Idiopathic pulmonary fibrosis (IPF) is characterized by a poor prognosis, with a progressive decline in lung function and a considerable variability in the disease's natural history. Besides lung transplantation (LTx), the only available treatments are anti-fibrosing drugs, which have shown to slower the disease course. Therefore, predicting the prognosis is of pivotal importance to avoid treatment delays, which may be fatal for patients with a high risk of progression. Previous studies showed that a multi-dimensional approach is practical and effective to create a reliable prognostic score for IPF. In the RIsk Stratification scorE (RISE), physiological parameters, an objective measure of patient-reported dyspnea and exercise capacity are combined to capture different domains of the complex pathophysiology of IPF.

This is an observational, multi-centre, prospective cohort study. A development cohort and a validation cohort will be included. Patients newly diagnosed with IPF based on the ATS/ERS criteria and multi-disciplinary discussion will be included in the study. A panel of chest radiologists and lung pathologists will further assess eligibility. At the first visit (time of diagnosis), and every 4-months, MRCDS, pulmonary function tests (FEV1, FVC and DLCO), and 6MWD will be recorded and patients will be prospectively followed for 3 years. Comorbidities will be considered. The radiographic extent of fibrosis on HRCT will be recalculated at a 2-year interval. RISE, Gender-Age-Physiology, CPI and Mortality Risk Scoring System will be calculated at 4-month intervals. Longitudinal changes of each variable considered will be assessed. The primary endpoint is 3-year LTx-free survival from the time of diagnosis. Secondary endpoints include several, clinically-relevant information to ensure reproducibility of results across a wide range of disease severity and in concomitance of associated pulmonary hypertension, emphysema.

The present study aims at validating RISE as a simple, straightforward, inexpensive and reproducible tool to guide clinical decision making in IPF and potentially as an endpoint for future clinical trials.

This is an observational, international, prospective cohort study including 2 large tertiary referral centres for interstitial lung disease (ILD)(London, Canada and Rome, Italy). Only patients newly diagnosed with IPF based on the American Thoracic Society/European Respiratory Society criteria and local multi-disciplinary discussion will be included in the study.

As a further inclusion step, for all patients who did not undergo a surgical lung biopsy (SLB), a panel of 3 chest radiologists with ILD expertise will examine each HRCT and patients will be included, if at least 2 out of 3 agree on a pattern of probable/definite UIP. For patients who underwent a SLB, a panel of 3 lung pathologists with ILD expertise will examine each biopsy and patients will be included, if at least 2 out of 3 agree on a pattern of probable/definite UIP.

All known causes of ILD (occupational, environmental, domestic exposures; drug-induced lung toxicity; connective tissue disease) will carefully excluded for the patient to be included in the study. Only patients newly diagnosed with IPF at participating centres will be included in the study. Comorbidities considered will include (associated pulmonary hypertension [APH], only if right heart catheterization[RHC]-proven), chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), left heart dysfunction (LHD), and sleep apnea (SA).

A development cohort and a validation cohort will be included in the study. In both cohorts. at the first visit (time of diagnosis) and at each subsequent visit at 4-month intervals, for a period of 3 years, Medical Research Council Dyspnea Score (MRCDS), pulmonary function tests (PFTs)(forced expiratory volume during the first second [FEV1], FVC and diffusing lung capacity for carbon monoxide [DLCO]), and 6MWD will be recorded. 6MWD % predicted will be calculated, as previously described.

The following events will be recorded in the study: death; lung transplant (LTx) referral; LTx; acute exacerbation (AEs); hospitalization for respiratory causes; start, stop and switch of anti-fibrotic therapy; start of supplemental home oxygen therapy; start and stop of physiotherapy program enrolments; progression of disease (see secondary endpoints).

The RISE will be first calculated, as previously described, on a scale from 1 to 3. However, a modified and improved version of the RISE will also be considered, both using the CALIPER-revised Composite Physiologic index (CPI) instead of the original version of CPI, and with a new 1 to 4 scale, which may allow for better stratification for mortality risk. If superior to the previous version of RISE, the modified version will be tested for validation.

