Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial

Ganesh Raghu, Bernt Van Den Blink, Mark J. Hamblin, A. Whitney Brown, Jeffrey A. Golden, Lawrence A. Ho, Marlies S. Wijsenbeek, Martina Vasakova, Alberto Pesci, Danielle E. Antin-Ozerkis, Keith C. Meyer, Michael Kreuter, Hugues Santin-Janin, Geert Jan Mulder, Brian Jack Bartholmai, Renu Gupta, Luca Richeldi

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50% and 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25% and 90% predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.

Original languageEnglish (US)
Pages (from-to)2299-2307
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume319
Issue number22
DOIs
StatePublished - Jun 12 2018

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Idiopathic Pulmonary Fibrosis
Vital Capacity
Randomized Controlled Trials
Placebos
Lung
Least-Squares Analysis
Nasopharyngitis
Tomography
Forced Expiratory Volume
Carbon Monoxide
Cough
Lung Diseases
Fatigue
Disease Progression
Therapeutics
Safety
Research
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

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Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial. / Raghu, Ganesh; Van Den Blink, Bernt; Hamblin, Mark J.; Whitney Brown, A.; Golden, Jeffrey A.; Ho, Lawrence A.; Wijsenbeek, Marlies S.; Vasakova, Martina; Pesci, Alberto; Antin-Ozerkis, Danielle E.; Meyer, Keith C.; Kreuter, Michael; Santin-Janin, Hugues; Mulder, Geert Jan; Bartholmai, Brian Jack; Gupta, Renu; Richeldi, Luca.

In: JAMA - Journal of the American Medical Association, Vol. 319, No. 22, 12.06.2018, p. 2299-2307.

Research output: Contribution to journalArticle

Raghu, G, Van Den Blink, B, Hamblin, MJ, Whitney Brown, A, Golden, JA, Ho, LA, Wijsenbeek, MS, Vasakova, M, Pesci, A, Antin-Ozerkis, DE, Meyer, KC, Kreuter, M, Santin-Janin, H, Mulder, GJ, Bartholmai, BJ, Gupta, R & Richeldi, L 2018, '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 - Journal of the American Medical Association, vol. 319, no. 22, pp. 2299-2307. https://doi.org/10.1001/jama.2018.6129
Raghu, Ganesh ; Van Den Blink, Bernt ; Hamblin, Mark J. ; Whitney Brown, A. ; Golden, Jeffrey A. ; Ho, Lawrence A. ; Wijsenbeek, Marlies S. ; Vasakova, Martina ; Pesci, Alberto ; Antin-Ozerkis, Danielle E. ; Meyer, Keith C. ; Kreuter, Michael ; Santin-Janin, Hugues ; Mulder, Geert Jan ; Bartholmai, Brian Jack ; Gupta, Renu ; Richeldi, Luca. / Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 319, No. 22. pp. 2299-2307.
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title = "Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial",
abstract = "IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50{\%} and 90{\%} predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25{\%} and 90{\%} predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2{\%}-6{\%}). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0{\%} men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7{\%}) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90{\%} CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90{\%} CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2{\%} [90{\%} CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1{\%} [90{\%} CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4 [90{\%} CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90{\%} CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18{\%} vs 5{\%}), fatigue (17{\%} vs 10{\%}), and nasopharyngitis (16{\%} vs 23{\%}). CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.",
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T1 - Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial

AU - Raghu, Ganesh

AU - Van Den Blink, Bernt

AU - Hamblin, Mark J.

AU - Whitney Brown, A.

AU - Golden, Jeffrey A.

AU - Ho, Lawrence A.

AU - Wijsenbeek, Marlies S.

AU - Vasakova, Martina

AU - Pesci, Alberto

AU - Antin-Ozerkis, Danielle E.

AU - Meyer, Keith C.

AU - Kreuter, Michael

AU - Santin-Janin, Hugues

AU - Mulder, Geert Jan

AU - Bartholmai, Brian Jack

AU - Gupta, Renu

AU - Richeldi, Luca

PY - 2018/6/12

Y1 - 2018/6/12

N2 - IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50% and 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25% and 90% predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.

AB - IMPORTANCE Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. OBJECTIVE To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. DESIGN, SETTING, AND PARTICIPANTS Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC 50% and 90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [DLCO] 25% and 90% predicted; and distance of 150 m on the 6-minute walk test). Study period was August 2015-May 2017. INTERVENTIONS Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. MAIN OUTCOMES AND MEASURES The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). RESULTS Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of DLCO (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). CONCLUSIONS AND RELEVANCE In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety.

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