Diabetic Kidney Disease
Conditions
Brief summary
The primary objective of this study is to evaluate whether selonsertib (SEL) can slow the decline in kidney function in participants with moderate to advanced diabetic kidney disease (DKD).
Detailed description
Following the screening period, eligible participants will enroll into a Run-in period of at least 5 weeks and receive placebo to match SEL for at least 1 week and then SEL for at least 4 weeks. After completing Run-in period, eligible participants will be randomized and receive either SEL or placebo to match SEL for at least 48 weeks.
Interventions
DRUGSEL
Tablet administered orally once daily
DRUGPlacebo
Tablet administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Participants received Run-in and Randomized treatments sequentially and in the Randomized Phase, the treatments were assigned in parallel.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of type 2 diabetes mellitus (T2DM) as per local guidelines. * Estimated glomerular filtration rate (eGFR) value calculated by central laboratory utilizing samples collected during screening and prior to enrollment of ≥ 20 mL/min/1.73 m\^2 to \< 60 mL/min/1.73 m\^2 with albuminuria * eGFR and urine albumin to creatinine ratio (UACR) must meet criteria a, b, or c * a: eGFR (mL/min/1.73 m\^2): ≥ 45 to \< 60; UACR (mg/g): ≥ 600 to 5000 * b: eGFR (mL/min/1.73 m\^2): ≥ 30 to \< 45; UACR (mg/g): ≥ 300 to 5000 * c: eGFR (mL/min/1.73 m\^2): ≥ 20 to \< 30; UACR (mg/g): ≥ 150 to 5000 * Treatment with either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) * Individuals not receiving an ACEi or ARB may be enrolled if there is documented intolerance to ACEi and ARB * Individuals receiving less-than-maximal dose of an ACEi or ARB may be enrolled if there is a documented reason that the maximum labeled dose of ACEi and ARB could not be reached * Individuals already receiving sodium-glucose co-transporter-2 (SGLT-2) inhibitors must be on a stable dose for at least 2 weeks prior to enrollment * Mean systolic blood pressure (SBP) must be \<160 mmHg and mean diastolic blood pressure (DBP) must be \<100 mmHg * Required baseline laboratory data, analyzed by central laboratory, within 30 days prior to enrollment Key
Exclusion criteria
* Hemoglobin A1c (HbA1c) \> 12.0% within 30 days prior to enrollment * Individuals with diagnosis of type 1 diabetes mellitus (T1DM) or maturity onset diabetes of the young (MODY) * Body mass index (BMI) \> 50 kg/m\^2 * UACR \> 5000 mg/g on any measurement during screening * End stage kidney disease (ESKD) (i.e., chronic hemodialysis, chronic peritoneal dialysis, or history of kidney transplantation) * Anticipated progression to ESKD (need for chronic hemodialysis, chronic peritoneal dialysis or receipt of kidney transplant) within 3 months after enrollment * Unstable cardiovascular disease * Pregnant or lactating females or planning to become pregnant or breastfeed during the study * Concurrent use of either 1. ACEi and ARB or 2. Mineralocorticoid receptor antagonist (MRA) or direct renin inhibitor (DRI) in combination with an ACEi or ARB for at least 2 weeks prior to Enrollment * Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the individual or impair the assessment of study results Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr) | Treatment-specific Baselines (From enrollment (Visit A) up to 14 days after Visit A for placebo and from Visit C up to 14 days after Visit C for SEL) | The values of eGFRcr were calculated using the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation (2009). eGFRcr = 141\*min(Standardized Serum Creatinine (Scr)/kappa, 1) \^alpha\*max(Scr/ kappa, 1)\^(-1.209)\*0.993\^Age\*1.018\[if female\]\*1.159\[if Black\], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment-specific Baselines = the average of Visits A and B values for Placebo, and the average of Visit C and Day 1 values for SEL. Visit A= enrollment, Visit B= 7-14 days after Visit A, Visit C= 21-28 days after Visit B, and Visit 1= 7-14 days after Visit C. |
