Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry

doi:10.1016/j.lanepe.2023.100690

. 2023 Jul 28:32:100690.

doi: 10.1016/j.lanepe.2023.100690. eCollection 2023 Sep.

Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry

Sivagurunathan Sutharsan¹, Stefanie Dillenhoefer², Matthias Welsner¹, Florian Stehling³, Folke Brinkmann⁴, Manuel Burkhart⁵, Helmut Ellemunter⁶, Anna-Maria Dittrich^{7

8}, Christina Smaczny⁹, Olaf Eickmeier¹⁰, Matthias Kappler¹¹, Carsten Schwarz¹², Sarah Sieber¹³, Susanne Naehrig¹⁴, Lutz Naehrlich^{15

16}; German CF Registry of the Mukoviszidose e.V. and participating CF sites

Collaborators, Affiliations

Collaborators

German CF Registry of the Mukoviszidose e.V. and participating CF sites:
Klaus Tenbrock, Claus Pfannenstiel, Dirk Steffen, Jochen Meister, Britta Welzenbach, Anette Scharschinger, Markus Kratz, Maike Pincus, Tobias Tenenbaum, Mirjam Stahl, Kerstin Landwehr, Stefanie Dillenhöfer, Hans Kössel, Petra Kaiser, Manfred Käding, Simone Stolz, Stefan Blaas, Jutta Hammermann, Monika Gappa, Antje Schuster, Dana Spittel, Sabine Zirlik, Sabina Schmitt, Florian Stehling, Sivagurunathan Sutharsan, Joachim Bargon, Malte Cremer, Christina Smaczny, Sebastian Fähndrich, Andrea Heinzmann, Lutz Nährlich, Stefan Kuhnert, Sebastian Schmidt, Bettina Wollschläger, Anna Nolde, Inka Held, Wolfgang Kamin, Felix C Ringshausen, Anna-Maria Dittrich, Sabine Wege, Olaf Sommerburg, Norbert Geier, Sara Lisa Fleser, Heinrike Wilkens, Helmut Ellemunter, Michael Lorenz, Paul Vöhringer, Martin Schebek, Christian Timke, Ingrid Bobis, Thomas Nüßlein, Doris Dieninghoff, Ernst Rietschel, Bastian Klinkhammer, Freerk Prenzel, Alexandra Wald, Axel Kempa, Folke Brinkmann, Eva Lücke, Ines Adams, Krystyna Poplawska, Simone Lehmkühler, Monika Bauck, Anne Pfülb, Rainald Fischer, Gudrun Schopper, Susanne Nährig, Matthias Griese, Jörg Grosse, Peter Küster, Birte KinderHolger Köster, Susanne Büsing, Margarethe Pohl, Carsten Schwarz, Andreas Artlich, Alexander Kiefer, Manfred Ballmann, Nikola Gjorgjevski, Markus A Rose, Friederike Ruf, Rolf Mahlberg, Wolfgang Thomas, Ute Graepler, Sebastian Bode, Hilipp Meyn, Josef Rosenecker, Cordula Koerner, Klaus-Michael Keller, Tina Teßmer, Helge Hebestreit, Gerhild Lohse

Affiliations

¹ Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Essen, Germany.
² Department of Pediatric Pulmonology, Cystic Fibrosis Center, University Children's Hospital of Ruhr University Bochum at St. Josef-Hospital, Bochum, Germany.
³ Pediatric Pulmonology and Sleep Medicine, Children's University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Pediatric Pneumology & Allergology, The University of Lübeck, University Medical Center Schleswig-Holstein, Campus Centrum Lübeck, Member of Airway Research Center North (ARCN) of the German Center of Lung Research (DZL), Lübeck, Germany.
⁵ Mukoviszidose Institut gGmbH (MI), Bonn, Germany.
⁶ Medical University of Innsbruck, Cystic Fibrosis Centre Innsbruck, Innsbruck, Austria.
⁷ Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
⁸ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Germany.
⁹ University Hospital Frankfurt/Main, Goethe University, Pneumology and Allergology, Christiane Herzog CF Center Frankfurt/Main, Frankfurt/Main, Germany.
¹⁰ Pediatric Allergology, Pulmonology & Cystic Fibrosis, Christiane Herzog CF Center- Frankfurt a.M., University Hospital Frankfurt a.M., Germany.
¹¹ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany.
¹² Division Cystic Fibrosis, HMU-Health and Medical University Potsdam, Clinic Westbrandenburg, Potsdam, Germany.
¹³ STAT-UP Statistical Consulting & Data Science GmbH, Munich, Germany.
¹⁴ Department of Internal Medicine V, Cystic Fibrosis Center for Adults, University Hospital, Ludwig Maximilian University (LMU) Munich, Germany.
¹⁵ Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany.
¹⁶ Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.

PMID: 37554663
PMCID: PMC10405057
DOI: 10.1016/j.lanepe.2023.100690

Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry

Sivagurunathan Sutharsan et al. Lancet Reg Health Eur. 2023.

