INPULSIS Trials

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Richeldi L, et al. "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis". The New England Journal of Medicine. 2014. 370(22):2071-2082.
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Clinical Question

Among patients with idiopathic pulmonary fibrosis, does nintedanib reduce the decline in FVC as compared to placebo?

Bottom Line

Among patients with idiopathic pulmonary fibrosis, nintedanib reduces the decline in FVC as compared to placebo.

Major Points

Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease characterized by progressive decline in lung function and an high rate of mortality. Prior to this trial, treatment options were limited. The combination of azathioprine, prednisone, and N-acetylcysteine being previously shown to be associated with higher rates of SAE, hospitalizations, and adverse events in the 2012 PANTHER trial.[1]

Nintedanib is an intracellular tyrosine kinase inhibitor which targets fibrogenic growth factors including fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor.[2] In the randomized, double-blind, controlled, phase 2 trial TOMORROW, nintedanib treatment was associated with a reduced decline in forced vital capacity (FVC) and acute exacerbations as compared to placebo.[3] The INPULSIS-1 and INPULSIS-2 were randomized, double-blind, multicenter, placebo-controlled, parallel-group phase 3 trials which studied the efficacy and safety of nintedanib in patients with IPF.

Participants were randomized to receive nintedanib (n=638) or placebo (n=413). The primary outcome was the annual rate of FVC decline. In both trials, nintedanib significantly reduced the annual decline in FVC as compared to placebo (INPULSIS-1: −114.7 ml vs. −239.9 ml; difference, 125.3 ml; 95% CI 77.7-172.8; P<0.001; INPULSIS-2: −113.6 ml vs. −207.3 ml; difference, 93.7 ml; 95% CI 44.8-142.7; P<0.001). However, nintedanib did not significantly reduce the time to first acute exacerbation as compared to placebo. The trials were not powered to determine statistically significant differences in mortality, however, a trend toward a reduced mortality was observed.[4]

The most common adverse reaction was diarrhea, which led to discontinuation of nintedanib (INPULSIS-I: 4.5% vs. to 0% in placebo; INPULSIS-II: 4.3% vs. 0.5% in placebo. The nintedanib group also observed a higher incidence of liver function test derangements. More importantly, more patients in the nintedanib groups had myocardial infarctions. The authors concluded that further observation is required to determine the significance of this finding.

Another recent trial on IPF, the ASCEND study, showed that pirfenidone significantly reduced disease progression.[5] There was an improvement in progression-free survival but not overall survival. Pirfenidone and nintedanib are important advancements in the treatment of IPF. These agents have been recommended (conditional, moderate confidence in effect estimates) in the recent clinical guidelines.[6]

Guidelines

ATS/ERS/JRS/ALAT (2015, adapted)[6]

  • Suggest use of nintedanib in IPF (conditional recommendation, moderate confidence in effect estimates)

Design

  • Multicenter, double-blind, randomized, placebo-controlled, parallel-group, phase 3 trials
  • N=1,066 (combined in both INPULSIS trials)
    • Nintedanib (n=638)
    • Placebo (n=413)
  • Setting: 205 sites in 24 countries
  • Enrollment: 2011-2012
  • Follow-up: 52 weeks treatment period followed by a follow-up at 4-weeks
  • Analysis: Intention-to-treat
  • Primary outcome: annual rate of decline in FVC

Population

Inclusion Criteria[7]

  • Age ≥40 years
  • IPF diagnosed within 5 years prior to enrollment
  • FVC ≥50% predicted
  • Diffusion capacity of the lung for carbon monoxide (DLCO) 30-79% of the predicted value
  • High-resolution computed tomography (HRCT) performed within the previous 12 months, with findings fulfilling either A, B and C; or either A or B and C
    • A: Definite honeycomb lung destruction with basal and peripheral predominance
    • B: Presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal and peripheral predominance
    • C: Atypical features are absent, specifically nodules and consolidation. Ground glass opacity, if present, is less extensive than reticular opacity pattern
  • Eligibility based on surgical lung biopsy findings (details in Table S2, supplementary appendix)[8]

Exclusion Criteria

  • Treatment with prednisone >15 mg/day or N-acetylcysteine within 2 weeks of screening
  • Treatment with cyclophosphamide, cyclosporine A, pirfenidone, azathioprine, or any investigational drug within 8 weeks of screening
  • Previously treated with nintedanib for >4 weeks
  • AST/ALT or bilirubin 1.5x above upper limit of normal
  • Myocardial infarction within 6 months prior to randomization
  • Unstable angina within 6 months prior to randomization
  • Obstructive airway disease
  • Likely to receive lung transplant during the study
  • A Requirement for full-dose therapeutic anticoagulation therapy or high-dose anti-platelet therapy.
  • Genetic predisposition to bleeding
  • Hemorrhagic stroke within 12 months prior to the second visit
  • Hemoptysis, GI bleed, major injury or surgery within 3 months prior to the second visit
  • INR> 2, PT and PTT prolonged by >50% above upper limit of normal
  • Genetic predisposition to thrombosis
  • Thrombotic events (eg, stroke, TIA) within 12 months prior to the second visit
  • Hypersensitivity to nintedanib
  • Life expectancy <2.5 years due to other comorbidities
  • Planned major surgery during the trial period
  • Active alcohol or drug abuse
  • Pregnancy or lactation

