Idiopathic Pulmonary Fibrosis, Pulmonary Fibrosis
Conditions
Keywords
pulmonary fibrosis, respiratory diseases
Brief summary
To assess the safety of treatment with pirfenidone (up to 3600 mg/d) in patients with pulmonary fibrosis/idiopathic pulmonary fibrosis (PF/IPF).
Detailed description
This study has been designed as a rollover study to collectively include safety data from various previous studies. In addition, InterMune has also initiated an Early Access Program to make pirfenidone available to a limited number of patients with idiopathic pulmonary fibrosis in the United States. This program is also being conducted under this protocol. Registration of patients with documented IPF has been closed as of October 2005.
Interventions
DRUGPirfenidone
up to 3600 mg/day of pirfenidone given orally administered in divided doses three times daily with food, for the duration of the study
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria: * Able to understand and sign an informed consent form * Understand the importance of adherence to study treatment and the study protocol, including concomitant medication restrictions, throughout the study period * Patients must be willing to travel to an approved regional center for all study-related visits Roll-Over Criteria: * Entry into study through rollover has been completed Criteria for Early Access Program patients: * Clinical symptoms consistent with IPF ≥3 months duration * Age 40 - 85, inclusive * At the time of registration with National Organization for Rare Disorders (NORD), patients with IPF must have a percent predicted forced vital capacity (FVC) of ≥50%, and percent predicted carbon monoxide diffusing capacity (DLCO) of ≥35% * At the time of enrollment in PIPF-002, (screening/baseline visit) percent predicted FVC must be ≥45%, and percent predicted DLCO must be ≥30% * High-resolution computed tomographic scan (HRCT) showing definite IPF. For patients with surgical lung biopsy showing definite or probable usual interstitial pneumonia (UIP), the HRCT criterion of probable IPF is sufficient * For patients aged \<50 years: open or video-assisted thoracoscopic (VATS) lung biopsy showing definite or probable UIP. In addition, no features supporting an alternative diagnosis on transbronchial biopsy or bronchoalveolar lavage if performed * For patients aged ≥50 years: at least one of the following diagnostic findings as well as the absence of any features on specimens resulting from any of these procedures that support an alternative diagnosis: 1) Open or VATS lung biopsy showing definite or probable UIP; 2) Transbronchial biopsy showing no features to support an alternative diagnosis; 3) Bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | Baseline to 28 days after the last dose of study treatment (maximum duration of treatment in study was 604 weeks) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs were classified as severe (Grade 3) in following cases: marked limitation in activity; some assistance usually required; medical intervention/ therapy required, hospitalization possible. Treatment-emergent AEs were those occurring on or after the first dosing day and up to 28 days after discontinuation of study treatment, and those occurring before treatment that worsened after the first study dose. AE included serious as well as non-serious AEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Predicted Forced Vital Capacity (FVC) | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480 | FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out from the lungs after full inspiration in the upright position, measured in liters. Predicted FVC is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (actual FVC value in liter)/(predicted FVC) \* 100% |
| Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480 | DLco is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. Predicted DLco is based on a formula using sex, age and height of a person. Predicted DLco = \[Hbg-corrected DLco value (in milliliters per minute per millimeter mercury \[mL/min/mmHg\])/predicted DLco\] \* 100% |
| Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480 | SpO2 is the percentage of oxygen saturation in the blood. Oxygen level (oxygen saturation) of the blood was measured using pulse oximetry on room air. |
| Overall Survival | First dosing of study treatment until death (up to 604 weeks) | Survival was analyzed as time from first study dose to death (all-cause mortality) with surviving participants censored at their last available assessment. |
Countries
United States
Participant flow
Pre-assignment details
Participants could enroll from Study PIPF-001 (a double-blind comparison of pirfenidone and prednisone in pulmonary fibrosis); individual-patient protocols (IPPs); investigator-sponsored Investigational New Drug applications (INDs) in idiopathic pulmonary fibrosis (IPF); and via an early access program (EAP) for participants with IPF.
