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The clinical efficacy of nintedanib in IPF was evaluated in one Phase 2 study (Study 1 [NCT00514683]) and two Phase 3 studies (Study 2 [NCT01335464] and Study 3 [NCT01335477]), involving a total of 1,231 IPF patients. These were randomized, double-blind, placebo-controlled studies comparing nintedanib 150 mg twice daily with placebo for a treatment duration of 52 weeks.
Study 2 and Study 3 shared an identical study design, while Study 1 was highly similar. Patients were randomized to receive nintedanib 150 mg twice daily or placebo at a ratio of 3:2 (1:1 in Study 1) for 52 weeks. Study 1 also included additional treatment arms (50 mg once daily, 50 mg twice daily, and 100 mg twice daily), which are not discussed further herein. The primary endpoint was the annual rate of decline in forced vital capacity (FVC). The time to first acute IPF exacerbation served as a key secondary endpoint in Study 2 and Study 3, and a secondary endpoint in Study 1. Additional secondary endpoints across all studies included the percentage change from baseline in predicted FVC and overall survival.
Eligible patients were required to have a confirmed diagnosis of IPF (per ATS/ERS/JRS/ALAT criteria) within 5 years prior to enrollment. The diagnosis was centrally adjudicated based on radiological findings and, when applicable, histopathological confirmation. Patients must be aged 40 years or older, with an FVC of ≥50% of the predicted value and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) ranging from 30% to 79% of the predicted value. Exclusion criteria included the presence of relevant airway obstruction (i.e., pre-bronchodilator FEV₁/FVC < 0.7), or patients deemed by investigators to be likely candidates for lung transplantation during the study period (patients listed for lung transplantation were eligible for inclusion). Patients with ALT, AST, or bilirubin levels > 1.5 times the upper limit of normal (ULN), known bleeding risk or diathesis, those receiving full-dose anticoagulant therapy, and individuals with a recent history of myocardial infarction or stroke were excluded. Patients were also excluded if they had received other investigational therapies, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks prior to trial entry, or N-acetylcysteine plus prednisone (> 15 mg/day or equivalent) within 2 weeks prior to enrollment. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). The mean age of patients was 67 years, with a mean predicted FVC percentage of 80%.
Based on a random coefficient regression model (adjusted for sex, height, and age), treatment with nintedanib resulted in a statistically significant reduction in the annual rate of FVC decline (mL/year) compared with placebo. The treatment effect on FVC was consistent across all three studies. The results of the annual FVC decline rate analysis in Study 1, Study 2, and Study 3 are as follows: In Study 1, the nintedanib group (n=84) and placebo group (n=83) exhibited annual FVC decline rates of -60 mL/year and -191 mL/year over 52 weeks, respectively, with a treatment difference of 131 mL/year versus placebo (95% CI: 27, 235). In Study 2, the nintedanib group (n=309) and placebo group (n=204) showed annual decline rates of -115 mL/year and -240 mL/year, respectively, representing a treatment difference of 125 mL/year versus placebo (95% CI: 78, 173). In Study 3, the nintedanib group (n=329) and placebo group (n=219) had annual decline rates of -114 mL/year and -207 mL/year, respectively, with a treatment difference of 94 mL/year versus placebo (95% CI: 45, 143).
The time-course plot of changes from baseline in Study 2 demonstrated a separation between the two treatment groups in the mean observed FVC change from baseline at all time points up to Week 52. Similar patterns were observed in Study 1 and Study 3.
The cumulative distribution plot of percentage change from baseline in predicted FVC at Week 52 in Study 2 indicated that the proportion of patients with FVC decline across all lung function categories was lower in the nintedanib group than in the placebo group. Study 3 yielded comparable results.
An acute IPF exacerbation was defined as unexplained worsening or new onset of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest X-ray and/or new parenchymal abnormalities on high-resolution computed tomography (HRCT), in the absence of pneumothorax or pleural effusion, with other causes ruled out. Acute IPF exacerbations were adjudicated in Study 2 and Study 3. In Study 1 (investigator-reported) and Study 3 (adjudicated), nintedanib treatment was associated with a significant reduction in the risk of first acute IPF exacerbation within 52 weeks compared with placebo (hazard ratio [HR]: 0.16, 95% CI: 0.04, 0.71 and HR: 0.20, 95% CI: 0.07, 0.56, respectively). In Study 2 (adjudicated), no significant difference was observed between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
In Study 2 and Study 3, overall survival with nintedanib versus placebo was evaluated as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed throughout the study duration and available follow-up period, regardless of the cause of death or whether patients continued treatment. No statistically significant difference in all-cause mortality was observed (pooled analysis of Study 2 and Study 3: HR 0.70, 95% CI: 0.43, 1.12).
The clinical efficacy of nintedanib in patients with chronic fibrosing ILD and a progressive phenotype was investigated in a randomized, double-blind, placebo-controlled Phase 3 trial (Study 5 [NCT02999178]). A total of 663 patients were randomized at a 1:1 ratio to receive nintedanib 150 mg twice daily or matching placebo for a minimum of 52 weeks. Randomization was stratified by the pattern of fibrosis on HRCT as assessed by central radiological review: 412 patients had a usual interstitial pneumonia (UIP)-like HRCT pattern, and 251 patients had other HRCT fibrosis patterns. Two co-primary populations were defined for the analysis of this trial: all patients (the overall population) and patients with a UIP-like HRCT fibrosis pattern.
The primary endpoint was the annual rate of decline in FVC (mL) over 52 weeks. Additional endpoints included the time to first acute ILD exacerbation and time to death.
Eligible patients had a clinical diagnosis of chronic fibrosing ILD, with relevant fibrosis (> 10% fibrotic features) on HRCT and evidence of progressive clinical manifestations (defined as a ≥ 10% decline in FVC within 24 months prior to screening, a ≥ 5% and < 10% decline in FVC accompanied by symptoms or radiological deterioration, or worsening symptoms plus radiological deterioration). Patients were required to have an FVC of ≥ 45% of the predicted value and a DLCO of 30% to < 80% of the predicted value. Enrollment required that patients had experienced disease progression despite receiving treatment deemed appropriate for their underlying ILD in clinical practice by the investigator.
Exclusion criteria included a diagnosis of IPF, presence of relevant airway obstruction (i.e., pre-bronchodilator FEV₁/FVC < 0.7), or significant pulmonary arterial hypertension. Patients with ALT, AST, or bilirubin levels > 1.5 × ULN, known bleeding risk or diathesis, those receiving full-dose anticoagulant therapy, and individuals with a recent history of myocardial infarction or stroke were excluded. Patients were also excluded if they had received other investigational therapies, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids > 20 mg/day within 4 weeks prior to randomization; cyclophosphamide within 8 weeks prior to randomization; rituximab within 6 months prior to randomization; or prior treatment with nintedanib or pirfenidone.
The majority of patients were Caucasian (74%) or Asian (25%). Patients were predominantly male (54%), with a mean age of 66 years and a mean predicted FVC percentage of 69%. A total of 49% of patients were never-smokers. The underlying clinical ILD diagnoses represented in the trial included hypersensitivity pneumonitis (26%), autoimmune ILDs (26%), idiopathic nonspecific interstitial pneumonia (19%), unclassifiable idiopathic interstitial pneumonia (17%), and other ILDs (12%).
FDA，2024.10