. 2023 Jul 28:32:100690.

doi: 10.1016/j.lanepe.2023.100690. eCollection 2023 Sep.

Authors

Collaborators

German CF Registry of the Mukoviszidose e.V. and participating CF sites:
Klaus Tenbrock, Claus Pfannenstiel, Dirk Steffen, Jochen Meister, Britta Welzenbach, Anette Scharschinger, Markus Kratz, Maike Pincus, Tobias Tenenbaum, Mirjam Stahl, Kerstin Landwehr, Stefanie Dillenhöfer, Hans Kössel, Petra Kaiser, Manfred Käding, Simone Stolz, Stefan Blaas, Jutta Hammermann, Monika Gappa, Antje Schuster, Dana Spittel, Sabine Zirlik, Sabina Schmitt, Florian Stehling, Sivagurunathan Sutharsan, Joachim Bargon, Malte Cremer, Christina Smaczny, Sebastian Fähndrich, Andrea Heinzmann, Lutz Nährlich, Stefan Kuhnert, Sebastian Schmidt, Bettina Wollschläger, Anna Nolde, Inka Held, Wolfgang Kamin, Felix C Ringshausen, Anna-Maria Dittrich, Sabine Wege, Olaf Sommerburg, Norbert Geier, Sara Lisa Fleser, Heinrike Wilkens, Helmut Ellemunter, Michael Lorenz, Paul Vöhringer, Martin Schebek, Christian Timke, Ingrid Bobis, Thomas Nüßlein, Doris Dieninghoff, Ernst Rietschel, Bastian Klinkhammer, Freerk Prenzel, Alexandra Wald, Axel Kempa, Folke Brinkmann, Eva Lücke, Ines Adams, Krystyna Poplawska, Simone Lehmkühler, Monika Bauck, Anne Pfülb, Rainald Fischer, Gudrun Schopper, Susanne Nährig, Matthias Griese, Jörg Grosse, Peter Küster, Birte KinderHolger Köster, Susanne Büsing, Margarethe Pohl, Carsten Schwarz, Andreas Artlich, Alexander Kiefer, Manfred Ballmann, Nikola Gjorgjevski, Markus A Rose, Friederike Ruf, Rolf Mahlberg, Wolfgang Thomas, Ute Graepler, Sebastian Bode, Hilipp Meyn, Josef Rosenecker, Cordula Koerner, Klaus-Michael Keller, Tina Teßmer, Helge Hebestreit, Gerhild Lohse

Affiliations

¹ Department of Pulmonary Medicine, University Hospital Essen-Ruhrlandklinik, Adult Cystic Fibrosis Center, University of Duisburg-Essen, Essen, Germany.
² Department of Pediatric Pulmonology, Cystic Fibrosis Center, University Children's Hospital of Ruhr University Bochum at St. Josef-Hospital, Bochum, Germany.
³ Pediatric Pulmonology and Sleep Medicine, Children's University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Pediatric Pneumology & Allergology, The University of Lübeck, University Medical Center Schleswig-Holstein, Campus Centrum Lübeck, Member of Airway Research Center North (ARCN) of the German Center of Lung Research (DZL), Lübeck, Germany.
⁵ Mukoviszidose Institut gGmbH (MI), Bonn, Germany.
⁶ Medical University of Innsbruck, Cystic Fibrosis Centre Innsbruck, Innsbruck, Austria.
⁷ Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
⁸ Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Germany.
⁹ University Hospital Frankfurt/Main, Goethe University, Pneumology and Allergology, Christiane Herzog CF Center Frankfurt/Main, Frankfurt/Main, Germany.
¹⁰ Pediatric Allergology, Pulmonology & Cystic Fibrosis, Christiane Herzog CF Center- Frankfurt a.M., University Hospital Frankfurt a.M., Germany.
¹¹ Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany.
¹² Division Cystic Fibrosis, HMU-Health and Medical University Potsdam, Clinic Westbrandenburg, Potsdam, Germany.
¹³ STAT-UP Statistical Consulting & Data Science GmbH, Munich, Germany.
¹⁴ Department of Internal Medicine V, Cystic Fibrosis Center for Adults, University Hospital, Ludwig Maximilian University (LMU) Munich, Germany.
¹⁵ Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany.
¹⁶ Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.

PMID: 37554663
PMCID: PMC10405057
DOI: 10.1016/j.lanepe.2023.100690

Abstract

Background: Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) improves multiple clinical outcomes in people with cystic fibrosis (pwCF) with at least one F508del allele. This study evaluated the real-world impact of ETI on lung function, nutritional status, pulmonary exacerbation frequency, and sweat chloride concentrations in a large group of pwCF.

Methods: This observational cohort study used data from the German CF Registry for pwCF who received ETI therapy and were followed up for a period of 12 months.

