Moderate to Advanced Diabetic Kidney Disease

The primary objective of this study is:  To evaluate whether SEL can slow the decline in kidney function, reduce the risk of kidney failure, or reduce the risk of death due to kidney disease in subjects with DKD The secondary objectives of this study are:  To evaluate the effect of SEL on cardiovascular morbidity and mortality in subjects with DKD  To assess the safety and tolerability of SEL in subjects with DKD The exploratory objectives of this study are:  To assess the effect of SEL on health related quality of life (HRQoL), work productivity, activity impairment, and functional status  To evaluate the effect of SEL on healthcare resource utilization  To evaluate the effect of SEL on albuminuria  To evaluate the association between biomarkers and response to SEL and further the understanding of the biology of DKD  To evaluate the PK of SEL

Selonsertib

Selonsertib

tablet

18mg/tab

The 2 primary efficacy endpoints of this study are:
• Clinical Endpoint: Time from randomization to the first occurrence of any of the following
adjudicated events:
 Confirmed ≥ 40% decline in eGFR from baseline, or
 Kidney failure (dialysis for at least 90 days, kidney transplantation, or confirmed
decrease in eGFR to < 15 mL/min/1.73 m2
for subjects without dialysis or kidney
transplantation), or
 Death due to kidney disease
• eGFR slope

The secondary endpoints of this study are:
• Time from randomization to adjudicated CV death or hospitalization for heart failure
• Time from randomization to the first occurrence of an adjudicated event in the CV composite endpoint (includes CV death, non-fatal MI, non-fatal stroke, or hospitalization for heart failure)
• Time from randomization to adjudicated CV death
• Time from randomization to adjudicated atrial fibrillation
• Time from randomization to adjudicated CV death or adjudicated kidney failure (dialysis for
at least 90 days, kidney transplantation, or confirmed decrease in eGFR to < 15 mL/min/1.73 m2 for subjects without dialysis or kidney transplantation)
• Time from randomization to adjudicated all-cause death (death occurring during the study from any cause) or adjudicated kidney failure (dialysis for at least 90 days, kidney transplantation, or confirmed decrease in eGFR to < 15 mL/min/1.73 m2
for subjects without dialysis or kidney transplantation)

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in this study:
1) Male or female between 18 (or ≥ age of majority in each jurisdiction if different than 18) and 80 years of age, inclusive
2) Prior diagnosis of T2DM with diagnostic modalities as per local guidelines. Must have hemoglobin A1c (HbA1c) > 6% within 30 days prior to Enrollment (Visit A) or be on active treatment for T2DM for at least 6 weeks prior to Enrollment (Visit A)
3) eGFR value calculated by central laboratory utilizing samples collected during Screening and prior to Enrollment (Visit A) of ≥ 20 mL/min/1.73 m² to < 60 mL/min/1.73 m² with albuminuria as measured by UACR
a) eGFR values will be calculated using the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation (2009); UACR will be determined by early morning void urine collection. Subjects can have up to 3 eGFR and 3 UACR collections during the Screening period. Any one of the eGFR values and any one of the UACR values collected during Screening may be used to satisfy this inclusion criterion. Qualifying eGFR and UACR values do not need to be collected on the same day
b) eGFR and UACR must meet criteria a, b, or c
Criteria eGFR (mL/min/1.73 m²) UACR (mg/g)
a ≥ 45 to < 60 ≥ 600
b ≥ 30 to < 45 ≥ 300
c ≥ 20 to < 30 ≥ 150
4) Treatment with either an ACEi or ARB at the maximum labeled or tolerated dose deemed appropriate for the subject by the investigator and/or per local SOC for at least 6 weeks prior to Enrollment, with a stable dose for at least 2 weeks prior to Enrollment
a) Subjects not receiving an ACEi or ARB may be enrolled if there is documented intolerance to ACEi and ARB
b) Subjects 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
5) Subjects already receiving SGLT-2 inhibitors must be on a stable dose at least 2 weeks prior to Enrollment
6) For females of childbearing potential (unless permanently sterile or post-menopausal, as described in Appendix 6), a negative serum pregnancy test at Screening
7) For male and female subjects of childbearing potential who engage in heterosexual intercourse, agreement to abstain or use protocol specified method(s) of contraception as described in Appendix 6
8) Male subjects must refrain from sperm donation from the Screening visit through 30 days following the last dose of study drug
9) Female subjects must refrain from egg donation or harvest from the Screening visit through 30 days following the last dose of study drug
10) Subjects must refrain from blood product donation from the Screening visit through 30 days following the last dose of study drug
11) Mean systolic blood pressure (SBP) must be < 160 mmHg and mean diastolic blood pressure (DBP) must be < 100 mmHg taken at two time-points at least five minutes apart within 30 days prior to Enrollment (Visit A)
12) Required baseline laboratory data within 30 days prior to Enrollment (Visit A) as shown in the table below
Organ System Parameter Required Value
Hematologic WBC, neutrophil, lymphocyte, and platelet count ≥ 0.75 x LLN to ≤ 1.5 x ULN
Hepatic Serum total bilirubin ≤ 1.5 × ULN
Serum ALT ≤ 1.5 × ULN
Serum AST
Pregnancy -HCGa Negative
Infection HIVb Negative HIV antibody
HBV Negative HBsAg and negative HBc antibody or positive HBc and negative for HBV DNA by quantitative PCR
HCV Negative HCV antibody or negative viral RNA (if HCV antibody is positive)
a For women of childbearing potential only; serum -HCG must be negative during Screening
b If screening test is positive, a negative confirmatory test will be required for eligibility
Abbreviations:  HCG = beta human chorionic gonadotropin, ALT = alanine aminotransferase, AST = aspartate aminotransferase, DNA = deoxyribonucleic acid, LLN = lower limit of normal, HBc antibody = anti hepatitis B core antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, PCR = polymerase chain reaction, RNA = ribonucleic acid, ULN = upper limit of normal, WBC = white blood count
13) Have either a normal 12-lead electrocardiogram (ECG) or an ECG with abnormalities that are not considered to be clinically significant by the investigator within 30 days prior to Enrollment (Visit A)
14) In the judgment of the investigator, participation in the study offers an acceptable benefit to risk ratio, taking into consideration the subject’s current DKD status, medical condition, and the potential benefits and risks of alternative treatments for DKD
15) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
16) Willing and able to give informed consent prior to any study specific procedures being performed

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) HbA1c > 12.0% within 30 days prior to Enrollment (Visit A)
2) In the investigator’s opinion, a condition other than T2DM is the primary etiology of DKD
3) If < 30 years of age, any history of chronic insulin therapy or diabetic ketoacidosis
4) Body mass index (BMI) > 50 kg/m2 at Enrollment (Visit A)
5) UACR > 5000 mg/g on any measurement during Screening
6) End stage renal disease (ESRD) (i.e., peritoneal dialysis, hemodialysis, or history of kidney transplantation)
7) Anticipated progression to ESRD (need for dialysis or receipt of kidney transplant) within 3 months after Enrollment (Visit A)
8) Unstable CV disease as defined by any of the following:
a) Myocardial infarction (MI), coronary artery bypass graft surgery, or coronary angioplasty within 3 months prior to Enrollment (Visit A)
b) Transient ischemic attack or cerebrovascular accident within 3 months prior to Enrollment (Visit A)