Overview of double-blind, placebo-controlled, randomised clinical trials evaluating different classes of pulmonary arterial hypertension drugs in patients with idiopathic pulmonary fibrosis (IPF) and/or interstitial lung disease (ILD)
| Trial | Patient population | Main inclusion criteria | Intervention | Primary end-point | Results | |
| PDE-5 inhibitors | STEP-IPF trial [32] | 180: 89 sildenafil 91 placebo | IPF at an advanced stage (DLCO <35% predicted) | Sildenafil versus placebo for 12 weeks | Proportion of patients with ≥20% increase on 6MWT | ☒ 10% (sildenafil) versus 7% (placebo) (p=0.39) |
| Soluble guanylate cyclase stimulators | RISE-IIP trial [33] | 147: 73 riociguat 74 placebo | IIP FVC >45% 6MWD 150–450 m WHO functional classes II–IV Pre-capillary PH confirmed by RHC SBP >95 mmHg No signs or symptoms of hypotension | Riociguat versus placebo for 26 weeks | Change from baseline in 6MWT | ☒ Study terminated early due to increased adverse events |
| Endothelin receptor antagonists | BPHIT trial [34] | 60: 40 bosentan 20 placebo | IIP Pre-capillary PH confirmed by RHC | Bosentan versus placebo for 16 weeks | Fall from baseline PVRI ≥20% | ☒ 28.0% (bosentan) versus 28.6% (placebo) (p=0.97) |
| ARTEMIS-IPF trial [35] | 494: 330 ambrisentan 164 placebo | Patients with IPF with minimal or no honeycombing on high-resolution computed tomography scan | Ambrisentan versus placebo | Time to IPF disease progression | ☒ 27.4% (ambrisentan) versus 17.2% (placebo) (p=0.01); trial terminated early due to increased disease progression in intervention group | |
| MUSIC trial [36] | 178: 119 macitentan 59 placebo | IPF of <3 years’ duration A histological pattern of usual interstitial pneumonia on surgical lung biopsy | Macitentan versus placebo for 12 months | Change from baseline in FVC | ☒ −0.2 L (macitentan) versus −0.2 L (placebo) (p=1.00) | |
| Prostanoids | INCREASE trial [37] | 326: 163 inhaled treprostinil 163 placebo | ILD and pre-capillary PH confirmed by RHC 6MWT >100 m | Treprostinil versus placebo for 16 weeks | Change from baseline in distance on 6MWT | ✓□☑ +21.1 m (treprostinil) versus −10.0 m (placebo) (p<0.001) |
| PDE-5 inhibitors on top of approved IPF therapy | INSTAGE trial [38] | 273: 137 nintedanib+sildenafil 136 nintedanib+placebo | IPF at an advanced stage (DLCO <35% predicted) | Nintedanib+sildenafil versus nintedanib+placebo for 24 weeks | Change from baseline in the total score on the SGRQ at week 12 | ☒ −1.28 versus −0.77 points (p=0.72) |
| Efficacy and safety of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH [16] | 177: 88 pirfenidone+sildenafil 89 pirfenidone+placebo | IPF at an advanced stage (DLCO <40% predicted) mPAP ≥20 mmHg with PAWP ≤15 mmHg on RHC or intermediate/high probability of group 3 PH on echocardiography | Pirfenidone+sildenafil versus pirfenidone+placebo for 52 weeks | Proportion of patients with disease progression | ☒ 73% (sildenafil) versus 70% (placebo) (p=0.65) |
PDE: phosphodiesterase; DLCO: diffusing capacity of the lung for carbon monoxide; 6MWT: 6-min walk test; IIP: idiopathic interstitial pneumonia; FVC: forced vital capacity; 6MWD: 6-min walk distance; WHO: World Health Organization; PH: pulmonary hypertension; RHC: right heart catheterisation; SBP: systolic blood pressure; PVRI: pulmonary vascular resistance index; SGRQ: St George's Respiratory Questionnaire; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; ☒: negative trial; ✓□☑: positive trial.