Clinical Trials In Idiopathic Pulmonary Fibrosis Research Articles

The future of clinical trials in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and limited therapeutic options. A multitude of promising compounds are currently being investigated; however, the design and conductance of late-phase clinical trials in IPF has proven particularly challenging. Despite promising phase 2 data, ziritaxestat, an autotaxin inhibitor, pentraxin-2, an endogenous protein that regulates wound healing and fibrosis, and pamrevlumab, a human monoclonal antibody against connective tissue growth factor, failed to show efficacy in phase 3 trials. Endpoint selection is critical for the design, execution, and success of clinical trials; recently, attention has been paid to the assessment of how patients feel, function, and survive with the aim of aligning scientific objectives and patient needs in IPF. External control arms are control patients that derive from historical randomized controlled trials, registries, or electronic health records. They are increasingly used to assess treatment efficacy in clinical trials owing to their potential to reduce study duration and cost and increase generalizability of findings. Advances in study design, end point selection and statistical analysis, and innovative strategies for more efficient enrolment of study participants have the potential to increase the likelihood of success of late-phase clinical trials in IPF.

Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. While antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objective: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n=875) and validation (n=347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naïve to antifibrotic therapy at time of biomarker measurement (n=555). Results: LCA independently identified two latent classes in both cohorts (p<0.0001). WAP four-disulfide core domain protein 2 (WFDC2) was the most important determinant of class membership across cohorts. Membership in Class 2 was characterized by higher biomarker concentrations and higher risk of death or transplantation (discovery: HR 2.02 [95% CI 1.64-2.48]; p<0.001; validation: HR 1.95 [1.34-2.82]; p<0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (pinteraction=0.030), with a favorable antifibrotic response in Class 2 (HR 0.64 [0.45-0.93]; p=0.018) but not in Class 1 (HR 1.19 [0.77-1.84]; p=0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and response to antifibrotics. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.

Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis.

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.

An adjudication algorithm for respiratory-related hospitalisation in idiopathic pulmonary fibrosis.

There is no standard definition of respiratory-related hospitalisation, a common end-point in idiopathic pulmonary fibrosis (IPF) clinical trials. As diverse aetiologies and complicating comorbidities can present similarly, external adjudication is sometimes employed to achieve standardisation of these events. An algorithm for respiratory-related hospitalisation was developed through a literature review of IPF clinical trials with respiratory-related hospitalisation as an end-point. Experts reviewed the algorithm until a consensus was reached. The algorithm was validated using data from the phase 3 ISABELA trials (clinicaltrials.gov identifiers NCT03711162 and NCT03733444), by assessing concordance between nonadjudicated, investigator-defined, respiratory-related hospitalisations and those defined by the adjudication committee using the algorithm. The algorithm classifies respiratory-related hospitalisation according to cause: extraparenchymal (worsening respiratory symptoms due to left heart failure, volume overload, pulmonary embolism, pneumothorax or trauma); other (respiratory tract infection, right heart failure or exacerbation of COPD); "definite" acute exacerbation of IPF (AEIPF) (worsening respiratory symptoms within 1 month, with radiological or histological evidence of diffuse alveolar damage); or "suspected" AEIPF (as for "definite" AEIPF, but with no radiological or histological evidence of diffuse alveolar damage). Exacerbations ("definite" or "suspected") with identified triggers (infective, post-procedural or traumatic, drug toxicity- or aspiration-related) are classed as "known AEIPF"; "idiopathic AEIPF" refers to exacerbations with no identified trigger. In the ISABELA programme, there was 94% concordance between investigator- and adjudication committee-determined causes of respiratory-related hospitalisation. The algorithm could help to ensure consistency in the reporting of respiratory-related hospitalisation in IPF trials, optimising its utility as an end-point.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Lipid metabolism in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology, which was characterized by irreversible lung function decrease and high mortality. Up till now, only two drugs, i.e. Pirfenidone and Nintedanib,have been approved by Food and Drug Administration (FDA) for therapy of IPF, and the treatment is less effective. Therefore, it is urgent to develop new therapeutic drugs. In recent years, studies had paid attention to lipid metabolism in IPF. In this review, we discussed recent major advances of lipid metabolism, biomarkers and clinical trials in IPF.

