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Trial registered on ANZCTR


Registration number
ACTRN12618001377224
Ethics application status
Approved
Date submitted
31/07/2018
Date registered
16/08/2018
Date last updated
16/08/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1b, Randomized, Blinded, Placebo-Controlled Study to
Evaluate the Effect of Selonsertib on Renal Function as Assessed
by Markers of Glomerular Filtration Rate in Subjects with Chronic
Kidney Disease
Scientific title
A Phase 1b, Randomized, Blinded, Placebo-Controlled Study to
Evaluate the Effect of Selonsertib on Renal Function as Assessed
by Markers of Glomerular Filtration Rate in Subjects with Chronic
Kidney Disease
Secondary ID [1] 295672 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Kidney Disease 309046 0
Condition category
Condition code
Renal and Urogenital 307937 307937 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 301998 0
Treatment: Drugs
Comparator / control treatment
Treatment B:
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 IV bolus over 1-2 minutes after completion of a standard meal.

On Days 1 through 28, subjects will be administered placebo once daily in the morning.

Placebo 18-mg tablets are available for blinding purposes. Each placebo tablet is identical to
SEL 18-mg tablets in their size, shape, and appearance and contains the same inactive
Ingredients (lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and iron oxide black).
Control group
Placebo

Outcomes
Primary outcome [1] 306912 0
Ratio of measured glomerular filtration rate (mGFR) using iohexol plasma clearance
(CLiohexol) mGFR(mL/min) = iohexol dose/AUCinf
Timepoint [1] 306912 0
Iohexol plasma clearance between Day 28 and Day -1
Secondary outcome [1] 350074 0
Estimated renal function by eGFR CKD-EPI
Timepoint [1] 350074 0
Ratio of mGFR between Day 7 and Day -1, and between Day 56 and Day -1
Secondary outcome [2] 350266 0
- To evaluate the safety and tolerability of SEL in subjects with CKD

This outcome determined by assessment of Hematology, blood Chemistry, Pharmacodynamic Samples (Serum), Urinalysis, Pharmacokinetic Samples – Iohexol, Pharmacokinetic Samples – SEL or placebo, Pharmacodynamic Samples (Serum), Plasma for Stored Biomarkers, Serum for Stored Biomarkers, Urinalysis, Pharmacodynamic Samples (Urine), Urine for Stored Biomarkers, adverse events and laboratory abnormalities.
Timepoint [2] 350266 0
The incidences of adverse events will be collected at screening, Days -8, -1, 1, 7, 14, 21, 28, 35, 42, 49, 56 and follow-up; and laboratory abnormalities at screening, Days -8, -1, 7, 14, 21, 28, 35, 42, 49, 56
Secondary outcome [3] 350268 0
PK parameters of SEL and GS-607509. Pharmacokinetic parameters will be listed and summarized for analytes iohexol, SEL, and GS-607509 (if applicable) by treatment group using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and maximum). Plasma concentrations of each analyte over time will be listed and summarized by treatment group. Plasma concentrations of each analyte over time will be plotted in semi-logarithmic and linear formats as mean ± standard deviation and as median (Q1, Q3), respectively.
Timepoint [3] 350268 0
PK samples will be collected on Days 7 and 28 at 0 (Predose), 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours post 'time zero'

Eligibility
Key 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.
Minimum age
30 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An Interactive Voice/Web Response System (IXRS) will be employed to manage subject
randomization and treatment assignments. It is the responsibility of the investigator to ensure that the subject is eligible for the study prior to enrollment. Subjects will be assigned a screening number at the time of consent.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization to SEL or placebo will be based on a randomization schedule prepared by Gilead and/or a designee before the start of the study. Eligible subjects will be centrally randomized via an IXRS. Prior to randomization, eligible subjects will be stratified by baseline eGFR
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
All randomized analysis set will include all subjects who were randomized in the study.
This is the primary analysis set for all safety listings.

The safety analysis set will include all randomized subjects who received at least 1 dose of study drug.

The PK analysis set will include all randomized subjects who received at least 1 dose of study drug (SEL) or iohexol and have at least 1 nonmissing PK concentration data for the analyte under evaluation reported by the PK laboratory.

The PD analysis set will include all randomized subjects who received at least 1 dose of study drug or iohexol and who have at least one evaluable change from Day -1 at postdose days in mGFR, or eGFRCKD-EPI.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
31/07/2018
Date of last participant enrolment
Anticipated
28/12/2018
Actual
Date of last data collection
Anticipated
8/03/2019
Actual
Sample size
Target
60
Accrual to date
1
Final
Recruitment outside Australia
Country [1] 10689 0
New Zealand
State/province [1] 10689 0
Country [2] 10690 0
Germany
State/province [2] 10690 0
Country [3] 10691 0
United States of America
State/province [3] 10691 0
Country [4] 10715 0
Czech Republic
State/province [4] 10715 0
Country [5] 10716 0
Hungary
State/province [5] 10716 0
Country [6] 10717 0
Slovakia
State/province [6] 10717 0

Funding & Sponsors
Funding source category [1] 300254 0
Commercial sector/Industry
Name [1] 300254 0
Gilead Sciences
Country [1] 300254 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences
Address
333 Lakeside Dr, Foster City, CA 94404, USA
Country
United States of America
Secondary sponsor category [1] 299690 0
None
Name [1] 299690 0
None
Address [1] 299690 0
None
Country [1] 299690 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301076 0
Western Institutional Review Board
Ethics committee address [1] 301076 0
1019 39th Avenue SE Suite 120, Puyallup, WA 98374-2115
Ethics committee country [1] 301076 0
United States of America
Date submitted for ethics approval [1] 301076 0
16/07/2018
Approval date [1] 301076 0
23/07/2018
Ethics approval number [1] 301076 0
20181628

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85798 0
Dr Richard Robson
Address 85798 0
Christchurch Clinical Studies Trust
31 Tuam Street Christchurch Central 8011
Country 85798 0
New Zealand
Phone 85798 0
+64 3 3729477
Fax 85798 0
Email 85798 0
richard@ccst.co.nz
Contact person for public queries
Name 85799 0
Ms Lorraine Ampaw
Address 85799 0
Gilead Sciences
333 Lakeside Dr, Foster City, CA 94404
Country 85799 0
United States of America
Phone 85799 0
+1 650-389-8793
Fax 85799 0
Email 85799 0
lorraine.ampaw@gilead.com
Contact person for scientific queries
Name 85800 0
Ms Lorraine Ampaw
Address 85800 0
Gilead Sciences
333 Lakeside Dr, Foster City, CA 94404
Country 85800 0
United States of America
Phone 85800 0
+1 650-389-8793
Fax 85800 0
Email 85800 0
lorraine.ampaw@gilead.com

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