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Trial registered on ANZCTR


Registration number
ACTRN12616001260415
Ethics application status
Approved
Date submitted
23/08/2016
Date registered
8/09/2016
Date last updated
8/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to evaluate safety and tolerability of GS -5801 in healthy subjects
Scientific title
A Phase 1 Study to Evaluate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of GS-5801, and the
Effect of Food on GS-5801 Pharmacokinetics in Healthy Subjects
Secondary ID [1] 289993 0
GS-US-405-2064
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis B Virus 300000 0
Condition category
Condition code
Infection 299895 299895 0 0
Other infectious diseases
Oral and Gastrointestinal 299910 299910 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
Cohort 1: 2 mg GS-5801 (1x 2 mg tablet) or placebo tablet. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14.
Cohort 2: 6 mg GS-5801 (3x 2 mg tablets) or placebo tablets. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14.
Cohort 3: 20 mg GS-5801 (1x 20 mg tablet) or placebo tablet. Fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14.
Cohort 4-6: between 2mg and 100 mg GS-5801 or placebo tablet(s). Fed or fasted. Dosing Day 1, Day 2-7 Washout, Dosing Days 8 - 14. Dose will be determined based on available safety, PK, and PD data from cohorts 1-3 which informs on the effect of food on the PK and PD of GS-5801.
Cohort 7: Day 1: 2mg to 100 mg GS-5801, single dose. Fasted. Day 2-7 Washout. Day 8: up to 100 mg GS-5801, single dose. Fed

Fasted state: no food or drinks except water, for at least 10 hours.
Fed state: study drug(s) will be administered at approximately the same time each day and within 5 minutes of completing a specified moderate-fat-calorie breakfast (~600 calories, 25% to 30% fat).

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] 295695 0
Treatment: Drugs
Comparator / control treatment
Placebo-to-match (PTM) GS-5801 tablets are identical in size, shape, color and appearance to the corresponding active strength GS-5801 tablets. The PTM GS-5801 tablet cores contain commonly used excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.
Control group
Placebo

Outcomes
Primary outcome [1] 299377 0
To evaluate the safety and tolerability of escalating single- and multiple- oral doses of GS-5801. The primary safety endpoints are the incidences of adverse events, vital signs and ECG measurements, and laboratory abnormalities assessments.
Timepoint [1] 299377 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, Day1, 2, 3, 8, 9, 10, 12, 14, 16, 18, 21, 28, end of trial
ECG: Screening, Day-1, Day1, 2, 3, 8, 9, 10, 14, 28, end of trial
Lab assessments: Screening, Day-1, Day1, 2, 3, 8, 9, 10, 12, 14, 16, 18, 21, 28, end of trial
Primary outcome [2] 299378 0
To characterize the single- and multiple-dose pharmacokinetics (PK) of GS-5801 and its metabolite GS-698080. The primary PK endpoints are single- and multiple- dose plasma PK parameters: AUClast, AUCinf (single dose), AUCtau (multiple dose), % AUCexp (single dose), Ctau (multiple dose), and Cmax, of GS-5801 and its metabolite GS-698080.
Timepoint [2] 299378 0
Part A and B (Cohorts 1-6): Intensive PK sampling will occur relative to dosing of GS-5801 or placebo at the following time points for each cohort:
Day 1: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Days 8-13: 0 (predose, = 5 min prior to dose)
Day 14: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Part C (Cohort 7): Intensive PK sampling will occur relative to dosing of GS-5801 at the
following time points:
Days 1 and 8: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Primary outcome [3] 299379 0
To perform a preliminary evaluation of the effect of concomitant food intake on the PK of GS-5801 and its metabolite GS-698080. The primary PK endpoints are single- and multiple- dose plasma PK parameters: AUClast, AUCinf (single dose), AUCtau (multiple dose), % AUCexp (single dose), Ctau (multiple dose), and Cmax, of GS-5801 and its metabolite GS-698080.
Timepoint [3] 299379 0
Part A and B (Cohorts 1-6): Intensive PK sampling will occur relative to dosing of GS-5801 or placebo at the following time points for each cohort:
Day 1: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Days 8-13: 0 (predose, = 5 min prior to dose)
Day 14: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Part C (Cohort 7): Intensive PK sampling will occur relative to dosing of GS-5801 at the
following time points:
Days 1 and 8: 0 (predose, = 5 min prior to dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 hours postdose.
Secondary outcome [1] 326990 0
NA
Timepoint [1] 326990 0
NA

Eligibility
Key inclusion criteria
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 aged 18 through 45 years of age, inclusive at screening
3. Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug
4. Have a calculated body mass index (BMI) of >=19.0 and =<30.0 kg/m2 at screening
5. 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)
6. Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission
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. Screening laboratory and 12-lead ECG evaluations must be without clinically significant abnormalities as assessed by the investigator
11. Have liver disease or liver function tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin below the upper limit of normal at screening
12. Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor
13. Must be willing and able to comply with all study requirements
14. Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Be a pregnant or lactating female
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 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, fish oil, protein powder, and/or paracetamol and/or ibuprofen and/or hormonal contraceptive medications
7. 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)
8. Significant serious skin disease, such as but not limited to rash, food allergy, eczema,
psoriasis, or uticaria
9. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
10. Known hypersensitivity to the study drugs their metabolites or to formulation excipients
11. 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
12. Syncope, palpitations, or unexplained dizziness
13. Implanted defibrillator or pacemaker
14. Liver disease, including Gilbert disease
15. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid
hypersecretory conditions requiring prolonged (> 6 months) medical treatment.
16. Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary.
17. 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 renal, 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.