| eGFRcr Slope | Treatment-specific Baselines through Week 84 | The values of eGFRcr were calculated using the CKD-EPI Creatinine Equation (2009). eGFRcr = 141\*min(Scr/kappa, 1) \^alpha\*max(Scr/kappa, 1)\^(-1.209)\*0.993\^Age\*1.018\[if female\]\*1.159\[if Black\], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment specific baselines for eGFRcr: average of Visit A (enrollment) and Visit B (7-14 days after Visit A) values for Placebo, and average of Visit C (21-28 days after Visit B, and Visit 1 (7-14 days after Visit C) values for SEL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Kidney Clinical Events at Week 48 | Week 48 | Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to \< 15 mL/min/1.73 m\^2 for participants without dialysis or kidney transplantation), or death due to kidney disease. |
| Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event | From randomization up to Week 101 | Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to \< 15 mL/min/1.73 m\^2 for participants without dialysis or kidney transplantation), or death due to kidney disease. This outcome measure was analyzed using event rate per 100 participant-years for first occurrence of kidney clinical event. Participant year was calculated as total follow-up duration across all participants in a given group. Follow-up duration was defined as time from Randomization to the earliest of study completion, premature study discontinuation, death, or event of interest in each row. |
| Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys) | Pre-run-in Baseline (Pre-run in Baseline = Average of visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values) | eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133\*min(Standardized Serum Cystatin (Scys)/0.8, 1) \^(-0.499)\*max(Scys/0.8, 1)\^(-1.328)\*0.996\^Age\*0.932\[if female\]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years. |
| eGFRcys Slope | Pre-run-in Baseline through Week 84 | eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133\*min(Scys/0.8, 1) \^(-0.499)\*max(Scys/0.8, 1)\^(-1.328)\*0.996\^Age\*0.932\[if female\]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years. Pre-run in Baseline = Average of visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values. |
Countries
Australia, Canada, Japan, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Japan, Canada, New Zealand, and Australia.
Pre-assignment details
961 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Run-in SEL 18 mg, Not Randomized Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period and were not randomized. | 47 |
| Randomized SEL 18 mg Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomized, and received SEL 18 mg tablet orally once daily for at least 48 weeks. | 154 |
| Randomized Placebo Participants received SEL 18 mg tablet orally once daily for at least 4 weeks in the Run-in period, were then randomized, and received placebo-to-match SEL tablet orally once daily for at least 48 weeks. | 156 |
| Total | 357 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Randomized Period | Death | 0 | 0 | 5 | 7 |
| Randomized Period | Investigator's Discretion | 0 | 0 | 2 | 2 |
| Randomized Period | Lost to Follow-up | 0 | 0 | 2 | 2 |
| Randomized Period | Withdrew Consent | 0 | 0 | 5 | 8 |
| Run-in Placebo Period | Enrollment Error | 13 | 0 | 0 | 0 |
| Run-in Placebo Period | Protocol Violation | 2 | 0 | 0 | 0 |
| Run-in Placebo Period | Run-in Failure | 4 | 0 | 0 | 0 |
| Run-in Placebo Period | Significant Non-Compliance with Study Drug | 1 | 0 | 0 | 0 |
| Run-in Placebo Period | Withdrew Consent | 2 | 0 | 0 | 0 |
| Run-in SEL Period | Death | 0 | 1 | 0 | 0 |
| Run-in SEL Period | Enrollment Error | 0 | 4 | 0 | 0 |
| Run-in SEL Period | Investigator's Discretion | 0 | 2 | 0 | 0 |
| Run-in SEL Period | Protocol Violation | 0 | 3 | 0 | 0 |
| Run-in SEL Period | Run-in Failure | 0 | 26 | 0 | 0 |
| Run-in SEL Period | Withdrew Consent | 0 | 10 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Randomized Placebo | Randomized SEL 18 mg | Run-in SEL 18 mg, Not Randomized |
|---|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 9.1 | 66 years STANDARD_DEVIATION 8.8 | 65 years STANDARD_DEVIATION 9.3 | 65 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 307 Participants | 136 Participants | 132 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 19 Participants | 21 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 89 Participants | 44 Participants | 41 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Black or African American | 52 Participants | 22 Participants | 26 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 10 Participants | 4 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 198 Participants | 84 Participants | 78 Participants | 36 Participants |
| Region of Enrollment Australia | 5 participants | 3 participants | 2 participants | 0 participants |
| Region of Enrollment Canada | 28 participants | 9 participants | 11 participants | 8 participants |
| Region of Enrollment Japan | 76 participants | 37 participants | 38 participants | 1 participants |
| Region of Enrollment New Zealand | 15 participants | 8 participants | 7 participants | 0 participants |
| Region of Enrollment United States | 233 participants | 99 participants | 96 participants | 38 participants |
| Sex: Female, Male Female | 111 Participants | 51 Participants | 48 Participants | 12 Participants |
| Sex: Female, Male Male | 246 Participants | 105 Participants | 106 Participants | 35 Participants |
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 / 384 | 1 / 357 | 5 / 154 | 7 / 156 |
| other Total, other adverse events | 0 / 0 | 37 / 357 | 55 / 154 | 49 / 156 |
| serious Total, serious adverse events | 0 / 0 | 16 / 357 | 45 / 154 | 45 / 156 |
Outcome results
Primary
eGFRcr Slope
The values of eGFRcr were calculated using the CKD-EPI Creatinine Equation (2009). eGFRcr = 141\*min(Scr/kappa, 1) \^alpha\*max(Scr/kappa, 1)\^(-1.209)\*0.993\^Age\*1.018\[if female\]\*1.159\[if Black\], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment specific baselines for eGFRcr: average of Visit A (enrollment) and Visit B (7-14 days after Visit A) values for Placebo, and average of Visit C (21-28 days after Visit B, and Visit 1 (7-14 days after Visit C) values for SEL.
Time frame: Treatment-specific Baselines through Week 84
Population: Participants in the Full Analysis Set (included all participants who were randomized in the study and received at least 1 dose of study drug in the randomization phase) with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized SEL 18 mg | eGFRcr Slope | -2.29 mL/min/1.73m^2/year | Standard Error 0.58 |
| Randomized Placebo | eGFRcr Slope | -3.49 mL/min/1.73m^2/year | Standard Error 0.58 |
Comparison: Estimates were from a random slope model with change in eGFRcr from treatment-specific Baselines at Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84 as outcome, including terms for treatment-specific Baseline eGFRcr, pre-run-in urine albumin to creatinine ratio (UACR) category (\< 1500 mg/g vs. \>= 1500 mg/g), concomitant use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors at Randomization, treatment group, week, and treatment-by-week interaction, where week has a random effect.p-value: 0.143995% CI: [-0.41, 2.81]Random Slope Model
Primary
Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr)
The values of eGFRcr were calculated using the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation (2009). eGFRcr = 141\*min(Standardized Serum Creatinine (Scr)/kappa, 1) \^alpha\*max(Scr/ kappa, 1)\^(-1.209)\*0.993\^Age\*1.018\[if female\]\*1.159\[if Black\], where kappa=0.7(females) or 0.9(males), alpha=-0.329(females) or -0.411(males). min indicates the minimum of Scr/kappa or 1, max indicates the maximum of Scr/kappa or 1, and age is in years. Treatment-specific Baselines = the average of Visits A and B values for Placebo, and the average of Visit C and Day 1 values for SEL. Visit A= enrollment, Visit B= 7-14 days after Visit A, Visit C= 21-28 days after Visit B, and Visit 1= 7-14 days after Visit C.
