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Trial registered on ANZCTR


Registration number
ACTRN12616001548426
Ethics application status
Approved
Date submitted
7/11/2016
Date registered
9/11/2016
Date last updated
24/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluate the Pharmacokinetics of GS-9876 in Subjects with Impaired Renal Function
Scientific title
A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of GS-9876 in Subjects with Impaired Renal Function
Secondary ID [1] 290464 0
GS-US-379-1932
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inflammatory Diseases 300830 0
Condition category
Condition code
Inflammatory and Immune System 300654 300654 0 0
Other inflammatory or immune system disorders
Inflammatory and Immune System 300655 300655 0 0
Rheumatoid arthritis
Inflammatory and Immune System 300656 300656 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cohort 1 (Moderate Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1.
Adaptive Cohort 2 (Severe Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1.
Adaptive Cohort 3 (Mild Renal Impairment): single oral dose of GS-9876 20 mg (2 × 10 mg tablet) in a fasted state on Day 1.

Based on safety and PK results from subjects with moderate renal impairment (Cohort 1), subjects with severe renal impairment (Cohort 2) and/or mild renal impairment (Cohort 3) will be enrolled. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or in parallel, as governed by safety and PK data in Cohort 1.

Dose administered following an overnight fast of at least 8 hours (no food or drink except water), study drug will be administered in the morning with 240 mL of water. Subjects will continue to fast until after collection of the 4-hour PK sample, relative to study drug dosing. Additionally, subjects will be restricted from water consumption 1 hour before until 2 hours after dosing, except for the 240 mL given with the study treatment.

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 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.
Intervention code [1] 296316 0
Treatment: Drugs
Comparator / control treatment
Matched healthy control subjects (normal renal function). Each cohort will consist of 10 subjects with renal impairment and 10 healthy control subjects.
Control group
Active

Outcomes
Primary outcome [1] 300078 0
To evaluate the pharmacokinetics (PK) of GS-9876 in subjects with impaired renal function relative to matched, healthy controls
The primary endpoints are PK parameters AUClast, AUCinf, and Cmax for GS-9876.
Timepoint [1] 300078 0
Intensive PK sampling will occur relative to dosing of GS-9876 at the following time points for each cohort.
Plasma PK:
Day 1: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose.
Urine PK:
Predose void, 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, and 96-120 hours postdose.
Secondary outcome [1] 328953 0
To evaluate the safety and tolerability of GS-9876 in subjects with normal and impaired renal function. The secondary endpoints include incidences of AEs, laboratory abnormalities, abnormal findings in vital signs and safety ECG monitoring.
Timepoint [1] 328953 0
Safety will be evaluated throughout the study. Incidences of adverse events will be monitored continuously from screening to end of study.
Vital signs: Screening, Day-1, 1, 2, 3, 4, 5, 6, 15, and early termination
ECG: Screening, Day-1, 1, 6, 15, and early termination
Lab assessments: Screening, Day-1, 1, 2, 3, 6, 15, and early termination

Eligibility
Key inclusion criteria
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) Be between 18 through 75 years of age, inclusive at screening
3) Must be able to comply with the smoking restrictions at the study site.
4) Have a calculated body mass index (BMI) of >=18 kg/m2 and <=36 kg/m2 at screening
5) Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission (Day -1).
6) Female subjects must refrain from egg donation and in vitro fertilization during treatment and until at least 36 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 (eg, Day -1),
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 in consultation with the sponsor
11) Must be willing and able to comply with all study requirements
12) Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
13) Subjects must have the following laboratory parameters at screening:
a) Hemoglobin >=8.0 g/dL (International System of Units [SI]: <80 g/L)
b) White blood cells >=3.0 x 10^3 cells/mm3 (SI: <3.0 x 10^9 cells/L)
c) Neutrophils >=1.5 x 10^3 cells/mm3 (SI: <1.5 x 10^9 cells/L)
d) Lymphocytes >=0.5 x 10^3 cells/mm3 (SI: <0.5 x 10^9 cells/L)
e) Platelets >=100 x 10^3 cells/mm3 (SI: <100 x 10^9 cells/L)
f) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <1.5 x ULN
g) Total bilirubin level <2 x ULN

Subjects with Renal Impairment:
1) Must have 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).
2) Have a creatinine clearance (CLcr) =<90 mL/min (using the Cockcroft-Gault method
based on serum creatinine and actual body weight as measured at screening, ie,
Male: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = CLcr (mL/min)
Female: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) x 0.85 = CLcr (mL/min)

Mild: CLcr 60-89 mL/min
Moderate: CLcr 30-59 mL/min
Severe: CLcr 15-29 mL/min

Healthy Matched Controlled Subjects (Normal Renal Function):
1) Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.
2) Have a creatinine clearance (CLcr) >=90 mL/min (using the Cockcroft-Gault method
based on serum creatinine and actual body weight as measured at screening, ie,
Male: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) = CLcr (mL/min)
Female: (140 – Age [years]) x (Weight [kg]) / 72 x (Serum Creatinine [mg/dL]) x 0.85 = CLcr (mL/min)
3) Match in age (+/- 10 years), gender, and body mass index (+/- 20%, 18 kg/m2 =< BMI =<36 kg/m2).
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All Subjects:
1) Be a lactating female
2) Have received any investigational compound 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 as judged by the investigator
4) Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody,
hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), 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 urticaria
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.
j) History of any major bleeding event defined as Grade 3 severity and above (as defined by the modified CTCAE 4.03) within the last year or personal or family history of bleeding disorder
k) Current use of chronic anticoagulant or anti-platelet agent, not including daily aspirin for cardiac prophylaxis.
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. This would include cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment.
9) Recent significant changes in the use of nicotine or nicotine containing products
(ie, initiation, substantial increase or decrease or cessation of use) in the 90 days prior to
study drug dosing, or anticipated significant changes in the use of nicotine or nicotine
containing products during the course of the study through the follow-up visit.

Subjects with Renal Impairment:
1) Require or are anticipated to require dialysis within 90 days of study dosing
2) Require during the study or have received moderate or strong inhibitors or inducers of
CYP3A within 2 weeks prior to study drug administration.

Healthy Matched Controlled Subjects (Normal Renal Function):
1) Have taken any prescription medications or over-the-counter medications, including herbal products and antacids, 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 and/or stable hormone replacement therapy in peri- /post-menopausal females

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)
Cohort 1 (Moderate Renal Impairment): Up to 20 subjects (10 per group, moderate renal impairment and matched healthy controls) for 8 evaluable subjects per group.

Adaptive Cohort 2 (Severe Renal Impairment): Up to 20 subjects (10 subjects with severe renal impairment and up to 10 matched healthy control subjects if none of the healthy subjects from a previous cohort is an appropriate match for a severe impairment
subject) for 8 evaluable subjects per group.

Adaptive Cohort 3 (Mild Renal Impairment): Up to 20 subjects (10 subjects with mild renal impairment and up to 10 matched healthy control subjects if none of the healthy subjects from a previous cohort is an appropriate match for a mild impairment
subject) for 8 evaluable subjects per group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
23/11/2016
Actual
21/11/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
24
Final
Recruitment outside Australia
Country [1] 8369 0
New Zealand
State/province [1] 8369 0
Country [2] 8370 0
Germany
State/province [2] 8370 0
Country [3] 8371 0
United States of America
State/province [3] 8371 0

Funding & Sponsors
Funding source category [1] 294876 0
Commercial sector/Industry
Name [1] 294876 0
Gilead Sciences, Inc
Country [1] 294876 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc
Address
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 293715 0
None
Name [1] 293715 0
Address [1] 293715 0
Country [1] 293715 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296254 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 296254 0
Ministry of Health Ethics Department
Freyberg Building Reception – Ground Floor
20 Aitken Street, Wellington 6011
Ethics committee country [1] 296254 0
New Zealand
Date submitted for ethics approval [1] 296254 0
02/11/2016
Approval date [1] 296254 0
22/11/2016
Ethics approval number [1] 296254 0
Ethics committee name [2] 299479 0
Chesapeake Institutional Review Board
Ethics committee address [2] 299479 0
6940 Columbia Gateway Drive,
Suite 110,
Columbia, Maryland
21046
Ethics committee country [2] 299479 0
United States of America
Date submitted for ethics approval [2] 299479 0
14/10/2016
Approval date [2] 299479 0
20/10/2016
Ethics approval number [2] 299479 0
Pro000019387

Summary
Brief summary
This is a Phase 1, open-label, parallel-group, adaptive, single-dose, multi-center,
pharmacokinetic study in subjects with renal impairment and matched healthy controls. A maximum of 60 subjects using an adaptive design that includes up to 3 enrolled cohorts. Adaptive Cohorts 2 and/or 3 will be enrolled as determined by safety and/or PK data in Cohort 1. Specifically, Cohort 2 (Severe Renal Impairment) will be evaluated if supported by safety and/or PK data from Cohort 1 (Moderate Renal Impairment). Cohort 3 (Mild Renal Impairment) will be evaluated if supported by safety and if substantial changes (>=2-fold mean difference from matched controls) in the exposure of GS-9876 is observed in subjects with moderate renal impairment in Cohort 1. Cohorts 2 and 3 may not be enrolled or may be enrolled sequentially or in parallel, as governed by safety and PK data in Cohort 1. Each control subject may be matched to multiple renal impaired subjects across different cohorts and can be matched to only 1 renal impaired subject within a cohort.
Trial website
Trial related presentations / publications
Public notes
The first ethics approval was received on 20 October 2016 in the United States and the first participant enrollment was on the 21 Nov 2016 in the US. This occurred prior to receiving ethics approval in NZ on the 22 Nov 2016.
Christchurch Clinical Studies Trust was activated on the 19 Dec 2016.

Contacts
Principal investigator
Name 70166 0
Dr Richard Robson
Address 70166 0
Christchurch Clinical Studies Trust Ltd
PO Box 2856
Christchurch, 8140
Country 70166 0
New Zealand
Phone 70166 0
+6433729477
Fax 70166 0
Email 70166 0
[email protected]
Contact person for public queries
Name 70167 0
Lorraine Ampaw
Address 70167 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 70167 0
United States of America
Phone 70167 0
+1(650)3898793
Fax 70167 0
Email 70167 0
[email protected]
Contact person for scientific queries
Name 70168 0
Lorraine Ampaw
Address 70168 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 70168 0
United States of America
Phone 70168 0
+1(650)3898793
Fax 70168 0
Email 70168 0
[email protected]

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