American Journal of Respiratory and Critical Care Medicine

Idiopathic pulmonary fibrosis (IPF) is the prototypic fibrosing lung disease, characterized by relentless progression and poor prognosis (1). Patients gradually deteriorate despite treatment with the current standard of care, nintedanib or pirfenidone (2). These drugs have been approved after decades of failed trials and heated discussion on the choice of the best efficacy endpoint. Endpoints have been investigated in thousands of patients before it was decided that the change of FVC over 1 year was the right one, a decision based mainly on the correlation between FVC changes and mortality and accepting that studies with mortality as endpoint were not feasible (3).

Measuring FVC is a simple, reproducible, and widely available tool to monitor IPF progression. Both substantial (⩾10%) and marginal (between 5% and 10%) declines in FVC at 6 months are associated with increased risk of death (46). One challenge in current clinical trials is allocation of patients to true placebo when approved treatments are available. The alternative strategy of identifying a treatment effect on top of antifibrotic treatment leaves smaller margins to detect differences and requires more patients and long trial duration. Therefore, novel strategies to improve trial efficiency in IPF are most needed.

In this issue of the Journal, Khan and colleagues (pp. 936–948) used a solid statistical approach to assess the reliability of a 3-month change in functional parameters as a surrogate efficacy endpoint in IPF trials (7). The authors performed a systematic review and meta-analysis using individual patient data from large IPF trials (certainly a strength of their study) to explore the relationships between a 3-month change in physiological parameters and clinically relevant outcomes. The data generated from almost 2,000 patients with IPF indicate that a 2.5% relative FVC decline at 3 months is associated with a 15% increased risk of mortality and a 30% increased likelihood of disease progression. An optimal threshold of 5.7% in FVC change at 3 months is predicting a significantly higher risk of death: the accuracy of this 3-month FVC change is comparable to a 10% change in a 12-month period.

In the treatment arms of six trials evaluating currently approved antifibrotics, a 2.5% relative FVC decline at 3 months is associated with a 20% risk increase in mortality and 46% greater likelihood of disease progression. Importantly, the comparison of FVC decline between treatment arms and their corresponding placebo arms showed that a statistically significant treatment effect is present after 3 months (40.9-ml difference between placebo and treatment arms, a relative change difference of 1.6%). The authors conclude that 3-month declines in lung function are predictive of disease progression, irrespective of antifibrotic treatment, and could serve as an earlier endpoint or a prognostic enrichment tool for future IPF trials.

Khan and colleagues should be praised for the methodological robustness of their study, providing an unbiased insight into the extent to which FVC change could be exploited. An efficacy endpoint measurable in a shorter timeframe could more rapidly provide evidence of (in)efficacy, optimizing the resources needed in IPF trials and making study participation more sustainable. Improving the efficiency of trials in IPF and pulmonary fibrosis in general should be a priority for the respiratory community. New opportunities are on the horizon, including the use of Bayesian approaches (8) and the implementation of home spirometry; 3-month change in FVC measured via handheld spirometers showed high sensitivity for predicting subsequent survival and could be used as an efficacy endpoint in short proof-of-concept trials (9), although recent findings suggest that this approach needs further validation (10, 11).

The findings of Khan and colleagues will also help to enroll patients with a more “progressive” disease. It will be important to validate these results in other nonidiopathic fibrotic lung diseases, as this additional evidence would also contribute to the ongoing process of defining what is “progressive” in patients with pulmonary fibrosis.

The advantages of using a 3-month interval in FVC change come at a price though. The authors estimate that a hypothetical trial using FVC decline at 3 months as the primary efficacy endpoint should approximately double the number of patients, as compared with a “standard” 12-month trial. Although more patients could feel encouraged to participate in shorter trials, this should be carefully balanced with the challenge of a most intensive recruitment phase, a challenge even more critical in the current coronavirus disease (COVID-19) pandemic era.

The current study included trials of a bygone IPF era when placebo arms were entirely formed by naive, untreated patients. Pirfenidone or nintedanib are now an essential component of the placebo groups in IPF trials, thus sensibly decreasing the rate of functional decline of this group. As such, it could be argued that a 3-month window to detect a treatment effect may not be the best fit, as separation of functional trend slopes of placebo and treatment arms could be delayed in time owing to smaller effect sizes. However, recent studies in IPF have also shown that the patients in the placebo arms with background therapy were more progressive than would have been expected (12). These patients were not (yet) included by the authors in their analyses. On the other hand, a short trial duration might increase acceptance of a “pure” placebo group of patients, at least in phase 2 trials.