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)
Central randomisation by phone/fax/computer.
Part A: (Cohorts 1-3): 10 per cohort (8 GS-5801, 2 placebo-to-match)
Part B: (Cohorts 4-6): 10 per cohort (8 GS-5801, 2 placebo-to-match)
Part C: (Cohort 7): 10 GS-5801
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation. Randomized 4:1 to receive either blinded GS-5801 (N=8) or matching placebo (N=2)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Part A (Cohorts 1-3): Randomized, blinded, placebo-controlled, single- and multiple-doses with staggered pre-specified dose escalations
Part B (Cohorts 4-6): Randomized, blinded, placebo-controlled, single- and multiple-doses with adaptive dose selection, and fed or fasted administration of GS-5801.
Part C (Cohort 7): Open-label, two-treatment, fixed-sequence, food effect with adaptive dose selection of GS-5801.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Study GS-US-405-2064 is closed. Although this compound was generally well tolerated by subjects, the preliminary data from the first two cohorts was sufficient to understand the safety profile of GS5801 within the allowable dosing limitations of the compound.
Date of first participant enrolment
Anticipated
1/10/2016
Actual
26/09/2016
Date of last participant enrolment
Anticipated
Actual
17/10/2016
Date of last data collection
Anticipated
Actual
24/11/2016
Sample size
Target
70
Accrual to date
Final
20
Recruitment outside Australia
Country [1] 8119 0
New Zealand
State/province [1] 8119 0

Funding & Sponsors
Funding source category [1] 294363 0
Commercial sector/Industry
Name [1] 294363 0
Gilead Sciences, Inc.
Country [1] 294363 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] 293204 0
None
Name [1] 293204 0
NA
Address [1] 293204 0
NA
Country [1] 293204 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295780 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 295780 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street, Wellington 6011
Ethics committee country [1] 295780 0
New Zealand
Date submitted for ethics approval [1] 295780 0
23/08/2016
Approval date [1] 295780 0
19/09/2016
Ethics approval number [1] 295780 0

Summary
Brief summary
This study will proceed in three parts, governed within and between parts by reviews of safety data and application of stopping rules. Based on safety and available pharmacokinetic (PK) and pharmacodynamic (PD) data, and at the discretion of the sponsor in consultation with the investigator, the adaptive cohorts may be repeated at the same dose level, be held until further data are available, or not be initiated at all.
Part A will proceed in 3 staggered pre-specified cohorts. Within each cohort, 10 unique subjects will be randomized 4:1 to receive either blinded GS-5801 (N=8) or matching placebo (N=2). All study drugs in Part A will be administered in a fasted state.
Part B: Based on available safety, PK, and PD data from cohorts in Part A,
doses for Part B (Cohorts 4 - 6) will be selected between 2 and 100 mg. Within each cohort, 10 unique subjects will be randomized 4:1 to receive either active GS-5801 (N=8) or matching placebo (N=2). Within each cohort, subjects may be administered up to 100 mg
GS-5801 once daily in either the fed or fasted state.
Part C: The dose of GS-5801 selected for evaluation in Cohort 7 will be determined based on review of available safety, PK, and PD data from Cohorts in Part A and/or B and will not exceed a dose previously evaluated in Parts A or B. 10 unique subjects will receive a single dose of GS-5801 (up to 100 mg) administered in the fasted state on Day 1, followed by a 6-day washout, and a second single dose of GS-5801 (up to 100 mg)
administered with a moderate-fat-calorie breakfast.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68462 0
Prof Edward Gane
Address 68462 0
Auckland Clinical Studies Limited
3 Ferncroft Street, Auckland 1042
Country 68462 0
New Zealand
Phone 68462 0
+64 9 373 3474
Fax 68462 0
Email 68462 0
[email protected]
Contact person for public queries
Name 68463 0
Mr Anuj Gaggar
Address 68463 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 68463 0
United States of America
Phone 68463 0
+1 650 358 1090
Fax 68463 0
Email 68463 0
[email protected]
Contact person for scientific queries
Name 68464 0
Mr Anuj Gaggar
Address 68464 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 68464 0
United States of America
Phone 68464 0
+1 650 358 1090
Fax 68464 0
Email 68464 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTargeting histone demethylase KDM5B for cancer treatment.2020https://dx.doi.org/10.1016/j.ejmech.2020.112760
Dimensions AIInnovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond2018https://doi.org/10.1016/j.antiviral.2018.05.005
N.B. These documents automatically identified may not have been verified by the study sponsor.