Efficacy of nintedanib on acute exacerbations reported as serious adverse events in the INPULSIS trials in idiopathic pulmonary fibrosis (IPF)

The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg−1, 5 mg·kg−1, or 15 mg·kg−1) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit–risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo −0.582%, 1 mg·kg−1−0.533%, 5 mg·kg−1−0.799% and 15 mg·kg−1−0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg−1−290 mL, 5 mg·kg−1−370 mL and 15 mg·kg−1−320 mL) compared with placebo (−130 mL). No effect on disease progression,DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg−1group (53.1%) compared with 1 mg·kg−1(15.2%), 15 mg·kg−1(21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.

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Rates and Characteristics of Serious Adverse Events (SAEs) in 210 Patients with Idiopathic Pulmonary Fibrosis (IPF) Treated with Interferon-Gamma 1b (IFN-gamma 1b) in an Open-Label Study

CHEST Journal ◽

10.1378/chest.126.4_meetingabstracts.772s ◽

2004 ◽

Vol 126 (4) ◽

pp. 772S

Author(s):

David A. Zisman ◽

Karen M. Starko ◽

Williamson Z. Bradford

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Interferon Gamma ◽

Open Label ◽

Serious Adverse Events ◽

Ifn Gamma ◽

Open Label Study ◽

Label Study

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Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities

Respiratory Research ◽

10.1186/s12931-021-01695-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ian Glaspole ◽

Francesco Bonella ◽

Elena Bargagli ◽

Marilyn K. Glassberg ◽

Fabian Caro ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Treatment Discontinuation ◽

Efficacy And Safety ◽

Data Set ◽

Proactive Management ◽

Comorbidity Burden ◽

Rate Of Decline ◽

The Impact

Abstract Background Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities. Methods Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age < 75 versus ≥ 75 years, by < 5 and ≥ 5 comorbidities, and by Charlson Comorbidity Index (CCI) ≤ 3 and > 3 at baseline. Results The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and < 75 years (difference 125.2 [90.1, 160.4]) (n = 1364) (p = 0.60 for treatment-by-time-by-subgroup interaction), in patients with < 5 comorbidities (difference: 107.9 [95% CI 65.0, 150.9]) (n = 843) and ≥ 5 comorbidities (difference 139.3 [93.8, 184.8]) (n = 847) (p = 0.41 for treatment-by-time-by-subgroup interaction) and in patients with CCI score ≤ 3 (difference: 106.4 [95% CI 70.4, 142.4]) (n = 1330) and CCI score > 3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%). Conclusions Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy. Trial registration: ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952.

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Initial therapeutic dose of corticosteroid for an acute exacerbation of IPF is associated with subsequent early recurrence of another exacerbation

Scientific Reports ◽

10.1038/s41598-021-85234-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryo Yamazaki ◽

Osamu Nishiyama ◽

Sho Saeki ◽

Hiroyuki Sano ◽

Takashi Iwanaga ◽

...

Keyword(s):

Risk Factors ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Therapeutic Dose ◽

Early Recurrence ◽

Time To Recurrence ◽

Acute Exacerbations ◽

Patient Groups ◽

The Mean ◽

Mean Time

AbstractSome patients with idiopathic pulmonary fibrosis (IPF) undergo recurrent acute exacerbations (AEs). This study aimed to elucidate the risk factors for recurrent AEs of IPF (AE-IPF). Consecutive patients with IPF admitted for their first AE-IPF between January 2008 and December 2018 were retrospectively recruited. Of 63 patients admitted for an AE-IPF and discharged alive, 9 (14.3%) developed a recurrence of AE within 1 year. The mean time to recurrence was 233 ± 103 days. Total doses (mg/month and mg/kg/month) of corticosteroids administered over day 1 to 30 after the AE were significantly higher in patients without recurrences of AE-IPF (5185 ± 2414 mg/month, 93.5 ± 44.0 mg/kg/month) than the doses in patients with recurrences (3133 ± 1990 mg/month, 57.2 ± 37.7 mg/kg/month) (p = 0.02 and p = 0.03, respectively). However, no differences were observed between the total doses of corticosteroids administered over days 31 to 60, 61 to 90, 91 to 120, and 151 to 180 after the AE. Furthermore, differences between the administration rates of immunosuppressive and antifibrotic treatments administered to the 2 patient groups were not significant. An increased total dose of corticosteroid administered over day 1 to 30 after an AE-IPF was associated with a decreased risk of subsequent recurrence of AE-IPF within 1 year after the first AE.

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Efficacy and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis patients: a systematic review and meta-analysis of randomised controlled trials

BMJ Open ◽

10.1136/bmjopen-2021-050004 ◽

2021 ◽

Vol 11 (12) ◽

pp. e050004

Author(s):

Wenjuan Wu ◽

Lingxiao Qiu ◽

Jizhen Wu ◽

Xueya Liu ◽

Guojun Zhang

Keyword(s):

Systematic Review ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Adverse Events ◽

Acute Exacerbation ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Efficacy And Safety ◽

Randomised Controlled

ObjectivesIdiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a common histological pattern of interstitial pneumonia. To analyse the efficacy and safety of pirfenidone in the treatment of IPF, a systematic review and meta-analysis was performed.DesignThis is a meta-analysis study.ParticipantsPatients were diagnosed as IPF.InterventionsUse of pirfenidone.Primary and secondary outcomeProgression-free survival (PFS), acute exacerbation and worsening of IPF and Impact on adverse events.MeasuresThe inverse variance method for the random-effects model was used to summarise the dichotomous outcomes, risk ratios and 95% CIs.ResultsA total of 9 randomised controlled trials with 1011 participants receiving pirfenidone and 912 controls receiving placebo were summarised. The pooled result suggested a statistically significant difference inall-cause mortality after pirfenidone use, with a summarised relative ratio of 0.51 (p<0.01). Longer PFS was observed in patients receiving pirfenidone compared with those who were given placebo (p<0.01). The IPF groups presented a high incidence of adverse events with a pooled relative ratio of 3.89 (p<0.01).ConclusionsPirfenidone can provide survival benefit for patients with IPF. Pirfenidone treatment was also associated with a longer PFS, a lower incidence of acute exacerbation and worsening of IPF.

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Acute exacerbations of idiopathic pulmonary fibrosis and the role of corticosteroids

Breathe ◽

10.1183/20734735.0086-2020 ◽

2020 ◽

Vol 16 (3) ◽

pp. 200086

Author(s):

Christopher J. Brereton ◽

Helen E. Jo

Keyword(s):

Disease Management ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Supportive Care ◽

Disease Process ◽

Evidence Base ◽

Fatal Complication ◽

Acute Exacerbations ◽

International Awareness

An acute exacerbation of idiopathic pulmonary fibrosis (AEIPF) is a potentially fatal complication of an already debilitating disease. Management is currently centred on delivering excellent supportive care and identifying reversible triggers. Despite growing international awareness and collaboration, no effective therapies have been identified. Corticosteroids are often the mainstay of treatment; however, the evidence base for their use is poor. Here, we review our current understanding of the disease process and how to manage it, with a focus on the role of corticosteroid therapy.

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