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

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00287716
• Collaborator: (none)
• Enrollment: 435
• Location: 1
• Arms: 3
• Actual Duration (Months): 27.9
• Patients Per Site Per Month: 15.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Pirfenidone; Drug: Placebo	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 435 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled, Phase 3, Three-Arm Study of the Safety and Efficacy of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis
• Actual Study Start Date: Jul 14, 2006
• Actual Primary Completion Date: Nov 10, 2008
• Actual Study Completion Date: Nov 10, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 2403 mg/day pirfenidone Active arm 1, 2403 mg/day pirfenidone dose group.	Drug: Pirfenidone; 1197 or 2403 mg/day given orally, and administered in divided doses three times daily with food, for the duration of the study.
Active Comparator: 1197 mg/day pirfenidone Active arm 2, 1197 mg/day pirfenidone.	Drug: Pirfenidone; 1197 or 2403 mg/day given orally, and administered in divided doses three times daily with food, for the duration of the study.
Placebo Comparator: placebo Placebo equivalent.	Drug: Placebo; Placebo equivalent, given orally, and administered in divided doses three times daily with food, for the duration of the study.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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).

4. 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.

5. Change in Percent Predicted Hemoglobin (Hb)-Corrected Carbon Monoxide Diffusing Capacity (DLco) of the Lungs [Baseline to Week 72]

6. 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.

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	InterMune, Inc.	Brisbane	California	United States	94005

Sponsors and Collaborators

• Genentech, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00287716
• Other Study ID Numbers: PIPF-004; Capacity 2
• First Posted: Feb 7, 2006
• Last Update Posted: May 22, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Genentech, Inc.: Idiopathic; Pulmonary; Fibrosis; Lung; Pirfenidone; InterMune
• Additional relevant MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Pirfenidone

Study Results

Participant Flow

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Period Title: Overall Study
STARTED	174	87	174
COMPLETED	136	70	143
NOT COMPLETED	38	17	31

Baseline Characteristics

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo	Total
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day	Total of all reporting groups
Overall Participants	174	87	174	435
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	75 43.1%	28 32.2%	73 42%	176 40.5%
>=65 years	99 56.9%	59 67.8%	101 58%	259 59.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.7 (8.15)	68 (7.63)	66.3 (7.53)	66.4 (7.83)
Sex: Female, Male (Count of Participants)
Female	56 32.2%	22 25.3%	46 26.4%	124 28.5%
Male	118 67.8%	65 74.7%	128 73.6%	311 71.5%
Region of Enrollment (participants) [Number]
United States	114 65.5%	58 66.7%	114 65.5%	286 65.7%
Europe	34 19.5%	18 20.7%	38 21.8%	90 20.7%
Mexico	2 1.1%	0 0%	1 0.6%	3 0.7%
Canada	21 12.1%	8 9.2%	18 10.3%	47 10.8%
Australia	3 1.7%	3 3.4%	3 1.7%	9 2.1%

Outcome Measures

1. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Severe decline of >=20%, death, or lung transplant	14	9	27
Moderate decline of <20% but >=10%	21	14	33
Mild decline of <10% but >=0%	97	51	90
Mild improvement of >0% but <10%	40	12	24
Moderate improvement of >=10%	2	1	0

2. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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.
Time Frame	Baseline to Week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Death or Disease Progression	45	28	62
Decline in Percent Predicted FVC >=10%	28	16	39
Decline in Percent Predicted DLco >=15%	9	5	9
Death Before Disease Progression	8	7	14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone 2403 mg/Day, Placebo
	Comments	The null hypothesis is that there is no treatment difference between the pirfenidone 2403 mg/day treatment group and the placebo treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Six-Minute Walk Test (6MWT)Distance
Description	The change from Baseline to week 72 in distance walked during the 6-Minute Walk Test as measured in meters (m).
Time Frame	Baseline to Week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Mean (Standard Deviation) [Change in Distance Walked in Meters]	-60 (121)	-76 (132)	-77 (135)

4. Secondary Outcome

Title	Change in Worst Oxygen Saturation by Pulse Oximetry (SpO2) Measurement Observed During the 6-Minute Walk Test
Description	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.
Time Frame	Baseline to Week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Mean (Standard Deviation) [Change,Worst Oxygen Saturation (Percent)]	-2 (4)	-1 (5)	-2 (5)

