Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000655145
Ethics application status
Approved
Date submitted
18/04/2019
Date registered
1/05/2019
Date last updated
24/03/2021
Date data sharing statement initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment
Scientific title
A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment
Secondary ID [1] 297873 0
Gilead Sciences, GS-US-402-4374
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic Steatohepatitis (NASH) 312291 0
Renal impairment 312292 0
Condition category
Condition code
Renal and Urogenital 310844 310844 0 0
Normal development and function of male and female renal and urogenital system
Oral and Gastrointestinal 310845 310845 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Group A- Eligible subjects (Non-smoking males and non-pregnant/non-lactating female subjects with body mass index (BMI) from 18 to 38 kg/m^2; ages 18-70 years inclusive with severe renal impairment (based on estimated glomerular filtration rate by Modification of Diet in Renal Disease [eGFR_{MDRD}] < 30 mL/min/1.73 m^2) at screening without clinical and/or laboratory evidence for worsening renal impairment within the screening period ) will be enrolled and will receive the following treatments:
*Single dose of GS-0976 20 mg (1 x 20 mg tablet) administered orally in the morning on Day 1 in fasted state
*Single dose of GS-9674 placebo-to-match (PTM) administered orally in the morning on Day 6 in fasted state
*Single dose of GS-9674 100 mg (1 x 100 mg tablet) administered orally in the morning on Day 7 in fasted state

During each treatment the corresponding drug (or PTM) will be administered at approximately the same time in the morning on Day 1 (GS-0976), Day 6 (GS-9674 PTM), and Day 7 (GS-9674) with 240 mL of water following an overnight fast (no food or drinks except water) for at least 10 hours. Following dosing, subjects will be restricted from food intake until after collection of the 4-hour blood draw. Other than the water provided with dosing, water and other fluids will be withheld for 1 hour before and until 2 hours after dose administration. Water may be freely consumed by all subjects following the 2-hour blood draw for the remainder of the collection period. A meal will be provided to subjects after the 4 hour post dose blood draw.
All meals and/or snacks given to subjects during their stay in the clinical study facility will be standardized for all subjects and should be similar in calorie and fat content per site practice and taken at approximately the same time each day.

Subjects will be confined to the study clinic starting at on Day -1 until completion of assessments on Day 11 or Day 20 per Investigator’s discretion to ensure compliance and for safety observation.

The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Where possible, IMP should be destroyed at the site. If the site has an appropriate standard operating procedure for drug destruction as determined by Gilead Sciences, the site may destroy used (empty or partially empty) and/or unused IMP supplies. If the site does not have acceptable procedures in place for drug destruction,study drug supplies can be returned to the designated depot following drug accountability and drug inventory reconciliation.
Intervention code [1] 314130 0
Treatment: Drugs
Comparator / control treatment
Group B- Eligible subjects (Each subject in the control group will be matched for age (+\- 10 years), gender, and BMI (+/- 15%) with a subject in the renal impairment group) will be enrolled and will receive the same treatments as Group A:
*Single dose of GS-0976 20 mg (1 x 20 mg tablet) administered orally in the morning on Day 1 in fasted state
*Single dose of GS-9674 PTM administered orally in the morning on Day 6 in fasted state
*Single dose of GS-9674 100 mg (1 x 100 mg tablet) administered orally in the morning on Day 7 in fasted state
Dosing in subjects with normal renal function will begin after a matched subject with severe renal impairment has completed PK assessments on Day 11.
Control group
Historical

Outcomes
Primary outcome [1] 319679 0
To evaluate the single-dose pharmacokinetics (PK) of GS-0976 and their respective metabolites in subjects with severe renal impairment or matched healthy controls with normal renal function. The following single dose plasma PK parameters of GS-0976 and their metabolites (if applicable) will be calculated as appropriate: AUC_{last}, AUC_{inf}, %AUC_{exp}, C_{max}, C_{last}, T_{max}, T_{last}, Lambda-z, apparent oral clearance after administration of the drug (parent only), apparent volume of distribution of the drug (parent only) and t_{1/2}. In addition, urine parameters including A_e, CLr may be estimated.
Timepoint [1] 319679 0
a) Intensive plasma PK sampling will be collected relative to study drug dosing on Day 1 at the following time-points: 0 (predose less than or equal to 5 min), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72 and 96 hours post-dose; Additional plasma samples will be collected on Days 14, 17 and 20