Baseline characteristics

From the nintedanib group in INPULSIS-2

  • Demographics: Age 66.4±7.9 years, males 77.8%
  • Background: ex-smoker 66.3%, non-smoker 31.3%, current smoker 2.4%
  • Diagnosis: time since diagnosis of IPF made: 1.6±1.3 years; surgical lung biopsy specimen available: 25.5%
  • Lung function tests: FVC 2673±776 mL, 80.0±18.1 percentage of predicted; FEV1:FVC 81.8±6.3%, DLCO 3.8±1.2 mmol/min/kPa; 47±14.5 percentage of predicted
  • Other measurements: BMI 27.6±4.6 kg/m2; oxygen saturation 95.8±2.6%; Total St. George’s Respiratory Questionnaire (SGRQ) score 39.5±20.5

Interventions

  • Patients were randomized in a 3:2 ratio to receive nintedanib (150 mg, twice daily) or placebo for 52 weeks, followed by a follow-up 4 weeks later
  • Spirometry was performed at baseline, 2, 4, 6, 12, 24, 36, and 52 weeks; and at the follow-up visit
  • Dose interruption or reduction from 150 mg to 100 mg twice daily was allowed for the management of adverse events, which was then resumed at 150 mg twice daily after the adverse event has resolved

Outcomes

Comparisons are nintedanib vs. placebo

Primary Outcome

Annual change in FVC
INPULSIS-1: −114.7 ml vs. −239.9 ml; difference 125.3 ml; 95% CI 77.7-172.8; P<0.001
INPULSIS-2: −113.6 ml vs. −207.3 ml; difference 93.7 ml; 95% CI 44.8-142.7; P<0.001

Secondary Outcomes

Time to the first acute exacerbation
INPULSIS-1: hazard ratio 1.15; 95% CI 0.54-2.42; P=0.67
INPULSIS-2: hazard ratio 0.38; 95% CI 0.19-0.77; P=0.005
Pooled analysis: hazard ratio 0.64; 95% CI 0.39-1.05; P=0.08
Change in total SGRQ score from baseline
INPULSIS-1: 4.34 vs. 4.39 points; difference −0.05; 95% CI −2.50 to 2.40; P=0.97
INPULSIS-2: 2.80 vs. 5.48 points; difference −2.69; 95% CI −4.95 to −0.43; P=0.02
Pooled analysis: difference −1.43 points; 95% CI −3.09 to 0.23; P=0.09
Change in symptoms domain of SGRQ score from baseline
INPULSIS-1: 1.56±1.104 vs. 3.89±1.351 points; difference -2.32 ; 95% CI −5.74 to 1.1; P=0.18
INPULSIS-2: 2.03±1.061 vs. 3.43±1.297 points; difference -1.40; 95% CI −4.69 to 1.88; P=0.4
Pooled analysis: 1.82±0.765 vs. 3.67±0.935 points; difference -1.85; 95% CI -4.22 to 0.51; P=0.12
Change in activity domain of SGRQ score from baseline
INPULSIS-1: 4.62±0.906 vs. 5.81±1.103 points; difference -1.19; 95% CI -3.99 to 1.61; P=0.40
INPULSIS-2: 3.89±0.863 vs. 7.20±1.052 points; difference -3.31; 95% CI -5.97 to -0.64; P=0.02
Pooled analysis: 4.24±0.625 vs. 6.54±0.761 points; difference -2.30; 95% CI -4.23 to -0.37 P=0.02
Change in impact domain of SGRQ score from baseline
INPULSIS-1: 4.87±0.923 vs. 4.01±1.113 points; difference 0.86; 95% CI -1.97 to 3.70; P=0.55
INPULSIS-2: 2.85±0.852 vs. 5.93±1.036 points; difference -3.08; 95% CI -5.71 to -0.45; P=0.02
Pooled analysis: 3.83±0.627 vs. 4.98±0.760 points; difference -1.15; 95% CI -3.08 to 0.78; P=0.24
Absolute change in FVC
INPULSIS-1: −95.1 ml vs. −205 ml; difference 109.9 ml; 95% CI 71.3-148.6; P<0.001
INPULSIS-2: −95.3 ml vs. −205 ml; difference 109.8 ml; 95% CI 70.9-148.6; P<0.001
Absolute change in FVC (% of predicted value)
INPULSIS-1: −2.8 vs. −6.0; difference 3.2; 95% CI 2.1-4.3; P<0.001
INPULSIS-2: −3.1 vs. −6.2; difference 3.1; 95% CI 1.9-4.3; P<0.001
FVC decline ≤5 percentage points at 52 weeks
INPULSIS-1: 52.8% vs. 38.2%; difference 1.85; 95% CI 1.28-2.66; P=0.001
INPULSIS-2: 53.2% vs. 39.3%; difference 1.79; 95% CI 1.26-2.55); P=0.001
FVC decline ≤10 percentage points at 52 weeks
INPULSIS-1: 70.6% vs. 56.9%; difference 1.91; 95% CI 1.32-2.79; P<0.001
INPULSIS-2: 69.6% vs. 63.9%; difference 1.29; 95% CI 0.89-1.86); P=0.18
All-cause mortality
Pooled analysis: 5.5% vs. 7.9%; hazard ratio 0.7, 95% CI 0.43-1.12; P=0.14
Mortality from respiratory causes
Pooled analysis: 3.8% vs. 5%; hazard ratio 0.74, 95% CI 0.41-1.34; P=0.34
Mortality between randomization and 28 days after the last dose of the study drug
Pooled analysis: 3.8% vs. 6.1%; hazard ratio 0.68, 95% CI 0.39-1.19; P=0.16

