Dataset Information

A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

ABSTRACT: INTRODUCTION:Components of the hedgehog signaling pathway are upregulated in patients with idiopathic pulmonary fibrosis (IPF). Vismodegib, a small-molecule inhibitor of hedgehog signaling, when used in combination with currently available antifibrotic therapy, may be more efficacious than antifibrotics alone. The objective of this study was to evaluate the safety and tolerability of vismodegib plus pirfenidone in patients with IPF. METHODS:Twenty-one patients were enrolled in a phase 1b open-label trial to receive vismodegib 150 mg plus pirfenidone 2403 mg/day once daily. Key endpoints were safety, tolerability, and pharmacokinetics. Exploratory endpoints included change from baseline to week 24 in % predicted forced vital capacity (FVC) and University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) scores, as well as pharmacodynamic changes in hedgehog biomarker C-X-C motif chemokine ligand 14 (CXCL14). RESULTS:All patients reported at least one treatment-emergent adverse event (AE), most frequently muscle spasms (76.2%). Serious AEs were reported in 14.3% of patients; one event of dehydration was considered related to vismodegib. One patient died due to IPF progression, unrelated to either treatment. More patients discontinued vismodegib than pirfenidone (42.9% vs. 33.3%, respectively). Changes from baseline to week 24 in % predicted FVC and UCSD-SOBQ scores were within known endpoint variability. In contrast to findings in basal cell carcinoma, vismodegib had no effect on circulating CXCL14 levels. CONCLUSION:The safety profile was generally consistent with the known profiles of both drugs, with no new safety signals observed in this small cohort. There was no pharmacodynamic effect on CXCL14 levels. Future development of vismodegib for IPF may be limited due to tolerability issues. TRIAL REGISTRATION:ClinicalTrials.gov NCT02648048. Plain language summary available for this article. FUNDING:F. Hoffmann-La Roche Ltd. and Genentech, Inc.

SUBMITTER: Prasse A

PROVIDER: S-EPMC6967289 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

Prasse Antje A Ramaswamy Murali M Mohan Shaun S Pan Lin L Kenwright Andrew A Neighbors Margaret M Belloni Paula P LaCamera Peter P PP

Pulmonary therapy 20190719 2

<h4>Introduction</h4>Components of the hedgehog signaling pathway are upregulated in patients with idiopathic pulmonary fibrosis (IPF). Vismodegib, a small-molecule inhibitor of hedgehog signaling, when used in combination with currently available antifibrotic therapy, may be more efficacious than antifibrotics alone. The objective of this study was to evaluate the safety and tolerability of vismodegib plus pirfenidone in patients with IPF.<h4>Methods</h4>Twenty-one patients were enrolled in a p ...[more]

PMID: 32026407

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Project description:IntroductionPIPF-002 was a phase 2, multicenter, open-label study of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) or other types of pulmonary fibrosis (PF). PIPF-002 terminated after pirfenidone became commercially available in the United States. The goal of PIPF-002 was to characterize the long-term safety of pirfenidone in these patients.MethodsBetween August 2003 and September 2006, 83 patients (IPF: 81, PF: 2) enrolled. Patients received pirfenidone in three divided doses daily, with the maintenance dose and schedule determined by enrollment group assignment. Treatment continued until patient withdrawal or study termination (2015). Treatment-emergent adverse events (TEAEs) were assessed by descriptive statistics.ResultsAt baseline, median age was 70 years, mean percent predicted forced vital capacity was 67.7%, 33.7% of patients had cardiac disorders, 51.8% had gastroesophageal reflux disease, and 63.9% were receiving concomitant prednisone. Median pirfenidone dose and exposure duration were 2400 mg/day and 3.0 years, respectively. Cumulative total exposure was 279.7 patient-exposure years (PEY). Most patients (98.8%) reported ≥ 1 TEAE, with an overall incidence rate of 460.5 per 100 PEY. The most frequent TEAEs (incidence rate per 100 PEY) were nausea (23.6), IPF progression (16.1), fatigue (11.8), dyspnea (11.4), upper respiratory tract infection (11.4), and cough (10.7). Serious TEAEs were reported in 49 patients; the most frequent serious TEAEs were IPF progression and pneumonia. The most common reason for discontinuation was TEAEs (35 patients; 12.5 patients per 100 PEY), most frequently IPF progression and nausea. Overall, 21 patients died (7.5 per 100 PEY); 16 deaths were IPF-related.ConclusionsLong-term safety and tolerability of pirfenidone findings in this study were consistent with the known safety profile of pirfenidone; no new safety signals were identified. These data support the continued use of pirfenidone in patients with IPF.FundingF. Hoffmann-La Roche Ltd./Genentech, Inc.Trial registrationClinicalTrials.gov identifier, NCT00080223. Plain language summary available for this article.

