Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF).

IntroductionThere is an unmet need for new treatments for idiopathic pulmonary fibrosis (IPF). The oral preferential phosphodiesterase 4B inhibitor, BI 1015550, prevented a decline in forced vital capacity (FVC) in a phase II study in patients with IPF. This study design describes the subsequent pivotal phase III study of BI 1015550 in patients with IPF (FIBRONEER-IPF). METHODS AND ANALYSIS: In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial. ETHICS AND DISSEMINATION: The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05321069.

Clinical trial simulations in pulmonary fibrosis: patient-focused insights and adaptations.

Background: Patient recruitment and retention are a challenge when conducting clinical trials in patients with pulmonary fibrosis, including idiopathic pulmonary fibrosis and other interstitial lung diseases. This study aimed to understand and address the barriers associated with trial participation for these populations. Methods: Nine patients, nine caregivers and three healthcare professionals participated in virtual simulations of planned phase III trials. During the simulations, participants received information about the trials and either tested a home spirometry device or watched a home spirometry demonstration, before providing their insights in debriefs. The findings were interpreted in advisory boards with representatives from patient organisations and expert investigators. Results: Regarding barriers to participation, patient fatigue and breathlessness were emphasised as posing challenges for travel, visit length and completion of onsite assessments. Lack of information, support and appreciation were also identified as factors that may exacerbate anxiety and negatively affect participant retention rates. Feedback on the home spirometry was mixed, with participants appreciating being able to complete the test at home but worrying about device handling. Based on the insights gained, patient-friendly adaptations were made to the trial protocol and conduct, including remote assessment of patient-reported outcomes, increased visit flexibility, travel support services, patient and caregiver information campaigns, and training of investigators on patients' needs. Conclusions: Participants identified important barriers to participation, which led to patient-friendly changes being made to the planned trials. As a result, participation in the planned trials should be less burdensome, with improved recruitment and retention rates, and ultimately, improved data quality.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Plain language summary: Clinical study of BI 1015550 as a potential treatment for idiopathic pulmonary fibrosis.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the main findings from a trial in people with idiopathic pulmonary fibrosis (also called IPF) that was recently published in the New England Journal of Medicine. IPF is a rare disease, where the lungs become more and more scarred, with breathing and oxygen uptake becoming increasingly difficult. This trial looked at the medication BI 1015550 as a potential treatment for IPF. It compared BI 1015550 to placebo (a dummy drug that does not contain any active ingredients) to investigate the effectiveness of the drug in treating people with IPF. The study also looked at the additional medical issues (referred to as adverse events) reported during the study. Some participants took approved treatments to reduce scarring (nintedanib or pirfenidone), and some did not. WHAT WERE THE RESULTS?: Overall, 147 people with IPF from 22 countries took part in the trial. The results showed that BI 1015550 prevented lung function from decreasing in people with IPF. There was no difference in the percentage of patients with medical issues rated as severe by the study physician with BI 1015550 or placebo. However, more people treated with BI 1015550 had diarrhoea. Among those treated with BI 1015550, 13 participants stopped their treatment due to medical issues, whereas treatment was not stopped due to medical issues for any participants treated with placebo. WHAT DO THE RESULTS MEAN?: These results provide evidence that BI 1015550 prevents lung function from worsening in people with IPF. Further clinical studies will be conducted in the future to test BI 1015550 in a larger group of people with IPF and other forms of lung scarring that get worse over time, and for a longer time period.

Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis.

Introduction: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF). Methods: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs). Results: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs. Conclusions: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.

Understanding diagnostic pathways in systemic sclerosis and systemic sclerosis-associated interstitial lung disease: A retrospective cohort study.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is usually detected in a patient known to have SSc but may be diagnosed prior to SSc. We probed an insurance database to investigate documentation of ILD prior to SSc. Using Optum's Clinformatics® Data Mart Database, we identified patients with an SSc index date between January 1, 2010, and September 30, 2015, based on International Classification of Diseases (ICD)-9-Clinical Modification (CM) codes, ≥2 medical claims associated with SSc on different dates within 1 year, and ≥3 years of continuous enrollment prior to SSc index date (ICD-9-CM cohort). We identified an ICD-10-CM cohort comprising patients with an SSc index date between October 1, 2017, and June 30, 2019, based on ICD-10-CM codes, ≥2 medical claims associated with SSc on different dates within 1 year, and ≥2 years of continuous enrollment prior to SSc index date. ILD was defined as ≥2 medical claims associated with ILD on different dates. The ICD-9-CM and ICD-10-CM cohorts comprised 1779 and 1032 patients, respectively. In these cohorts, respectively, 7.6% and 9.3% of patients had their second medical claim associated with ILD prior to their SSc index date, and 4.3% and 5.6% of patients had their second medical claim associated with ILD >1 year prior to the SSc index date. In this analysis, 4% to 6% of patients with SSc had claims for ILD >1 year prior to a claim for SSc. These data show that SSc can affect the lung early and demonstrate the importance of screening patients with SSc for ILD and patients with ILD for SSc.

Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

RATIONALE: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. OBJECTIVES: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. METHODS: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. MEASUREMENTS AND MAIN RESULTS: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. CONCLUSIONS: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress.

Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and α-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, ß-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible cross-talk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis.

Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, interstitial infiltrates in lung parenchyma and restriction on pulmonary function testing. IPF is the most common and severe of the idiopathic interstitial pneumonias, with most individuals progressing to respiratory failure. Multiple lines of evidence reveal prominent roles for alveolar epithelial cells (AECs) in disease. The current disease paradigm is that ongoing or repetitive injurious stimuli in the presence of a genetic or acquired dysfunctional type II AEC phenotype results in increased AEC injury/apoptosis, deficiencies in regeneration of normal alveolar structure and aberrant lung repair and fibroblast activation, leading to progressive fibrosis. Although the nature of injurious events and processes involved in aberrant repair of the alveolar epithelium are not well understood, ongoing investigations provide hope to better understand mechanisms by which AECs maintain homeostasis or contribute to fibrosis. These strategies may hold promise for developing novel treatment approaches for IPF.

The prevalence of asthma in an NCAA Division I collegiate athletic program.

PURPOSE: To determine the prevalence of asthma among all varsity athletes in a large National Collegiate Athletic Association (NCAA) Division I program. METHODS: We retrospectively reviewed the medical records for all varsity athletes at The Ohio State University (OSU). Data were abstracted from patient charts that contained a Medical Health Questionnaire, annual physical examinations, and medical encounters by the OSU Sports Medicine staff. A diagnosis of asthma was defined by self-report of physician diagnosis as recorded in the medical record. RESULTS: Overall, 130 of 763 (17.0%) athletes had a diagnosis of asthma. Females (67/280 or 23.9%) had a significantly higher prevalence of asthma than males (63/483 or 13.0%) (p value = 0.001). There was no significant difference in the prevalence of asthma between high- and low-ventilation sports. (p value = 0.201). CONCLUSIONS: The prevalence of asthma among varsity athletes at The Ohio State University is 17.0%, which is significantly higher than the reported prevalence of asthma in the general United States population between 18 to 24 years of age. More females had asthma in our study population than males. These data will allow for future studies and development of focused screening programs of collegiate athletes.