Progress of Statin Therapy in the Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by the proliferation of fibroblasts and aberrant accumulation of extracellular matrix. These changes are accompanied by structural destruction of the lung tissue and the progressive decline of pulmonary function. In the past few decades, researchers have investigated the pathogenesis of IPF and sought a therapeutic approach for its treatment. Some studies have shown that the occurrence of IPF is related to pulmonary inflammatory injury; however, its specific etiology and pathogenesis remain unknown, and no effective treatment, with the exception of lung transplantation, has been identified yet. Several basic science and clinical studies in recent years have shown that statins, the traditional lipid-lowering drugs, exert significant antifibrotic effects, which can delay the progression of IPF and impairment of pulmonary function. This article is aimed at summarizing the current understanding of the pathogenesis of IPF, the progress of research on the use of statins in IPF models and clinical trials, and its main molecular targets.

EGFR Signaling in Lung Fibrosis.

In this review article, we will first provide a brief overview of the ErbB receptor–ligand system and its importance in developmental and physiological processes. We will then review the literature regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial–mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans.

SummaryBackgroundα-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.MethodsWe examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).FindingsWe found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells’ being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.InterpretationSenescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.FundingThis work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

Three-Month FVC Change: A Trial Endpoint for Idiopathic Pulmonary Fibrosis Based on Individual Participant Data Meta-analysis.

Rationale: Novel therapies for idiopathic pulmonary fibrosis (IPF) are in development, but there remains uncertainty about the optimal trial endpoint. An earlier endpoint would enable assessment of a greater number of therapies in adaptive trial designs. Objectives: To determine whether short-term changes in FVC, DlCO, and six-minute-walk distance could act as surrogate endpoints to accelerate early-phase trials in IPF. Methods: Individual participant data (IPD) from IPF clinical trials were included in a two-step random-effects meta-analysis to determine whether baseline or 3-month changes in FVC, DlCO, and 6-minute-walk distance were associated with mortality or disease progression in placebo arms. Three-month and 12-month FVC decline endpoints were compared with treatment arm data from antifibrotic studies by meta-regression. Measurements and Main Results: IPD were available from 12 placebo cohorts totaling 1,819 participants, with baseline and 3-month changes in all physiological variables independently associated with poorer outcomes. Treatment data were available from six cohorts with 1,684 participants. For each 2.5% relative decline in FVC over 3 months, there was an associated 15% (adjusted hazard ratio, 1.15; 95% confidence interval [CI], 1.06-1.24; I2 = 59.4%) and 20% (adjusted hazard ratio, 1.20; 95% CI, 1.12-1.28; I2 = 18.0%) increased risk for mortality in untreated and treated individuals, respectively. An FVC change treatment effect was observed between treatment and placebo arms at 3 months (difference in FVC change of 42.9 ml; 95% CI, 24.0-61.8 ml; P < 0.001). Conclusions: IPD meta-analysis demonstrated that 3-month changes in physiological variables, particularly FVC, were associated with mortality among individuals with IPF. FVC change over 3 months may hold potential as a surrogate endpoint in IPF adaptive trials.

VARIABILITY IN CENTRAL AND LOCAL MEASUREMENT OF FVC IN IDIOPATHIC PULMONARY FIBROSIS: AN EXPLORATORY ANALYSIS FROM THE CAPACITY, ASCEND, AND RIFF (COHORT A) TRIALS

VARIABILITY IN CENTRAL AND LOCAL MEASUREMENT OF FVC IN IDIOPATHIC PULMONARY FIBROSIS: AN EXPLORATORY ANALYSIS FROM THE CAPACITY, ASCEND, AND RIFF (COHORT A) TRIALS

Standardization of the 6-min walk test in clinical trials of idiopathic pulmonary fibrosis

The 6-min walk test (6MWT) is an important measure of functional capacity in idiopathic pulmonary fibrosis (IPF) and has been an endpoint of several IPF clinical trials. However, current guidance for the 6MWT offers insufficient advice on standardization, particularly oxygen supplementation, for clinical trials. Three physicians experienced with the 6MWT and IPF developed a standardized protocol for the 6MWT based on existing clinical guidelines and published literature. The protocol comprises guidance on test conditions, pre-defined parameters to measure at specified timepoints, and step-by-step instructions on conducting the test. The standardized test will be evaluated in the large-scale phase 3 ISABELA trials (NCT03711162; NCT03733444). The test is conducted indoors, using standardized equipment, along a flat, straight, 30-m unobstructed corridor; tests for each individual are performed by the same administrators at the same time of day; warm-up prior to testing is prohibited; supplemental oxygen tanks are permitted and moved by the patient in the same manner for each test; precise wording is used to instruct and encourage patients. Contraindications and stopping criteria are specified. Key assessments include: 6-min walk distance, distance walked at 1 and 3 min, the Borg CR10 scale, heart rate, blood pressure, and oxygen desaturation levels. A standardized 6MWT for IPF will enable more reliable comparisons between clinical trials and limit variability, optimizing use as an endpoint. Application of the standardized 6MWT in the ISABELA program will allow its correlation with other clinically important endpoints and may lead to novel composite endpoints for use in future trials.Submission category: Study Design, Statistical Design, Study Protocols.Submission classifications: Clinical study methodology; Clinical trial design; Clinical trials; Pulmonary disease; Pulmonary disease clinical trial; Respiratory medicine.

The importance of interventional timing in the bleomycin model of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5-7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.

Modelling Forced Vital Capacity in Idiopathic Pulmonary Fibrosis: Optimising Trial Design.

IntroductionForced vital capacity is the only registrational endpoint in idiopathic pulmonary fibrosis clinical trials. As most new treatments will be administered on top of standard of care, estimating treatment response will become more challenging. We developed a simulation model to quantify variability associated with forced vital capacity decline.MethodsThe model is based on publicly available clinical trial summary and home spirometry data. A single, illustrative trial setting is reported. Model assumptions are 400 subjects randomised 1:1 to investigational drug or placebo over 52 weeks, 50% of each group receiving standard of care (all-comer population), and a 90-mL treatment difference in annual forced vital capacity decline. Longitudinal profiles were simulated and the impact of varying clinical scenarios evaluated.ResultsPower to detect a significant treatment difference was 87–97%, depending on the analysis method. Repeated measures analysis generally outperformed analysis of covariance and mixed linear models, particularly with missing data (as simulated data were non-linear). A 15% yearly random dropout rate led to 0.6–5% power loss. Forced vital capacity decline-related dropout introduced greater power loss (up to 12%), as did subjects starting/stopping standard of care or investigational drug. Power was substantially lower for a 26-week trial due to the smaller assumed treatment effect at week 26 (sample size would need doubling to reach a power similar to that of a 52-week trial).ConclusionsOur model quantifies forced vital capacity decline and associated variability, with all the caveats of background therapy, permitting robust power calculations to inform future idiopathic pulmonary fibrosis clinical trial design.FundingGalapagos NV (Mechelen, Belgium).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01093-3) contains supplementary material, which is available to authorized users.

Design of Idiopathic Pulmonary Fibrosis Clinical Trials in the Era of Approved Therapies.

The approval of nintedanib and pirfenidone for treatment of idiopathic pulmonary fibrosis has introduced complexity into the design of clinical trials for new drugs on many levels. Placebo-controlled trials excluding background therapy may have issues with feasibility. Those that allow background therapy must consider the possibility of drug-drug interactions with existing therapies, as well as the narrower therapeutic window available to demonstrate incremental slowing of lung function decline with a new agent. While many trial participants will already be on background therapy, a significant number will not, complicating the study design and analysis. Various approaches to improve the efficiency of IPF clinical trials include attempts to validate new endpoints and biomarkers that reflect functional status or quality of life as well as the use of pragmatic and adaptive trial designs.

Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p < 0.001; PRO-C6 p = 0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as ‘slope to month 3’: HIGH slope, slope > 0 vs. LOW slope, slope < =0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p = 0.080); PINP (HR 0.76, p = 0.309); PRO-C6 (HR 1.14, p = 0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR = 1.84, CI 1.03–3.27, p = 0.038, HR = 2.44, CI 1.39–4.31, p = 0.002; HR = 2.19, CI 1.25–3.82, p = 0.006; HR = 2.13 CI 1.21–3.75, p = 0.009 respectively).Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.