Participants by arm
| Arm | Count |
|---|---|
| Pirfenidone Pirfenidone was administered orally, in divided doses, three times daily at a maximum dose of up to 3600 mg/d. At the start of treatment in this study, doses for participants with no previous pirfenidone exposure and for those who took their last dose \>4 weeks before enrollment were titrated to their maintenance dose based on body weight and tolerability. Dose titration was also required after a dosing interruption of \>28 days. Pirfenidone was administered for a maximum duration of 604 weeks in this study. | 83 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 23 |
| Overall Study | Death | 21 |
| Overall Study | Lung Transplantation | 9 |
| Overall Study | Non-compliance With Study Treatment | 7 |
| Overall Study | Participant unwilling to continue | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 13 |
Baseline characteristics
| Characteristic | Pirfenidone |
|---|---|
| Age, Continuous | 68.5 years STANDARD_DEVIATION 9.15 |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 81 / 83 |
| serious Total, serious adverse events | 49 / 83 |
Outcome results
Primary
Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE
An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs were classified as severe (Grade 3) in following cases: marked limitation in activity; some assistance usually required; medical intervention/ therapy required, hospitalization possible. Treatment-emergent AEs were those occurring on or after the first dosing day and up to 28 days after discontinuation of study treatment, and those occurring before treatment that worsened after the first study dose. AE included serious as well as non-serious AEs.
Time frame: Baseline to 28 days after the last dose of study treatment (maximum duration of treatment in study was 604 weeks)
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | Any AE | 98.8 percentage of participants |
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | SAE | 59.0 percentage of participants |
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | Severe AE | 36.1 percentage of participants |
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | Life-threatening AE | 21.7 percentage of participants |
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | AEs leading to death | 25.3 percentage of participants |
| Pirfenidone | Percentage of Participants With a Treatment-Emergent Adverse Event (AE), Serious AE (SAE), Severe AE, Life-threatening AE, Death or Discontinuation Because of an AE | AE leading to study treatment discontinuation | 43.4 percentage of participants |
Secondary
Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco)
DLco is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. Predicted DLco is based on a formula using sex, age and height of a person. Predicted DLco = \[Hbg-corrected DLco value (in milliliters per minute per millimeter mercury \[mL/min/mmHg\])/predicted DLco\] \* 100%
Time frame: Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480
Population: All treated participants. n = participants who were evaluable for specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Baseline (n=74) | 38.0 percent predicted DLco | Standard Deviation 13.36 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 24 (n=65) | 39.5 percent predicted DLco | Standard Deviation 13.56 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 48 (n=55) | 37.1 percent predicted DLco | Standard Deviation 13.55 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 72 (n=49) | 37.0 percent predicted DLco | Standard Deviation 12.01 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 96 (n=44) | 38.0 percent predicted DLco | Standard Deviation 12.35 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 120 (n=41) | 35.7 percent predicted DLco | Standard Deviation 12.55 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 144 (n=37) | 38.5 percent predicted DLco | Standard Deviation 13.47 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 168 (n=33) | 36.7 percent predicted DLco | Standard Deviation 12.98 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 192 (n=27) | 37.2 percent predicted DLco | Standard Deviation 11.34 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 216 (n=28) | 35.8 percent predicted DLco | Standard Deviation 11.31 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 240 (n=22) | 35.5 percent predicted DLco | Standard Deviation 12.67 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 264 (n=15) | 37.5 percent predicted DLco | Standard Deviation 9.69 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 288 (n=14) | 42.9 percent predicted DLco | Standard Deviation 18.43 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 312 (n=14) | 38.6 percent predicted DLco | Standard Deviation 9.54 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 336 (n=10) | 33.7 percent predicted DLco | Standard Deviation 6.41 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 360 (n=7) | 37.1 percent predicted DLco | Standard Deviation 11.19 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 384 (n=5) | 38.3 percent predicted DLco | Standard Deviation 13.16 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 408 (n=4) | 38.1 percent predicted DLco | Standard Deviation 9.41 |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 432 (n=1) | 33.9 percent predicted DLco | — |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 456 (n=1) | 11.6 percent predicted DLco | — |
| Pirfenidone | Hemoglobin (Hgb)-Corrected Percent-Predicted Carbon Monoxide Diffusing Capacity (DLco) | Week 480 (n=1) | 38.9 percent predicted DLco | — |
Secondary
Overall Survival
Survival was analyzed as time from first study dose to death (all-cause mortality) with surviving participants censored at their last available assessment.
