Month

01

Day

Anticipated trial start date

2020

Year

10

Month

11

Day

Last follow-up date

2027

Year

10

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2024

Year

09

Month

10

Day

Last modified on

2025

Year

09

Month

29

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000063381