Project description:Idiopathic pulmonary fibrosis (IPF) lacks effective treatment. Pirfenidone has been used to treat IPF patients. N-acetylcysteine (NAC) exerts antioxidant and antifibrotic effects on IPF cases.This study is a double-blind, modified placebo-controlled, randomized phase II trial of pirfenidone in Chinese IPF patients. We randomly assigned the enrolled Chinese IPF patients with mild to moderate impairment of pulmonary function to receive either oral pirfenidone (1800 mg per day) and NAC (1800 mg per day) or placebo and NAC (1800 mg per day) for 48 weeks. The primary endpoints were the changes in forced vital capacity (FVC) and walking distance and the lowest SPO2 during the 6-minute walk test (6MWT) at week 48. The key secondary endpoint was the progression-free survival time. This study is registered in ClinicalTrials.gov as number NCT01504334.Eighty-six patients were screened, and 76 cases were enrolled (pirfenidone + NAC: 38; placebo + NAC: 38). The effect of pirfenidone treatment was significant at the 24th week, but this effect did not persist to the 48th week. At the 24th week, the mean decline in both FVC and ΔSPO2 (%) during the 6MWT in the pirfenidone group was lower than that in the control group (-0.08 ± 0.20 L vs -0.22 ± 0.29 L, P = 0.02 and -3.44% ± 4.51% vs -6.29% ± 6.06%, P = 0.03, respectively). However, there was no significant difference between these 2 groups at the 48th week (-0.15 ± 0.25 L vs -0.25 ± 0.28 L, P = 0.11 and -4.25% ± 7.27% vs -5.31% ± 5.49%, P = 0.51, respectively). The pirfenidone treatment group did not achieve the maximal distance difference on the 6MWT at either the 24th or the 48th week. But pirfenidone treatment prolonged the progression-free survival time in the IPF patients (hazard ratio = 1.88, 95% confidence interval: 1.092-3.242, P = 0.02). In the pirfenidone group, the adverse event (AE) rate (52.63%) was higher than that in the control group (26.3%, P = 0.03). Rash was more common in the pirfenidone group (39.5% vs 13.2%, P = 0.02).Compared with placebo combined with high-dose NAC, pirfenidone combined with high-dose NAC prolonged the progression-free survival of Chinese IPF patients with mild to moderate impairment of pulmonary function. (ClinicalTrials.gov number, NCT01504334).

Project description:Background: Pirfenidone is an anti-fibrotic agent used to treat patients with idiopathic pulmonary fibrosis (IPF). Managing adverse drug events and ensuring compliance with pirfenidone treatment for a prolonged period are important to reduce the rate of disease progression. To maximize the benefits of pirfenidone treatment, we established and evaluated an ambulatory care pharmacy practice, a model of pharmacist-physician collaborative management, for patients receiving pirfenidone. Methods: We conducted a retrospective chart review of 76 consecutive patients treated with pirfenidone in the Kobe City Medical Center General Hospital, Japan, between January 2012 and January 2019. The first group (61 patients) received pirfenidone treatment as conventional management, whereas the second group (15 patients) started pirfenidone based on collaborative pharmacist-physician management. The drug discontinuation rate and time to drug discontinuation were compared between the groups. To analyze factors associated with pirfenidone discontinuation, we used a multivariate Cox regression analysis to evaluate the baseline characteristics of patients, including those receiving the collaborative management. Clinical outcomes were compared using a propensity score matched analysis. Results: In the collaborative management group, pharmacists made 56 suggestions, including suggestions for supportive care (51 suggestions), to the physicians. Among these suggestions, 52 were accepted by the physicians. The discontinuation rates at 3 [6.7% (1/15) vs. 26.2% (16/61)] and 6 [9.1% (1/11) vs. 36.1% (22/61)] months were lower in the collaborative management group than in the conventional management group. Multivariate analysis revealed that collaborative management [hazard ratio (HR) 0.34, 95% CI 0.08-0.96, p = 0.041] and predicted baseline forced vital capacity <60% (HR 2.13, 95% CI 1.17-3.85, p = 0.015) were significantly associated with pirfenidone discontinuation. The time to drug discontinuation was also significantly longer in the collaborative management group than in the conventional management group (p = 0.034, log-rank test). Propensity score matched analysis confirmed a significant correlation between collaborative management and drug discontinuation time (HR 0.20, 95% CI 0.03-0.84, p = 0.027). Conclusions: We established an ambulatory care pharmacy practice for out-patients with IPF receiving pirfenidone. The results suggest that collaborative management may help prevent pirfenidone discontinuation compared with conventional management.

Dataset Information

A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

Publications

A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

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