5. Secondary Outcome

Title	Change in Percent Predicted Hemoglobin (Hb)-Corrected Carbon Monoxide Diffusing Capacity (DLco) of the Lungs
Time Frame	Baseline to Week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Mean (Standard Deviation) [Change in Percent Predicted DLco]	-8 (10)	-9 (11)	-10 (12)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Mean (Standard Deviation) [Change in Percent Predicted FVC]	-8.0 (16.47)	-10.0 (16.68)	-12.4 (18.45)

7. Secondary Outcome

Title	Change in Dyspnea Score
Description	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.
Time Frame	Baseline to Week 72

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Mean (Standard Deviation) [Change in Dyspnea Score]	12 (24)	14 (25)	15 (26)

8. Secondary Outcome

Title	Worsening of Idiopathic Pulmonary Fibrosis (IPF)
Description	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 Frame	Time to acute IPF exacerbation, IPF-related death, lung transplant or respiratory hospitalization, whichever comes first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pirfenidone 2403 mg/Day	Pirfenidone 1197 mg/Day	Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day	pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day	placebo equivalent, given as 3 divided doses 3 times/day
Measure Participants	174	87	174
Number [Number of Patients Who Worsened]	26	10	30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pirfenidone 2403 mg/Day, Placebo
	Comments	The null hypothesis is that there is no treatment difference between the pirfenidone 2403-mg/d treatment group and the placebo treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Pirfenidone 2403 mg/Day		Pirfenidone 1197 mg/Day		Placebo
Arm/Group Description	pirfenidone, total daily dose of 2403 mg/day, given as 3 divided doses 3 times/day		pirfenidone, total daily dose of 1197 mg/day, given as 3 divided doses 3 times/day		placebo equivalent, given as 3 divided doses 3 times/day
All Cause Mortality
	Pirfenidone 2403 mg/Day		Pirfenidone 1197 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Pirfenidone 2403 mg/Day		Pirfenidone 1197 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/174 (34.5%)		28/87 (32.2%)		58/174 (33.3%)
Blood and lymphatic system disorders
Anaemia	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Bone Marrow Failure	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Disseminated Intravascular Coagulation	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Haemorrhagic Disorder	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Cardiac disorders
Acute Myocardial Infarction	1/174 (0.6%)		0/87 (0%)		1/174 (0.6%)
Angina Pectoris	2/174 (1.1%)		2/87 (2.3%)		1/174 (0.6%)
Arteriosclerosis Coronary Artery	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Atrial Fibrillation	1/174 (0.6%)		3/87 (3.4%)		1/174 (0.6%)
Atrial Flutter	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Atrioventricular Block Complete	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Atrioventricular Block Second Degree	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Cardiac Failure Congestive	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
COR Pulmonale Acute	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Coronary Artery Disease	0/174 (0%)		3/87 (3.4%)		2/174 (1.1%)
Coronary Artery Occlusion	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Hypertrophic Cardiomyopathy	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Myocardial Infarction	0/174 (0%)		2/87 (2.3%)		4/174 (2.3%)
Myocardial Ischaemia	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Palpitations	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Right Ventricular Failure	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Tachycardia	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Ventricular Arrhythmia	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Ear and labyrinth disorders
Vertigo	1/174 (0.6%)		1/87 (1.1%)		0/174 (0%)
Endocrine disorders
Adrenal Insufficiency	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Eye disorders
Eye Haemorrhage	0/174 (0%)		1/87 (1.1%)		1/174 (0.6%)
Maculopathy	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Retinal Vein Occulusion	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Gastrointestinal disorders
Abdominal Compartment Syndrome	0/174 (0%)		0/87 (0%)		0/174 (0%)
Abdominal Pain Upper	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Colitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Colonic Obstruction	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Colonic Polyp	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Diarrhoea	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Diverticulum	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Erosive Duodenitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Gastrointestinal Haemorrhage	0/174 (0%)		1/87 (1.1%)		1/174 (0.6%)
Gastrooesophageal Reflux Disease	2/174 (1.1%)		0/87 (0%)		0/174 (0%)
