Tables
- TABLE 1
Major randomised controlled trials of antifibrotics among patients with idiopathic pulmonary fibrosis (IPF)
Phase Patients Intervention Duration Primary outcome(s) Key secondary outcome(s) Nintedanib TOMORROW [25] II 432 Randomised to 1 of 4 doses nintedanib or placebo 52 weeks Annual rate of FVC decline 60 mL·year−1 in nintedanib 150 mg twice daily group versus 190 mL·year−1 in placebo group Lower incidence of AE-IPF, small decrease in SGRQ with nintedanib 150 mg twice daily INPULSUS I [7] III 515 IPF patients Randomised 3:2 ratio to nintedanib 150 mg twice daily or placebo 52 weeks Annual rate of decline FVC −114.7 mL nintedanib versus −239.9 mL placebo (p<0.01) No significant difference in time to first AE or proportion with AE INPULSIS II [7] III 551 IPF patients Randomised 3:2 ratio to nintedanib 150 mg twice daily or placebo 52 weeks Annual rate of decline FVC −113.6 mL nintedanib versus −207.3 mL placebo (p<0.01) Increase in time to first AE in nintedanib group and lower proportion with AE in nintedanib group; significant small increase in SGRQ in nintedanib group Pirfenidone CAPACITY I (004) [26] III 435 IPF patients Randomised 2:1:2 pirfenidone 2403 mg·day−1, pirfenidone 1197 mg·day−1 or placebo 72 weeks Mean decline FVC −8% pirfenidone versus −12.4% placebo (p<0.01) Decreased proportion of patients with ≥10% decline in FVC; prolonged PFS CAPACITY II (006) [26] III 344 IPF patients Randomised 1:1 pirfenidone 2403 mg·day−1 or placebo 72 weeks Mean decline FVC −9% pirfenidone versus −9.6% placebo (p=0.5) Reduced decline in 6MWD ASCEND [8] III 555 with IPF (surgical biopsy required if possible UIP) Randomised to pirfenidone 801 mg three times daily or placebo 52 weeks Proportion of patients with ≥10% decline in FVC or death reduced by 47.9% pirfenidone versus placebo (p<0.01) Decreased decline in 6MWD, improved PFS Combination nintedanib and pirfenidone Safety and pharmacokinetics of nintedanib and pirfenidone in IPF [27] II n=50: 25 patients on pirfenidone ≥3 months; 25 patients not on antifibrotic Nintedanib (100 mg twice daily or 150 mg twice daily) or placebo added to pirfenidone 14 days (100 mg), 28 days (150 mg) Adverse events: 10 out of 21 patients on combination; 9 out of 17 patients on only nintedanib Nintedanib did not affect pharmacokinetics of pirfenidone FVC: forced vital capacity; AE: adverse event; SGRQ: St George's Respiratory Questionnaire; PFS: progression-free survival; 6MWD: 6-min walk distance; UIP: usual interstitial pneumonia.
- TABLE 2
Ongoing clinical trials of antifibrotic medications in non-idiopathic pulmonary fibrosis (IPF) fibrotic interstitial lung diseases (ILDs)
Name Phase Patients Intervention Duration Primary outcome Key secondary outcomes Nintedanib NCT02597933 [91] Safety and Efficacy of 150 mg Nintedanib Twice Daily in Systemic Sclerosis (SENSCIS) III n=580, SSc-pulmonary fibrosis Nintedanib 150 mg twice daily or placebo added to exisiting treatment (stable dose methotrexate, MMF and/or prednisone ≤10 mg daily) 52 weeks Annual rate of decline FVC (mL) Time to all-cause mortality, absolute change dyspnoea score, Modified Rodan Skin Score, SGRQ, change in FVC % pred, change DLCO NCT02999178 [92] Efficacy and Safety of Nintedanib in Patients with Progressive Fibrosing-ILD (INBUILD®) III n=663, progressive fibrosing ILD (see text) Nintedanib 150 mg twice daily or placebo 52 weeks Annual rate of decline FVC Change in K-BILD score, time to first AE or death, time to progression (≥10% decrease FVC or death) NCT03283007 [93] Nintedanib in Lung Transplant Recipients with BOS Grade 1–2 (INFINITx-BOS) III n=80, ≥6 months post-lung transplant with BOS Nintedanib 150 mg twice daily or placebo (patients already on azithromycin) 6 months Rate of decline in FEV1 (mL) over 6 months Change 6MWD, change SGRQ, change in BOS grade, absolute change oxygen saturation Pirfenidone NCT02821689 [94] Pirfenidone in Progressive ILD Associated with Clinically Amyopathic Dermatomyositis IV n=60, CADM with ILD 1800 mg pirfenidone total per day or placebo added on to existing treatment 52 weeks Overall survival Change in HRCT score, change in PFT from baseline NCT03221257 [95] Scleroderma Lung Study III – Combining Pirfenidone with Mycophenolate (SLSIII) II n=150, SSc-pulmonary fibrosis Pirfenidone (target dose 801 mg three times daily) or placebo+MMF (target dose of 1500 mg twice daily) 18 months Change in FVC % pred Change DLCO % pred, change modified Rodan Skin Score, SGRQ, dyspnoea assessment score, change from baseline ILD by computer-quantified HRCT DRKS00009822 [96] Exploring Efficacy and Safety of Pirfenidone for Progressive, Non-IPF Lung Fibrosis (RELIEF) II Collagen vascular disease-associated fibrosis, fibrotic NSIP, cHP, asbestos-related lung fibrosis Pirfenidone (801 mg three times daily) or placebo 48 weeks Absolute change in FVC (%) from baseline to week 48 Time to disease worsening, change in DLCO, 6MWD, SGRQ and EQ-5D NCT03099187 [97] A Study of Pirfenidone in Patients with Unclassifiable Progressive Fibrosing Interstitial Lung Disease II n=252, nonclassifiable ILD (cannot be classified to a specific category of ILD with moderate or high level of confidence with MDD) Pirfenidone (801 mg three times daily) or placebo (stable dose MMF allowed) 24 weeks Rate of decline in FVC over 24 weeks Change in FVC (% pred), change in DLCO (% pred), change in FVC of >5%, change in FVC of >10%, change in 6MWD, change in symptom scores (dyspnoea, cough), SGRQ score, AE-IPF, PFS NCT03385668 [98] Pilot Study of Pirfenidone in Pulmonary Fibrosis with Anti-myeloperoxidase Antibodies (PIRFENIVAS) II 15 patients with+anti-MPO antibody and pulmonary fibrosis (definite or possible UIP or NSIP on HRCT) Pirfenidone (2403 mg total daily dose) (no placebo group) 52 weeks Absolute change FVC % pred Treatment emergent adverse events, change FVC % pred, 6MWD, change % DLCO, PFS NCT02808871 [99] Phase II Study of Pirfenidone in Patients with RA-ILD (TRAIL1) II 270 patients with RA-ILD Pirfenidone 801 mg three times daily or placebo 52 weeks Composite end-point: ≥10% decline in FVC or death Relative decline DLCO (≥15%), relative decline in FVC (≥10%), acute exacerbation, dyspnoea scores, SGRQ NCT03260556 [100] Pirfenidone for Progressive Fibrotic Sarcoidosis (PirFS) IV 60 patients with sarcoidosis and >20% fibrosis on HRCT (stable immunosuppressive medications and/or ≤ 20 mg prednisone/day for 2 months prior allowed) Pirfenidone 801 mg three times daily or placebo 24 months Time until clinical worsening Change in FVC, change in composite physiologic index NCT02958917 [90] Study of Efficacy and Safety of Pirfenidone in Patients with Fibrotic Hypersensitivity Pneumonitis N/A 40 patients with fibrotic hypersensitivity pneumonitis Pirfenidone 801 mg three times daily or placebo 52 weeks Mean change in FVC PFS, ≥5% mean change FVC, acute exacerbation, 6MWD NCT02496182 [89] Pirfenidone in the Chronic Hypersensitivity Pneumonitis Treatment (Picheon) II/III n=60, cHP Pirfenidone (1800 mg or 1200 mg total daily dose) or placebo in addition to conventional therapy (prednisone and azathioprine) 52 weeks Change in FVC Inflammation and fibrosis grade on HRCT (Kazerooni scale), 6MWD, SGRQ score NCT02262299 [101] European Trial of Pirfenidone in BOS, A European Multi-center Study (EPOS) II/III n=80, ≥6 months post-lung transplant with grade 1–3 BOS Pirfenidone 801 mg three times daily or placebo (patients already on azithromycin) 26 weeks Change in FEV1 (in L) over 26 weeks % change in FEV1, % change FVC, change in % pred DLCO, change 6MWD, change BOS grade, hospitalisation, survival SSc: systemic sclerosis; MMF: mycophenolate mofetil; FVC: forced vital capacity; SGRQ: St George's Respiratory Questionnaire; % pred: % predicted; DLCO: diffusing capacity of the lung for carbon monoxide; K-BILD: King's Brief Interstitial Lung Disease questionnaire; AE: adverse event; BOS: bronchiolitis obliterans syndrome; FEV1: forced expiratory volume in 1 s; 6MWD: 6-min walk distance; CADM: clinically amyopathic dermatomyositis; HRCT: high-resolution computed tomography; PFT: pulmonary function test; NSIP: nonspecific interstitial pneumonia; cHP: chronic hypersensitivity pneumonitis; EQ-5D: EuroQuol five-dimensions questionnaire; MDD: multidisciplinary discussion; MPO: myeloperoxidase; UIP: usual interstitial pneumonia; PFS: progression-free survival; RA: rheumatoid arthritis.
Vol 28 Issue 153
Table of Contents
Antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis
