Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Idiopathic, Pulmonary, Fibrosis, IPF
Brief summary
The primary objectives of this study are to determine the effect of simtuzumab (GS-6624) on progression-free survival (PFS) as determined by either a categorical decline in forced vital capacity (FVC) or all-cause mortality, in all participants enrolled or in a subset of participants who are classified as lysyl oxidase-like-2 (LOXL2) high based on a prespecified level in serum at baseline.
Interventions
DRUGSimtuzumab
125 mg/mL single-dose vials administered subcutaneously once a week
DRUGSimtuzumab placebo
Simtuzumab placebo single-dose vials administered subcutaneously once a week
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female subjects from 45 to 85 years of age * Definite IPF within 3 years prior to screening * Be able to walk at least 50 meters Key
Exclusion criteria
* Significant diseases other than IPF * Obstructive lung disease * Aortic aneurysm greater than or equal to 3.5 cm in diameter * Treatment with immunosuppressive, cytotoxic, or antifibrotic drugs \< 28 days prior to randomization are not permitted. * N-acetylcysteine is permitted provided the individual has been on a stable dose for \> 4 weeks prior to screening * Concomitant use of pirfenidone or nintedanib must be in accordance with the approved prescribing instructions in the country where the site is located * Individuals actively listed for lung transplant are excluded. However individuals at transplant centers with long waiting times (greater than 1 year) may be permitted to enter the study after discussion with Medical Monitor. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Up to 148 weeks | Progression free survival (PFS) was defined as the categorical decrease in forced vital capacity (FVC) % predicted (≥ 10% relative decrease in FVC and ≥ 5% absolute decrease in FVC from baseline) with confirmation at a consecutive visit at least 2 weeks later using the same criteria. |
| PFS Among the Participants With sLOXL2 ≥ 50th Percentile | Up to 148 weeks | — |
| PFS Among the Participants With sLOXL2 ≥ 75th Percentile | Up to 148 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in FVC % Predicted | Weeks 54, 106, and 130 | * FVC was defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted was defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition. * Adjusted means were from mixed model repeated measures (MMRM) model with baseline FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130 * The relative change was calculated as 100% \* ( value at later time point minus value at baseline ) / value at baseline, with lower values indicating a decrease and higher values indicating an increase. |
| Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations | Up to 148 weeks | — |
| Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations | Up to 148 weeks | — |
| Overall Survival (OS) | Up to 151 weeks | Overall survival was defined as the time from randomization date to death that occurred prior to the last dose date plus 30 days. |
| Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Weeks 58, 106, and 130 | * Adjusted means were from MMRM model with baseline 6MWD, FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase. |
| Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 58, 106, and 130 | * The SGRQ is a disease-specific questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase. |
| Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death | Up to 148 weeks | — |
| Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile | Up to 151 weeks | — |
| Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile | Up to 151 weeks | — |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Israel, Italy, Poland, South Korea, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, and Asia Pacific. The first participant was screened on 31 January 2013. The last study visit occurred on 23 February 2016.
