None listed
Conditions
Brief summary
In Phase 1 clinical studies of SEL, small, dose-dependent increases in serum creatinine with resulting decreases in calculated creatinine clearance have been observed. These changes occurred early in the dosing period and were reversible upon cessation of study drug. In the majority of subjects, calculated creatinine clearance values remained within the normal range despite the decreases observed following initiation of study drug. In a Phase 2 study of SEL in subjects with diabetic kidney disease (DKD), a dose-dependent, acute decrease in eGFR was observed in the first 4-weeks of treatment, which was similar in magnitude (percent change) as the decrease observed in Phase 1 studies of SEL in healthy subjects. The objectives of this study are to further characterize the mechanism of decreased creatinine clearance and thereby the acute decrease in and reversibility of eGFR observed during SEL dosing in a population with renal impairment and to specifically determine whether SEL affects mGFR as determined by iohexol clearance, which is freely filtered at the glomerulus but does not undergo active renal tubular secretion or reabsorption. The dose of SEL to be used in this study is 18-mg once daily for 28 days. SEL 18-mg was the highest dose of SEL evaluated in the dose-ranging Phase 2 study in DKD patients and is the proposed dose to be evaluated in a planned Phase 3 study. Selection of this dose is based on safety, efficacy, and PK data from Phase 1 and Phase 2 studies, including 48 weeks of treatment in subjects with moderate to severe renal impairment.
Interventions
Treatment A: On Days -1, 7, 28, and 56, all subjects will receive iohexol
[1500-mg Iodine as 5 mL of a 300-mg iodine/mL solution], administered in the morning as an intravenous (IV) bolus over 1-2 minutes after completion of a standard meal.
On Days 1 through 28, subjects will be administered 18-mg [1 x 18--mg tablet] SEL selonsertib (SEL) once daily in the morning.
The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the stu
Treatment A: On Days -1, 7, 28, and 56, all subjects will receive iohexol [1500-mg Iodine as 5 mL of a 300-mg iodine/mL solution], administered in the morning as an intravenous (IV) bolus over 1-2 minutes after completion of a standard meal. On Days 1 through 28, subjects will be administered 18-mg [1 x 18--mg tablet] SEL selonsertib (SEL) once daily in the morning. The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study centre will be administered by qualified study centre staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff will be accurately recorded, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Used and unused study drug supplies, including empty containers, are to be returned to the shipping facility from which it came for destruction following drug accountability and drug inventory reconciliation. The standard meals will ensure patients consume approximately <2g sodium for the day. There are no other specific requirements for these meals.
Sponsors
Gilead Sciences
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. 1) Prior diagnosis of CKD 2) Male or female between 30 and 80 years of age, inclusive 3) eGFR collected at screening greater than or equal to 20 to less than 60 mL/min/1.73m2 eGFR screening value will be determined by the CKD-EPI equation: eGFR(male) = 141 x Min(SCr/0.9, 1)^-0.411 x Max(SCr/0.9, 1)^-1.209 x 0.993^Age x [1.159 if Black] eGFR(female) = 141 x Min(SCr/0.7, 1)^-0.329 x Max(SCr/0.7)^, 1)^-1.209 x 0.993^Age × [1.159 if Black] × 1.018 SCr is serum creatinine in mg/dL; Age is in year. 4) Female subjects of childbearing potential must have a negative serum pregnancy test. 5) Male subjects or female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception. 6) Male subjects must refrain from sperm donation from the screening visit through 90 days following the last dose of study drug 7) Subjects must refrain from blood product donation through 30 days following the last dose of study drug 8) Serum total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) 9) Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) less than or equal to 2x ULN 10) White blood cells (WBC), neutrophil count, lymphocyte count, and platelet count greater than or equal to 0.75 x LLN to less than or equal to1.5 x ULN as confirmed by central laboratory 11) Negative blood screen for HIV antibody 12) Negative blood screen for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBc Ab), or positive blood screen for HBcAb and negative blood screen for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by quantitative PCR 13) Negative blood screen for HCV antibody or negative blood screen for HCV viral ribonucleic acid (RNA) (if HCV antibody is positive) 14) Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator. 15) In the judgment of the investigator, participation in the study offers an acceptable benefit/risk ratio when considering current CKD disease status, medical condition, and the potential benefits and risks of alternative treatments for CKD 16) Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions 17) Willing and able to give informed consent prior to any study-specific procedures being performed.
Exclusion criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 1) Known hypersensitivity to iohexol, iodinated contrast, iodine, iodide containing products, or shellfish 2) Use of any prohibited concomitant medications 3) Pregnant or lactating females 4) Any laboratory abnormality or condition that, in the investigator’s opinion, could adversely affect the safety of the subject or impair the assessment of study results, including unstable kidney function (e.g., acute kidney injury, rapid decline in kidney function, etc.) 5) Participation in another investigational study within 30 days or within 5 half-lives of the prior investigational agent (whichever is longer) prior to screening and throughout the study. 6) Concurrent participation in another therapeutic clinical study 7) Known hypersensitivity to the study drug (SEL/placebo), the metabolites, or formulation excipient 8) Presence of any condition that could, in the opinion of the investigator, compromise the subject’s ability to participate in the study, such as history of substance abuse, alcoholism, or a psychiatric condition.
Outcome results
None listed