Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec 13;22(1):475.
doi: 10.1186/s12890-022-02281-8.

Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial

Anna J Podolanczuk #  1 , John S Kim #  2 , Christopher B Cooper  3 , Joseph A Lasky  4 , Susan Murray  5 , Justin M Oldham  6 , Ganesh Raghu  7 , Kevin R Flaherty  6 , Cathie Spino  5 , Imre Noth  2 , Fernando J Martinez  8 ; PRECISIONS Study Team
Collaborators, Affiliations

Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial

Anna J Podolanczuk et al. BMC Pulm Med. .

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.

Methods: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.

Discussion: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.

Keywords: Clinical trial; IPF; N-acetylcysteine; Protocol.

PubMed Disclaimer

Conflict of interest statement

Dr. Podolanczuk grants from NIH (NHLBI K23HL140199), grants from American Lung Association, consulting fees from Regeneron, Roche, Imvaria, Boehring Ingelheim, and personal fees from National Association for Continuing Medical Education and EBSCO/DynaMed. Dr. Kim reports grants from NIH (NHLBI K23 award 150301) during the conduct of the study; he also reports grant funding from the Pulmonary Fibrosis Foundation outside the submitted work, and servin on a data and safety monitoring board (unpaid) for convalescent plasma trial for COVID-19. Dr. Cooper reports grants from NIH/NHLBI, Foundation NIH and the COPD Foundation, during the conduct of the study; he also reports personal fees from PulmonX, GlaxoSmithKline, Chiesi, NUVAIRA, MGC Diagnostics and Horizon Therapeutics, outside the submitted work. Dr. Lasky reports grants from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, Veracyte, United Therapeutics, participation on an advisory board for Galecto, and a leadership role in the Pulmonary Fibrosis Foundation. Dr. Murray reports grant funding from the NIH (U24 HL145265) during the conduct of the study. Dr. Oldham reports grants from National Institutes of Health and an issued patent related to this work, along with personal fees from Boehringer Ingelheim, Roche/Genentech, AmMax Bio, Lupin pharmaceuticals and Endeavor BioMedicines unrelated to this work. Dr. Raghu reports receiving research grants from the National Institutes of Health for this trial. Dr Raghu reports receiving fees for serving as an ad hoc discussant from Bristol Myers Squibb and United Therapeutics, receiving consulting fees from Veracyte, receiving fees for reviewing investigator initiated research grant proposals from Boehringer Ingelheim, providing unpaid consulting services for Biogen, Bellerophon Therapeutics, Blade Therapeutics, FibroGen, Nitto, Roche/Genentech, and Novartis, serving (unpaid) on a data and safety monitoring board for Avalyn, and No other potential conflict of interest relevant to this manuscript. Dr. Flaherty reports grants from Boehringer Ingelheim, royalties from UpToDate, consulting fees from Roche/Genentech, Bellerophonm, Respivant, Shionogi, DevPro, Astra Zeneca, Pure Health, Horizon, Fibrogen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, PureTech, Trevi, CSL Behring, Daewong, Dispersol, Immumet, NeRRe Therapeutics, Insilco; he is also the Steering Committee Chair for the Pulmonary Fibrosis Foundation. Dr. Spino reports grants from NHLBI (1R01HL136682, 1U24HL154946, 1R61HL15840, and 1U24HL145265). Dr. Noth reports grant funding from NIH (NHLBI UG3HL145266), royalties from UpToDate, Licensing fees for Protein Markers in IPF, consulting fees from Boehringer Ingelheim and Sanofi, patents for FVC gene signature predictor, pending patent for PCSK6, and serving on data safety monitoring board for Yale COVID trials. Dr. Martinez reports funding from Afferent/Merck, Bayer, Biogen, Nitto, Novartis, Patara/Respivant, Promedior/Roche, Veracyte for serving on a steering committee for ILD studies, consulting fees from Abvie, Boehringer Ingelheim, BMS, Bridge Biotherapeutics, Csl Behring, DevPro, Genentech, IQVIA, Sanofi, Shionogi, twoXAR, Veracyte, honoraria from United Therapeutics, support for attending meetings from Boehringer Ingelheim, Csl Behring, Patara/Respivant, and participation on data safety monitoring boards for Biogen, and Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
Schematic overview of the organizational structure for the PRECISIONS clinical trial. SABER Statistical Analysis of Biomedical and Educational Research unit, NIH National Institute of Health
See this image and copyright information in PMC

References

    1. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378(19):1811–1823. doi: 10.1056/NEJMra1705751. - DOI - PubMed
    1. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11. Lancet Respir Med. 2014;2(7):566–572. doi: 10.1016/S2213-2600(14)70101-8. - DOI - PubMed
    1. King TE, Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–2092. doi: 10.1056/NEJMoa1402582. - DOI - PubMed
    1. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–2082. doi: 10.1056/NEJMoa1402584. - DOI - PubMed
    1. Behr J, Prasse A, Wirtz H, Koschel D, Pittrow D, Held M, Klotsche J, Andreas S, Claussen M, Grohe C et al: Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry. Eur Respir J 2020;56(2). - PubMed

Publication types

MeSH terms

Associated data