b) All urine voided will be collected, starting predose (within a 12-hour period prior to Day 1 dose, -12–0 hours interval), and continuing over the following collection intervals post Day 1 dose as below: 0-6, 6-12, 12-24, 24-48, 48-72 and 72-96 hours post-dose.
Primary outcome [2] 319888 0
To evaluate the single-dose PK of GS-9674 and their respective metabolites in subjects with severe renal impairment or matched healthy controls with normal renal function.The following single dose plasma PK parameters of GS-9674 and their metabolites (if applicable) will be calculated as appropriate: AUC_{last}, AUC_{inf}, %AUC_{exp}, C_{max}, C_{last}, T_{max}, T_{last}, Lambda-z, apparent oral clearance after administration of the drug (parent only), apparent volume of distribution of the drug (parent only) and t_{1/2}. In addition, urine parameters including A_e, CLr may be estimated.
Timepoint [2] 319888 0
a) Intensive plasma PK sampling will be collected relative to study drug dosing on Day 7 at the following time-points: 0 (predose less than or equal to 5 min), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72 and 96 hours post-dose; Additional plasma samples will be collected on Days 14, 17 and 20

b) All urine voided will be collected, starting predose (within a 12-hour period prior to Day 7 dose, -12–0 hours interval), and continuing over the following collection intervals post Day 7 dose as below: 0-6, 6-12, 12-24, 24-48, 48-72 and 72-96 hours post-dose.
Secondary outcome [1] 369136 0
To evaluate the safety and tolerability of administration of single doses of GS-9674 and GS-0976 in subjects with severe renal impairment or matched healthy controls with normal renal function. This outcome determined by assessment of electrocardiogram (ECG), physical examination, vital signs, BMI, clinical laboratory tests in blood and urine, creatinine clearance, evaluation of adverse events (AEs) and concomitant medication.
Timepoint [1] 369136 0
1) ECG Assessment at screening, day-1, pre-dose, and 3 hours post dose on Day 1 and 7, and Day of Discharge,or Early Termination (ET) visit (if applicable)

2) Complete physical exam: Screening, and Day -1; Symptom-driven physical exam: Days 1, 7, and Day of Discharge, or ET visit (if applicable)

3) Vital signs (resting blood pressure, heart rate, respiration rate, pulse oximetry, and body temperature): Screening, Day -1, Day 1 (pre-dose and 3 hours post-dose), Day 7 (pre-dose and 3 hours post-dose), Days 11, 14, 17, and 20, or ET visit, if applicable

4) BMI-Height and weight will be collected at screening for calculation of BMI; Weight will be measured at Day-1 and Day 20.

5) Clinical laboratory tests :
a) Hematology, chemistry, and urinalysis: Screening, Day -1, Day 3, Day 6, Day 9, and Day of Discharge, or ET visit, if applicable
b) Coagulation panel (prothrombin time, partial thromboplastin time [PTT], and international normalized ratio [INR]): Screening
c) Urine drug and alcohol assessments: Screening, Day -1, (On Day -1 Urine Drug and Alcohol test will be done at the clinic prior to dosing. An additional urine sample will also be sent to the central lab for processing)
d) Pregnancy test (female subjects of childbearing potential only): Serum pregnancy test will be performed at Screening, Day 11 (if Day of Discharge), and Day 20, or ET visit (if applicable). Urine pregnancy test will be performed at the clinic on Day 1 prior to dosing.
e) FSH (Female subjects less than or equal to 54 years old with amenorrhea greater than 12 months): Screening
f) Hepatitis B virus, hepatitis C virus, human immunodeficiency virus type 1 testing: Screening

6) Assessment of AEs and concomitant medications will continue throughout the study. The following known/possible AEs were seen in previous studies with GS-0976 and GS-9674 :
a) In previous studies with GS-0976, side effects seen in >10% of NASH subjects were:
*Gastrointestinal symptoms including abdominal pain, nausea, and diarrhea
*Increased blood triglycerides (fats in the blood) without symptoms
*Influenza
*Increased alkaline phosphatase (enzyme in the liver, bone, and intestine) without symptoms

b)Most frequent side effects seen in GS-9674-treated subjects were:
• Headache
• Diarrhea
• Back Pain
• Mild to moderate increased liver tests occurred in some subjects treated with GS-9674 and placebo. Liver test abnormalities in these subjects resolved with discontinuation of GS-9674
• Mild to moderate increased LDL cholesterol



