Diabetic Kidney Disease
Conditions
Keywords
Diabetic Kidney Disease, Gilead
Brief summary
The primary objective of this study is to determine the effect of selonsertib (formerly GS-4997) on estimated glomerular filtration rate (eGFR) decline in participants with diabetic kidney disease (DKD). Participants will be randomized with a 1:1:1:1 allocation to receive 1 of 3 doses of selonsertib (2 mg, 6 mg, or 18 mg) or matching placebo.
Interventions
DRUGSelonsertib
Tablets administered orally once daily
DRUGPlacebo to match selonsertib
Tablets administered orally once daily
Sponsors
Gilead Sciences
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
Key Inclusion Criteria: * Adult male or females with prior diagnosis of Diabetic Kidney Disease * Type 2 diabetes mellitus diagnosis for at least 6 months * eGFR (MDRD) at screening ≥ 15 mL/min/1.73m\^2 to \< 60 mL/min/1.73m\^2 * Urine albumin to creatinine ratio (UACR) as follows: * Stage/Stratum 3a: eGFR range 45 to \< 60 mL/min; UACR ≥ 600 mg/g * Stage/Stratum 3b: eGFR range 30 to \< 45 mL/min; UACR ≥ 300 mg/g * Stage/Stratum 4: eGFR range 15 to \< 30 mL/min; UACR ≥ 150 mg/g * Receiving angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) at a minimum dose deemed appropriate for the individual by the investigator and be at a stable dose for the last three months * Individuals not on ACEi/ARB may be screened if there is documented intolerance to ACE inhibitor and/or ARB Key
Exclusion criteria
* Type 1 diabetes mellitus * HbA1c \> 9.5% * Non-diabetic kidney disease * UACR \> 5000 mg/g on any measurement during screening * End stage renal disease (ESRD; receiving peritoneal dialysis, hemodialysis, or status post renal transplantation) or anticipated to occur within the treatment period * Unstable cardiovascular disease * Pregnant or lactating females Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in eGFR From Baseline at Week 48 | Baseline; Week 48 | The values of eGFR were calculated using the MDRD equation: eGFR = 175 x Serum Creatinine\^-1.154 × age\^-0.203 × 1.212 (if participant is black) × 0.742 (if female). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48 | Baseline; Week 48 | Baseline was the average of the last 2 values prior to randomization and the last value on or after the randomization date, but prior to or on the first dose date. Urine Albumin to Creatinine Ratio= urine albumin/urine creatinine. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States and Canada. The first participant was screened on 30 June 2014. The last study visit occurred on 22 August 2016.
Pre-assignment details
893 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Selonsertib 2 mg Selonsertib 2 mg tablet once daily for 48 weeks | 81 |
| Selonsertib 6 mg Selonsertib 6 mg tablet once daily for 48 weeks | 84 |
| Selonsertib 18 mg Selonsertib 18 mg tablet once daily for 48 weeks | 83 |
| Placebo Placebo tablet once daily for 48 weeks | 85 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 | 3 |
| Overall Study | Death | 1 | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 2 |
| Overall Study | Missing study completion status | 0 | 1 | 0 | 0 |
| Overall Study | Non-Compliance with Study Drug | 0 | 1 | 0 | 1 |
| Overall Study | Progression to End Stage Renal Disease | 2 | 3 | 2 | 1 |
| Overall Study | Progressive Disease | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 0 |
| Overall Study | Withdrew Consent | 2 | 6 | 9 | 5 |
Baseline characteristics
| Characteristic | Selonsertib 2 mg | Selonsertib 6 mg | Selonsertib 18 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 8.1 | 62 years STANDARD_DEVIATION 8.1 | 63 years STANDARD_DEVIATION 9 | 62 years STANDARD_DEVIATION 7.9 | 63 years STANDARD_DEVIATION 8.3 |
| Estimated Glomerular Filtration Rate (eGFR) | 31.6 mL/min/1.73 m^2 STANDARD_DEVIATION 10.92 | 31.9 mL/min/1.73 m^2 STANDARD_DEVIATION 11.58 | 31.1 mL/min/1.73 m^2 STANDARD_DEVIATION 10.44 | 31.4 mL/min/1.73 m^2 STANDARD_DEVIATION 11.87 | 31.5 mL/min/1.73 m^2 STANDARD_DEVIATION 11.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 31 Participants | 33 Participants | 30 Participants | 119 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 53 Participants | 50 Participants | 55 Participants | 214 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized Race Black | 20 Participants | 23 Participants | 11 Participants | 19 Participants | 73 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 53 Participants | 57 Participants | 68 Participants | 61 Participants | 239 Participants |
| Region of Enrollment Canada | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 12 Participants |
| Region of Enrollment United States | 79 Participants | 81 Participants | 80 Participants | 81 Participants | 321 Participants |
| Sex: Female, Male Female | 28 Participants | 20 Participants | 27 Participants | 32 Participants | 107 Participants |
| Sex: Female, Male Male | 53 Participants | 64 Participants | 56 Participants | 53 Participants | 226 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 81 | 47 / 84 | 55 / 83 | 48 / 85 |
| serious Total, serious adverse events | 24 / 81 | 20 / 84 | 20 / 83 | 16 / 85 |
Outcome results
Primary
Change in eGFR From Baseline at Week 48
The values of eGFR were calculated using the MDRD equation: eGFR = 175 x Serum Creatinine\^-1.154 × age\^-0.203 × 1.212 (if participant is black) × 0.742 (if female).
Time frame: Baseline; Week 48
Population: Full Analysis Set included all randomized participants who took at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selonsertib 2 mg | Change in eGFR From Baseline at Week 48 | -2.83 mL/min/1.73 m^2 | Standard Error 0.86 |
| Selonsertib 6 mg | Change in eGFR From Baseline at Week 48 | -2.37 mL/min/1.73 m^2 | Standard Error 0.87 |
| Selonsertib 18 mg | Change in eGFR From Baseline at Week 48 | -4.07 mL/min/1.73 m^2 | Standard Error 0.89 |
| Placebo | Change in eGFR From Baseline at Week 48 | -3.20 mL/min/1.73 m^2 | Standard Error 0.85 |
p-value: 0.75595% CI: [-2, 2.75]MMRM
p-value: 0.49295% CI: [-1.55, 3.23]MMRM
p-value: 0.48195% CI: [-3.29, 1.56]MMRM
Secondary
Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48
Baseline was the average of the last 2 values prior to randomization and the last value on or after the randomization date, but prior to or on the first dose date. Urine Albumin to Creatinine Ratio= urine albumin/urine creatinine.
Time frame: Baseline; Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selonsertib 2 mg | Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48 | 28.4 percentage of participants |
| Selonsertib 6 mg | Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48 | 21.4 percentage of participants |
| Selonsertib 18 mg | Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48 | 27.7 percentage of participants |
| Placebo | Percentage of Participants Achieving at Least a 30% Reduction From Baseline in Albuminuria (As Measured by Urine Albumin to Creatinine Ratio) at Week 48 | 30.6 percentage of participants |
p-value: 0.79895% CI: [-16.1, 11.7]Cochran-Mantel-Haenszel
p-value: 0.17595% CI: [-22.3, 4]Cochran-Mantel-Haenszel
p-value: 0.68695% CI: [-16.6, 10.9]Cochran-Mantel-Haenszel