Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research

EUSTAR Collaborators

doi:10.1016/j.chest.2022.09.044

Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research

EUSTAR Collaborators

Abstract

Background: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. Research Question: Do enrichment strategies for progressive ILD impact efficacy, representativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database? Study Design and Methods: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline ≥10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. Results: In total, 2,258 patients with SSc-ILD were included: 31.2% of the patients met SENSCIS criteria; 5.8% of the patients met SLS II criteria; 1.6% of the patients met focuSSced criteria, and 67.7% (1,529) of the patients did not meet any criteria. In the first 12 ± 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was –0.1%, in patients who fulfilled criteria from focuSSced was –3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. Interpretation: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.

Original language	English
Journal	Chest
Volume	163
Issue number	3
Pages (from-to)	586-598
Number of pages	13
ISSN	0012-3692
DOIs	https://doi.org/10.1016/j.chest.2022.09.044
Publication status	Published - 03.2023

Funding

This study was partially funded by Boehringer Ingelheim International GmbH (BI), Ingelheim am Rhein, Germany. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for the development of the manuscript. Editorial support was provided by Callan L. Attwell, BSc, BN, of AMICULUM Limited, which was contracted and funded by BI. Editorial support and formatting assistance, in part, were provided by Hannah Cook, PhD, of MediTech Media, UK, and was contracted and funded by BI. This analysis, using the EUSTAR database, was funded by BI. Author contributions: A.-M. H.-V. and O. D. contributed to the literature search, figures, study design, data collection, data analysis, data interpretation, and writing and approved the final version of the review. C. B. contributed to the figures, study design, data analysis, data interpretation, writing and has approved the final version of the review. P. A. and L. P. A. contributed to the literature search, data collection, data interpretation, and writing and approved the final version of the review. L. C. S. C. E. H. M. L. C. M. G. R. P. P. P. P. S. G. V. O. K.-B. and Y. A. contributed to the literature search, data collection, data interpretation, and writing and approved the final version of the review. Role of sponsors: Authors maintained full editorial control over the content of the manuscript and were responsible for all final decisions on manuscript content, for final approval of the version for submission, and of the version for publication. BI was given the opportunity to review the manuscript for medical as well as scientific accuracy and intellectual property considerations, if applicable. EUSTAR collaborators: Alessandra Vacca, Monserrato, Italy: Alessandro Giollo, Verona, Italy; Alexandra Balbir-Gurman, Haifa, Israel; Ana Maria Gheorghiu, Bucharest, Romania; Antonella Marcoccia, Roma, Italy; Ariane Herrick, Salford, United Kingdom; Mislav Radic, Split, Croatia; Bojana Stamenkovic, Nis, Serbia; Branimir Anic, Zagreb, Croatia; Brigitte Granel, Marseille, France; Camillo Ribi, Lausanne, Switzerland; Carlo Francesco Selmi, Rozzano, Italy; Milano Carlos de la Puente, Madrid, Spain; Carolina de Souza Müller, Curitiba -Parana, Brasil: Christopher Denton, London, United Kingdom; Cristiane Kayser, São Paulo, Brasil: Cristina-Mihaela Tanaseanu, Bucharest, Romania; Dominik Majewski, Poznan, Poland; Doron Rimar, Haifa, Israel; Dorota Krasowska, Lublin, Poland; Douglas Veale, Dublin, Ireland; Ulrich Walker, Basel, Switzerland; Eduardo Kerzberg, Buenos Aires, Argentina; Elena Rezus, Romania; Elisabetta Zanatta, Padova, Italy; Elise Siegert, Berlin, Germany Ellen De Langhe, Leuven, Belgium; Fahrettin Oksel, BornovaIzmir, Turkey; Francesca Ingegnoli, Milano, Italy; Francesco Paolo Cantatore, Foggia, Italy; Gabriela Szücs, Debrecen, Hungary; Giovanna Cuomo, Italy; Goda Seskute, Lithuania; VilniusIra Litinsky, Tel-Aviv Israel; Ivan Castellví, Barcelona, Spain; Jadranka Morovic-Vergles, Zagreb, Croatia; Jean Sibilia, Strasbourg, France; Jörg Henes, Tübingen, Germany; Kamal Solanki, Hamilton, New Zealand; Katja Perdan-Pirkmajer, Ljubljana, Slovenia; Kristine Herrmann, Dresden, Germany; Lesley Ann Saketkoo, New Orleans; Lisa Stamp, Christchurch, New Zealand; Luc Mouthon, Paris-Cochin, France; Maria João Salvador, Coimbra, Portugal; Maria Rosa Pozzi, Monza, Italy; Maria Üprus, Tallin, Estonia; Marie Vanthuyne, Bruxelles, Belgium; Merete Engelhart, Hellerup, Denmark; Michaela Köhm, Frankfurt a.M. Germany; Michele Iudici, Geneva, Switzerland; Murat Inanc, Capa Istanbul, Turkey; Nihal Fathi, Assiut Omer, Egypt; Nuri Pamuk, Iasi, Turkey; Paloma García de la Peña Lefebv, Madrid, Spain; Patricia E. Carreira, Madrid, Spain; Dominique Farge Bancel, Paris, France; Luca Moroncini, Ancona, Italy; C. Montecucco, Pavia, Italy; Codrina Ancuta, Iasi, Romania; Cord Sunderkötter, Muenster, Germany; Ulf Müller-Ladner, Bad-Nauheim, Germany; Edoardo Rosato, Roma, Italy; Eugene J. Kucharz, Katowice, Poland; Florenzo Iannone, Bari, Italy; Francesco Del Galdo, Leeds, United Kingdom; Hadi Poormoghim, Teheran, Iran; Ina Kötter, Hamburg, Germany; Jörg Distler, Erlangen, Germany; Maurizio Cutolo, Genova, Italy; Mohammed Tikly, Johannesburg, South Africa; Nemanja Damjanov, Belgrade, Serbia; Nicolas Hunzelmann, Köln, Germany; P. Vlachoyiannopoulos, Athens, Greece; Paul Hasler, Aarau, Switzerland; Piercarlo Sarzi Puttini, Milano, Italy; Piotr Wiland, Wroclaw, Poland; Radim Becvar, Praha, Czech Republic; Sule Yavuz, Istanbul, Turkey; Zbigniew Zdrojewski, Gdansk, Poland; Raffaele Pellerito, Torino, Italy; Rosario Foti, Catania, Italy; Ruxandra Maria Ionescu, Bucharest, Romania; Sabine Adler, Bern, Switzerland; Sarah Kahl, Bad Bramstedt, Germany; Sergey Moiseev, Moscow, Russia; Simon Stebbings, Dunedin, New Zealand; Simona Rednic, Cluj-Napoca, Romania; Simone Negrini, Genova, Italy; Stefan Heitmann, Stuttgart, Germany; Susanne Ullman, Copenhagen, Denmark; Svetlana Agachi, Chisinau, Republic of Moldova; Thierry Martin, Strasbourg, France; Tim Schmeiser, Wuppertal-Elberfeld, Germany; Valeria Riccieri, Roma, Italy; Vanessa Smith, Gent, Belgium; Vera Bernardino, Lisbon, Portugal; Vera Ortiz-Santamaria, Granollers, Spain; Vivien M. Hsu, New Brunswick, NJ; Walid Ahmed Abdel Atty Mohamed, Alexandria, Egypt. Additional information: The e-Figures and e-Tables are available online under “Supplementary Data.”

