Table 1.
Products That Have Failed in Phase II/III Trials in Idiopathic Pulmonary Fibrosis
| Agent | Hypothesized Mechanism of Action | Clinical Trial, Name and clinicaltrials.gov Identifier | Study Design/Sample Size, Planned or Enrolled | Primary Endpoint | Outcome (Reference) |
|---|---|---|---|---|---|
| Warfarin | Anticoagulant | ACE-IPF NCT00957242 | Phase III, randomized, double-blind, placebo-controlled trial; n = 256 | Composite of time to death, hospitalization or ≥10% decline FVC | Terminated due to increased deaths in warfarin arm at interim analysis (134) |
| Bosentan | Dual endothelin-receptor antagonist | BUILD-1 NCT00071461 | Phase III, randomized, double-blind, placebo-controlled trial; n = 158 | Δ 6MWD at 12 mo | No significant difference between groups (135) |
| BUILD-3 NCT00391443 | Phase III, randomized, double-blind, placebo-controlled trial; n = 616 | Time to IPF worsening* or death at 8–32 mo | No significant difference between groups (136) | ||
| Macitentan | Dual endothelin-receptor antagonist | MUSIC NCT00903331 | Phase II, randomized, double-blind, placebo-controlled trial; n = 178 | Δ FVC at 12 mo | No significant difference between groups (137) |
| Ambrisentan | Endothelin A receptor antagonist | ARTEMIS-IPF NCT00768300 | Phase III, randomized, double-blind, placebo-controlled trial; n = 660 | Time to disease progression† or death over 4 yr | Terminated due to futility at interim analysis (138) |
| Interferon (IFN-γ1b) | Immunoregulatory cytokine | NCT00047645 | Phase III, randomized, double-blind, placebo-controlled trial; n = 330 | Progression-free survival‡ over 48 wk | No significant difference between groups (139) |
| INSPIRE NCT00075998 | Phase III, randomized, double-blind, placebo-controlled trial; n = 826 | Overall survival at 90–96 wk | Terminated due to futility at second interim analysis (140) | ||
| Sildenafil | Phosphodiesterase-5 inhibitor | STEP-IPF NCT00517933 | Phase III, randomized, double-blind, placebo-controlled trial; n = 180 | Proportion subjects with ≥20% increase in 6MWD at 12 wk | No significant difference between groups (141) |
| Imatinib mesylate | Tyrosine kinase inhibitor | Imatinib-IPF NCT00131274 | Phase II–III, randomized, double-blind placebo-controlled trial; n = 119 | Time to disease progression§ or death over 96 wk | No significant difference between groups (142) |
| Octreotide | Somatostatin analog | FIBROSAND NCT00463983 | Phase II, open-label study of octreotide only; n = 25 | Treatment failure|| or death over 48 wk | Trend decline in FVC and DlCO compared with historical control subjects (143) |
| Etanercept | TNF-α inhibitor | NCT00063869 | Phase II, randomized, double-blind, placebo-controlled trial; n = 87 | Δ FVC, DlCO% predicted corrected for Hb and P(A–a)O2 at rest at 48 wk | No significant difference between groups (144) |
| Carlumab (CNTO 888) | Anti-CCL2 antibody | NCT00786201 | Phase II, randomized, double-blind, placebo-controlled trial; n = 126 | Δ FVC / 4-wk interval over 52 wk | Terminated due to futility at interim analysis at 24 wk (145) |
| QAX576 | Anti–IL-13 monoclonal antibody | NCT01266135 | Phase II, randomized, double-blind, placebo-controlled trial; n = 60 | Safety, tolerability and Δ FVC at 52 wk | Terminated; no information available |
| CC-930 | JNK inhibitor | NCT01203943 | Phase II, randomized, double-blind, placebo-controlled trial; n = 28 | Type, frequency, severity and relationship of adverse events over 4 wk | Terminated as benefit/ risk profile did not support continuation |
| Prednisone/azathioprine/NAC | Immunosuppression | PANTHER-IPF NCT00650091 | Phase III, randomized, double-blind, placebo-controlled trial; n = 77 on triple therapy vs. n = 78 on placebo | Δ FVC at 60 wk | Interim analysis showed excess numbers of deaths, hospitalizations, and serious adverse events in the triple therapy group (46) |
| NAC | Antioxidant | PANTHER-IPF NCT00650091 | Phase III, randomized, double-blind, placebo-controlled trial; n = 133 on NAC vs. n = 131 on placebo | Δ FVC at 60 wk | No significant difference between groups (64) |
Definition of abbreviations: 6MWD = 6-minute-walk distance; ACE-IPF = Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis; ARTEMIS-IPF = A Placebo-Controlled Trial of Ambrisentan in Idiopathic Pulmonary Fibrosis; BUILD = Bosentan Use in Interstitial Lung Disease; DlCO = diffusing capacity of the lung for carbon monoxide; FIBROSAND = Treatment of Idiopathic Pulmonary Fibrosis with Long Acting Octreotide; INSPIRE = Effect of Interferon Gamma-1b on Survival in Patients with Idiopathic Pulmonary Fibrosis; IPF = idiopathic pulmonary fibrosis; JNK = c-Jun N-terminal kinase; MUSIC = Macitentan for the Treatment of Idiopathic Pulmonary Fibrosis; NAC = N-acetylcysteine; P(A–a)O2 = alveolar to arterial oxygen pressure difference; PANTHER-IPF = Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis; STEP-IPF = Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis; TNF = tumor necrosis factor.
Acute exacerbation of IPF or ≥10% decrease in FVC plus ≥15% decrease in absolute DlCO from baseline (confirmed by two tests conducted ≥4 wk apart).
Respiratory hospitalization or categorical decrease in lung function from baseline (≥10% decrease in FVC plus ≥5% decrease in DlCO or a ≥15% decrease in DlCO plus ≥5% decrease in FVC).
Progression defined as ≥10% decrease in FVC or ≥5 mm Hg increase in P(A–a)O2 at rest from baseline (confirmed by a second test 4–14 wk later).
At least 10% decrease in FVC from baseline.
At least 10% decrease in FVC from baseline between consecutive measurements (with a ≥12-wk interval between them).