Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study

<h3>Background</h3> Pulmonary rehabilitation is associated with benefit in IPF. However, those with advanced disease may have difficulties participating as ventilatory limitation may restrict whole-body exercise. Neuromuscular electrical stimulation (NMES) offers a home-based rehabilitation strategy to enhance muscle strength that is unaffected by ventilatory limitation. We aimed to investigate whether home-based NMES is acceptable to people with IPF, and whether it brings improved physical performance, muscle strength and quality of life to those with severe breathlessness. <h3>Methods</h3> We undertook a parallel-group, randomised placebo-controlled, assessor-blinded feasibility trial with participants randomised (1:1) to usual care (unsupervised home-based exercise training with exercise manual and weekly telephone support) with either placebo or active NMES (30 minutes daily stimulation of quadriceps) for six weeks, with 12 week follow-up and embedded, topic-guided, qualitative interviews. The primary outcomes were feasibility measures: patient flow and recruitment, intervention uptake, assessor and participant blinding, completion rates. Secondary outcomes included clinical measures (six minute walk test (6MWT), accelerometer-measured physical activity levels quadriceps maximum voluntary contraction, rectus femoris cross-sectional area, Kings Brief Interstitial Lung Disease questionnaire) measured at baseline, six and 12 weeks. <h3>Results</h3> Feasibility outcomes are shown in figure 1. The groups were well-matched at baseline, but the intervention group had a higher median (25th, 75th centile) 6MWT distance than the control group (326 (150, 361) versus 240 (130, 325) metres). The assessor remained blinded to group allocation but three (27%) patients in the control group were unblinded. There was no significant between-group differences in device use or home-exercise performance. Due to the small numbers of participants in each group, it was not possible to test for within- or between-group differences. However, there was a trend towards a greater reduction in time spent sedentary in the intervention group. Four patients in the control group experienced a serious adverse event compared to one patient in the intervention group. Analysis of qualitative interviews (n=6) indicated that that the intervention was acceptable and feasible to patients but many found the telephone support and home-exercise diary burdensome. <h3>Conclusion</h3> This study, although acceptable to patients, should not be developed into a definitive trial because of recruitment challenges.

IntroductionIn the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF.MethodsData were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension).ResultsIn the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (− 141.5 mL) and non-advanced IPF (− 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were − 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF.ConclusionsThese results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF.Trial RegistrationsASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-023-02565-3.

Background: Phase 3 trials showed that nintedanib reduced decline in FVC with acceptable safety profiles in mild to moderate idiopathic pulmonary fibrosis (IPF), however, those in advanced IPF remain unclear. Objectives: The aim of the study was to investigate the efficacy and safety of nintedanib in patients with advanced IPF compared with those without. Methods: We reviewed clinical data of 72 IPF patients who have participated in clinical trial for nintedanib in Asan Medical Center. Patients with lung function, FVC Results: Of 72 patients, 36 (50.0%) were in advanced group and 37 (51.4%) have received nintedanib over 24 weeks. Decline in FVC and TLC were reduced at 6 months after treatment (ΔFVC [6 months] = -1.9% [before] vs. -1.3% [after], ΔTLC = -3.2% vs. +0.5%) in mild to moderate IPF, however, only decline in TLC was reduced in advanced IPF (ΔTLC = -4.3% vs. +2.8%). Advanced group showed similar rate of adverse events (AEs) (86.1% [advanced] vs. 83.3% [mild to moderate]) and discontinuation of treatment due to AE (19.4% vs. 22.2%) compared with mild to moderate group, however, advanced group showed tendency to have more serious AE (41.7% vs. 27.8%, p = 0.216). The most common AE was diarrhea (30.6% vs. 44.4%) in both. The mortality was similar (16.7% vs. 13.9%, p = 0.743) and the most common cause of death was acute exacerbation of disease (5.6% vs. 8.3%) in both. Conclusions: Patients in advanced IPF showed tendencies to be stabilized in lung function and have more serious AE compared with those without advanced IPF. Use of nintedanib in advanced IPF need to be further evaluated by prospective study.

Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF. We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival. Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23]). In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF.

Data from controlled clinical studies in patients with more advanced idiopathic pulmonary fibrosis (IPF) could inform clinical practice, but they are limited, since this sub-population is usually excluded from clinical trials. These exploratory post-hoc analyses of the open-label, long-term extension study RECAP (NCT00662038) aimed to assess the efficacy and safety of pirfenidone in patients with more advanced IPF. Patients were categorised according to the extent of lung function impairment at baseline: more advanced (percent predicted FVC <50% and/or DLco <35%) and less advanced (percent predicted FVC ≥50% and DLco ≥35%).Overall, 596 patients with baseline FVC and/or DLco values available were included in the analyses; 187 patients had more advanced disease, and 409 patients had less advanced disease. Mean percent predicted FVC declined throughout 180 weeks of treatment in both more and less advanced disease subgroups. Both subgroups exhibited a similar pattern of adverse events; however, adverse events related to IPF progression were experienced by a higher proportion of patients with more advanced versus less advanced disease. Discontinuation rates due to any reason, adverse events related to IPF progression, or deaths were each higher in the more advanced versus the less advanced disease subgroup.These analyses found that longer-term pirfenidone treatment resulted in a similar rate of lung function decline and safety profile in patients with more advanced versus less advanced IPF, and the data suggest that pirfenidone is efficacious, well tolerated, and a feasible treatment option in patients with more advanced IPF.

Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study - Rationale and study design.

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Background: Currently there is major lack of knowledge on the diagnostic and therapeutic management of patients with Idiopathic Pulmonary Fibrosis (IPF) and lung cancer (LC). Objectives: 1) To identify variations in diagnostic and management strategies across different institutions. 2) To provide rationale for a consensus statement on this issue. Results: This was a joint-survey by ERS Assemblies 8, 11 ad 12. The survey consisted of 25 questions. 494 physicians from 68 different countries and 5 continents responded to the survey. 94% of participants were pulmonologists and 1.8% thoracic surgeons and 1.9% oncologists. 67% and 21.6% were from University and non-University hospitals, respectively and 26.3% were treating > 50 patients with IPF per year. 97.7% involved MDT approaches on diagnosis and management. Regular low-dose HRCT scan was used by 49.5% of the respondents to screen for LC in IPF. PET scan and EBUS bronchoscopy was performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. 83% of respondents continue anti-fibrotics following LC diagnosis; safety precautions during surgical interventions including low-tidal volume were applied by 67%. Stereotactic radiotherapy was used to treat patients with advanced IPF (DLCO Conclusions: Considering the heterogeneous practices in LC-IPF became evident, most respondents called for a consensus statement.

Background: Although phase 3 trials showed significant efficacy and acceptable safety profiles for pirfenidone in mild-to-moderate idiopathic pulmonary fibrosis (IPF), data on advanced IPF are limited. Objectives: The study aimed to evaluate the efficacy and safety of pirfenidone in advanced IPF patients. Methods: The clinical data of 138 IPF patients (advanced group: 27%) treated with pirfenidone were retrospectively reviewed and compared between advanced and non-advanced groups. Advanced IPF was defined as (1) forced vital capacity (FVC) < 50% predicted or (2) diffusing capacity for carbon monoxide < 30% predicted. Results: The mean treatment duration was 51.3 weeks, and lung function analysis was performed in 81 patients (17 in the advanced group). Changes in FVC and total lung capacity (TLC) were significantly reduced at 6 months after treatment in both the advanced (ΔFVC [6 months]: –6.3 [before] vs. 0.7% predicted [after]; ΔTLC: –5.3 vs. 0.8) and non-advanced (ΔFVC: –3.4 vs. 0.5; ΔTLC: –3.1 vs. –0.9) groups. The rate of decline in FVC and TLC was significant before treatment, but not after treatment in the advanced (FVC: –1.27 [before] vs. 0.21% predicted/month [after]; TLC: –0.89 vs. –0.15) and non-advanced (FVC: –0.60 vs. –0.20; TLC: –0.54 vs. –0.17) groups. The advanced group showed a similar rate of adverse events (AEs) (78.4 vs. 88.1%, p = 0.270), but more serious AEs (40.5 vs. 10.9%, p < 0.001) including death (24.3 vs. 5.0%, p = 0.002). Conclusions: In advanced IPF, pirfenidone showed similar efficacy and safety to non-advanced IPF except for serious AEs, which may be due to the advanced status itself.

Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial

BackgroundCurrently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue.MethodsThis was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions.ResultsFour hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (DLCO) <35%) and otherwise operable nonsmall cell lung cancer (NSCLC) by 54% of respondents and doublet platinum regimens and immunotherapy for metastatic disease by 25% and 31.9%, respectively. Almost all participants (93%) replied that a consensus statement for the management of these patients is highly warranted.ConclusionThe diagnosis and management of IPF-lung cancer (LC) is heterogeneous with most respondents calling for a consensus statement.

