Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis

A Randomized, Double-Blind, Placebo Controlled, Phase 3 Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis

The purposes of this study are to assess the efficacy of treatment with pirfenidone 2403 milligrams per day compared with placebo in patients with idiopathic pulmonary fibrosis (IPF)and to assess the safety of treatment with pirfenidone 2403 milligrams per day compared with placebo in patients with idiopathic pulmonary fibrosis.

This is a Phase 3, randomized, double-blind, placebo-controlled, safety and efficacy study of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF). Approximately 320 patients at approximately 50 centers will be randomly assigned (1:1) to receive pirfenidone 2403 milligrams or placebo equivalent administered in divided doses three times per day (TID) with food. The primary outcome variable will be the absolute change in percent predicted Forced Vital Capacity from Baseline to Week 72. Patients will be randomized by geographic region. Patients will receive blinded study treatment from the time of randomization until the last patient randomized has been treated for 72 weeks. A Data Monitoring Committee (DMC) will periodically review safety and efficacy data to ensure patient safety. After week 72, patients who meet the Progression of Disease (POD) definition, which is a ≥ 10% absolute decrease in percent predicted Forced Vital Capacity or a ≥ 15% absolute decrease in percent predicted carbon monoxide diffusing capacity (DLco), will be eligible to receive permitted idiopathic pulmonary fibrosis therapies in addition to their blinded study drug. Permitted idiopathic pulmonary therapies include corticosteroids, azathioprine, cyclophosphamide and N-acetyl-cysteine (with restrictions).

2403 mg/day given orally, and administered in divided doses three times daily with food, for the duration of the study.

Placebo equivalent, given orally, and administered in divided doses three times daily with food, for the duration of the study.

Mean Change in Percent Predicted Forced Vital Capacity (FVC) as measured from baseline to week 72. It is calculated as the simple difference between baseline Percent Predicted FVC measurements and week 72 Percent Predicted FVC measurements.

Based on the change in baseline percent predicted FVC at week 72, patients were assigned to 1 of 5 categories: mild decline (<10% but >=0% decline), moderate decline (<20% but >=10% decline), severe decline (>=20% decline), mild improvement (>0% but <10% improvement), or moderate improvement (>=10% improvement). Those who died or had a lung transplant before Week 72 were included in the severe decline category. The results indicate the number of patients who experience Categorical Change in Percent Predicted Forced Vital Capacity.

Progression is defined as the first occurrence of a 10% absolute decline from baseline in percent predicted Forced Vital Capacity, a 15% absolute decline from baseline in percent predicted hemoglobin(Hgb)-corrected carbon monoxide diffusing capacity (DLco), or, death.

The change from Baseline to week 72 in distance walked during the 6-Minute Walk Test. This measure was calculated as the simple difference between baseline distanced walked over 6 minutes and week 72 distance walked over 6 minutes as measured in meters (m).

Change in Worst Oxygen Saturation by Pulse Oximetry (SpO2) Measurement Observed During the 6-Minute Walk Test

The change from baseline to week 72 in worst oxygen saturation during the 6-Minute Walk Test as measure by Pulse Oximetry (SpO2) Level. It is calculated as the simple difference between baseline SpO2 measurements and week 72 SpO2 measurements.

Change in Percent Predicted Hemoglobin (Hb)-Corrected Carbon Monoxide Diffusing Capacity (DLco) of the Lungs

The change from baseline to week 72 in Percent Predicted Hemoglobin (Hb)-Corrected Carbon Monoxide Diffusing Capacity (DLco) of the Lungs. It is calculated as the simple difference between baseline DLco measurements and week 72 DLco measurements.

The mean change from baseline to week 72 in Dyspnea score was measured by the University of San Diego Shortness of Breath Questionnaire (UCSD SOBQ). The SOBQ is used to assess shortness of breath with various activities of daily living (for example, brushing ones teeth or mowing the lawn). Patients rated the severity of their shortness of breath experienced on an average day during the past week on a 6 point scale (0 to 5),with 0= not at all breathless, 4= severely breathless and 5= Maximally or unable to do because of breathlessness.

Worsening of IPF was defined by the occurrence of any of the following events: Acute IPF exacerbation, IPF-related death, Lung transplantation, or Respiratory hospitalization.

Time to acute IPF exacerbation, IPF-related death, lung transplant or respiratory hospitalization, whichever comes first.

Primary Inclusion criteria: diagnosis of idiopathic pulmonary fibrosis 40 to 80 years of age Forced Vital Capacity ≥ 50% predicted value carbon monoxide diffusing capacity (DLco) ≥ 35% predicted value either Forced Vital Capacity or carbon monoxide diffusing capacity (DLco) ≤ 90% predicted value no improvement in past year able to walk 150 meters in 6 minutes and maintain saturation ≥ 83% while on no more than 6 liters per minute supplemental oxygen Primary Exclusion criteria: unable to undergo pulmonary function testing evidence of significant obstructive lung disease or airway hyper-responsiveness in the clinical opinion of the investigator, the patient is expected to need and be eligible for a lung transplant within 72 weeks of randomization active infection liver disease cancer or other medical condition likely to result in death within 2 years diabetes pregnancy or lactation substance abuse personal or family history of long QT syndrome other IPF treatment unable to take study medication withdrawal from other IPF trials

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