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VA Journal Club March 23, 2015
Julie Lin, MD
IPF
• ~100,000 people in USA have IPF– Median survival is 2 to 5 years, similar to NSCLCa– Prevalence: 13-20/100,000 people worldwide
• Unclear etiology • Lower lobe predominance • Honeycombing• Sub-pleural involvement• Slowly progressive symptoms – sob, dry cough,
DOE• Exacerbations
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.Raghu G, et al. Am J Respir Crit Care Med. 2006;174:810-816.
Risk Factors for IPF
• Risk factors
– Familial
– Smoking
• Possible associated factors
– Environment (eg, wood or metal dust)
– Gastroesophageal reflux disease (GERD)
– Infectious agents
HRCT Diagnosis of IPF
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
Prone scans are best for showing subtle abnormalities
IPF Findings
Irregular reticular opacities
Subpleural, posterior, lower-lobe
predominance
Traction bronchiectasis
Honeycombing
Minimal ground-glass opacities
Mild lymph node enlargement
Consider Alternate Diagnosis
Pleural effusion
Pleural thickening
Moderate ground-glass opacities
Nodules
Scattered cysts
What is Nintedanib?
• Tyrosine kinase receptor inhibitor
• Receptors are involved in the pathogenesis of IPF – FGFR, PDGFR, VEGFR
Summary of the Facts
• Authors: – Luca Richeldi, M.D., Ph.D., Roland M. du Bois, M.D., Ganesh Raghu,
M.D., Arata Azuma, M.D., Ph.D., Kevin K. Brown, M.D., Ulrich Costabel, M.D., Vincent Cottin, M.D., Ph.D., Kevin R. Flaherty, M.D., David M. Hansell, M.D., Yoshikazu Inoue, M.D., Ph.D., Dong Soon Kim, M.D., Martin Kolb, M.D., Ph.D., Andrew G. Nicholson, D.M., Paul W. Noble, M.D., Moisés Selman, M.D., Hiroyuki Taniguchi, M.D., Ph.D., Michèle Brun, M.Sc., Florence Le Maulf, M.Sc., Mannaïg Girard, M.Sc., Susanne Stowasser, M.D., Rozsa Schlenker-Herceg, M.D., Bernd Disse, M.D., Ph.D., and Harold R. Collard, M.D., for the INPULSIS Trial Investigators*
• Funding Source: Boehringer Ingelheim
Summary of the Facts
• Research Question:
– Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis – Two Phase 3 trials to evaluate the efficacy and safety of treatment with 150 mg of nintedanib twice daily in patients with IPF
Summary of the Facts
• Study Design:
– The INPULSIS studies were randomized, doubleblind, placebo-controlled, parallel-group trials performed at 205 sites in 24 countries in the Americas, Europe, Asia, and Australia.
Summary of the Facts
• Study Design (continued)
– Randomly assigned in a 3:2 ratio to receive 150 mg of nintedanib twice daily or placebo for 52 weeks
– Interactive telephone and Web-based response system for randomization
Summary of the Facts
• Study subjects: – 1066 patients
• 515 patients in INPULSIS-1 • 551 patients in INPULSIS-2
– Inclusion Criteria: • 40 years of age or older • Dx of IPF within the previous 5 years. • FVC > 50% or more of the predicted value• DLCO = 30 -79% of the predicted value• HRCT chest within last 12 months• Concomitant therapy with up to 15 mg of prednisone per day, or the
equivalent, was permitted if the dose had been stable for 8 or more weeks before screening
Summary of the Facts
• Study subjects continued:
– Exclusion criteria:
• Patients receiving other therapies for IPF, including high-dose prednisone, azathioprine, N-acetylcysteine, and any investigational treatments for idiopathic pulmonary fibrosis
Summary of the Facts
• Variables: – Spirometry
– St. George’s Respiratory Questionnaire
• Endpoints: – Primary: annual rate of decline in FVC (measured in
milliliters per year).
– Secondary: • The time to the first acute exacerbation (as reported by a
site investigator)
• The change from baseline in the total score on the St. George’s Respiratory Questionnaire (SGRQ)
Nintedanib (mL/yr) Placebo (mL/yr) %Reduction
INPULSIS-1 115 240 52% p<0.001
INPULSIS-2 114 207 45% p<0.001
POOLED DATA 114 224 49% p<0.001
Results: Primary Outcome
Annual rate of FVC decline
Secondary Endpoint FindingsINPULSIS-1 INPULSIS-2 Pooled Data
Secondary Placebo Nintedanib Placebo Nintendanib Placebo Nintendanib
Time to Exacerb HR 1.15
P=0.67
HR 0.38
P=0.005
HR 0.64
P=0.08
Risk of Exacerb(incidence per 100 pt years)
5.6 6.6
P=0.68
10.2 3.9
P=0.007
8.0 5.2
P=0.08
SGRQ 4.39 4.34
P=0.97
5.48 2.80
P=0.02
N/A 3.53
P=0.09
DFVC (ml) -205 -95.1
P=<0.001
-205 -95.3
P=<0.001
-205 -94.5
P=<0.001
DFVC (%) -6.0 -2.8
P=<0.001
-6.2 -3.1
P=<0.001
-6.1 -2.9
P=<0.001
<5% decline 38% 53%
P=0.001
39% 53%
P=0.001
39% 53%
P=0.001
<10% decline 57% 71%
P=0.001
64% 70%
P=0.18
61% 70%
P=0.001
Adverse Reactions Compared to Placebo
Conclusions
• In both the INPULSIS trials, nintedanibsignificantly reduced the rate of decline in FVC over the 52-week treatment period.
• No consistent effect of nintedanib on the time to the first acute exacerbation or on the change in the total SGRQ score
• Diarrhea – common side effect. Premature discontinuation of the study medication was less than 5%
Assessment of validity
• Conflicts of interest among authors and funding source? – Yes – funded by the company that made the drug
• Study design appropriate? – Yes– Two parallel study design
• Study setting/inclusion/exclusion criteria appropriate? – Yes – Smoking Status?
• Control and comparison groups appropriately defined? – Yes
• Predictors and outcomes valid and clinically relevant? – Yes and debatable…
Clinical relevance?
• Study outcome was that drug reduced rate of decline in FVC
• Other outcome variables to consider
• Clinical significance of these results – no significant change in symptoms
• Would you give this drug?
Take home points
• Clinical relevance of endpoints
• Utility of two parallel studies vs one large study
• Randomized groups, other factors? i.e. smoking
Special thanks to Dr. YarbroughJournal Club mentor