BackgroundPhase 3 trials have shown that nintedanib reduces the decline in forced vital capacity (FVC) in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF) with acceptable safety profiles; however, its effects on advanced IPF are unclear. We investigated the efficacy and safety of nintedanib in patients with advanced IPF.MethodsProspective data were obtained from 108 IPF patients administered at least one dose of nintedanib. Of these patients, 47.2% had advanced IPF (FVC < 50% predicted, or diffusing capacity < 30% predicted).ResultsThe median treatment duration was 42.2 weeks. Nintedanib significantly reduced the decline rate in both FVC (− 0.55% [before] vs. -0.32% [after] predicted/month, p = 0.020) and total lung capacity (TLC) (− 0.35% vs. -0.06% predicted/month, p < 0.001) in all patients. A significant improvement in FVC decline rate after treatment was also observed in the advanced group (− 0.77% vs. -0.22% predicted/month, p = 0.003), but not in the non-advanced group (− 0.41% vs. -0.33% predicted/month, p = 0.564). Adverse events occurred in 97.2% of the cohort, including diarrhoea (50.0%) and anorexia (45.4%). Following adjustment for treatment duration, no inter-group difference in odds ratio was observed for the occurrence of adverse events. However, the advanced group showed a higher frequency of treatment interruption (68.0% vs. 40.0%), mainly as a result of disease progression (47.1% vs. 36.4%).ConclusionsThe efficacy and safety profiles of nintedanib in the advanced group were comparable to those in the non-advanced group except for a higher frequency of discontinuation, which may be due to the advanced status itself.

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control.

Introduction: Lymphocytes T have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), but their role in advanced disease is not fully explained and remains controversial. Aims: The aim of our study was to investigate subsets of lung tissue lymphocytes T in advanced COPD and IPF patients undergoing transplantation and compare them to healthy lung tissue from donors, who were used as controls. Methods: Lung tissue was obtained from 9 patients with COPD and 9 patients with IPF as well as 7 donor patients. The tissue lymphocytes (Th1, Th2, Th17, Treg, activation markers and differentiation of CD8 cells) were analyzed with flow cytometry and the expression of transcription factors was analyzed by qPCR. Results: The most prominent finding was more than 20-fold increase of Th1 cells in COPD and IPF compared to healthy controls (median 6.8% (IQR 2.7-15.5) and 6.9% (4.2-10,2) respectively vs. 0.28% (0.12-1.06) of lymphocytes, p 0,001). Flow cytometric differences in Th1 were confirmed with upregulation of TBET1 transcription factors. Furthermore, in COPD and IPF patients all CD8 T cell were fully differentiated cytotoxic phenotype (more than 98.7%). The proportions of those cells were also markedly increased (median 12.6% (8.9-22.6) and 15.2% (9.6-27.6) respectively vs. 2.3% (1.0-10.8) of lymphocytes, p 0.013). Conclusions: Our results indicate that the inflammation in advanced COPD and IPF predominantly involves Th1 lymphocytes and CD8+ lymphocytes with the greatest cytotoxic potential. Importantly, in COPD and IPF at a final stage of disease the exaggerated inflammation pattern seems to be highly comparable.

The aim of this study was to evaluate the risk factors for and outcomes of acute exacerbations in patients with advanced idiopathic pulmonary fibrosis (IPF), and to examine the relationship between disease severity and neovascularisation in explanted IPF lung tissue. 55 IPF patients assessed for lung transplantation were divided into acute (n=27) and non-acute exacerbation (n=28) groups. Haemodynamic data was collected at baseline, at the time of acute exacerbation and at lung transplantation. Histological analysis and CD31 immunostaining to quantify microvessel density (MVD) was performed on the explanted lung tissue of 13 transplanted patients. Acute exacerbations were associated with increased mortality (p=0.0015). Pulmonary hypertension (PH) at baseline and acute exacerbations were associated with poor survival (p<0.01). PH at baseline was associated with a significant risk of acute exacerbations (HR 2.217, p=0.041). Neovascularisation (MVD) was significantly increased in areas of cellular fibrosis and significantly decreased in areas of honeycombing. There was a significant inverse correlation between mean pulmonary artery pressure and MVD in areas of honeycombing. Acute exacerbations were associated with significantly increased mortality in patients with advanced IPF. PH was associated with the subsequent development of an acute exacerbation and with poor survival. Neovascularisation was significantly decreased in areas of honeycombing, and was significantly inversely correlated with mean pulmonary arterial pressure in areas of honeycombing.