A 2-Year Observational Study in Patients Suffering from Idiopathic Pulmonary Fibrosis and Treated with Pirfenidone: A French Ancillary Study of PASSPORT

Background: The European observational, prospective PASSPORT study evaluated the long-term safety of pirfenidone under real-world conditions in idiopathic pulmonary fibrosis (IPF), over up to 2 years following its initiation. Objectives: The FAS (French Ancillary Study) assessed the clinical outcomes of IPF patients participating in PASSPORT (n = 192). Methods: Efficacy data were collected retrospectively and prospectively. The primary efficacy endpoints were: change in percent predicted forced vital capacity (FVC) and change in the distance travelled during the 6-min walk test (6MWD). Results: The mean baseline FVC was 71.7% of predicted value. The mean absolute change in the percentage of predicted FVC was –2.4% and –3.8% at months 12 and 24. The mean change in 6MWD was 8.6 and 3.1 m at months 12 and 24, with a range of 23.4–51.7 m. Acute IPF exacerbation and pulmonary hypertension occurred in 20.0 and 8.4% of patients, respectively. The most common reasons for prematurely discontinuing PASSPORT were adverse drug reactions (ADRs) related to pirfenidone (31.3%), death (11.5%), and disease progression (10.9%). The median progression-free survival was 18.4 months (95% CI 12.9, not estimable). The median exposure was 16.3 months (0.5–28.5). The most frequently reported ADRs leading to pirfenidone discontinuation were decreased weight (4.2%), rash (4.2%), and photosensitivity reactions (3.1%). Conclusions: The efficacy data of FAS are consistent with the efficacy results of published phase III clinical trials in IPF. Approximately one third of IPF patients treated with pirfenidone in real-life settings were still under treatment 2 years after initiation. Safety data are consistent with the known safety profile of pirfenidone.

A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis

Preclinical studies have demonstrated that low-dose carbon monoxide (CO) can abrogate experimental lung fibrosis. To test the therapeutic role of inhaled CO, we designed a clinical study in patients with idiopathic pulmonary fibrosis (IPF). We conducted a multicenter, phase IIa, double-blinded, sham-controlled, clinical trial. Patients with IPF were randomized to treatment with inhaled CO at 100 to 200 parts per million or to inhaled 21%oxygen for 2h daily, twice weekly, for 12weeks. The primary study end point was the difference in change in matrix metalloproteinase-7 (MMP7) serum concentration after 12weeks of treatment. Secondary end points included pulmonary function test measures, 6-min walk distance, rates of adverse events, acute exacerbation, hospitalization and death, and quality of life measures. Fifty-eight subjects were randomized to treatment with inhaled CO (n= 29) or placebo (n= 29). Despite modest increases in CO blood levels, the change in MMP7 concentrations after 12weeks of treatment did not significantly differ between the study arms (MMP7 difference at week 12,-0.90ng/mL; 95%CI,-4.18 to 2.38ng/mL). No differences were observed in physiologic measures, incidence of acute exacerbations, hospitalization, death, or patient-reported outcomes. Importantly, no differences in distribution of adverse events were noted between the treatment arms. Inhaled CO is well tolerated and can be safely administered to patients with IPF in the ambulatory setting; however, inhaled CO did not result in significant changes in study end points. Our findings support testing the efficacy of inhaled therapies in future IPF clinical trials. ClinicalTrials.gov; No.: NCT01214187; URL: www.clinicaltrials.gov.

The disturbed redox-balance in pulmonary fibrosis is modulated by the plant flavonoid quercetin

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed pulmonary redox balance associated with inflammation. To restore this balance, antioxidants are often suggested as therapy for IPF but previous clinical trials with these compounds and their precursors have not been successful in the clinic. The exogenous antioxidant quercetin, which has a versatile antioxidant profile and is effective in restoring a disturbed redox balance, might be a better candidate. The aim of this study was to evaluate the protective effect of quercetin on oxidative and inflammatory markers in IPF. Here, we demonstrate that IPF patients have a significantly reduced endogenous antioxidant defense, shown by a reduced total antioxidant capacity and lowered glutathione and uric acid levels compared to healthy controls. This confirms that the redox balance is disturbed in IPF. Ex vivo incubation with quercetin in blood of both IPF patients and healthy controls reduces LPS-induced production of the pro-inflammatory cytokines IL-8 and TNFα. This anti-inflammatory effect was more pronounced in the blood of the patients. Our pro-fibrotic in vitro model, consisting of bleomycin-triggered BEAS-2B cells, shows that quercetin boosts the antioxidant response, by increasing Nrf2 activity, and decreases pro-inflammatory cytokine production in a concentration-dependent manner. Collectively, our findings implicate that IPF patients may benefit from the use of quercetin to restore the disturbed redox balance and reduce inflammation.

