Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Idiopathic Pulmonary Fibrosis, IPF, Idiopathic Interstitial Pneumonia, Interstitial Lung Disease, Lung Fibrosis
Brief summary
This is a Phase 3 trial to evaluate the efficacy and safety of 30 milligrams (mg)/kilogram (kg) intravenous (IV) infusions of pamrevlumab administered every 3 weeks as compared to placebo in participants with IPF.
Detailed description
This is a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of pamrevlumab in participants with IPF. Participants who are not being treated with approved IPF therapies (that is, nintedanib or pirfenidone) may be eligible for screening. Examples of reasons participants may not be treated with approved IPF therapies include but are not limited to: * Intolerant or not responsive to approved IPF therapies * Ineligible to receive these therapies * Participant voluntarily declines to receive approved IPF therapies after being fully informed of the potential benefits/risks NOTE: No participant should discontinue an approved IPF therapy for the purpose of enrolling in this study. The study consists of the following study periods: * Main (double blind, placebo-controlled) phase: * Screening period: Up to 6 weeks * Treatment period: 48 weeks * Optional, open-label extension (OLE) phase of pamrevlumab: o Access to pamrevlumab will be available until the last participant completes 48 weeks of treatment in the OLE phase, or pamrevlumab is commercially available for the indication of IPF, or the Sponsor decides to end the OLE phase, whichever occurs first. * Follow-up period/final safety assessments: * 28 days after last dose * 60 days after last dose: follow-up phone call, for a final safety assessment During the treatment period, co-administration of an approved IPF therapy (that is, pirfenidone or nintedanib) is acceptable if clinically indicated in the Investigator's opinion, provided that the Investigator assesses the potential risks/benefits of combining approved IPF therapies with blinded study treatment. Participants who discontinue study treatment for any reason should be encouraged to remain in the study and be followed for all study visits and assessments. Participants who complete the Week 48 visit of the main study (regardless of the number of study drug infusions received) will be eligible to participate in the optional OLE phase of the study that offers continuing access to pamrevlumab regardless of randomization assignment in the main study.
Interventions
DRUGPamrevlumab
Pamrevlumab will be administered per dose and schedule specified in the arm description.
DRUGPlacebo
Placebo matching to pamrevlumab will be administered per schedule specified in the arm description.
Sponsors
FibroGen
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 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Diagnosis of IPF as defined by American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japan Radiological Society (JRS)/Latin American Thoracic Association (ALAT) guidelines within the past 7 years prior to study participation. 2. High-resolution computed tomography (HRCT) scan at screening, with ≥10% to \<50% parenchymal fibrosis (reticulation) and \<25% honeycombing. 3. FVCpp value \>45% and \<95% at screening and Day 1 (prior to randomization). 4. Diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted and corrected by hemoglobin (Hb) value ≥25% and ≤90% at screening (determined locally). 5. Not currently receiving treatment for IPF with an approved therapy (that is, pirfenidone or nintedanib) for any reason, including prior intolerance or lack of response to an approved IPF therapy, or choice to forego treatment with an approved IPF therapy after a full discussion with the Investigator regarding risks/benefits of such therapy. Key
Exclusion criteria
1. Previous exposure to pamrevlumab. 2. Evidence of significant obstructive lung disease. 3. Female participants who are pregnant or nursing. 4. Smoking within 3 months of screening and/or unwilling to avoid smoking throughout the study. 5. Interstitial lung disease other than IPF. 6. Sustained improvement in the severity of IPF during the 12 months prior to screening. 7. History of other types of respiratory diseases including diseases or disorders of the airways, lung parenchyma, pleural space, mediastinum, diaphragm, or chest wall. 8. Medical conditions (for example, myocardial infarction \[MI\]/stroke within the past 6 month), or logistical challenges that in the opinion of the Investigator preclude the participant's adequate participation in the study. 9. Acute IPF exacerbation during screening or randomization. 10. Use of any investigational drugs or unapproved therapies, or participation in any clinical trial with an investigational new drug within 30 days prior to screening. Or use of approved IPF therapies (that is, pirfenidone or nintedanib) within 1 week prior to screening. 11. History of allergic or anaphylactic reaction to human, humanized, chimeric or murine monoclonal antibodies, or to any component of the excipient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DB Period (Main Study Cohort): Change From Baseline in FVC at Week 48 | Baseline, Week 48 | FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that could forcibly be blown out after full inspiration in the upright position, measured in liters. Least square (LS) mean and standard error (SE) were calculated using mixed model for repeated measures (MMRM). |
| DB Period (Japan Extension Cohort): Change From Baseline in FVC at Week 48 | Baseline, Week 48 | FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that could forcibly be blown out after full inspiration in the upright position, measured in liters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48 | Baseline, Week 48 | The QLF volume was calculated as QLF = total lung capacity volume multiplied by percentage (%) of quantitative lung fibrosis for fibrosis of the whole lung. LS mean and SE was calculated using MMRM. |
| DB Period (Main Study Cohort): Time to First Acute IPF Exacerbation | Up to Week 48 | Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks. |
| DB Period (Main Study Cohort): Time to Disease Progression | Up to Week 48 | Time to disease progression was defined as the number of weeks from randomization to either the first occurrence of an absolute ≥10% decline from baseline in percent predicted FVC (FVCpp) or all-cause death, whichever occurred first. Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks. |
| DB Period (Main Study Cohort): Time to First Respiratory Hospitalizations | Up to Week 48 | Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks. |
| DB Period (Main Study Cohort): Time to All-Cause Mortality | Up to Week 48 | Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks. |
| DB Period (Main Study Cohort): Time to First Occurrence of Any Component of the Clinical Composite Endpoint | Up to Week 48 | The components of the clinical composite endpoint included acute IPF exacerbation, respiratory hospitalization, or death. Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks. |
Countries
Argentina, Australia, Chile, China, Hong Kong, Russia, South Korea, Taiwan, United States
Participant flow
Pre-assignment details
The study included a double-blind (DB) period (main study cohort and Japan extension cohort) and an open-label extension (OLE) period. OLE period was not conducted in Japan. The efficacy outcome measures data were not collected for Japan cohorts due to early termination of study.
