Kidney Disease, Chronic
Conditions
Brief summary
This study is open to adults with a type of kidney disease called focal segmental glomerulosclerosis (FSGS). The purpose of this study is to find out whether a medicine called BI 764198 improves the health of the kidneys in people with FSGS. Three different doses of BI 764198 are tested in this study. Participants are put into 4 groups randomly, which means by chance. Three of the groups receive different doses of BI 764198 and one group receives placebo. Participants are in the study for about 4 months. For about 3 months, they take BI 764198 or placebo as capsules once a day. Placebo capsules look like BI 764198 capsules but do not contain any medicine. Participants visit the study site about 10 times. You can participate in this study from your home. In this case a research nurse will visit you for the study visits. Kidney health is assessed based on the analysis of urine samples, which participants collect at home. At the end of the study, the results are compared between the different groups. During the study, the doctors also regularly check the general health of the participants.
Interventions
DRUGBI 764198
One single capsule of 20 milligrams (mg), 40 mg, or 80 mg of BI 764198 orally, once a day.
DRUGPlacebo
One single capsule of placebo matching BI 764198 orally, once a day.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients 18 years to 75 years (both inclusive) of age on the day of signing informed consent. * Patients diagnosed with biopsy proven primary Focal Segmental Glomerulosclerosis (FSGS) or documented Transient Receptor Potential Cation subfamily C Member 6 (TRPC6) gene mutation causing FSGS prior to screening visit. * Urine Protein-Creatinine Ratio (UPCR) ≥ 1000 mg/g based on first morning void urine sample during screening. * Patients treated with corticosteroids must be on a stable dose for at least 4 weeks prior to screening visit with no plan to change the dose until end of trial treatment. * Patients treated with Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin II Receptor Blockers (ARBs), finerenone, aldosterone inhibitors, or Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors should be on a stable dose for at least 4 weeks prior to screening visit with no plan to change the dose until end of trial treatment. * Body Mass Index (BMI) of ≤ 40 kg/m² at screening visit. * Women of childbearing potential (WOCBP) must be willing and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the informed consent form (ICF) and in the study protocol. Further inclusion criteria apply.
Exclusion criteria
* Known monogenic (with the exception of TRPC6 gene mutations) or clinical or histologic evidence of secondary FSGS. * Documented Alport syndrome, Nail Patella syndrome, diabetic nephropathy, Immunoglobulin A (IgA)-nephropathy, lupus nephritis, or monoclonal gammopathy (e.g., multiple myeloma). * Concomitant use of calcineurin inhibitors. * Concomitant treatment with cytotoxic agents (cyclophosphamide, chlorambucil), or CD20 monoclonal antibody, e.g., rituximab, within 5 half-lives before screening visit. Note: use of other immunosuppression therapies considered as standard of care may be allowed as long as the patient remains on stable dose throughout the study. * Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m² at screening visit. * Time between start of the Q-wave and end of the T-wave in an electrocardiogram interval corrected for heart rate (QTc) intervals (QT interval corrected for heart rate using the method of Fridericia - QTcF) greater than 450 ms in males or greater than 470 ms in females, or any other clinically relevant electrocardiogram (ECG) findings (at the investigator's discretion) at screening visit. * Detection of graded cataract by Lens Opacities Classification System III (LOCS III) higher than NC1/NO1, C0, P0 in the slit lamp eye examination at screening visit. Planned cataract surgery during participation in the study. Patients with cataract who have undergone lens replacement are not excluded. * Women who are pregnant, nursing, or who plan to become pregnant while in the study. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12 | At baseline and Week 12. | Predicted probability of patients as a percentage - predicted percentage of patients - achieving at least 25% reduction in 24-hour urine protein creatinine ratio (UPCR) relative to baseline at Week 12 (responders) is reported. Baseline was the average of two 24-hour urine samples collected before Visit 2 (Week 0). Patients who either missed their Week 12, 24-hour UPCR assessment or their Week 12, 24-hour UPCR assessment, occurred later than 5 days after the last dose (Residual Effect Period), were considered as non-responders. The predicted probability of response was calculated using a logistic regression utilizing corticosteroid use at randomization and baseline 24-hr UPCR as covariates and is presented as a percentage. |
| Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR) | At baseline and at Week 12. | Relative change from baseline at Week 12 in 24-hour urine protein creatinine ratio (UPCR), is reported. Baseline was the average of two 24-hour urine samples collected before Visit 2 (Week 0). An analysis of covariance (ANCOVA) model was used to estimate the relative change in UPCR from baseline to Week 12 with corticosteroid use at randomization and baseline 24-hr UPCR as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12 | At Week 1 and Week 12. | Median change in 24-hour urine protein creatinine ratio (UPCR) relative to Visit 3 (Week 1) at Week 12, is calculated by subtracting the 24-hour UPCR, \[Week 12\] - \[Week 1\] values per patient, then by calculating the median of these changes, per treatment group. |
| Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13 | At baseline and at Week 13. | Median change in 24-hour urine protein creatinine ratio (UPCR) relative to baseline at Week 13, is calculated by subtracting the 24-hour UPCR, \[Week 13\] - \[baseline\] values per patient,then by calculating the median of these changes, per treatment group. Baseline was the average of two, 24-hour urine samples collected before Visit 2 (Week 0). |
| Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12 | At baseline and at Week 12. | Median change in 24-hour urinary excretion rate relative to baseline at Week 12, is calculated by subtracting the urinary excretion rate, \[Week 12\] - \[baseline\], values per patient, then by calculating the median of these changes, per treatment group. Baseline was the average of two, 24-hour urine samples collected before Visit 2 (Week 0). |
| Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | At 671.917 hours and at 2015.917 hours after first drug administration. | Pre-dose Plasma Concentration of BI 764198 at steady-state (Cpre,ss ) at Week 4 and Week 12 is reported. |
Countries
Australia, Belgium, China, France, Germany, Italy, New Zealand, Spain, United Kingdom, United States
Participant flow
Recruitment details
Randomized, double-blind, parallel group trial to assess the efficacy of 3 doses of BI 764198 (20 mg, 40 mg, and 80 mg) compared to placebo in patients with primary focal segmental glomerulosclerosis (FSGS), or patients with monogenic FSGS as a result of TRPC6 mutations.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 764198 20 mg Patients with primary focal segmental glomerulosclerosis (FSGS) or patients with monogenic FSGS as a result of TRPC6 mutations took daily one single capsule of 20 milligrams (mg) of BI 764198 orally for 12 weeks. | 18 |
| BI 764198 40 mg Patients with primary focal segmental glomerulosclerosis (FSGS) or patients with monogenic FSGS as a result of TRPC6 mutations took daily one single capsule of 40 milligrams (mg) of BI 764198 orally for 12 weeks. | 15 |
| BI 764198 80 mg Patients with primary focal segmental glomerulosclerosis (FSGS) or patients with monogenic FSGS as a result of TRPC6 mutations took daily one single capsule of 80 milligrams (mg) of BI 764198 orally for 12 weeks. | 15 |
| Placebo Patients with primary focal segmental glomerulosclerosis (FSGS) or patients with monogenic FSGS as a result of TRPC6 mutations took daily one single capsule of placebo-matching BI 764198 orally for 12 weeks. | 14 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 0 | 0 |
| Overall Study | Not treated | 0 | 1 | 2 | 2 |
| Overall Study | Protocol deviation | 0 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | BI 764198 20 mg | Total | Placebo | BI 764198 80 mg | BI 764198 40 mg |
|---|---|---|---|---|---|
| Age, Continuous | 41.2 Years STANDARD_DEVIATION 15 | 40.7 Years STANDARD_DEVIATION 12.6 | 42.2 Years STANDARD_DEVIATION 11.1 | 39.8 Years STANDARD_DEVIATION 10.5 | 39.8 Years STANDARD_DEVIATION 13.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 10 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 52 Participants | 14 Participants | 13 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 12 Participants | 4 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 39 Participants | 9 Participants | 9 Participants | 10 Participants |
| Sex: Female, Male Female | 9 Participants | 25 Participants | 7 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 37 Participants | 7 Participants | 13 Participants | 8 Participants |
| Urine Protein-Creatinine Ratio (UPCR) from 24-hour Urine | 4.4865 Ratio STANDARD_DEVIATION 3.0188 | 3.9709 Ratio STANDARD_DEVIATION 2.8565 | 4.5166 Ratio STANDARD_DEVIATION 2.9342 | 2.6767 Ratio STANDARD_DEVIATION 2.2209 | 4.0508 Ratio STANDARD_DEVIATION 3.0012 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 15 | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 14 / 18 | 10 / 15 | 10 / 15 | 10 / 14 |
| serious Total, serious adverse events | 3 / 18 | 0 / 15 | 1 / 15 | 1 / 14 |
Outcome results
Primary
Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12
Predicted probability of patients as a percentage - predicted percentage of patients - achieving at least 25% reduction in 24-hour urine protein creatinine ratio (UPCR) relative to baseline at Week 12 (responders) is reported. Baseline was the average of two 24-hour urine samples collected before Visit 2 (Week 0). Patients who either missed their Week 12, 24-hour UPCR assessment or their Week 12, 24-hour UPCR assessment, occurred later than 5 days after the last dose (Residual Effect Period), were considered as non-responders. The predicted probability of response was calculated using a logistic regression utilizing corticosteroid use at randomization and baseline 24-hr UPCR as covariates and is presented as a percentage.