Time frame: First dosing of study treatment until death (up to 604 weeks)
Population: All treated participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone | Overall Survival | 508.7 weeks |
Secondary
Percent Predicted Forced Vital Capacity (FVC)
FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out from the lungs after full inspiration in the upright position, measured in liters. Predicted FVC is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (actual FVC value in liter)/(predicted FVC) \* 100%
Time frame: Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480
Population: All treated participants. n = participants who were evaluable for specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Baseline (n=78) | 67.7 percent predicted FVC | Standard Deviation 18.7 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 24 (n=71) | 67.5 percent predicted FVC | Standard Deviation 17.11 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 48 (n=57) | 68.7 percent predicted FVC | Standard Deviation 17.36 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 72 (n=50) | 68.4 percent predicted FVC | Standard Deviation 16.2 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 96 (n=47) | 67.9 percent predicted FVC | Standard Deviation 17.76 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 120 (n=44) | 67.7 percent predicted FVC | Standard Deviation 18.03 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 144 (n=39) | 66.1 percent predicted FVC | Standard Deviation 18.22 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 168 (n=35) | 65.7 percent predicted FVC | Standard Deviation 17.74 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 192 (n=28) | 67.8 percent predicted FVC | Standard Deviation 18.32 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 216 (n=28) | 68.7 percent predicted FVC | Standard Deviation 21.97 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 240 (n=22) | 65.3 percent predicted FVC | Standard Deviation 16.8 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 264 (n=15) | 70.1 percent predicted FVC | Standard Deviation 13.26 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 288 (n=14) | 76.6 percent predicted FVC | Standard Deviation 18.71 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 312 (n=14) | 71.1 percent predicted FVC | Standard Deviation 14.03 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 336 (n=10) | 64.9 percent predicted FVC | Standard Deviation 13.61 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 360 (n=7) | 60.9 percent predicted FVC | Standard Deviation 15 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 384 (n=6) | 68.4 percent predicted FVC | Standard Deviation 17.43 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 408 (n=4) | 65.1 percent predicted FVC | Standard Deviation 11.84 |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 432 (n=1) | 61.5 percent predicted FVC | — |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 456 (n=1) | 78.4 percent predicted FVC | — |
| Pirfenidone | Percent Predicted Forced Vital Capacity (FVC) | Week 480 (n=1) | 80.9 percent predicted FVC | — |
Secondary
Resting Oxygen Saturation by Pulse Oximetry (SpO2)
SpO2 is the percentage of oxygen saturation in the blood. Oxygen level (oxygen saturation) of the blood was measured using pulse oximetry on room air.
Time frame: Baseline, Weeks 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480
Population: All treated participants. n = participants who were evaluable for specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Baseline (n=72) | 94.5 percentage of oxygen saturation | Standard Deviation 3.53 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 24 (n=55) | 94.4 percentage of oxygen saturation | Standard Deviation 4.14 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 48 (n=47) | 94.8 percentage of oxygen saturation | Standard Deviation 3.05 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 72 (n=41) | 94.9 percentage of oxygen saturation | Standard Deviation 3.01 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 96 (n=36) | 94.9 percentage of oxygen saturation | Standard Deviation 2.77 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 120 (n=35) | 94.8 percentage of oxygen saturation | Standard Deviation 2.46 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 144 (n=33) | 94.8 percentage of oxygen saturation | Standard Deviation 2.78 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 168 (n=25) | 94.0 percentage of oxygen saturation | Standard Deviation 3.18 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 192 (n=22) | 94.9 percentage of oxygen saturation | Standard Deviation 2.59 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 216 (n=23) | 95.2 percentage of oxygen saturation | Standard Deviation 2.33 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 240 (n=17) | 95.5 percentage of oxygen saturation | Standard Deviation 2.67 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 264 (n=11) | 95.7 percentage of oxygen saturation | Standard Deviation 1.56 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 288 (n=10) | 94.6 percentage of oxygen saturation | Standard Deviation 4.09 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 312 (n=11) | 95.8 percentage of oxygen saturation | Standard Deviation 2.48 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 336 (n=9) | 94.4 percentage of oxygen saturation | Standard Deviation 2.35 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 360 (n=7) | 94.9 percentage of oxygen saturation | Standard Deviation 4.02 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 384 (n=7) | 94.0 percentage of oxygen saturation | Standard Deviation 2.77 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 408 (n=6) | 94.8 percentage of oxygen saturation | Standard Deviation 2.86 |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 432 (n=1) | 95.0 percentage of oxygen saturation | — |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 456 (n=1) | 97.0 percentage of oxygen saturation | — |
| Pirfenidone | Resting Oxygen Saturation by Pulse Oximetry (SpO2) | Week 480 (n=3) | 95.0 percentage of oxygen saturation | Standard Deviation 2 |