Findings: The study included 2645 pwCF from 67 centres in Germany (mean age 28.0 ± 11.5 years). Over the first year after ETI was initiated, percent predicted forced expiratory volume in 1 s (ppFEV₁) increased by 11.3% (95% confidence interval [CI] 10.8-11.8, p < 0.0001), body mass index (BMI) z-score increased by 0.3 (95% CI 0.3-0.4, p < 0.0001) in individuals aged 12 to <18 years and BMI in adults increased by 1.4 kg/m² (95% CI 1.3-1.4, p < 0.0001), pulmonary exacerbations decreased by 75.9% (p < 0.0001) and mean sweat chloride concentration decreased by 50.9 mmol/L (95% CI -52.6, -49.3, p < 0.0001). Improvements in ppFEV₁ over the first year of therapy were greater in pwCF who had not previously received cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (12.6% [95% CI 11.9-13.4] vs. 9.7% [95% CI 9.0-10.5] in those with prior CFTR modulator treatment.

Interpretation: These real-world data are consistent with the findings of randomised clinical trials, and support the use of ETI as a highly effective treatment option for pwCF who have at least one F508del allele.

Funding: None.

Keywords: Body mass index; Cystic fibrosis; Elexacaftor/tezacaftor/ivacaftor; Lung function; Pulmonary exacerbation; Real-world evidence; Sweat chloride.

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Conflict of interest statement

SS received personal fees or grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Vertex Pharmaceuticals, Boehringer Ingelheim, Corbus Pharmaceuticals, Insmed Germany GmbH and Ionis Pharmaceuticals outside the submitted work. SD participated in the Advance program, financially supported by Vertex Pharmaceuticals. MW received personal fees from Vertex Pharmaceuticals, Chiesi, CSL Behring, and Grifols outside of the submitted work. CSm received personal fees from Vertex Pharmaceuticals outside the submitted work. FS has no conflict of interest. FB has no conflict of interest. MB receives payments from Mukoviszidose Institut gGmbH. AMD received personal fees from Vertex outside of the submitted work and institutional payments from Vertex for the conduct of clinical studies. HE received personal fees Vertex Pharmaceuticals and Insmed Germany GmbH outside the submitted work. CS received personal fees or grants from Chiesi, GlaxoSmithKline, Boehringer Ingelheim, Vertex Pharmaceuticals and GILEAD outside the submitted work. OE received personal fees or grants from Boerhringer Ingelheim, Chiesi, Corbus Pharmaceuticals, GILEAD, Novartis, Vertex Pharmaceuticals outside the submitted work. MK has no conflict of interest. SaS receives payments for statistical analysis of data that were made to STAT-UP Statistical Consulting & Data Science GmbH. SN received institutional payments from Vertex for the conduct of clinical studies. LN received institutional payments from The German Center of Lung research and Vertex Pharmaceuticals for the conduct of clinical studies, was the medical lead of the German CF Registry and the Pharmacovigilance Study manager of the European Cystic Fibrosis Society Patient Registry and received Medial Writing support from Articulate Science.

Figures

**Fig. 1**
**Participant flow chart**. BMI, body mass index; CF, cystic fibrosis; ETI, elexacaftor/tezacaftor/ivacaftor; ppFEV1, percent predicted forced expiratory volume in 1 s.

**Fig. 2**
**Change in percent predicted forced expiratory volume in 1 s.** Change over time before and after initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy (left panel) and change in severity category from the year before to the year after initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy (right panel). ppFEV₁, percent predicted forced expiratory volume in 1 s.

**Fig. 3**
**Change in body mass index**. Changes over time before and after initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy (left panels) and changes in severity category from the year before to the year after initiation of ETI therapy (right panels) for adults (A) and adolescents (B). BMI, body mass index; pwCF, people with cystic fibrosis.

**Fig. 4**
**Change in number of exacerbations**. Change in total number of exacerbations in the year before and the year after initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy (left panel) and change in exacerbation severity category in the year before vs. the year after initiation of ETI therapy (right panel). pwCF, people with cystic fibrosis.

See this image and copyright information in PMC

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[1] Bell S.C., Mall M.A., Gutierrez H., et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):65–124. - PMC - PubMed

[2] Bell S.C., Mall M.A., Gutierrez H., et al. The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2020;8(1):65–124. - PMC - PubMed

[3] Guo J., Garratt A., Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022;21(3):456–462. - PubMed

[4] Guo J., Garratt A., Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022;21(3):456–462. - PubMed

[5] Naehrlich L., Burkhart M., Basler C., et al. Mukoviszidose e.V.; Bonn: 2021. Annual report German CF registry.

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[8] Shteinberg M., Haq I.J., Polineni D., Davies J.C. Cystic fibrosis. Lancet. 2021;397(10290):2195–2211. - PubMed

[9] Birket S.E., Chu K.K., Liu L., et al. A functional anatomic defect of the cystic fibrosis airway. Am J Respir Crit Care Med. 2014;190(4):421–432. - PMC - PubMed

[10] Birket S.E., Chu K.K., Liu L., et al. A functional anatomic defect of the cystic fibrosis airway. Am J Respir Crit Care Med. 2014;190(4):421–432. - PMC - PubMed

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Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry

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Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry

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