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1016/j.chest.2022.09.044

Cite this

@article{e179958ff4bd4ae4b01b5cd1747d51e1,

title = "Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research",

abstract = "Background: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. Research Question: Do enrichment strategies for progressive ILD impact efficacy, representativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database? Study Design and Methods: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline ≥10\%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. Results: In total, 2,258 patients with SSc-ILD were included: 31.2\% of the patients met SENSCIS criteria; 5.8\% of the patients met SLS II criteria; 1.6\% of the patients met focuSSced criteria, and 67.7\% (1,529) of the patients did not meet any criteria. In the first 12 ± 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was –0.1\%, in patients who fulfilled criteria from focuSSced was –3.7\%, and in patients who fulfilled criteria from SLS II was 2.3\%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC\% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. Interpretation: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.",

author = "Hoffmann-Vold, \{Anna Maria\} and Cathrine Brunborg and Paolo Air{\`o} and Ananyeva, \{Lidia P.\} and L{\'a}szl{\'o} Czirj{\'a}k and Serena Guiducci and Eric Hachulla and Mengtao Li and Carina Mihai and Gabriela Riemekasten and Sfikakis, \{Petros P.\} and Gabriele Valentini and Otylia Kowal-Bielecka and Yannick Allanore and Oliver Distler and Alessandra Vacca and Alessandro Giollo and Alexandra Balbir-Gurman and Gheorghiu, \{Ana Maria\} and Antonella Marcoccia and Ariane Herrick and Mislav Radic and Bojana Stamenkovic and Branimir Anic and Brigitte Granel and Camillo Ribi and Selmi, \{Carlo Francesco\} and \{Carlos de la Puente\}, Milano and \{de Souza M{\"u}ller\}, Carolina and Christopher Denton and Cristiane Kayser and Tanaseanu, \{Cristina Mihaela\} and Dominik Majewski and Doron Rimar and Dorota Krasowska and Douglas Veale and Ulrich Walker and Eduardo Kerzberg and Elena Rezus and Elisabetta Zanatta and Elise Siegert and \{De Langhe\}, Ellen and Fahrettin Oksel and Francesca Ingegnoli and Cantatore, \{Francesco Paolo\} and Gabriela Sz{\"u}cs and Giovanna Cuomo and Goda Seskute and Kristine Herrmann and \{EUSTAR Collaborators\} and Sarah Kahl",