Time frame: Treatment-specific Baselines (From enrollment (Visit A) up to 14 days after Visit A for placebo and from Visit C up to 14 days after Visit C for SEL)
Population: The Full Analysis Set included all participants who were randomized in the study, and received at least one dose of study drug in the Randomization Phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized SEL 18 mg | Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr) | 32.7 mL/min/1.73m^2 | Standard Deviation 10.59 |
| Randomized Placebo | Treatment-specific Baseline Estimated Glomerular Filtration Rate Based on Creatinine (eGFRcr) | 34.9 mL/min/1.73m^2 | Standard Deviation 10.81 |
Secondary
eGFRcys Slope
eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133\*min(Scys/0.8, 1) \^(-0.499)\*max(Scys/0.8, 1)\^(-1.328)\*0.996\^Age\*0.932\[if female\]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years. Pre-run in Baseline = Average of visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values.
Time frame: Pre-run-in Baseline through Week 84
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Randomized SEL 18 mg | eGFRcys Slope | -3.79 mL/min/1.73m^2/year | Standard Error 0.51 |
| Randomized Placebo | eGFRcys Slope | -4.23 mL/min/1.73m^2/year | Standard Error 0.51 |
Comparison: Estimates were from a random slope model with change in eGFRcys from pre-run-in Baseline at Weeks 4, 8, 12, 24, 36, 48, 60, 72, and 84 as outcome, including terms for pre-run-in Baseline eGFRcys, pre-run-in UACR category (\< 1500 mg/g vs. \>= 1500 mg/g), concomitant use of SGLT-2 inhibitors at Randomization, treatment group, week, and treatment-by-week interaction, where week has a random effect.p-value: 0.539995% CI: [-0.97, 1.86]Random Slope Model
Secondary
Percentage of Participants With Kidney Clinical Events at Week 48
Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to \< 15 mL/min/1.73 m\^2 for participants without dialysis or kidney transplantation), or death due to kidney disease.
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized SEL 18 mg | Percentage of Participants With Kidney Clinical Events at Week 48 | 9.1 percentage of participants |
| Randomized Placebo | Percentage of Participants With Kidney Clinical Events at Week 48 | 9.0 percentage of participants |
p-value: 0.835395% CI: [-10.9, 11.4]Cochran-Mantel-Haenszel
Secondary
Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys)
eGFRcys = Estimated Glomerular Filtration Rate calculated by CKD-EPI Cystatin C Equation (2012). eGFR = 133\*min(Standardized Serum Cystatin (Scys)/0.8, 1) \^(-0.499)\*max(Scys/0.8, 1)\^(-1.328)\*0.996\^Age\*0.932\[if female\]. min indicates the minimum of Scys/0.8 or 1, max indicates the maximum of Scr/0.8 or 1, and age is in years.
Time frame: Pre-run-in Baseline (Pre-run in Baseline = Average of visit A (Enrollment) and Visit B (7-14 days after Visit A) eGFRcys values)
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized SEL 18 mg | Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys) | 33.6 mL/min/1.73m^2 | Standard Deviation 11.81 |
| Randomized Placebo | Pre-run-in Baseline Estimated Glomerular Filtration Rate Based on Cystatin C (eGFRcys) | 32.4 mL/min/1.73m^2 | Standard Deviation 10.94 |
Secondary
Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event
Kidney clinical events were defined as any of the following events: confirmed ≥ 40% decline in eGFRcr from baseline, or kidney failure (dialysis performed for at least 4 weeks, kidney transplantation, or confirmed decrease in eGFRcr to \< 15 mL/min/1.73 m\^2 for participants without dialysis or kidney transplantation), or death due to kidney disease. This outcome measure was analyzed using event rate per 100 participant-years for first occurrence of kidney clinical event. Participant year was calculated as total follow-up duration across all participants in a given group. Follow-up duration was defined as time from Randomization to the earliest of study completion, premature study discontinuation, death, or event of interest in each row.
Time frame: From randomization up to Week 101
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized SEL 18 mg | Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event | 13.4 events per 100 participant-years |
| Randomized Placebo | Time From Randomization to First Occurrence of a Kidney Clinical Event: Event Rate Per 100 Participant-years for First Occurrence of Kidney Clinical Event | 9.8 events per 100 participant-years |
p-value: 0.20195% CI: [0.81, 2.72]Stratified Log-Rank