Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial
Authors: Podolanczuk Anna J. , Kim John S. , Cooper Christopher B. , Lasky Joseph A. , Murray Susan , Oldham Justin M. , Raghu Ganesh , Flaherty Kevin R. , Spino Cathie , Noth Imre , Martinez Fernando J. ,   for the PRECISIONS Study Team, Freiheit Elizabeth , Martin-Schwarze Adam , Szparza Ashley , Naik Tanvi , Edwards Rex , Bernard Gordon , Barnbaum Deborah , de Andrade Joao , Knoell Daren , Lindenauer Peter , Rogatko Andre , Temprosa Marinella , Ma Shwu-Fan , Strickland Emma , Sheth Jamie , Lee Joyce , Nickerson-Nutter Cheryl , Lebo David , Belloli Elizabeth , Flaherty Candace , Whelan Timothy , Lento Max , Case Amy , Nwosu Ugonna , Kottmann Matthew , Criner Gerard , Juhas Julie , Mooney Joshua , Smith Jeanette , Limper Andrew , Daley Shannon , Paul Tessy , Althulth Yousef , Newton Chad , Gordon Rhoda Annoh , Strek Mary , Maleckar Spring , Kim Hyun , DeGrote Mandi , Blissell Reba , Kaner Robert , Peters Elizabeth , Morris Alicia , Hamblin Mark , Ward Carime , Boente Ryan , Willig Meghan , Bhatt Nitin , Hood Benjamin , Wilson Cathleen , Chaudhary Sachin , Erickson Heidi , Lengel Haylie , Dilling Daniel , Montesi Sydney , Fromson Caroline , Maher Toby , Nambiar Anoop , Pomroy Hilda , Scholand Mary Beth , Kirkpatrick Chloe , Lancaster Lisa , Del Greco Jim , Weigt Stephen Sam , Callahan Eileen 
Published: December 2022

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