Validation of the Risk Stratification Score in Idiopathic Pulmonary Fibrosis

• ClinicalTrials.gov Identifier: NCT02632123
• Recruitment Status: Recruiting
• First Posted: December 16, 2015
• Last Update Posted: December 10, 2020
• Sponsor: Lawson Health Research Institute
• Information provided by (Responsible Party): Lawson Health Research Institute

Study Description

Brief Summary:

Idiopathic pulmonary fibrosis (IPF) is a progressing scarring disease of the lungs with an average survival of only 30-36 months since the time of diagnosis, in the absence of treatment. The clinical course of IPF is highly variable, with some patients remaining stable for a prolonged period of time, even in the absence of medical treatment, while others experience rapid and relentless progression. In some cases, the clinical course consists of a stepwise rather than steady decline, with periods of stability alternating with acute respiratory worsening. The variability in clinical course makes it challenging to define prognosis in these patients and, importantly, to determine the right time window for lung transplantation (LTx) referral, listing and priority status on the waiting list.

The risk stratification score (RISE) is a new, multi-dimensional staging system for IPF based on the MRC dyspnea score, on physiology variables (pulmonary function tests) captured in the Composite Physiologic Index (CPI), and on the 6-minute walk distance. RISE showed to predict survival in newly diagnosed patients with IPF better than any other individual clinical, functional or radiographic variable. RISE also predicted survival on the waiting list in patients assessed and listed for LTx. The objective of this study is to validate this staging system in a large cohort of patients newly diagnosed with IPF and followed for at least 3 years.

Condition or disease
Idiopathic Pulmonary Fibrosis

Detailed Description:

The objective of this study is to validate the RISE as a reliable tool to predict survival in patients newly diagnosed with IPF and prospectively followed for a period of at least 3 years, or until death or lung transplant.

This is an observational, prospective cohort study.

Inclusion criteria will be:

• a new diagnosis of IPF based on the American Thoracic Society/European Respiratory Society criteria (Am J Respir Crit Care Med 2018;198:e44-e68) and based on multi-disciplinary discussion with Chest Radiologist and, when a surgical lung biopsy is available, Lung Pathologist.
• a pattern consistent with UIP/IPF will be further confirmed by at least 2 expert radiologists, unless a surgical lung biopsy is available and MDD confirms a diagnosis of IPF.

Exclusion criteria:

• diagnosis of ILD other than IPF.
• not a new diagnosis of IPF.

Patients newly diagnosed with IPF will be included in the study.

Patients will be reassessed at 4 months intervals and at each visit the MRC dyspnea score (MRCDS), pulmonary function tests (FEV1, FVC and DLCO), and 6-minute walk distance (6MWD) will be recorded. RISE will be calculated ad described in Eur Respir J 2012;40:101-109.

MRCDS, PFTs and 6MWD are part of the standard of care in IPF and are routinely obtained at each visit of IPF patients in the ILD clinic (every 4 months).

Pulmonary function tests will be performed according to the ERS/ATS guidelines (Eur Respir J 2005;26:319-38).

A 2nd HRCT will be repeated at 24 months from the time of diagnosis, or sooner if clinically indicated. The HRCT visual fibrosis score on each HRCT will be calculated, as described in Respir Res 2020;21(1):119. Longitudinal changes will be considered as well.

All relevant comorbidities (cardio-vascular disease, diabetes, sleep apnea, chronic obstructive pulmonary disease) will be taken into consideration.

Enrollment in pulmonary rehabilitation physiotherapy will be considered and recorded. The length of the enrollment will be considered.

Hospital admission for respiratory reasons will be considered and recorded.

Treatment start and stop dates will recorded. Each switch of therapy will be recorded as well.

All protocol violations will be recorded.

Patients will be prospectively followed for a period of at least 3 years and mortality events will be recorded. Three-year lung transplant-free survival will be the primary endpoint.

Acute exacerbations (AEs) of IPF, as defined in AJR Am J Roentgenol 1997;168:79-83, will also be recorded. AEs will be a secondary endpoint.

Progression of disease will be defined as either: >10% absolute reduction in forced vital capacity (FVC) % pred; >50 m decline in 6-minute walk distance (6MWD); admission to hospital for respiratory causes; lung transplantation assessment; or death Progression of disease will be a secondary endpoint.

Patients who received a lung transplant will be censored.