Participants by arm
| Arm | Count |
|---|---|
| DB Period (Main Study Cohort): Pamrevlumab Participants received pamrevlumab 30 mg/kg by IV infusion every 3 weeks for up to 48 weeks in the DB period and continued to receive the same dose of pamrevlumab for up to 48 weeks in the OLE period or until pamrevlumab was commercially available for the indication of IPF, or the sponsor decided to end the OLE period, whichever occurred first. | 181 |
| DB Period (Main Study Cohort): Placebo Participants received placebo matched to pamrevlumab by IV infusion every 3 weeks for up to 48 weeks in the DB period. Participants received pamrevlumab 30 mg/kg by IV infusion every 3 weeks for up to 48 weeks in the OLE period or until pamrevlumab was commercially available for the indication of IPF, or the sponsor decided to end the OLE period, whichever occurred first. | 175 |
| DB Period (Japan Extension Cohort): Pamrevlumab Participants received pamrevlumab 30 mg/kg by IV infusion every 3 weeks for up to 48 weeks. | 18 |
| DB Period (Japan Extension Cohort): Placebo Participants received placebo matched to pamrevlumab by IV infusion every 3 weeks for up to 48 weeks. | 19 |
| Total | 393 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| DB Period (48 Weeks) | Adverse Event | 2 | 5 | 1 | 2 |
| DB Period (48 Weeks) | Death | 13 | 17 | 1 | 0 |
| DB Period (48 Weeks) | Disease Progression | 2 | 0 | 0 | 0 |
| DB Period (48 Weeks) | Investigator Decision | 2 | 2 | 0 | 0 |
| DB Period (48 Weeks) | Lung Transplant | 0 | 1 | 0 | 0 |
| DB Period (48 Weeks) | Noncompliance with the Study Drug | 1 | 1 | 0 | 0 |
| DB Period (48 Weeks) | Participant Decision | 9 | 12 | 1 | 1 |
| DB Period (48 Weeks) | Study terminated by sponsor | 0 | 0 | 1 | 4 |
| DB Period (48 Weeks) | Withdrawal by Subject | 6 | 3 | 0 | 1 |
| OLE (Maximum Exposure: 153.1 Weeks) | Adverse Event | 7 | 1 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Death | 12 | 12 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Disease Progression | 1 | 0 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Investigator Decision | 2 | 2 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Lung Transplant | 2 | 1 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Other than specified | 1 | 0 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Participant Decision | 12 | 13 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Protocol Deviation | 1 | 0 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Study terminated by sponsor | 84 | 88 | 0 | 0 |
| OLE (Maximum Exposure: 153.1 Weeks) | Withdrawal by Subject | 7 | 5 | 0 | 0 |
Baseline characteristics
| Characteristic | DB Period (Japan Extension Cohort): Pamrevlumab | DB Period (Main Study Cohort): Placebo | DB Period (Main Study Cohort): Pamrevlumab | DB Period (Japan Extension Cohort): Placebo | Total |
|---|---|---|---|---|---|
| Age, Customized ≤64 Years | 3 Participants | 28 Participants | 41 Participants | 5 Participants | 77 Participants |
| Age, Customized 65 - 74 Years | 10 Participants | 94 Participants | 77 Participants | 5 Participants | 186 Participants |
| Age, Customized ≥75 Years | 5 Participants | 53 Participants | 63 Participants | 9 Participants | 130 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 44 Participants | 54 Participants | 0 Participants | 98 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 131 Participants | 127 Participants | 19 Participants | 295 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Forced Vital Capacity (FVC) Japan Extension Cohort | 2.5864 liters STANDARD_DEVIATION 0.5521 | — | — | 2.5486 liters STANDARD_DEVIATION 0.5153 | 2.5670 liters STANDARD_DEVIATION 0.5264 |
| Forced Vital Capacity (FVC) Main Study Cohort | — | 2.4161 liters STANDARD_DEVIATION 0.6453 | 2.3668 liters STANDARD_DEVIATION 0.6185 | — | 2.3911 liters STANDARD_DEVIATION 0.6314 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 69 Participants | 63 Participants | 19 Participants | 169 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 0 Participants | 104 Participants | 117 Participants | 0 Participants | 221 Participants |
| Sex: Female, Male Female | 5 Participants | 49 Participants | 49 Participants | 3 Participants | 106 Participants |
| Sex: Female, Male Male | 13 Participants | 126 Participants | 132 Participants | 16 Participants | 287 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 181 | 22 / 175 | 1 / 18 | 2 / 19 | 17 / 129 | 14 / 123 |
| other Total, other adverse events | 129 / 181 | 121 / 175 | 17 / 18 | 16 / 19 | 76 / 129 | 75 / 123 |
| serious Total, serious adverse events | 51 / 181 | 60 / 175 | 5 / 18 | 8 / 19 | 42 / 129 | 33 / 123 |
Outcome results
Primary
DB Period (Japan Extension Cohort): Change From Baseline in FVC at Week 48
FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that could forcibly be blown out after full inspiration in the upright position, measured in liters.