Pre-assignment details
1250 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Simtuzumab Simtuzumab 125 mg/mL administered subcutaneously once a week | 272 |
| Simtuzumab Placebo Simtuzumab placebo administered subcutaneously once a week | 272 |
| Total | 544 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 24 | 20 |
| Overall Study | Death | 21 | 26 |
| Overall Study | Investigator Discretion | 7 | 3 |
| Overall Study | Lack of Efficacy | 3 | 2 |
| Overall Study | Participant never dosed with study drug | 1 | 0 |
| Overall Study | Progressive disease | 11 | 6 |
| Overall Study | Protocol defined criteria for withdrawal | 9 | 11 |
| Overall Study | Protocol Violation | 0 | 3 |
| Overall Study | Study terminated by sponsor | 160 | 161 |
| Overall Study | Withdrew consent | 36 | 40 |
Baseline characteristics
| Characteristic | Simtuzumab | Total | Simtuzumab Placebo |
|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 7.6 | 68.1 years STANDARD_DEVIATION 7.34 | 68.5 years STANDARD_DEVIATION 7.07 |
| Baseline Serum LOXL2 | 89.8 pg/mL STANDARD_DEVIATION 70.06 | 88.2 pg/mL STANDARD_DEVIATION 61.48 | 86.7 pg/mL STANDARD_DEVIATION 51.99 |
| Forced vital capacity (FVC) Percent Predicted | 61.4 FVC % predicted STANDARD_DEVIATION 12.17 | 61.8 FVC % predicted STANDARD_DEVIATION 12.19 | 62.3 FVC % predicted STANDARD_DEVIATION 12.22 |
| FVC % Predicted Category Mild | 37 Participants | 83 Participants | 46 Participants |
| FVC % Predicted Category Moderate | 152 Participants | 302 Participants | 150 Participants |
| FVC % Predicted Category Severe | 83 Participants | 159 Participants | 76 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 71 Participants | 36 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 12 Participants | 7 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 267 Participants | 531 Participants | 264 Participants |
| Race/Ethnicity, Customized Not Permitted | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 231 Participants | 460 Participants | 229 Participants |
| Region of Enrollment Australia | 11 Participants | 29 Participants | 18 Participants |
| Region of Enrollment Belgium | 10 Participants | 14 Participants | 4 Participants |
| Region of Enrollment Canada | 10 Participants | 24 Participants | 14 Participants |
| Region of Enrollment Czech Republic | 6 Participants | 12 Participants | 6 Participants |
| Region of Enrollment France | 24 Participants | 36 Participants | 12 Participants |
| Region of Enrollment Germany | 22 Participants | 40 Participants | 18 Participants |
| Region of Enrollment Israel | 7 Participants | 12 Participants | 5 Participants |
| Region of Enrollment Italy | 8 Participants | 14 Participants | 6 Participants |
| Region of Enrollment Korea, Republic of | 34 Participants | 69 Participants | 35 Participants |
| Region of Enrollment Poland | 15 Participants | 28 Participants | 13 Participants |
| Region of Enrollment Spain | 11 Participants | 24 Participants | 13 Participants |
| Region of Enrollment Switzerland | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 12 Participants | 33 Participants | 21 Participants |
| Region of Enrollment United States | 102 Participants | 208 Participants | 106 Participants |
| Sex: Female, Male Female | 45 Participants | 92 Participants | 47 Participants |
| Sex: Female, Male Male | 227 Participants | 452 Participants | 225 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 31 / 271 | 32 / 272 |
| other Total, other adverse events | 237 / 271 | 246 / 272 |
| serious Total, serious adverse events | 101 / 271 | 97 / 272 |
Outcome results
Primary
PFS Among the Participants With sLOXL2 ≥ 50th Percentile
Time frame: Up to 148 weeks
Population: Participants in the ITT Analysis Set with serum LOXL2 (sLOXL2) ≥ 50th percentile in peripheral blood were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | PFS Among the Participants With sLOXL2 ≥ 50th Percentile | 11.7 months |
| Simtuzumab Placebo | PFS Among the Participants With sLOXL2 ≥ 50th Percentile | 14.3 months |
p-value: 0.85195% CI: [0.74, 1.43]Log Rank
Primary
PFS Among the Participants With sLOXL2 ≥ 75th Percentile
Time frame: Up to 148 weeks
Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | PFS Among the Participants With sLOXL2 ≥ 75th Percentile | 11.6 months |
| Simtuzumab Placebo | PFS Among the Participants With sLOXL2 ≥ 75th Percentile | 16.9 months |
p-value: 0.47595% CI: [0.72, 2]Log Rank
Primary
Progression Free Survival
Progression free survival (PFS) was defined as the categorical decrease in forced vital capacity (FVC) % predicted (≥ 10% relative decrease in FVC and ≥ 5% absolute decrease in FVC from baseline) with confirmation at a consecutive visit at least 2 weeks later using the same criteria.