Time frame: At baseline and Week 12.
Population: Full Analysis Set (FAS): all patients who were randomized and treated with evaluable measurements of 24-hr UPCR at baseline and at least one 24-hr UPCR measurement after the first dose. Patients who either missed their Week 12, 24-hour UPCR assessment or their Week 12, 24-hour UPCR assessment, occurred later than 5 days after the last dose (Residual Effect Period), were considered as non-responders and were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 764198 20 mg | Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12 | 48.9 Predicted percentage of patients |
| BI 764198 40 mg | Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12 | 16.0 Predicted percentage of patients |
| BI 764198 80 mg | Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12 | 38.5 Predicted percentage of patients |
| Placebo | Achievement of at Least 25% Reduction in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 12 | 11.4 Predicted percentage of patients |
Comparison: Logistic regression utilizing corticosteroid use at randomization and baseline 24-hr UPCR as covariates.95% CI: [1.59, 118.14]
Comparison: Logistic regression utilizing corticosteroid use at randomization and baseline 24-hr UPCR as covariates.95% CI: [0.16, 19.48]
Comparison: Logistic regression utilizing corticosteroid use at randomization and baseline 24-hr UPCR as covariates.95% CI: [0.86, 73.57]
Primary
Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR)
Relative change from baseline at Week 12 in 24-hour urine protein creatinine ratio (UPCR), is reported. Baseline was the average of two 24-hour urine samples collected before Visit 2 (Week 0). An analysis of covariance (ANCOVA) model was used to estimate the relative change in UPCR from baseline to Week 12 with corticosteroid use at randomization and baseline 24-hr UPCR as covariates.
Time frame: At baseline and at Week 12.
Population: Full Analysis Set (FAS): all patients who were randomized and treated with evaluable measurements of 24-hr UPCR at baseline and at least one 24-hr UPCR measurement after the first dose. Patients who either missed their Week 12, 24-hour UPCR assessment or their Week 12, 24-hour UPCR assessment, occurred later than 5 days after the last dose (Residual Effect Period), were not included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 764198 20 mg | Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR) | -38.44 Percentage of change in 24-hour UPCR |
| BI 764198 40 mg | Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR) | -2.39 Percentage of change in 24-hour UPCR |
| BI 764198 80 mg | Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR) | -21.52 Percentage of change in 24-hour UPCR |
| Placebo | Relative Change From Baseline at Week 12 of 24-hour Urine Protein Creatinine Ratio (UPCR) | 2.28 Percentage of change in 24-hour UPCR |
Comparison: An analysis of covariance (ANCOVA) model was used to estimate the change in UPCR from baseline to Week 12 with corticosteroid use at randomization and baseline 24-hr UPCR as covariates.p-value: 0.002495% CI: [-56.17, -17.36]ANCOVA
Comparison: An analysis of covariance (ANCOVA) model was used to estimate the change in UPCR from baseline to Week 12 with corticosteroid use at randomization and baseline 24-hr UPCR as covariates.p-value: 0.790695% CI: [-32.92, 35.77]ANCOVA
Comparison: An analysis of covariance (ANCOVA) model was used to estimate the change in UPCR from baseline to Week 12 with corticosteroid use at randomization and baseline 24-hr UPCR as covariates.p-value: 0.132595% CI: [-45.83, 8.7]ANCOVA
Secondary
Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12
Median change in 24-hour urinary excretion rate relative to baseline at Week 12, is calculated by subtracting the urinary excretion rate, \[Week 12\] - \[baseline\], values per patient, then by calculating the median of these changes, per treatment group. Baseline was the average of two, 24-hour urine samples collected before Visit 2 (Week 0).