The choice of using FVC decline as a standalone primary endpoint should not be taken for granted. The incorporation of alternative outcomes could enhance trial efficiency. If backed by validation and consensus on implementation strategies (13), patient-reported outcomes will be given higher priority in the design of future IPF trials. Quantitative assessment of chest imaging via computer-aided imaging analysis could increase sensitivity to capture subtle changes in lung parenchyma indicating progressive disease (1416). The radiological extent of pulmonary fibrosis was included as secondary endpoint in the recent successful phase 2 trial of pamrevlumab, which showed to decrease fibrotic progression on computed tomography scan at 12 months (17). Change over time in lung function will probably remain the mainstay for assessing drug efficacy in IPF. Khan and colleagues show that shorter trials may be a way forward. Nonetheless, a shorter timeframe for change in lung function should be complemented by other outcomes of interest to maximize trial effectiveness and capture a range of benefits beyond slowing down disease progression, as our goal is to halt and ideally reverse pulmonary fibrosis, making patients feel better.

1. Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med 2020;383:958968.
2. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018;378:18111823.
3. Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis–FDA review of pirfenidone and nintedanib. N Engl J Med 2015;372:11891191.
4. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:459466.
5. Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:830836.
6. Richeldi L, Ryerson CJ, Lee JS, Wolters PJ, Koth LL, Ley B, et al. Relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis. Thorax 2012;67:407411.
7. Khan FA, Stewart I, Moss S, Fabbri L, Robinson KA, Johnson SR, et al. Three-month FVC change: a trial endpoint for idiopathic pulmonary fibrosis based on individual participant data meta-analysis. Am J Respir Crit Care Med 2022;205:936948.
8. Zampieri FG, Casey JD, Shankar-Hari M, Harrell FE Jr, Harhay MO. Using Bayesian methods to augment the interpretation of critical care trials. An overview of theory and example reanalysis of the alveolar recruitment for acute respiratory distress syndrome trial. Am J Respir Crit Care Med 2021;203:543552.
9. Russell AM, Adamali H, Molyneaux PL, Lukey PT, Marshall RP, Renzoni EA, et al. Daily home spirometry: An effective tool for detecting progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016;194:989997.
10. Noth I, Cottin V, Chaudhuri N, Corte TJ, Johannson KA, Wijsenbeek M, et al.; INMARK trial investigators. Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial. Eur Respir J 2021;58:2001518.
11. Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2020;8:147157.
12. Raghu G, van den Blink B, Hamblin MJ, Brown AW, Golden JA, Ho LA, et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: a randomized clinical trial. JAMA 2018;319:22992307.
13. Aronson KI, Danoff SK, Russell A-M, Ryerson CJ, Suzuki A, Wijsenbeek MS, et al. Patient-centered outcomes research in interstitial lung disease: an official American Thoracic Society research statement. Am J Respir Crit Care Med 2021;204:e3e23.
14. Jacob J, Bartholmai BJ, Rajagopalan S, Kokosi M, Nair A, Karwoski R, et al. Automated quantitative computed tomography versus visual computed tomography scoring in idiopathic pulmonary fibrosis: validation against pulmonary function. J Thorac Imaging 2016;31:304311.
15. Jacob J, Bartholmai BJ, Rajagopalan S, Kokosi M, Nair A, Karwoski R, et al. Mortality prediction in idiopathic pulmonary fibrosis: evaluation of computer-based CT analysis with conventional severity measures. Eur Respir J 2017;49:1601011.
16. Maldonado F, Moua T, Rajagopalan S, Karwoski RA, Raghunath S, Decker PA, et al. Automated quantification of radiological patterns predicts survival in idiopathic pulmonary fibrosis. Eur Respir J 2014;43:204212.
17. Richeldi L, Fernández Pérez ER, Costabel U, Albera C, Lederer DJ, Flaherty KR, et al. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2020;8:2533.

Originally Published in Press as DOI: 10.1164/rccm.202201-0018ED on February 8, 2022

Author disclosures are available with the text of this article at www.atsjournals.org.

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