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

Study Overview
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Brief Summary
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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
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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.

Official Title
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MOSAIC - A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study Evaluating the Efficacy and Safety of Selonsertib in Subjects With Moderate to Advanced Diabetic Kidney Disease

Conditions
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Diabetic Kidney Disease

Intervention / Treatment
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* Drug: SEL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 ACEi and ARB or 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Participants received Run-in and Randomized treatments sequentially and in the Randomized Phase, the treatments were assigned in parallel.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selonsertib<br>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. | Drug: SEL<br>* Tablet administered orally once daily<br>Drug: Placebo<br>* Tablet administered orally once daily<br>|
| Placebo Comparator: Placebo<br>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. | Drug: SEL<br>* Tablet administered orally once daily<br>Drug: Placebo<br>* Tablet administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | Treatment-specific Baselines through Week 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 48 | 
| 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. | From randomization up to Week 101 | 
| 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. | 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 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. | Pre-run-in Baseline through Week 84 |