Haemorrhoids	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Ileitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Internal Hernia	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Intestinal Obstruction	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Large Intestinal Haemorrhage	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Localised Intraabdominal Fluid Correction	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Megacolon	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Oesophagitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Pancreatitis Acute	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Peritoneal Haemorrhage	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Umbilical Hernia	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Volvulus	0/174 (0%)		1/87 (1.1%)		1/174 (0.6%)
General disorders
Chest Pain	5/174 (2.9%)		3/87 (3.4%)		3/174 (1.7%)
Fatigue	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Impaired Healing	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Non-Cardiac Chest Pain	2/174 (1.1%)		0/87 (0%)		2/174 (1.1%)
Oedema Peripheral	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Vestibulitis	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Hepatobiliary disorders
Cholecystitis	1/174 (0.6%)		0/87 (0%)		2/174 (1.1%)
Cholecystitis Acute	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Cholelithiasis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Infections and infestations
Abdominal Wall Infection	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Appendicitis	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Bronchitis	2/174 (1.1%)		2/87 (2.3%)		2/174 (1.1%)
Cellulitis	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Clostridium Difficile Colitis	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Diverticulitis	0/174 (0%)		1/87 (1.1%)		1/174 (0.6%)
Empyema	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Gastroenteritis	0/174 (0%)		0/87 (0%)		2/174 (1.1%)
Influenza	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Lobar Pneumonia	2/174 (1.1%)		2/87 (2.3%)		2/174 (1.1%)
Lower Respiratory Tract Infection	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Lower Respiratory Tract Infection Viral	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Orchitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Perianal Abscess	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Pneumonia	4/174 (2.3%)		3/87 (3.4%)		6/174 (3.4%)
Pneumonia Primary Atypical	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Post Procedural Infection	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Respiratory Tract Infection	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Septic Shock	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Sinusitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Staphylococcal Infection	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Tracheitis	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Tracheobronchitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Urinary Tract Infection Bacterial	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Urinary Tract Infection Fungal	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Vulval Abscess	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Injury, poisoning and procedural complications
Burns First Degree	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Burns Second Degree	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Fall	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Muscle Rupture	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Post Procedural Myocardial Infarction	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Investigations
Blood Amylase Increased	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Gamma-Glutamyltransferase Increasesd	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Liver Function Test Abnormal	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Metabolism and nutrition disorders
Fluid Overload	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Hyperkalaemia	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Back Pain	1/174 (0.6%)		1/87 (1.1%)		0/174 (0%)
Osteoporotic Fracture	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Pain in Extremity	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Rheumatoid Arthritis	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Pancreas	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Bile Duct Cancer	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Bladder Cancer	2/174 (1.1%)		0/87 (0%)		0/174 (0%)
Bladder Neoplasm	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Breast Cancer	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Colon Cancer	1/174 (0.6%)		1/87 (1.1%)		1/174 (0.6%)
