Study to Evaluate the Efficacy and Safety of Selonsertib in Participants With Moderate to Advanced Diabetic Kidney Disease

Phase 2

Completed

Conditions: Diabetic Kidney Disease

Interventions: Drug: SEL
Drug: Placebo

Registration Number: NCT04026165

Lead Sponsor: Gilead Sciences

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 384

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/Exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Selonsertib	SEL	Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks. Randomized Period: Participants will be randomized to receive SEL 18 mg for at least 48 weeks.
Selonsertib	Placebo	Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks. Randomized Period: Participants will be randomized to receive SEL 18 mg for at least 48 weeks.
Placebo	SEL	Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks. Randomized Period: Participants will be randomized to receive placebo-to-match SEL for at least 48 weeks.
Placebo	Placebo	Run-in Period (5 Weeks): Participants will receive placebo-to-match SEL for at least one week and then SEL 18 mg for at least 4 weeks. Randomized Period: Participants will be randomized to receive placebo-to-match SEL for at least 48 weeks.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.

Trial Locations

Locations (109): Arizona Kidney Disease and Hypertension Centers
🇺🇸
Glendale, Arizona, United States
AKDHC Medical Research Services, LLC
🇺🇸
Tucson, Arizona, United States
Clearview Medical Research, LLC
🇺🇸
Canyon Country, California, United States
Kidney Disease Medical Group, Inc.
🇺🇸
Glendale, California, United States
Renal Consultants Medical Group
🇺🇸
Granada Hills, California, United States
Marin Endocrine Care & Research, Inc.
🇺🇸
Greenbrae, California, United States
California Institute of Renal Research
🇺🇸
San Diego, California, United States
Academic Medical Research Institute
🇺🇸
Los Angeles, California, United States
Rose Salter Medical Research Foundation
🇺🇸
Newport Beach, California, United States
Valley Renal Medical Group Research
🇺🇸
Northridge, California, United States
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Arizona Kidney Disease and Hypertension Centers
🇺🇸Glendale, Arizona, United States