Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) Trial

Study Overview
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Brief Summary
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The purpose of this study is to compare the effect of n-acetylcysteine (NAC) plus standard care with matched placebo plus standard of care in patients diagnosed with idiopathic pulmonary fibrosis (IPF) who have the TOLLIP rs3750920 TT genotype. The study will compare the time to a composite endpoint of relative decline in lung function [10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or all-cause mortality] The secondary objectives will be to examine the effect of NAC on the components of the primary composite endpoint, the rates of clinical events, change in physiology, change in health status, and change in respiratory symptoms.

Detailed Description
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This is a multi-center, randomized, double-blind, placebo-controlled trial of NAC or placebo in about 200 participants with IPF with a TOLLIP rs3750920 TT genotype. Eligible participants will be randomized in a 1:1 fashion to NAC or placebo, stratified by stable concomitant IPF therapy use (i.e., pirfenidone or nintedanib administered for at least 6 weeks prior to screening) versus no pirfenidone or nintedanib use. Participants will receive 600 mg NAC orally or matched placebo to take three times daily for 24 months.

Official Title
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Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) Trial

Conditions
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Idiopathic Pulmonary Fibrosis

Intervention / Treatment
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* Drug: N-acetyl cysteine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 40 years of age Diagnosed with IPF according to 2018 ATS/ERS/JRS/ALAT, confirmed by enrolling investigator Signed informed consent If taking pirfenidone or nintedanib, must be on stable dose for at least 6 weeks prior to enrollment visit Confirmed rs3570920 TT TOLLIP genotype Exclusion Criteria: Pregnancy or planning to become pregnant Women of childbearing potential not willing to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of <1% per year during study participation Significant medical, surgical or psychiatric illness that in the opinion of the investigator would affect subject safety, including liver and renal failure Receipt of an investigational drug or biological agent within the previous 4 weeks of the screening visit or 5 times the half-life, if longer Supplemental or prescribed NAC therapy within 60 days of enrollment Listed for lung transplantation at the time of screening History of lung cancer Inability to perform spirometry Forced vital capacity (FVC) less than 45% predicted, using the global lung function index (GLI) equation at Visit 1 Active respiratory infection requiring treatment with antibiotics within 4 weeks of Visit 1

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible participants will be randomized in a 1:1 fashion to NAC or placebo, stratified by stable concomitant IPF therapy use (i.e., pirfenidone or nintedanib administered for at least 6 weeks prior to screening) versus no pirfenidone or nintedanib use. Participants will receive 600 mg NAC orally three times daily or matched placebo for 24 months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-acetylcysteine<br>600 mg oral N-acetylcysteine (NAC) three times daily for 24 months. | Drug: N-acetyl cysteine<br>* 600 mg N-acetylcysteine (NAC) oral tablets three times daily for 24 months.<br>* Other names: NAC;|
| Placebo Comparator: Placebo<br>Placebo tablet three times daily for 24 months. | Drug: Placebo<br>* Matching oral placebo tablet three times daily for 24 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to one of the following composite endpoint criteria: 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplant or death from any cause. | This is a composite endpoint of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplant or death from any cause. Respiratory hospitalizations will be determined by a blinded clinical events classification (adjudication) committee. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to one of the following composite criteria: 10% relative decline in FVC % predicted, first respiratory hospitalization, lung transplant or death from any cause. | This is a composite endpoint of time to 10% relative decline in FVC % predicted, based on the global lung initiative (GLI) reference equation, first respiratory hospitalization, lung transplant or death from any cause. Respiratory hospitalizations will be determined by a blinded clinical events classification (adjudication) committee. | 24 months | 
| Time to death from any cause |  | 24 months | 
| Time to first respiratory hospitalization | Respiratory hospitalizations will be determined by a blinded clinical events classification (adjudication) committee. | 24 months | 
| Time to 10% relative decline in FVC |  | 24 months | 
| Time to lung transplant |  | 24 months | 
| Time to 10% relative decline in FVC %predicted |  | 24 months | 
| Time to first all-cause hospitalization |  | 24 months | 
| Annualized rate of respiratory hospitalizations |  | 24 months | 
| Annualized rate of non-elective, all-cause hospitalizations |  | 24 months | 
| Proportion of participants undergoing lung transplant during follow-up |  | 24 months | 
| Change in FVC from randomization at 12 months |  | 12 months | 
| Change in FVC % predicted from randomization at 12 months |  | 12 months | 
| Change in FVC from randomization at 24 months |  | 24 months | 
| Change in FVC % predicted from randomization at 24 months |  | 24 months | 
| Change in diffusing capacity of the lung for carbon monoxide (DLCO) uncorrected for hemoglobin from randomization at 12 months |  | 12 months | 
| Change in DLCO from randomization at 24 months |  | 24 months | 
| Change in patient reported outcomes scores for the Leicester Cough Questionnaire (LCQ) from randomization at 12 months. |  | 12 months | 
| Change in patient reported outcomes scores for the EuroQoL EQ-5D Questionnaire from randomization at 12 months. |  | 12 months | 
| Change in patient reported outcomes scores for the University of California, San Diego Shortness of Breath (UCSD-SOB) Questionnaire from randomization at 12 months. |  | 12 months | 
| Change in patient reported outcomes scores for the King's Brief Interstitial Lung Disease (K-BILD) Questionnaire from randomization at 12 months. |  | 12 months | 
| Change in patient reported outcomes scores for the St. George's Respiratory Questionnaire (SGRQ) from randomization at 12 months. |  | 12 months | 
| Change in patient reported outcomes scores for the Leicester Cough Questionnaire (LCQ) from randomization at 24 months |  | 24 months | 
| Change in patient reported outcomes scores for the EuroQoL EQ-5D Questionnaire from randomization at 24 months |  | 24 months | 
| Change in patient reported outcomes scores for the University of California, San Diego Shortness of Breath (UCSD-SOB) Questionnaire from randomization at 24 months |  | 24 months | 
| Change in patient reported outcomes scores for the King's Brief Interstitial Lung Disease (K-BILD) Questionnaire from randomization at 24 months |  | 24 months | 
| Change in patient reported outcomes scores for the St. George's Respiratory Questionnaire (SGRQ) from randomization at 24 months |  | 24 months | 
| Proportion of participants with and number of treatment-emergent adverse events, serious adverse events, adverse events leading to discontinuation, and unanticipated problems |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IPF, Pulmonary Fibrosis, n-acetylcysteine, NAC