How Do Patients With Idiopathic Pulmonary Fibrosis in the Real World Compare With Eligibility Criteria for Clinical Trials?

SESSION TITLE: Diffuse Lung Disease 2 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Few data are available describing how the characteristics of patients with idiopathic pulmonary fibrosis (IPF) in the real world compare with those eligible for participation in clinical trials. We compared the characteristics of patients with IPF enrolled in the ongoing Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry with eligibility criteria for recent clinical trials in IPF. METHODS: The IPF-PRO Registry includes patients recently diagnosed with IPF at the enrolling site. We compared the characteristics of patients in the IPF-PRO Registry (regardless of whether they were treated with antifibrotic drugs) with eligibility criteria for clinical trials. Data were analyzed from patients enrolled at 18 ILD centers in the US from 5 June 2014 to 24 October 2016 who had complete information on treatment status at baseline defined as status of nintedanib or pirfenidone use prior to, at the time of, or within 30 days after enrollment into the registry. The proportions of patients who met the key eligibility criteria for participation in the INPULSIS trials of nintedanib or the ASCEND trial of pirfenidone at enrollment were analyzed descriptively. RESULTS: Of 419 patients analyzed, 73.9% were male, median age was 70 years, 55.4% were treated with nintedanib or pirfenidone at baseline. At enrollment, median FVC was 69.8% predicted and median DLco was 41.6% predicted. All patients met the inclusion criteria for diagnosis of IPF within the previous 5 or 4 years as required in INPULSIS or ASCEND, respectively. All patients met the age criterion of ≥40 years and 92.8% met the age criteria of 40-80 years as required in INPULSIS and ASCEND, respectively. Of patients with available values at enrollment for FVC (n=371) and DLco (n=360), most patients met the trials’ eligibility criteria for lung function impairment. As required in INPULSIS, 90.3% of patients had FVC ≥50% predicted and 78.1% had DLco between 30% and 79% predicted. As required in ASCEND, 76.5% had FVC between 50% and 90% predicted and 78.6% had DLco between 30% and 90% predicted. Of patients with HRCT data available (n=412), 92.2% had an HRCT performed in the previous 12 months (as required in INPULSIS). Of patients with data available on 6-minute walk test (6MWT) at enrollment (n=281), 94.3% of patients had a 6MWT distance of ≥150 m (as required in ASCEND). CONCLUSIONS: While the designs of registries and randomized controlled trials differ, comparison of registry-enrolled patients to eligibility criteria for clinical trials may provide insights for evaluation of antifibrotic drug prescribing patterns or treatment response in a real-world setting. Although there are similarities in the patient population enrolled in clinical trials and in the IPF-PRO Registry, the IPF-PRO Registry includes a broader population. CLINICAL IMPLICATIONS: The ongoing IPF-PRO Registry will provide insights into the characteristics of patients with IPF, current practice in diagnosis and treatment, and the clinical course of the disease. Assessing the characteristics and the journey for patients with IPF enrolled in the IPF-PRO Registry will provide more information on the real-world population. Primary source of funding: Boehringer Ingelheim Pharmaceuticals, Inc. DISCLOSURE: Victoria Gamerman: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Daniel Culver: Consultant fee, speaker bureau, advisory committee, etc.: Advisory board for steering commitee (Boehringer Ingelheim) Thomas Leonard: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Craig Conoscenti: Employee: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Scott Palmer: Grant monies (from industry related sources): Grant paid by Boehringer Ingelheim to Duke Clinical Research Institute (DCRI) The following authors have nothing to disclose: Margaret Salisbury, Megan Neely, Eric Yow No Product/Research Disclosure Information