Figures
- FIGURE 1
Schematic illustration of the published reports of prospective, double-blind, randomised clinical trials over the past 25 years (the time axis is not linear). The size of the spot corresponds to the sample size of the clinical trial.
- FIGURE 2
Natural course of lung function decline in placebo-treated patients with idiopathic pulmonary fibrosis (IPF) from the time of enrolment in clinical trials to 72 weeks. The decline in forced vital capacity (FVC) from baseline is approximately 150–200 mL·year–1 (0.15–0.2 L·year–1). The symbols denote the mean (or median [21, 22]) change from baseline in FVC [16, 17, 21, 22, 24, 26, 31–33, 64] or vital capacity (VC) [14, 28, 29] in the placebo groups of Phase-II and Phase-III clinical trials in patients with IPF. The black line denotes the mean decline in FVC in healthy subjects aged 60 years based on FVC measurements taken between 1987–1989, 1990–1992 and 2011–2013 [65].
Tables
- TABLE 1
Overview of Phase-II and Phase-III trials of investigational treatments for idiopathic pulmonary fibrosis (IPF)
Study name Treatment 1 Treatment 2 Study design Primary endpoint(s) Results IFIGENIA [14] Prednisone + azathioprine + NAC (n=80) Prednisone + azathioprine (n=75) Phase-III, randomised Change in VC and DLCO from baseline at month 12 Significant benefits from triple therapy were demonstrated for both endpoints
Absolute between-group differences for mean change from baseline in VC and DLCO at month 12 were 0.18 L (95% CI: 0.03–0.32; p=0.02) and 0.75 mmol·min−1·kPa−1 (95% CI: 0.27–1.23; p=0.003), respectivelyPANTHER-IPF [15] NAC + prednisone + azathioprine (n=77)# Placebo (n=131) Phase-III, randomised Change in FVC from baseline at week 60 The NAC + prednisone + azathioprine arm was terminated due to an increased rate of death and hospitalisation versus a placebo PANTHER-IPF [16] NAC (n=133) Placebo (n=131) Phase-III, randomised Change in FVC from baseline at week 60 No significant difference was observed between NAC and a placebo for the primary endpoint (mean changes in FVC of −0.18 L and −0.19 L, respectively; p=0.77) Interferon gamma-1b trial [17] Interferon gamma-1b (n=162) Placebo (n=168) Phase-III, randomised Time to disease progression (decline in FVC ≥10% of predicted or increase in P(A–a)O2 of ≥5 mmHg at rest) or death No significant difference was observed between interferon gamma-1b and a placebo for the primary endpoint (median of 439 and 344 days, respectively; p=0.5) INSPIRE [18] Interferon gamma-1b (n=551) Placebo (n=275) Phase-III, randomised Survival Trial was terminated when an interim analysis showed no significant difference between interferon gamma-1b and a placebo for the primary endpoint (HR 1.15; 95% CI: 0.77–1.71; p=0.50) ACE-IPF [19] Warfarin (n=72) Placebo (n=73) Phase-III, randomised Composite of time to death, hospitalisation (non-bleeding, non-elective), or absolute decline in FVC ≥10% of predicted Trial terminated after mean follow-up of 28 weeks, when interim analysis showed higher mortality with warfarin versus a placebo (14 deaths versus 3 deaths; p=0.005) BUILD-1 [20] Bosentan (n=74) Placebo (n=84) Phase-III, randomised Change in 6-MWD from baseline at month 12 No significant difference was observed between bosentan and a placebo for the primary endpoint (mean changes of −52 m and −34 m, respectively; p=0.23) BUILD-3 [21] Bosentan (n=407) Placebo (n=209) Phase-III, randomised Time to worsening of IPF (decline in FVC ≥10% of predicted and decline in DLCO ≥15% of predicted, or acute exacerbation) or death No significant difference was observed between bosentan and a placebo for the primary endpoint (HR 0.85; 95% CI: 0.66–1.10; p=0.21) MUSIC [22] Macitentan (n=119) Placebo (n=59) Phase-II, randomised Change in FVC from baseline at month 12 No significant difference was observed between macitentan and a placebo for the primary endpoint (median change of −0.20 L in both groups) ARTEMIS-IPF [23] Ambrisentan (n=329) Placebo (n=163) Phase-III, randomised Time to disease progression (defined as death, respiratory hospitalisation, or categorical decline in lung function (FVC ≥10% of predicted plus DLCO ≥5% of predicted, or FVC ≥5% of predicted plus DLCO ≥15% of predicted) (event-driven) Trial terminated after interim analysis showed a low likelihood of demonstrating efficacy on the primary endpoint Etanercept trial [24] Etanercept (n=46) Placebo (n=41) Phase-II, randomised Changes in FVC (% predicted), DLCO (% predicted), and P(A–a)O2 (at rest) from baseline at week 48 No significant differences were observed between etanercept and a placebo for the lung function endpoints STEP-IPF [25] Sildenafil (n=89) Placebo (n=91) Phase-III, randomised for 12 weeks followed by 12-week open-label extension ≥20% increase in 6-MWD at week 12 No significant difference was observed between sildenafil and a placebo on the primary endpoint (10% and 7% of patients, respectively; p=0.39) Imatinib trial [26] Imatinib (n=59) Placebo (n=60) Phase-II, randomised for 96 weeks Time to disease progression (defined as decline in FVC from baseline of >10% of predicted) or death No significant difference was observed between imatinib and a placebo on the primary endpoint (HR 1.05; 95% CI: 0.56–1.96; p=0.89) Simtuzumab trial [27] Simtuzumab (n=272) Placebo (n=272) Phase-II, randomised Progression-free survival (defined as death or a categorical decline in FVC (% predicted) from baseline, i.e. ≥10% relative decline and ≥5% absolute decline) Trial was terminated when interim analysis showed no significant difference between simtuzumab and a placebo on progression-free survival (HR 1.13; 95% CI: 0.88–1.45; p=0.33) Pirfenidone trial [28] Pirfenidone (n=72)¶ Placebo (n= 35) Phase-II, randomised, in Japanese patients Change from baseline in lowest SpO2 during a 6-min steady-state exercise test at month 6 Trial terminated when interim analysis showed no significant difference between pirfenidone and a placebo for the primary endpoint at month 6 (increase of 0.64% versus decrease of 0.55%, respectively; p=0.15) Pirfenidone trial [29] Pirfenidone (n=55-108)+ Placebo (n=104) Phase-III, randomised in Japanese patients Original: change from baseline in lowest SpO2 during a 6-min steady-state exercise test at week 52
Revised: change in VC from baseline at week 52Significant benefits were seen with high-dose pirfenidone versus a placebo for change in VC at week 52 (−0.09 L versus −0.16 L; p=0.0416) CAPACITY [30] Pirfenidone (n=87–345)§ Placebo (n=347) Phase-III, randomised (two trials) Change in FVC (% predicted) from baseline at week 72 Significant benefits were observed with pirfenidone (dose: 2403 mg·day−1) versus a placebo for the primary endpoint in CAPACITY-2 (−8.0% versus −12.4%; p=0.001) but not in CAPACITY-1 (−9.0% versus −9.6%, respectively; p=0.50) ASCEND [31] Pirfenidone (n=278)ƒ Placebo (n=277) Phase-III, randomised Change in FVC (% predicted) from baseline at week 52 Significant benefits were observed for pirfenidone versus a placebo for the primary endpoint (p<0.001) TOMORROW [32] Nintedanib (n=85–86)## Placebo (n=85) Phase-II, randomised Annual rate of decline in FVC Reduced FVC decline with nintedanib (150 mg twice daily) versus a placebo (−0.06 L versus −0.19 L; p=0.06 with closed testing procedure; p=0.01 with hierarchical testing procedure) INPULSIS [33] Nintedanib (n=638)¶¶ Placebo (n=423) Phase-III, randomised (two trials) Annual rate of decline in FVC Significant benefits were observed for nintedanib versus a placebo for the primary endpoint in INPULSIS-1 (−114.7 mL versus −239.9 mL; p<0.001) and INPULSIS-2 (−113.6 mL versus −207.3 mL; p<0.001) NAC: N-acetylcysteine; VC: vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; FVC: forced vital capacity; HR: hazard ratio; P(A-a)O2: alveolar to arterial oxygen pressure difference; 6-MWD: 6-min walk distance; SpO2: arterial oxygen saturation measured by pulse oximetry. #: compared with NAC (n=81) and placebo (n=78); ¶: 200–600 mg (three times daily); +: pirfenidone dose: high (n=108), low (n=55); §: pirfenidone dose: 1197 mg·day−1 (n=87), 2403 mg·day−1 (n=345); ƒ: pirfenidone dose: 2403 mg·day−1; ##: nintedanib dose: 50 mg once daily (n=86), 50 mg twice daily (n=86), 100 mg twice daily (n=86), 150 mg twice daily (n=85); ¶¶: nintedanib dose: 150 mg twice daily.
- TABLE 2
Current recommendations for the pharmacological treatment of idiopathic pulmonary fibrosis (IPF) [36]
Agent Guidance# Strength of guidance Warfarin Strong recommendation against use Moderate confidence in effect estimates NAC, prednisone and azathioprine Strong recommendation against use Low confidence in effect estimates NAC monotherapy Conditional recommendation against use Low confidence in effect estimates Bosentan Conditional recommendation against use Low confidence in effect estimates Macitentan Conditional recommendation against use Low confidence in effect estimates Ambrisentan Strong recommendation against use Low confidence in effect estimates Sildenafil Conditional recommendation against use Moderate confidence in effect estimates Imatinib Strong recommendation against use Moderate confidence in effect estimates Anti-acid therapy¶ Conditional recommendation for use Very low confidence in effect estimates Nintedanib Conditional recommendation for use Moderate confidence in effect estimates Pirfenidone Conditional recommendation for use Moderate confidence in effect estimates NAC: N-acetylcysteine; #: Strong recommendation: most patients would want the suggested course of action. Conditional recommendation: the majority of patients would want the suggested course of action. Different choices will be appropriate for different patients depending on individual values and preferences. ¶: Although anti-acid therapy received a conditional recommendation for use in this guideline, this was not based on evidence from prospective randomised controlled trials. No such trials have been conducted and are needed to determine the risk–benefit ratio in patients with IPF without symptomatic gastroesophageal reflux.
Supplementary Material