Lung Adenocarcinoma Metastatic	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Lung Cancer Metastatic	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Metastases to Lung	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Ovarian Cancer Metastatic	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Prostate Cancer	0/174 (0%)		1/87 (1.1%)		2/174 (1.1%)
Rectal Cancer	0/174 (0%)		2/87 (2.3%)		0/174 (0%)
Small Cell Lung Cancer Metastatic	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Small Cell Lung Cancer Stage Unspecified	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Tonsil Cancer	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Nervous system disorders
Anoxic Encephalopathy	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
carotid Artery Stenosis	0/174 (0%)		1/87 (1.1%)		1/174 (0.6%)
Cerebral Artery Occlusion	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Cerebrovascular Accident	1/174 (0.6%)		0/87 (0%)		1/174 (0.6%)
Hemiparesis	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Migraine with Aura	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Presyncope	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Syncope	3/174 (1.7%)		1/87 (1.1%)		1/174 (0.6%)
Thrombotic Stroke	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Transient Ischaemic Attack	1/174 (0.6%)		0/87 (0%)		1/174 (0.6%)
Psychiatric disorders
Depression	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Suicidal Ideation	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Renal and urinary disorders
Calculus Urinary	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Renal Failure Acute	1/174 (0.6%)		2/87 (2.3%)		0/174 (0%)
Renal Failure Chronic	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Stress Urinary Incontinence	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Urethral Disorder	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Urinary Retention	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Cystocele	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Prostatitis	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Acute Respiratory Failure	2/174 (1.1%)		0/87 (0%)		3/174 (1.7%)
Cough	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Dyspnoea	0/174 (0%)		1/87 (1.1%)		3/174 (1.7%)
Haemoptysis	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Hypoxia	1/174 (0.6%)		0/87 (0%)		2/174 (1.1%)
Idiopathic Pulmonary Fibrosis	13/174 (7.5%)		5/87 (5.7%)		14/174 (8%)
Pleural Effusion	1/174 (0.6%)		1/87 (1.1%)		0/174 (0%)
Pneumonia Aspiration	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Pneumonitis	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Pneumothorax	3/174 (1.7%)		2/87 (2.3%)		0/174 (0%)
Pulmonary Embolism	1/174 (0.6%)		3/87 (3.4%)		1/174 (0.6%)
Pulmonary Haemorrhage	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Respiratory Distress	0/174 (0%)		0/87 (0%)		1/174 (0.6%)
Respiratory Failure	2/174 (1.1%)		3/87 (3.4%)		2/174 (1.1%)
Skin and subcutaneous tissue disorders
Lichen Sclerosus	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Photosensitivity Reaction	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Rash	1/174 (0.6%)		0/87 (0%)		0/174 (0%)
Vascular disorders
Aortic Aneurysm	2/174 (1.1%)		1/87 (1.1%)		0/174 (0%)
Hypertension	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Orthostatic Hypertension	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Shock Haemorrhagic	0/174 (0%)		1/87 (1.1%)		0/174 (0%)
Other (Not Including Serious) Adverse Events
	Pirfenidone 2403 mg/Day		Pirfenidone 1197 mg/Day		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	171/174 (98.3%)		86/87 (98.9%)		169/174 (97.1%)
Gastrointestinal disorders
Abdominal distension	15/174 (8.6%)	16	3/87 (3.4%)	3	12/174 (6.9%)	14
Abdominal pain	16/174 (9.2%)	18	6/87 (6.9%)	7	7/174 (4%)	10
Asthenia	15/174 (8.6%)	18	10/87 (11.5%)	11	5/174 (2.9%)	5
Dyspepsia	30/174 (17.2%)	34	12/87 (13.8%)	17	16/174 (9.2%)	34
Nausea	60/174 (34.5%)	96	22/87 (25.3%)	27	32/174 (18.4%)	37
Stomach discomfort	14/174 (8%)	16	4/87 (4.6%)	5	4/174 (2.3%)	4
Vomiting	24/174 (13.8%)	34	11/87 (12.6%)	14	7/174 (4%)	9
Investigations
Weight decreased	15/174 (8.6%)	15	8/87 (9.2%)	8	7/174 (4%)	8
Metabolism and nutrition disorders
Anorexia	19/174 (10.9%)	20	9/87 (10.3%)	11	7/174 (4%)	7
Decreased appetite	17/174 (9.8%)	18	3/87 (3.4%)	3	1/174 (0.6%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	20/174 (11.5%)	28	9/87 (10.3%)	10	13/174 (7.5%)	15
Nervous system disorders
Dizziness	33/174 (19%)	42	14/87 (16.1%)	18	17/174 (9.8%)	19
Psychiatric disorders
Insomnia	22/174 (12.6%)	27	13/87 (14.9%)	14	12/174 (6.9%)	13
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	16/174 (9.2%)	20	2/87 (2.3%)	2	5/174 (2.9%)	9
Skin and subcutaneous tissue disorders
Photosensitivity reaction	25/174 (14.4%)	40	6/87 (6.9%)	6	2/174 (1.1%)	4
Pruritus	12/174 (6.9%)	15	5/87 (5.7%)	8	6/174 (3.4%)	8
Rash	53/174 (30.5%)	75	15/87 (17.2%)	27	18/174 (10.3%)	25
Vascular disorders
Hot flush	11/174 (6.3%)	11	3/87 (3.4%)	3	2/174 (1.1%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.