Time frame: At baseline and at Week 12.
Population: Full Analysis Set (FAS): all patients who were randomized and treated with evaluable measurements of 24-hr UPCR at baseline and at least one 24-hr UPCR measurement after the first dose. Patients, who either missed their Week 12 urinary excretion rate measure or their Week 12 urinary excretion rate measure occurred later than 5 days after the last dose (Residual Effect Period), were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 764198 20 mg | Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12 | -0.5036 grams/day |
| BI 764198 40 mg | Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12 | -0.4056 grams/day |
| BI 764198 80 mg | Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12 | -0.8967 grams/day |
| Placebo | Change in 24-hour Urinary Protein Excretion Relative to Baseline at Week 12 | 0.0809 grams/day |
Secondary
Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13
Median change in 24-hour urine protein creatinine ratio (UPCR) relative to baseline at Week 13, is calculated by subtracting the 24-hour UPCR, \[Week 13\] - \[baseline\] values per patient,then by calculating the median of these changes, per treatment group. Baseline was the average of two, 24-hour urine samples collected before Visit 2 (Week 0).
Time frame: At baseline and at Week 13.
Population: Full Analysis Set (FAS): all patients who were randomized and treated with evaluable measurements of 24-hr UPCR at baseline and at least one 24-hr UPCR measurement after the first dose. Only patients with both a valid baseline and Week 13, 24-hour UPCR value were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 764198 20 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13 | -0.4985 grams/grams |
| BI 764198 40 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13 | -0.151 grams/grams |
| BI 764198 80 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13 | -0.3033 grams/grams |
| Placebo | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Baseline at Week 13 | 0.0795 grams/grams |
Secondary
Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12
Median change in 24-hour urine protein creatinine ratio (UPCR) relative to Visit 3 (Week 1) at Week 12, is calculated by subtracting the 24-hour UPCR, \[Week 12\] - \[Week 1\] values per patient, then by calculating the median of these changes, per treatment group.
Time frame: At Week 1 and Week 12.
Population: Full Analysis Set (FAS): all patients who were randomized and treated with evaluable measurements of 24-hr UPCR at baseline and at least one 24-hr UPCR measurement after the first dose. Only patients with both a valid Visit 3 and Week 12, 24-hour UPCR value were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 764198 20 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12 | -0.035 grams/grams |
| BI 764198 40 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12 | 0.712 grams/grams |
| BI 764198 80 mg | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12 | -0.4435 grams/grams |
| Placebo | Change in 24-hour Urine Protein Creatinine Ratio (UPCR) Relative to Visit 3 at Week 12 | 0.106 grams/grams |
Secondary
Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12
Pre-dose Plasma Concentration of BI 764198 at steady-state (Cpre,ss ) at Week 4 and Week 12 is reported.
Time frame: At 671.917 hours and at 2015.917 hours after first drug administration.
Population: All patients who received at least one dose of trial medication and who provide at least one pre-dose concentration that was not excluded due to protocol violation relevant to the evaluation of pharmacokinetics (PK) or due to PK non-evaluability. Patients with no available pre-dose concentration were not included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BI 764198 20 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 4 | 119 nanomole/liter | Geometric Coefficient of Variation 47.2 |
| BI 764198 20 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 12 | 114 nanomole/liter | Geometric Coefficient of Variation 85.9 |
| BI 764198 40 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 4 | 266 nanomole/liter | Geometric Coefficient of Variation 64.7 |
| BI 764198 40 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 12 | 328 nanomole/liter | Geometric Coefficient of Variation 64.6 |
| BI 764198 80 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 4 | 683 nanomole/liter | Geometric Coefficient of Variation 66.5 |
| BI 764198 80 mg | Pre-dose Plasma Concentration of BI 764198 at Steady-state (Cpre,ss ) at Week 4 and Week 12 | Week 12 | 509 nanomole/liter | Geometric Coefficient of Variation 45.7 |