Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
This is a prospective, phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of garadacimab in subjects with idiopathic pulmonary fibrosis (IPF).
Interventions
DRUGGaradacimab
Participants received garadacimab intravenous (IV) loading dose followed by 3 subcutaneous (SC) doses.
DRUGPlacebo
Participants received a matching placebo IV loading dose, followed by 3 SC doses.
Sponsors
CSL Behring
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 40 years of age * Documented diagnosis of IPF
Exclusion criteria
* History of clinically significant cardiovascular disease, including myocardial infarction, unstable ischemic heart disease, congestive heart failure, or angina during the 6 months before screening * Sinoatrial or atrioventricular block, uncontrolled hypertension * Active bleeding or current clinically significant coagulopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent (TE) Serious Adverse Events (SAEs) | Up to 22 weeks | A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event. |
| Percentage of Participants With TE SAEs | Up to 22 weeks | A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event |
| Number of Participants With TE Adverse Events of Special Interests (AESIs) | Up to 22 weeks | The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the Investigator, Thromboembolic events (non-systemic thrombosis \[e.g., localized thrombosis associated with vascular access\] was not considered an AESI), and Severe hypersensitivity including anaphylaxis. |
| Percentage of Participants With TE-AESIs | Up to 22 weeks | The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the Investigator, Thromboembolic events (non-systemic thrombosis \[e.g., localized thrombosis associated with vascular access\] was not considered an AESI), and Severe hypersensitivity including anaphylaxis. |
| Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma | At Day 36 and Day 92 after the first treatment | — |
| Percentage of Participants With Garadacimab Induced ADAs in Plasma | At Day 36 and Day 92 after the first treatment | — |
| Number of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as Adverse Events (AEs) | Up to 14 weeks after treatment | — |
| Percentage of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as AEs | Up to 14 weeks after treatment | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Plasma Concentration (Ctrough) After SC Administration of Garadacimab | At Day 36 and Day 64 | — |
| Mean Percentage of Baseline in FXIIa-mediated Kallikrein Activity | Baseline and at Day 92 | Percent baseline is calculated by using the formula visit value / baseline value multiplied by 100, percent baseline is reported as percentage in the outcome measure. |
| Maximum Plasma Concentration (Cmax) (Last SC Dosing Interval Only) of Garadacimab | After dosing on Day 64 | — |
| Time to Maximum Plasma Concentration (Tmax) (Last SC Dosing Interval Only) of Garadacimab | After dosing on Day 64 | — |
| Area Under the Plasma Concentration-time Curve Over the Dose Interval (AUC0-tau) (Last SC Dosing Interval Only) of Garadacimab | After dosing on Day 64 | — |
| Ctrough After IV Administration of Garadacimab | At Day 8 | — |
| Cmax After IV Administration of Garadacimab | After dosing on Day 1 | — |
| Tmax After IV Administration of Garadacimab | After dosing on Day 1 | — |
| Mean Change From Baseline in FXIIa-mediated Kallikrein Activity | Baseline and at Day 92 | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 47 study sites in 11 countries (Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Poland, Spain, the United Kingdom \[UK\], and the United States of America \[USA\]). No participants from Italy were enrolled in the study.