Time frame: Baseline, Week 48
Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Japan Extension Cohort): Change From Baseline in FVC at Week 48 | -0.0445 liters | Standard Deviation 0.1805 |
| DB Period (Main Study Cohort) - Placebo | DB Period (Japan Extension Cohort): Change From Baseline in FVC at Week 48 | -0.1835 liters | Standard Deviation 0.2389 |
Primary
DB Period (Main Study Cohort): Change From Baseline in FVC at Week 48
FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that could forcibly be blown out after full inspiration in the upright position, measured in liters. Least square (LS) mean and standard error (SE) were calculated using mixed model for repeated measures (MMRM).
Time frame: Baseline, Week 48
Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Change From Baseline in FVC at Week 48 | -0.26 liters | Standard Error 0.046 |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Change From Baseline in FVC at Week 48 | -0.33 liters | Standard Error 0.05 |
p-value: 0.292695% CI: [-0.06, 0.19]Mixed Models Analysis
Secondary
DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48
The QLF volume was calculated as QLF = total lung capacity volume multiplied by percentage (%) of quantitative lung fibrosis for fibrosis of the whole lung. LS mean and SE was calculated using MMRM.
Time frame: Baseline, Week 48
Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48 | 251.38 liters | Standard Error 38.01 |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48 | 267.96 liters | Standard Error 38.763 |
| DB Period (Japan Extension Cohort): Pamrevlumab | DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48 | 45.08 liters | Standard Error 88.265 |
| DB Period (Japan Extension Cohort): Placebo | DB Period (Main Study Cohort and Japan Extension Cohort): Change From Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48 | 78.18 liters | Standard Error 119.3 |
Secondary
DB Period (Main Study Cohort): Time to All-Cause Mortality
Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks.
Time frame: Up to Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Time to All-Cause Mortality | NA weeks |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Time to All-Cause Mortality | NA weeks |
Secondary
DB Period (Main Study Cohort): Time to Disease Progression
Time to disease progression was defined as the number of weeks from randomization to either the first occurrence of an absolute ≥10% decline from baseline in percent predicted FVC (FVCpp) or all-cause death, whichever occurred first. Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks.
Time frame: Up to Week 48
Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Time to Disease Progression | 54.3 weeks |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Time to Disease Progression | 50.7 weeks |
Secondary
DB Period (Main Study Cohort): Time to First Acute IPF Exacerbation
Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks.
Time frame: Up to Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Time to First Acute IPF Exacerbation | 62.7 weeks |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Time to First Acute IPF Exacerbation | NA weeks |
Secondary
DB Period (Main Study Cohort): Time to First Occurrence of Any Component of the Clinical Composite Endpoint
The components of the clinical composite endpoint included acute IPF exacerbation, respiratory hospitalization, or death. Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks.
Time frame: Up to Week 48
Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Time to First Occurrence of Any Component of the Clinical Composite Endpoint | 62.7 weeks |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Time to First Occurrence of Any Component of the Clinical Composite Endpoint | NA weeks |
Secondary
DB Period (Main Study Cohort): Time to First Respiratory Hospitalizations
Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. Hence, the 'Median Time to Event' is longer than the reported timeframe of 48 weeks.
Time frame: Up to Week 48
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DB Period (Main Study Cohort) - Pamrevlumab | DB Period (Main Study Cohort): Time to First Respiratory Hospitalizations | 62.7 weeks |
| DB Period (Main Study Cohort) - Placebo | DB Period (Main Study Cohort): Time to First Respiratory Hospitalizations | NA weeks |