Time frame: Up to 148 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | Progression Free Survival | 12.6 months |
| Simtuzumab Placebo | Progression Free Survival | 15.4 months |
p-value: 0.32995% CI: [0.88, 1.45]Log Rank
Secondary
Absolute Change From Baseline in 6 Minute Walk Distance (6MWD)
* Adjusted means were from MMRM model with baseline 6MWD, FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time frame: Weeks 58, 106, and 130
Population: Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Simtuzumab | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 58 | -33.76 Meters | Standard Error 6.617 |
| Simtuzumab | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 106 | -37.43 Meters | Standard Error 9.71 |
| Simtuzumab | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 130 | -71.20 Meters | Standard Error 19.14 |
| Simtuzumab Placebo | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 58 | -14.70 Meters | Standard Error 6.596 |
| Simtuzumab Placebo | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 106 | -24.30 Meters | Standard Error 10.318 |
| Simtuzumab Placebo | Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) | Week 130 | -31.65 Meters | Standard Error 18.458 |
Secondary
Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score
* The SGRQ is a disease-specific questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time frame: Week 58, 106, and 130
Population: Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Simtuzumab | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 58 | 6.07 units on a scale | Standard Error 1.015 |
| Simtuzumab | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 106 | 10.34 units on a scale | Standard Error 1.425 |
| Simtuzumab | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 130 | 18.10 units on a scale | Standard Error 2.424 |
| Simtuzumab Placebo | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 58 | 3.62 units on a scale | Standard Error 1.01 |
| Simtuzumab Placebo | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 106 | 6.54 units on a scale | Standard Error 1.559 |
| Simtuzumab Placebo | Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score | Week 130 | 1.08 units on a scale | Standard Error 2.473 |
Secondary
Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations
Time frame: Up to 148 weeks
Population: Participants in the ITT Analysis Set with adjudicated respiratory hospitalizations were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Simtuzumab | Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations | 5 Participants |
| Simtuzumab Placebo | Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations | 5 Participants |
Secondary
Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations
Time frame: Up to 148 weeks
Population: Participants in ITT Analysis Set with total hospitalizations were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Simtuzumab | Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations | 99 Participants |
| Simtuzumab Placebo | Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations | 84 Participants |
Secondary
Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death
Time frame: Up to 148 weeks
Population: Participants in the ITT Analysis Set with adjudicated deaths were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Simtuzumab | Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death | 17 Participants |
| Simtuzumab Placebo | Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death | 13 Participants |
Secondary
Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile
Time frame: Up to 151 weeks
Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 50th percentile in peripheral blood were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile | NA months |
| Simtuzumab Placebo | Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile | NA months |
p-value: 0.98895% CI: [0.43, 2.28]Log Rank
Secondary
Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile
Time frame: Up to 151 weeks
Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile | NA months |
| Simtuzumab Placebo | Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile | NA months |
p-value: 0.92595% CI: [0.3, 2.99]Log Rank
Secondary
Overall Survival (OS)
Overall survival was defined as the time from randomization date to death that occurred prior to the last dose date plus 30 days.
Time frame: Up to 151 weeks
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simtuzumab | Overall Survival (OS) | NA months |
| Simtuzumab Placebo | Overall Survival (OS) | NA months |
p-value: 0.60295% CI: [0.61, 2.37]Log Rank
Secondary
Relative Change From Baseline in FVC % Predicted
* FVC was defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted was defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition. * Adjusted means were from mixed model repeated measures (MMRM) model with baseline FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130 * The relative change was calculated as 100% \* ( value at later time point minus value at baseline ) / value at baseline, with lower values indicating a decrease and higher values indicating an increase.
Time frame: Weeks 54, 106, and 130
Population: Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Simtuzumab | Relative Change From Baseline in FVC % Predicted | Week 54 | -9.20 Percent change in FVC % predicted | Standard Error 0.643 |
| Simtuzumab | Relative Change From Baseline in FVC % Predicted | Week 106 | -13.70 Percent change in FVC % predicted | Standard Error 0.883 |
| Simtuzumab | Relative Change From Baseline in FVC % Predicted | Week 130 | -18.09 Percent change in FVC % predicted | Standard Error 1.712 |
| Simtuzumab Placebo | Relative Change From Baseline in FVC % Predicted | Week 54 | -8.88 Percent change in FVC % predicted | Standard Error 0.658 |
| Simtuzumab Placebo | Relative Change From Baseline in FVC % Predicted | Week 106 | -12.16 Percent change in FVC % predicted | Standard Error 0.908 |
| Simtuzumab Placebo | Relative Change From Baseline in FVC % Predicted | Week 130 | -11.83 Percent change in FVC % predicted | Standard Error 1.6 |