Three-Arm Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis

Conditions

Idiopathic Pulmonary Fibrosis

Keywords

Idiopathic, Pulmonary, Fibrosis, Lung, Pirfenidone, InterMune

Brief summary

The objectives of this study are to assess the safety and efficacy of treatment with pirfenidone 2403 milligrams per day (mg/d) compared with placebo in patients with idiopathic pulmonary fibrosis (IPF), to assess the safety and efficacy of treatment with pirfenidone 1197 mg/d in patients with idiopathic pulmonary fibrosis and to characterize the pharmacokinetic disposition of pirfenidone in patients with idiopathic pulmonary fibrosis.

Detailed description

This is a Phase 3, randomized, double blind, placebo-controlled, three-arm, safety and efficacy study of pirfenidone in patients with idiopathic pulmonary fibrosis. Approximately 400 patients at approximately 70 centers will be randomly assigned (2:2:1) to receive either 2403 milligrams (mg) of pirfenidone, placebo equivalent, or 1197 mg of pirfenidone administered in divided doses three times per day (TID) with food. 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 FVC or a ≥ 15% absolute decrease in percent predicted carbon monoxide diffusing capacity (DLco), will be eligible to receive permitted IPF therapies in addition to their blinded study drug. Permitted IPF therapies include corticosteroids, azathioprine, cyclophosphamide and N-acetyl-cysteine (with restrictions).

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Interventions

DRUGPirfenidone

1197 or 2403 mg/day given orally, and administered in divided doses three times daily with food, for the duration of the study.

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 80 Years

Healthy volunteers

No

Inclusion criteria

Primary Inclusion criteria: * diagnosis of idiopathic pulmonary fibrosis * 40 to 80 years of age * Forced Vital Capacity greater than or equal to 50% predicted value * Carbon monoxide diffusing capacity greater than or equal to 35% predicted value * either Forced Vital Capacity or Carbon monoxide diffusing capacity less than or equal to 90% predicted value * no improvement in past year * able to walk 150 meters in 6 minutes and maintain saturation greater than or equal to 83% while on no more than 6 liters per minute (L/min) supplemental oxygen Primary

Exclusion criteria

* unable to undergo pulmonary function testing * evidence of significant obstructive lung disease or airway hyper-responsiveness * in opinion of investigator patient is expected to need and be eligible for a lung transplant within 72 weeks after 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 (Q wave,T wave) syndrome * other IPF treatment * unable to take study medication * withdrawal from other IPF trials

Design outcomes

Primary

Measure	Time frame	Description
Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	From baseline up to 72 weeks	Mean Change in Percent Predicted Forced Vital Capacity (FVC) as measured from baseline to week 72.

Secondary

Measure	Time frame	Description
Progression-free Survival (PFS)	Baseline to Week 72	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.
Change in Six-Minute Walk Test (6MWT)Distance	Baseline to Week 72	The change from Baseline to week 72 in distance walked during the 6-Minute Walk Test as measured in meters (m).
Change in Worst Oxygen Saturation by Pulse Oximetry (SpO2) Measurement Observed During the 6-Minute Walk Test	Baseline to Week 72	The change from baseline to week 72 in worst oxygen saturation during the 6-Minute Walk Test as measure by Pulse Oximetry (SpO2) Level is calculated as the simple difference between baseline SpO2 measurements and week 72 SpO2 measurements.
Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	baseline up to 72 weeks	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 experienced a Categorical Change in Percent Predicted Forced Vital Capacity.
Change in Dyspnea Score	Baseline to Week 72	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 Idiopathic Pulmonary Fibrosis (IPF)	Time to acute IPF exacerbation, IPF-related death, lung transplant or respiratory hospitalization, whichever comes first.	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.
Change in Percent Predicted Hemoglobin (Hb)-Corrected Carbon Monoxide Diffusing Capacity (DLco) of the Lungs	Baseline to Week 72	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
Pirfenidone 2403 mg/Day pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	174
Pirfenidone 1197 mg/Day pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	87
Placebo placebo equivalent, given as 3 divided doses 3 times/day	174
Total	435

Baseline characteristics

Characteristic	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	99 Participants	59 Participants	101 Participants	259 Participants
Age, Categorical Between 18 and 65 years	75 Participants	28 Participants	73 Participants	176 Participants
Age, Continuous	65.7 years STANDARD_DEVIATION 8.15	68 years STANDARD_DEVIATION 7.63	66.3 years STANDARD_DEVIATION 7.53	66.4 years STANDARD_DEVIATION 7.83
Region of Enrollment Australia	3 participants	3 participants	3 participants	9 participants
Region of Enrollment Canada	21 participants	8 participants	18 participants	47 participants
Region of Enrollment Europe	34 participants	18 participants	38 participants	90 participants
Region of Enrollment Mexico	2 participants	0 participants	1 participants	3 participants
Region of Enrollment United States	114 participants	58 participants	114 participants	286 participants
Sex: Female, Male Female	56 Participants	22 Participants	46 Participants	124 Participants
Sex: Female, Male Male	118 Participants	65 Participants	128 Participants	311 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	171 / 174	86 / 87	169 / 174
serious Total, serious adverse events	60 / 174	28 / 87	58 / 174

Outcome results

Primary

Absolute Change in Percent Predicted Forced Vital Capacity (FVC)

Mean Change in Percent Predicted Forced Vital Capacity (FVC) as measured from baseline to week 72.

Time frame: From baseline up to 72 weeks

Arm	Measure	Value (MEAN)	Dispersion
Pirfenidone 2403 mg/Day	Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	-8.0 Change in Percent Predicted FVC	Standard Deviation 16.47
Pirfenidone 1197 mg/Day	Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	-10.0 Change in Percent Predicted FVC	Standard Deviation 16.68
Placebo	Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	-12.4 Change in Percent Predicted FVC	Standard Deviation 18.45

Secondary

Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)

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 experienced a Categorical Change in Percent Predicted Forced Vital Capacity.

Time frame: baseline up to 72 weeks

Arm	Measure	Group	Value (NUMBER)
Pirfenidone 2403 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild improvement of >0% but <10%	40 Patients
Pirfenidone 2403 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild decline of <10% but >=0%	97 Patients
Pirfenidone 2403 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Severe decline of >=20%, death, or lung transplant	14 Patients
Pirfenidone 2403 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate decline of <20% but >=10%	21 Patients
Pirfenidone 2403 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate improvement of >=10%	2 Patients
Pirfenidone 1197 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild decline of <10% but >=0%	51 Patients
Pirfenidone 1197 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Severe decline of >=20%, death, or lung transplant	9 Patients
Pirfenidone 1197 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate decline of <20% but >=10%	14 Patients
Pirfenidone 1197 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild improvement of >0% but <10%	12 Patients
Pirfenidone 1197 mg/Day	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate improvement of >=10%	1 Patients
Placebo	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate improvement of >=10%	0 Patients
Placebo	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild improvement of >0% but <10%	24 Patients
Placebo	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Severe decline of >=20%, death, or lung transplant	27 Patients
Placebo	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Mild decline of <10% but >=0%	90 Patients
Placebo	Categorical Assessment of Absolute Change in Percent Predicted Forced Vital Capacity (FVC)	Moderate decline of <20% but >=10%	33 Patients

Secondary

Change in Dyspnea Score

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.