Pre-assignment details
A total of 131 potential participants were screened for eligibility. Out of these, 81 participants met all selection criteria and were enrolled in the study, and 50 individuals failed to meet the selection criteria and were not enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Garadacimab Participants received garadacimab IV loading dose followed by 3 SC doses. | 40 |
| Placebo Participants received a matching placebo IV loading dose, followed by 3 SC doses. | 41 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Garadacimab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 38 Participants | 38 Participants | 76 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Continuous | 72.6 years STANDARD_DEVIATION 6.19 | 72.9 years STANDARD_DEVIATION 6.17 | 72.8 years STANDARD_DEVIATION 6.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 39 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 40 Participants | 40 Participants | 80 Participants |
| Region of Enrollment Australia | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Austria | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Belgium | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Canada | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Denmark | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Germany | 3 Participants | 4 Participants | 7 Participants |
| Region of Enrollment Poland | 5 Participants | 4 Participants | 9 Participants |
| Region of Enrollment Spain | 1 Participants | 3 Participants | 4 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 19 Participants | 21 Participants | 40 Participants |
| Sex: Female, Male Female | 14 Participants | 21 Participants | 35 Participants |
| Sex: Female, Male Male | 26 Participants | 20 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 40 | 1 / 41 |
| other Total, other adverse events | 18 / 40 | 19 / 41 |
| serious Total, serious adverse events | 5 / 40 | 2 / 41 |
Outcome results
Primary
Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma
Time frame: At Day 36 and Day 92 after the first treatment
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure and the Number Analyzed (n), included all participants who were evaluated for this outcome measure for the specified timepoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Garadacimab | Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma | At Day 36 | 1 Participants |
| Garadacimab | Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma | At Day 92 | 1 Participants |
| Placebo | Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma | At Day 36 | 2 Participants |
| Placebo | Number of Participants With Garadacimab Induced Anti Drug Antibodies (ADAs) in Plasma | At Day 92 | 1 Participants |
Primary
Number of Participants With TE Adverse Events of Special Interests (AESIs)
The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the Investigator, Thromboembolic events (non-systemic thrombosis \[e.g., localized thrombosis associated with vascular access\] was not considered an AESI), and Severe hypersensitivity including anaphylaxis.
Time frame: Up to 22 weeks
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Garadacimab | Number of Participants With TE Adverse Events of Special Interests (AESIs) | 2 Participants |
| Placebo | Number of Participants With TE Adverse Events of Special Interests (AESIs) | 0 Participants |
Primary
Number of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as Adverse Events (AEs)
Time frame: Up to 14 weeks after treatment
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Garadacimab | Number of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as Adverse Events (AEs) | 0 Participants |
| Placebo | Number of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as Adverse Events (AEs) | 0 Participants |
Primary
Number of Participants With Treatment-emergent (TE) Serious Adverse Events (SAEs)
A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event.
Time frame: Up to 22 weeks
Population: This analysis was performed on the safety analysis set (SAS). The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Garadacimab | Number of Participants With Treatment-emergent (TE) Serious Adverse Events (SAEs) | 5 Participants |
| Placebo | Number of Participants With Treatment-emergent (TE) Serious Adverse Events (SAEs) | 2 Participants |
Primary
Percentage of Participants With Garadacimab Induced ADAs in Plasma
Time frame: At Day 36 and Day 92 after the first treatment
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure and the Number Analyzed (n), included all participants who were evaluated for this outcome measure for the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Garadacimab | Percentage of Participants With Garadacimab Induced ADAs in Plasma | At Day 36 | 2.6 Percentage of participants |
| Garadacimab | Percentage of Participants With Garadacimab Induced ADAs in Plasma | At Day 92 | 2.6 Percentage of participants |
| Placebo | Percentage of Participants With Garadacimab Induced ADAs in Plasma | At Day 36 | 5.4 Percentage of participants |
| Placebo | Percentage of Participants With Garadacimab Induced ADAs in Plasma | At Day 92 | 2.8 Percentage of participants |
Primary
Percentage of Participants With TE-AESIs
The following TEAEs were considered as AESIs: Bleeding events that were abnormal in the opinion of the Investigator, Thromboembolic events (non-systemic thrombosis \[e.g., localized thrombosis associated with vascular access\] was not considered an AESI), and Severe hypersensitivity including anaphylaxis.
