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