At the end of the study period, both baseline RISE and longitudinal changes of RISE will be tested as predictors of mortality. Other individual variables that will also be tested as predictors of mortality will include: age at the time of diagnosis; time between onset of symptoms and diagnosis (months); gender; body mass index; smoking history (pack-years); PFTs; 6MWD (both meters and % predicted); desaturation during the 6-minute walk test; HRCT visual fibrosis score; Gender-Age-Physiology (GAP) Index (Ann Intern Med 2012;156:684-691); Composite Physiologic Index (Am J Respir Crit Care Med 2033;167:962-969) and Mortality Risk Scoring System with Ascertainable Predictors (Am J Respir Crit Care Med 2011;184:459-66). Longitudinal changes of these variables will be considered as well.

Planned secondary analyses include the comparison of 3-year survival in the following subgroups:

• Patients with HRCT pattern typical for UIP vs. non-typical.
• Patients with autoimmune markers (although not meeting criteria for interstitial pneumonia with autoimmune features) vs. those without.
• Patients with concomitant emphysema vs. those without.
• Patients on pirfenidone vs. patients on nintedanib.

Values will expressed as mean±SD. Comparisons between survivors and non-survivors will be made with unpaired t-test or with the Mann-Whitney U-test, where appropriate.

The optimal cut-off value for different variables to detect mortality or AE will assessed using receiver operating characteristics (ROC) analysis.

Survival will evaluated using Kaplan-Meier curves and the log-rank test. Cox proportional hazards regression analysis will used to identify significant variables predicting survival status.

Variance inflation factors of variables predicting endpoint will be calculated to rule out the possibility of multicollinearity and demonstrate that the variables are truly independent.

Results will be summarized as hazard ratios, representing the relative risk of dying as a result of a specific characteristic during the observation period.

Variables selected via univariate analysis (p<0.05) will evaluated in the multivariate Cox regression analysis.

Areas under the curve (AUC) were compared according to the methods of DeLong et al. (Biometrics 188;44:837-845).

Fine-Gray competing risk regression analysis will be used to account for the competing risks of lung transplant and death (J Am Stat Assoc 1999;94:496-509). p-values <0.05 will regarded as significant.

Study Design

• Study Type: Observational
• Estimated Enrollment: 500 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Validation of the Risk Stratification Score in Idiopathic Pulmonary Fibrosis
• Actual Study Start Date: December 2015
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Groups and Cohorts

Group/Cohort
Idiopathic pulmonary fibrosis; Patients newly diagnosed with idiopathic pulmonary fibrosis

Outcome Measures

Primary Outcome Measures :

1. Survival [ Time Frame: 3 years ]
   Primary outcome is 3-year survival since the time of diagnosis

Secondary Outcome Measures :

1. Acute exacerbation of IPF [ Time Frame: 3 years ]
   Secondary outcome is the incidence of acute exacerbations since the time of diagnosis
2. Clinical progression [ Time Frame: 3 years ]
   Time to either: decline of FVC >10% pred; decline of 6-min walk distance >50 m; hospitalization for respiratory causes; lung transplant assessment; or death.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Patients newly diagnosed with idiopathic pulmonary fibrosis.

Criteria

Inclusion Criteria:

• A new diagnosis of IPF based on the American Thoracic Society/European Respiratory Society criteria (Am J Respir Crit Care Med 2018;198:e44-e68) and confirmed by a panel of expert chest radiologists and lung pathologists in the context of multi-disciplinary discussion.

Exclusion Criteria:

• Interstitial lung disease other than IPF
• Not a new diagnosis of IPF

Contacts and Locations

Contacts

Contact: Marco Mura, MD, PhD; +1-5196676744; marco.mura@lhsc.on.ca

Locations

Canada, Ontario

London Health Science Centre; Recruiting

London, Ontario, Canada, N6A 5W9

Contact: Marco Mura, MD, PhD +15196676744 marco.mura@lhsc.on.ca

Contact: Mena Gaed, MBCCh, MSc +15196858500 ext 73451 mena.gaed@lhsc.on.ca

Principal Investigator: Marco Mura, MD, PhD

Sponsors and Collaborators

Lawson Health Research Institute

More Information

• Responsible Party: Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT02632123
• Other Study ID Numbers: 10010803
• First Posted: December 16, 2015
• Last Update Posted: December 10, 2020
• Last Verified: June 2020

Keywords provided by Lawson Health Research Institute:

idiopathic pulmonary fibrosis; outcome; prognosis; survival; staging

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Idiopathic Interstitial Pneumonias; Lung Diseases, Interstitial