Secondary outcome [2] 369137 0
To evaluate farnesoid X receptor (FXR) activation by GS-9674 as measured by pharmacodynamic (PD) markers in subjects with severe renal impairment or matched healthy controls with normal renal function.
Timepoint [2] 369137 0
Plasma and/or Serum PD Collection: blood samples will be collected relative to dosing of GS-9674 to measure PD biomarkers including but not limited to fibroblast growth factor 19 (FGF19 ) and C4 (7-alpha-hydroxy-4-cholesten-3- one) for GS-9674 at the following time points for each cohort:

*Day 6: 0 (predose, less than or equal to 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, and 16 hours post-dose (relative to Day 6 dosing time, predose of Day 7 will be used as 24 hour timepoint for Day 6)

*Day 7: 0 (pre-dose, less than or equal to 5 minutes prior to dosing), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose (relative to Day 7 dosing time)

*A blood sample for PD analysis will also be collected at the ET visit (if applicable) and may be analyzed.

Eligibility
Key inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
A) All Subjects
1. Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
2. Male or female aged 18 through 70 years of age, inclusive at screening
3. Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 6 months prior to the first dose of study drug
4. Have a calculated BMI of greater than or equal to 18.0 and less than or equal to 38.0 kg/m^2 at screening
5. Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 (unless permanently sterile or in postmenopausal state)
6. Female subjects must refrain from egg donation and in vitro fertilization during treatment and until at least 30 days after the last dose of study drug
7. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
8. Male subjects must refrain from sperm donation from clinic admission, throughout the study period, and continuing for at least 90 days following the last dose of study drug
9. Subjects have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug
10. Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator
11. Must be willing and able to comply with all study requirements

B) Subjects with Severe Renal Impairment
12. Must have a diagnosis of chronic (> 6 months), stable renal impairment with no clinically significant change in renal function status within 90 days prior to study drug administration (Day 1).
13. Estimated glomerular filtration rate (eGFR) using the MDRD equation must be less than 30 mL/min/1.73m^2, based on serum creatinine as measured at the screening evaluation eGFR (mL/min/1.73 m^2) = 175 × (*Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
*Scr – serum creatinine
14. Must have the following laboratory parameters at screening:
a. Total bilirubin < 2.0 mg/dL
b. Serum albumin greater than or equal to 2.5 g/dL
c. INR < 1.5, unless on a prescribed medication known to alter this test
d. Platelets > 90,000 mm^3
e. Hemoglobin > 8.5 g/dL
f. AST less than or equal to 2x ULN
g. ALT less than or equal to 2x ULN

C) Healthy Matched Control Subjects
15. Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
16. eGFR using the MDRD equation must be greater than 90 mL/min/1.73m^2, based on serum creatinine as measured during screening evaluation eGFR (mL/min/1.73 m^2) = 175 × (*Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
17. Screening laboratory evaluations (hematology, chemistry, and urinalysis) must fall within the normal range of the local laboratory’s reference ranges unless the results had been determined by the investigator to have no clinical significance.
18. Match in age (+\- 10 years), gender, and BMI (+\- 15%, greater than or equal to 18 to less than or equal to 38 kg/m ) with the respective subject in the renal impairment group
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects who meet any of the following exclusion criteria will not be enrolled in this study:
A) All subjects
1. Be pregnant or lactating
2. Have received any study drug within 30 days prior to study dosing
3. Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
4. Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody
5. Have poor venous access that limits phlebotomy
6. Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
7. Have a history of any of the following:
a. Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticarial
b. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
c. Known hypersensitivity to the study drugs their metabolites or to formulation excipients
d. Significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years
e. Syncope, palpitations, or unexplained dizziness
f. Implanted defibrillator or pacemaker
g. Liver disease, including Gilbert disease
h. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment
i. Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary
8. Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol

B) Subjects with Severe Renal Impairment
9. Require or anticipated to require dialysis within 90 days of study entry
10. History of clinically significant medical condition other than renal impairment, which in the opinion of the investigator may interfere with the conduct of the study
11. Received treatment with trimethoprim or cimetidine (affects the elimination of creatinine) or with competitors of renal tubular excretion (e.g. probenecid, chronic high dose non-steroidal anti-inflammatory drugs) within 28 days of Day -1
12. Received known nephrotoxic drugs (e.g. aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamindine, cyclosporine, tacrolimus, herbal remedies) within 28 days of Day -1
13. Aside from renal insufficiency expected laboratory values, abnormal laboratory values, that in the opinion of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol


C) Healthy Matched Controlled Subjects
14. Positive test for drugs of abuse, including alcohol at Screening or on Day -1
15. Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
1) Pharmacokinetics:
Plasma concentrations and PK parameters for each analyte will be listed and summarized using descriptive statistics by renal function group.
In addition, an analysis of variance (ANOVA) model with renal function group as a fixed effect will be fitted to the natural logarithmic transformation of PK parameters (area under the concentration versus time curve from time zero to the last quantifiable concentration (AUC_{last}), area under the concentration versus time curve extrapolated to infinite time (AUC_{inf}), maximum observed concentration of drug (C_{max})) for each analyte. Two-sided 90% confidence intervals (CIs) will be calculated for the ratios of the geometric least-squares means (GLSM) of PK parameters for GS-9674, GS-0976 and their metabolites between severe renal impairment group and the control (normal renal function) group.
If determined, PK urine concentrations and parameters for each analyte will be listed by subject and summarized by renal function group using descriptive statistics.

2) Pharmacodynamics:
PD data may be listed and summarized using descriptive statistics by renal function.

3) Sample Size:
With 16 (8 per group) evaluable subjects, the estimated two-sided 90% CI of the GLSM ratio of severe renal impairment group vs control (normal renal function), with regards to AUC_{last}, AUC_{inf} and C_{max} of GS-9674 and GS-0976 would be within [0, 2] with greater than or equal to 99% probability for GS-9674, and greater than or equal to 73% probability for GS-0976, if the estimated GLSM ratio were 1.0. This is assuming a standard deviation (SD) of no more than 0.27 and 0.58 on a natural logarithm scale for GS-9674 and GS-0976 respectively. These are supported by previous Gilead studies GS-US-454-4315 and GS-US-426-3987. With 25% overage, a total sample size of 20 subjects (10 per group) will be required.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2019
Actual
24/07/2019
Date of last participant enrolment
Anticipated
31/10/2020
Actual
7/12/2020
Date of last data collection
Anticipated
29/12/2020
Actual
18/12/2020
Sample size
Target
20
Accrual to date
Final
20
Recruitment outside Australia
Country [1] 21398 0
Germany
State/province [1] 21398 0
Munchen
Country [2] 21409 0
New Zealand
State/province [2] 21409 0
Christchurch, Auckland
Country [3] 21410 0
United States of America
State/province [3] 21410 0
Florida, Puerto Rico, Minnesota
Country [4] 21411 0
Romania
State/province [4] 21411 0
Bucharest

Funding & Sponsors
Funding source category [1] 302396 0
Commercial sector/Industry
Name [1] 302396 0
Gilead Sciences Inc
Country [1] 302396 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences Inc
Address
333 Lakeside Dr, Foster City, CA 94404, USA
Country
United States of America
Secondary sponsor category [1] 302287 0
None
Name [1] 302287 0
Address [1] 302287 0
Country [1] 302287 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303068 0
Advarra Institutional Review Board
Ethics committee address [1] 303068 0
Ethics committee country [1] 303068 0
United States of America
Date submitted for ethics approval [1] 303068 0
19/03/2019
Approval date [1] 303068 0
22/03/2019
Ethics approval number [1] 303068 0
Pro00033003
Ethics committee name [2] 303619 0
Southern Health and Disability Ethics Committee
Ethics committee address [2] 303619 0
Ethics committee country [2] 303619 0
New Zealand
Date submitted for ethics approval [2] 303619 0
Approval date [2] 303619 0
18/06/2019
Ethics approval number [2] 303619 0
19/STH/89

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92354 0
Dr Richard Robson
Address 92354 0
Christchurch Clinical Studies Trust Ltd
Level 4, 264 Antigua Street
Christchurch, 8011, New Zealand
Country 92354 0
New Zealand
Phone 92354 0
+64 3 3729477
Fax 92354 0
Email 92354 0
[email protected]
Contact person for public queries
Name 92355 0
Christine Mkaya
Address 92355 0
Gilead Sciences
333 Lakeside Dr. Foster City CA 94404
Country 92355 0
United States of America
Phone 92355 0
+1 650 425 5293
Fax 92355 0
Email 92355 0
[email protected]
Contact person for scientific queries
Name 92356 0
Christine Mkaya
Address 92356 0
Gilead Sciences
333 Lakeside Dr. Foster City CA 94404
Country 92356 0
United States of America
Phone 92356 0
+1 650 425 5293
Fax 92356 0
Email 92356 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
due to the commercial value of these data


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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