note = "Publisher Copyright: {\textcopyright} 2022 American College of Chest Physicians",

year = "2023",

month = mar,

doi = "10.1016/j.chest.2022.09.044",

language = "English",

volume = "163",

pages = "586--598",

journal = "Chest",

issn = "0012-3692",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research

AU - Hoffmann-Vold, Anna Maria

AU - Brunborg, Cathrine

AU - Airò, Paolo

AU - Ananyeva, Lidia P.

AU - Czirják, László

AU - Guiducci, Serena

AU - Hachulla, Eric

AU - Li, Mengtao

AU - Mihai, Carina

AU - Riemekasten, Gabriela

AU - Sfikakis, Petros P.

AU - Valentini, Gabriele

AU - Kowal-Bielecka, Otylia

AU - Allanore, Yannick

AU - Distler, Oliver

AU - Vacca, Alessandra

AU - Giollo, Alessandro

AU - Balbir-Gurman, Alexandra

AU - Gheorghiu, Ana Maria

AU - Marcoccia, Antonella

AU - Herrick, Ariane

AU - Radic, Mislav

AU - Stamenkovic, Bojana

AU - Anic, Branimir

AU - Granel, Brigitte

AU - Ribi, Camillo

AU - Selmi, Carlo Francesco

AU - Carlos de la Puente, Milano

AU - de Souza Müller, Carolina

AU - Denton, Christopher

AU - Kayser, Cristiane

AU - Tanaseanu, Cristina Mihaela

AU - Majewski, Dominik

AU - Rimar, Doron

AU - Krasowska, Dorota

AU - Veale, Douglas

AU - Walker, Ulrich

AU - Kerzberg, Eduardo

AU - Rezus, Elena

AU - Zanatta, Elisabetta

AU - Siegert, Elise

AU - De Langhe, Ellen

AU - Oksel, Fahrettin

AU - Ingegnoli, Francesca

AU - Cantatore, Francesco Paolo

AU - Szücs, Gabriela

AU - Cuomo, Giovanna

AU - Seskute, Goda

AU - Herrmann, Kristine

AU - EUSTAR Collaborators

AU - Kahl, Sarah

PY - 2023/3

Y1 - 2023/3

N2 - Background: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. Research Question: Do enrichment strategies for progressive ILD impact efficacy, representativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database? Study Design and Methods: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline ≥10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. Results: In total, 2,258 patients with SSc-ILD were included: 31.2% of the patients met SENSCIS criteria; 5.8% of the patients met SLS II criteria; 1.6% of the patients met focuSSced criteria, and 67.7% (1,529) of the patients did not meet any criteria. In the first 12 ± 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was –0.1%, in patients who fulfilled criteria from focuSSced was –3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. Interpretation: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.

AB - Background: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort. Research Question: Do enrichment strategies for progressive ILD impact efficacy, representativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database? Study Design and Methods: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline ≥10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. Results: In total, 2,258 patients with SSc-ILD were included: 31.2% of the patients met SENSCIS criteria; 5.8% of the patients met SLS II criteria; 1.6% of the patients met focuSSced criteria, and 67.7% (1,529) of the patients did not meet any criteria. In the first 12 ± 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was –0.1%, in patients who fulfilled criteria from focuSSced was –3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression. Interpretation: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.

UR - https://www.scopus.com/pages/publications/85150001158

UR - https://www.mendeley.com/catalogue/92e19174-3d13-3024-aee9-25501c7d5255/

U2 - 10.1016/j.chest.2022.09.044

DO - 10.1016/j.chest.2022.09.044

M3 - Journal articles

C2 - 36244404

AN - SCOPUS:85150001158

SN - 0012-3692

VL - 163

SP - 586

EP - 598

JO - Chest

JF - Chest

IS - 3

ER -

Cohort Enrichment Strategies for Progressive Interstitial Lung Disease in Systemic Sclerosis From European Scleroderma Trials and Research

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