Time frame: Up to 22 weeks
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Garadacimab | Percentage of Participants With TE-AESIs | 5.0 Percentage of participants |
| Placebo | Percentage of Participants With TE-AESIs | 0 Percentage of participants |
Primary
Percentage of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as AEs
Time frame: Up to 14 weeks after treatment
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Garadacimab | Percentage of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as AEs | 0.0 Percentage of participants |
| Placebo | Percentage of Participants With TE Clinically Significant Abnormalities in Laboratory Assessments Reported as AEs | 0.0 Percentage of participants |
Primary
Percentage of Participants With TE SAEs
A TE SAE is defined as an SAE reported at or after the start of the first administration of study treatment. A SAE is defined as any untoward medical occurrence that at any dose results in: death, life-threatening event, initial or prolongation of existing hospitalization, disability or incapacity, congenital anomaly or birth defect, or any other medically significant event
Time frame: Up to 22 weeks
Population: This analysis was performed on the SAS. The SAS was defined as all participants who received any portion of an IV infusion or SC injection of garadacimab or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Garadacimab | Percentage of Participants With TE SAEs | 12.5 Percentage of participants |
| Placebo | Percentage of Participants With TE SAEs | 4.9 Percentage of participants |
Secondary
Area Under the Plasma Concentration-time Curve Over the Dose Interval (AUC0-tau) (Last SC Dosing Interval Only) of Garadacimab
Time frame: After dosing on Day 64
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Area Under the Plasma Concentration-time Curve Over the Dose Interval (AUC0-tau) (Last SC Dosing Interval Only) of Garadacimab | 18094.6128 h*ug/mL | Standard Deviation 6977.9036 |
Secondary
Cmax After IV Administration of Garadacimab
Time frame: After dosing on Day 1
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Cmax After IV Administration of Garadacimab | 79.636 ug/mL | Standard Deviation 31.4406 |
Secondary
Ctrough After IV Administration of Garadacimab
Time frame: At Day 8
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Ctrough After IV Administration of Garadacimab | 18.6054 ug/mL | Standard Deviation 7.9685 |
Secondary
Maximum Plasma Concentration (Cmax) (Last SC Dosing Interval Only) of Garadacimab
Time frame: After dosing on Day 64
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Maximum Plasma Concentration (Cmax) (Last SC Dosing Interval Only) of Garadacimab | 37.41 ug/mL | Standard Deviation 15.507 |
Secondary
Mean Change From Baseline in FXIIa-mediated Kallikrein Activity
Time frame: Baseline and at Day 92
Population: This analysis was performed on pharmacodynamic analysis set (PDS). The PDS was defined as all participants in the SAS for whom analysis results were obtained for \>= 1 of the exploratory biomarkers of interest. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Mean Change From Baseline in FXIIa-mediated Kallikrein Activity | -0.0258 Nanomoles/liter/minutes (nmol/L/mins) | Standard Deviation 0.0657 |
| Placebo | Mean Change From Baseline in FXIIa-mediated Kallikrein Activity | 0.0072 Nanomoles/liter/minutes (nmol/L/mins) | Standard Deviation 0.0706 |
Secondary
Mean Percentage of Baseline in FXIIa-mediated Kallikrein Activity
Percent baseline is calculated by using the formula visit value / baseline value multiplied by 100, percent baseline is reported as percentage in the outcome measure.
Time frame: Baseline and at Day 92
Population: This analysis was performed on PDS. The PDS was defined as all participants in the SAS for whom analysis results were obtained for \>= 1 of the exploratory biomarkers of interest. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Garadacimab | Mean Percentage of Baseline in FXIIa-mediated Kallikrein Activity | 129.56 Percent baseline | Standard Deviation 215.689 |
| Placebo | Mean Percentage of Baseline in FXIIa-mediated Kallikrein Activity | 124.83 Percent baseline | Standard Deviation 68.872 |
Secondary
Time to Maximum Plasma Concentration (Tmax) (Last SC Dosing Interval Only) of Garadacimab
Time frame: After dosing on Day 64
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Garadacimab | Time to Maximum Plasma Concentration (Tmax) (Last SC Dosing Interval Only) of Garadacimab | 165.4585 Hours (h) |
Secondary
Tmax After IV Administration of Garadacimab
Time frame: After dosing on Day 1
Population: This analysis was performed on PKS. The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Garadacimab | Tmax After IV Administration of Garadacimab | 0.1000 h |
Secondary
Trough Plasma Concentration (Ctrough) After SC Administration of Garadacimab
Time frame: At Day 36 and Day 64
Population: This analysis was performed on pharmacokinetic analysis set (PKS). The PKS was defined as all participants in the SAS who received \>= 1 dose of garadacimab with \>= 1 measurable concentration of garadacimab after administration. Here, the Overall Number of Participants Analyzed (N) included all participants who were evaluated for this outcome measure and the Number Analyzed (n), included all participants who were evaluated for this outcome measure for the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Garadacimab | Trough Plasma Concentration (Ctrough) After SC Administration of Garadacimab | At Day 36 | 16.445 Microgram/milliliter (ug/mL) | Standard Deviation 6.0362 |
| Garadacimab | Trough Plasma Concentration (Ctrough) After SC Administration of Garadacimab | At Day 64 | 17.123 Microgram/milliliter (ug/mL) | Standard Deviation 7.9383 |