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Clinical Trial
. 2018 Jun 12;319(22):2299-2307.
doi: 10.1001/jama.2018.6129.

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  1 , Bernt van den Blink  2 , Mark J Hamblin  3 , A Whitney Brown  4 , Jeffrey A Golden  5 , Lawrence A Ho  1 , Marlies S Wijsenbeek  6 , Martina Vasakova  7 , Alberto Pesci  8 , Danielle E Antin-Ozerkis  9 , Keith C Meyer  10 , Michael Kreuter  11 , Hugues Santin-Janin  12 , Geert-Jan Mulder  2 , Brian Bartholmai  13 , Renu Gupta  2 , Luca Richeldi  14
Affiliations
Clinical Trial

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 et al. JAMA. .

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.

Trial registration: clinicaltrials.gov Identifier: NCT02550873.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Raghu reports receipt of grant support to his institution for study costs for the clinical trial and personal fees for consulting during the conduct of the study; and for consulting outside the submitted work: receipt of personal fees and other from Boehringer Ingelheim and Sanofi; personal fees from Promedior, Fibrogen, Patara, and Veracyte; and other from Gilead Sciences, Roche-Genentech, Bristol-Myers Squibb, Bellorophon, and Nitto. Dr Hamblin reports receipt of research grant support from Promedior during the conduct of the study; and outside the submitted work: a clinical trial research grant and a medical education grant from Boehringer Ingelheim, and clinical trial research grants from Genentech, Biogen, Fibrogen, and Global Blood Therapeutics; and personal fees from Boehringer Ingelheim and Genentech for serving as a contracted speaker. Dr Brown reports receipt of grants and personal fees from Promedior during the conduct of the study; and receipt of personal fees from Genentech (advisory board), Theravance Biopharma (consulting fees), and Pilot for IPF (honorarium for curriculum development for CME programs) outside the submitted work. Dr Golden reports receipt of a research support grant from Promedior. Dr Ho has reports receipt of personal fees from Genentech and Boehringer Ingelheim for serving on an advisory board. Dr Wijsenbeek reports receipt of research grants to her institution from Boehringer Ingelheim and Intermune/Hoffman la Roche, personal fees and other from Boehringer Ingelheim and Intermune/Hoffman la Roche; and other from Galapagos. Dr Antin-Ozerkis reports receipt of grants to her institution from Promedior during the conduct of the study and grants from Genentech, Fibrogen, and Boehringer Ingelheim outside the submitted work. Dr Meyer reports receipt of research grants from the National Institutes of Health (NIH), Genentech/Roche, InterMune, Parion, Nivalis, Promedior; and personal fees for speaking engagements from the University of Nebraska and Practice Point Communications and National Jewish Health. Dr Kreuter’s institution has received research support from Roche and Boehringer Ingelheim. Dr Kreuter reports receit of independent grants to his institution and personal fees from Roche and form Boehringer Ingelheim and personal fees for consulting work from AstraZeneca, GlaxoSmithKline, Galapagos, and Chiesi. Dr Santin-Janin reports receipt of other from Venn Life Sciences, the contractor that provided statistical analysis for this study. Dr Mulder reports being a nonexecutive director on the board of Promedior. Dr Bartholmai reports receipt of personal fees from Promedior for serving as a scientific advisor during the conduct of the study; personal fees from Imbio outside the submitted work; and a pending patent (licensee, Mayo Clinic) for systems and methods for analyzing in vivo tissue volumes using medical imaging. Dr Richeldi reports receipt of research grants from InterMune; and personal fees from InterMune, Roche, Fibrogen, and Promedior (advisory board member), Sanofi, ImmuneWorks, Celgene, Nitto, and Bristol-Myers Squibb (consulting), Shionogi (speaker), Boehringer Ingelheim (steering committee), and DynaMed (editorial activity). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in a Trial of Recombinant Human Pentraxin 2 vs Placebo for Idiopathic Pulmonary Fibrosis
IPF indicates idiopathic pulmonary fibrosis. aRandomization ratio of 2:1 for recombinant human pentraxin 2 to placebo. bPatients receiving a stable dosage of pirfenidone or nintedanib.
Figure 2.
Figure 2.. Least-Squares Mean Change (Primary End Point) and Observed Mean Change in Forced Vital Capacity Percentage of Predicted Value From Baseline to Week 28
For panel A, the between-group difference was 2.3 (90% CI, 1.1 to 3.5; P = .001) for all patients, 2.0 (90% CI, −0.2 to 4.1; P = .13) for patients not receiving concurrent pirfenidone or nintedanib, and 2.6 (90% CI, 1.3 to 4.0; P = .002) for patients receiving concurrent pirfenidone or nintedanib. FVC indicates forced vital capacity.
Figure 3.
Figure 3.. Least-Squares Mean Change (Secondary End Point) and Observed Mean Change in 6-Minute Walk Distance From Baseline to Week 28
For panel A, the between-group difference was 31.3 (90% CI, 17.4 to 45.1; P<.001) for all patients, 77.2 (90% CI, 25.2 to 129.3; P = .02) for patients not receiving concurrent pirfenidone or nintedanib, and 21.6 (90% CI, −1.2 to 44.4; P = .12) for patients receiving concurrent pirfenidone or nintedanib.
See this image and copyright information in PMC

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