OFEV® (nintedanib)INPULSIS® trial design and baseline characteristics

Last updated 08.09.2015

These slides are provided by Boehringer Ingelheim for medical to medical education only.

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.

INCLUSION AND EXCLUSION CRITERIA

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.

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.

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.

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.

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.

ENDPOINTS

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.

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.

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.

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.

BASELINE CHARACTERISTICS

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.

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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