Patients will be prospectively followed for a period of 3 years from the time of diagnosis and enrolment. PFTs and 6MWD will be obtained at 4 months intervals, at each visit at participating centres. All multi-dimensional scores will be calculated at 4-months intervals corresponding to each visit. A 2nd HRCT will be obtained at the 2-year visit, or sooner if clinically indicated, and as per clinicians' discretion. The HRCT fibrosis score will be then recalculated on the 2nd scan. Deaths, LTx, AEs and hospitalizations due to respiratory causes will be recorded. All protocol violations (missing visits, delayed visits, data not obtained at individual visits) will be systematically recorded. Every interruption or change in course of therapy, as well as initiation of supplemental home oxygen therapy will be recorded. When available, hemodynamic data from RHCs will be considered. Since 2D echocardiograms alone are unreliable in predicting the presence of APH in IPF, they will not be considered.

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 will also be tested as predictors of mortality, including age at the time of diagnosis, time between onset of symptoms and diagnosis (months), gender, body mass index, smoking history (pack-years), FVC, DLCO, 6MWD (meters and % predicted), HRCT visual fibrosis score at the time of diagnosis, and other multi-dimensional scores (Gender-Age-Physiology [GAP], CPI, Mortality Risk Scoring System [MRSS]). In the validation cohort, we will seek to confirm and validate results obtained in the development cohort.

PATIENT SELECTION Inclusion criteria A new diagnosis of IPF based on ATS/ERS criteria, confirmed by local multi-disciplinary discussion (MDD). A panel of 3 chest radiologists with ILD expertise will review each HRCT and patients will be included, if at least 2 out of 3 agree on a pattern of probable/definite UIP. A panel of 3 lung pathologists with ILD expertise will review each SLB and patients will be included, if at least 2 out of 3 agree on a pattern of probable/definite UIP.

Exclusion criteria ILD other than IPF Previous (rather than new) diagnosis of IPF Exclusion determined by the chest radiologists' or lung pathologists' panel Age <18 years Patient not able to provide informed consent

MRC dyspnea score, pulmonary function tests and 6-minute walk test Dyspnea, defined as "the unpleasant sensation of labored or difficult breathing" was rated by using the MRCDS, which specifically measures perceived respiratory disability24. This scale grades the effect of breathlessness on daily activities. PFTs and 6-minute walk test (6MWT) will be performed according to ERS/ATS guidelines and the ATS guidelines, respectively. A reference equation was used to calculate 6MWD percent predicted (% pred). The distance-saturation product will be considered.

High resolution chest CT scans A quantitative fibrosis score on HRCT will be obtained at the time of diagnosis and on the repeat HRCT. The score will be calculated as previously described12 by each of the chest radiologists, and the average of the scores will then be calculated. Interobserver variability will be evaluated. The presence and severity of coronary calcifications will be evaluated as absent, mild, moderate or severe.

Longitudinal follow-up After diagnosis, patients are seen at 4-month intervals, for a period of 3 years in both the development and validation cohort. At each visit, MRCDS, PFTs and 6MWT will be obtained. Patients may be seen more often at the clinician's discretion. After completion of the 3 years follow-up period, patients who are still alive without a LTx will continue to be followed regularly until required recruitment is completed, as long-term follow-up is part of secondary endpoints.

Statistical Analysis and sample size calculation Values will be expressed as mean ± standard deviation. The Kolmogorov-Smirnov test will be used for distribution analysis. Interobserver variability among chest radiologists and lung pathologists will be assessed with Weighted kappa coefficients29. Comparisons between survivors and non-survivors will be made with unpaired t-test or with the Mann-Whitney U-test, where appropriate. Variance inflation factors of the predicting variables included in RISE will be calculated to rule out the possibility of multicollinearity and demonstrate that the variables are truly independent30. The optimal cut-off value for different variables to endpoints will be assessed using receiver operating characteristics analysis. Cox proportional hazards regression analysis will used to identify significant variables predicting survival status. 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 be evaluated in the multivariate Cox regression analysis. Once patients are listed for LTx, death and LTx become competing events. In order to account for the competing risks of LTx and death in a population of patients undergoing LTx assessment, the Fine-Gray competing risk regression analysis will also be used to identify significant variables predicting independent survival status. Results will be summarized as subdistribution hazard ratios, representing the relative risk of dying prior to LTx. Survival will be further evaluated using Kaplan-Meier curves and the log-rank test.

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

Patients newly diagnosed with idiopathic pulmonary fibrosis.