Adverse Events

Comparisons are nintedanib vs. placebo

Adverse events: INPULSIS-1: 96.4% vs. 88.7%; INPULSIS-2: 94.5% vs. 90.4%

Serious adverse events: INPULSIS-1: 31.1% vs. 27%; INPULSIS-2: 29.8% vs. 32.9%
Severe adverse events: INPULSIS-1: 31.1% vs. 27%; INPULSIS-2: 29.8% vs. 32.9%
Fatal adverse events: INPULSIS-1: 3.9% vs. 4.9%; INPULSIS-2: 7.6% vs. 9.6%
Adverse events leading to discontinuation of treatment
Gastrointestinal-related: INPULSIS-1: 8.4% vs. 1.5%; INPULSIS-2: 6.4% vs. 0.9%
Respiratory, thoracic, and mediastinal-related: INPULSIS-1: 3.9% vs. 4.9%; INPULSIS-2: 2.4% vs. 8.2%
Cardiac-related: INPULSIS-1: 1.6% vs. 2%; INPULSIS-2: 0.6% vs. 1.4%
Investigation results: INPULSIS-1: 3.2% vs. 0.5%; INPULSIS-2: 2.4% vs. 0.5%
General disorders and conditions involving study-site: INPULSIS-1: 2.6% vs. 1.5%; INPULSIS-2: 0.6% vs. 0.5%
Most common adverse events
Diarrhea: INPULSIS-1: 61.5% vs. 18.6%; INPULSIS-2: 63.2% vs. 18.3%  
Nausea: INPULSIS-1: 22.7% vs. 5.9%; INPULSIS-2: 26.1% vs. 7.3%  
Nasopharyngitis: INPULSIS-1: 12.6% vs. 16.7%; INPULSIS-2: 14.6% vs. 15.5%  
Cough: INPULSIS-1: 15.2% vs. 12.7%; INPULSIS-2: 11.6% vs. 14.2%  
Progression of IPF: INPULSIS-1: 10% vs. 10.3%; INPULSIS-2: 10% vs. 18.3%  
Bronchitis: INPULSIS-1: 11.7% vs. 13.7%; INPULSIS-2: 9.4% vs. 7.8%
Upper respiratory tract infection: INPULSIS-1: 9.1% vs. 8.8%; INPULSIS-2: 9.1% vs. 11%
Dyspnea: INPULSIS-1: 7.1% vs. 11.3%; INPULSIS-2: 8.2% vs. 11.4%
Decreased appetite: INPULSIS-1: 8.4% vs. 6.9%; INPULSIS-2: 12.8% vs. 4.6%
Vomiting: INPULSIS-1: 12.9% vs. 2%; INPULSIS-2: 10.3% vs. 3.2%
Weight loss: INPULSIS-1: 8.1% vs. 6.4%; INPULSIS-2: 11.2% vs. 0.9%

Criticisms

  • The trials provided limited insight into the effects of nintedanib in patients with more severe disease or with an acute exacerbation.[4]
  • At the time of publication, there is uncertainty if nintedanib has durable effects beyond 1 year.[4]
  • There was a higher incidence of myocardial infarction in patients who received nintedanib (1.5-1.6% vs. 0.5%). The significance of this needs to be determined.[9]

Funding

  • Boehringer Ingelheim
  • National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit
  • NIHR Respiratory Disease Biomedical Research Unit

Further Reading

  1. Raghu G et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012. 366:1968-77.
  2. Wollin L et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015. 45:1434-45.
  3. Richeldi L et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2011. 365:1079-87.
  4. 4.0 4.1 4.2 Hunninghake GM & A new hope for idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014. 370:2142-3.
  5. King TE, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England Journal of Medicine. 2014. 370(22):2083-2092.
  6. 6.0 6.1 Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19. doi: 10.1164/rccm.201506-1063ST.
  7. Study protocol
  8. Supplementary appendix
  9. Lake F. Nintedanib reduced decline in FVC in idiopathic pulmonary fibrosis. Ann Intern Med. 2014 Oct 21;161(8):JC5. doi: 10.7326/0003-4819-161-8-201410210-02005.