1. INPULSIS® trial design and baseline characteristics
OFEV® (nintedanib)
INPULSIS® trial design and baseline characteristics
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These slides are provided by Boehringer Ingelheim for medical to medical education only.

2. Study design
Double-blind, placebo-controlled Phase III studies with replicate design
52-week treatment period followed by 4-week follow-up
3:2 randomisation ratio for nintedanib:placebo
Treatment interruption and/or dose reduction to 100 mg bid allowed to manage adverse events
Patients who prematurely discontinued trial drug were asked to attend all visits as planned
Visits 6a, 7a and 8a were for blood sampling for laboratory tests only. EOT, end of treatment; R, randomization. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

3. Inclusion and exclusion criteria

4. Key inclusion criteria
Age ≥40 years
Diagnosis of IPF within 5 years of randomization
Chest HRCT performed within 12 months of screening
HRCT pattern, and, if available, surgical lung biopsy pattern, consistent with diagnosis of IPF, as assessed centrally by one expert radiologist and one expert pathologist
FVC ≥50% predicted
DLCO 30–79% predicted
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

5. Eligibility criteria based on HRCT
To qualify to enter the INPULSIS® trials if a surgical lung biopsy was not available, criteria A and B and C; or A and C; or B and C had to be met
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

6. Histopathological criteria used for review of surgical lung biopsies
The following histopathological criteria were applied for the review of surgical lung biopsies. In cases where there was disagreement between the radiologist and pathologist, the two experts discussed the case and reached a consensus as to whether the patient should be included
UIP, usual interstitial pneumonia. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

7. Key exclusion criteria
FEV1/FVC <0.7 (pre-bronchodilator)
Liver enzyme elevations i.e. AST or ALT or bilirubin >1.5x ULN
Myocardial infarction within 6 months or unstable angina within 1 month of randomization
Treatment with N-acetylcysteine or prednisone >15 mg/day or equivalent within 2 weeks of screening
Treatment with pirfenidone, azathioprine, cyclophosphamide, cyclosporine A or any investigational drug within 8 weeks of screening
Requirement for fibrinolysis, full-dose therapeutic anticoagulation, or high-dose antiplatelet therapy
Likely to receive a lung transplant during the study (in investigator’s opinion)
AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; FEV1, forced expiratory volume in 1 second. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

8. Concomitant medication allowed during the trials
Prednisone ≤15 mg/day or equivalent if the dose had been stable for ≥8 weeks prior to screening
In cases of acute exacerbation, any treatments could be initiated or increased as deemed appropriate by the investigator
After 6 months, patients who experienced deterioration could receive any of the following treatments at the investigator’s discretion:
Azathioprine
Cyclophosphamide
Cyclosporine A
N-acetylcysteine
Prednisone >15 mg/day or equivalent
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

9. Endpoints

10. Endpoints (1/3) Primary endpoint
Annual rate of decline in FVC (mL/year)
Key secondary endpoints
Time to first acute exacerbation (investigator-reported) over 52 weeks
Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score over 52 weeks
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

11. Endpoints (2/3) Secondary endpoints included:
Absolute change from baseline in FVC (mL and % predicted) at week 52
Proportion of FVC responders (patients who did not have an absolute decline in FVC % predicted of >5% or >10%) at week 52
All-cause mortality and respiratory mortality over 52 weeks (measured as time to death)
On-treatment mortality*
*Deaths that occurred between randomization and 28 days after last trial drug intake.
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

12. Endpoints (3/3)
Safety
Safety was assessed by clinical and laboratory evaluation and the recording of adverse events
Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 16.1
Analyses were descriptive
Analyses were based on patients who received ≥1 dose of study medication
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

13. Methodology for calculating slope of FVC decline (primary analysis)
The primary endpoint was analyzed using a random coefficient regression model including sex, age and height as covariates. All available FVC values from baseline to week 52 were used, including FVC measurements from the follow-up visit for patients who prematurely discontinued trial medication and did not complete study visits until week 52.
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

14. Baseline characteristics

15. Demographic data and baseline characteristics (1/2)
*In France it is not permitted to collect data on race. SD, standard deviation.
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

16. Demographic data and baseline characteristics (2/2)
*n=202 for placebo and n=298 for nintedanib in INPULSIS®-1; n=217 for placebo and n=329 for nintedanib in INPULSIS®-2. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

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