INPULSIS-1 vs INPULSIS-2: Key Differences
INPULSIS-1 and INPULSIS-2 were replicate phase 3 trials with identical designs that showed consistent efficacy of nintedanib in slowing FVC decline in IPF, but differed in their secondary endpoint results for acute exacerbations. 1, 2
Trial Design Similarities
Both trials were conducted with the same fundamental structure:
- Identical patient populations: 1,066 patients total enrolled across both studies with clinical diagnosis of idiopathic pulmonary fibrosis 1
- Same randomization scheme: 3:2 ratio to receive nintedanib 150 mg twice daily versus placebo 1, 2
- Same duration: 52-week follow-up period in both trials 1, 2
- Same primary endpoint: Annual rate of decline in forced vital capacity (FVC) 1, 2
- Same key secondary endpoints: Time to first acute exacerbation and change in St. George's Respiratory Questionnaire total score 2
Critical Differences in Results
Primary Endpoint (FVC Decline)
INPULSIS-1:
- Nintedanib: -114.7 ml/year
- Placebo: -239.9 ml/year
- Difference: 125.3 ml (95% CI: 77.7-172.8; P<0.001) 1, 2
INPULSIS-2:
- Nintedanib: -113.6 ml/year
- Placebo: -207.3 ml/year
- Difference: 93.7 ml (95% CI: 44.8-142.7; P<0.001) 2
The magnitude of treatment effect was numerically larger in INPULSIS-1 (125.3 ml vs 93.7 ml), though both were highly statistically significant. 2
Secondary Endpoint: Acute Exacerbations (Major Divergence)
INPULSIS-1:
- No significant difference between nintedanib and placebo groups
- Hazard ratio: 1.15 (95% CI: 0.54-2.42; P=0.67) 1, 2
INPULSIS-2:
- Significant benefit with nintedanib versus placebo
- Hazard ratio: 0.38 (95% CI: 0.19-0.77; P=0.005) 1, 2
This represents the most clinically meaningful difference between the two trials—INPULSIS-2 demonstrated a 62% reduction in acute exacerbations while INPULSIS-1 showed no effect. 2
Pooled Analysis Results
When analyzed together, the trials showed:
- Mortality: No significant benefit (RR 0.70; 95% CI: 0.44-1.11) 1
- Acute exacerbations: No significant benefit (HR 0.64; 95% CI: 0.39-1.05) 1
- FVC decline >10%: Fewer patients with nintedanib (RR 1.16; 95% CI: 1.06-1.27) 1
Safety Profile (Consistent Across Both Trials)
The adverse event profile was remarkably similar:
INPULSIS-1:
- Diarrhea: 61.5% (nintedanib) vs 18.6% (placebo) 2
INPULSIS-2:
- Diarrhea: 63.2% (nintedanib) vs 18.3% (placebo) 2
Both trials showed significantly more adverse events with nintedanib (RR 1.07; 95% CI: 1.03-1.11), but no significant increase in serious adverse events. 1 Diarrhea led to discontinuation in less than 5% of patients in both studies. 2
Clinical Interpretation
The divergent acute exacerbation results likely reflect the unpredictable nature and low event rates of acute exacerbations rather than true differences in drug efficacy. 1 The pooled analysis showing a hazard ratio of 0.64 (not reaching statistical significance) suggests a potential benefit that individual trials were underpowered to detect consistently. 1
The consistent reduction in FVC decline across both trials (primary endpoint met in both) provided the robust evidence base for the ATS/ERS/JRS/ALAT conditional recommendation to use nintedanib in IPF patients. 1 The recommendation emphasized that this puts high value on slowing disease progression measured by FVC decline, while acknowledging the common adverse effect of diarrhea that patients must be informed about when deciding on treatment. 1