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Trial registered on ANZCTR


Registration number
ACTRN12617000700336
Ethics application status
Approved
Date submitted
4/05/2017
Date registered
16/05/2017
Date last updated
9/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study in Healthy Volunteers to Evaluate UDP glucuronosyl transferase (UGT) and Cytochrome (CYP) P450 - Mediated Drug-Drug Interactions Between GS-9688 and Probe Drugs
Scientific title
A Phase 1 Study in Healthy Volunteers to Evaluate UDP glucuronosyl transferase (UGT) and Cytochrome (CYP) P450 - Mediated Drug-Drug Interactions Between GS-9688 and Probe Drugs
Secondary ID [1] 291846 0
GS-US-389-3979
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis B 303096 0
Condition category
Condition code
Infection 302555 302555 0 0
Other infectious diseases
Oral and Gastrointestinal 302556 302556 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 (CYP3A inhibitor): Voriconazole (VORI) 200 mg oral tablet (N = 25 for 23 evaluable)
Cohort 2 (UGT inhibitor): Probenecid (PBC) 500 mg oral tablet (N = 25 for 23 evaluable)
Cohort 3 (CYP1A2/CYP3A inhibitor): Ciprofloxacin (CIPRO) 500 mg oral tablet (N = 25 for 23 evaluable)
Cohort 4 (CYP450/UGT Inducer): Rifampin (RIF) 600 mg oral tablet (N = 25 for 23 evaluable)

Following completion of screening and admission assessments (on Day -1), eligible subjects will be enrolled to a treatment in one of 4 cohorts. Cohorts may be run in parallel.
Within each cohort, study treatments will be administered starting on Day 1 as follows:
Treatment A: Single dose of GS-9688 1 mg oral tablet will be administered in the AM on Days 1 and 8.
Treatment B: VORI 200 mg twice daily (BID) will be administered for 2 days on Days 7 and 8. The single dose of GS-9688 1 mg oral tablet will be administered in the morning of Day 8 1 hour after VORI dose.
Treatment C: PBC 500 mg twice daily (BID) will be administered for 2 days on Days 7 and 8 with a single dose of GS-9688 1 mg oral tablet administered in the morning of Day 8 1 hour after PBC dose.
Treatment D: CIPRO 500 mg twice daily (BID) will be administered for 2 days on Days 7 and 8. The single dose of GS-9688 1 mg oral tablet will be administered in the morning of Day 8 1 hour after CIPRO dose.
Treatment E: Single dose of GS-9688 2 mg oral tablet will be administered in the AM on Day 1 and Day 8.
Treatment F: RIF 600 mg once a day (QD) administered in PM for 7 days (Days 2-8) with a single dose of GS-9688 2 mg oral tablet administered in AM of Days 2 to 8. The last dose of RIF will be administered in the PM on Day 8.

Cohort 1: Treatment A & B
Cohort 2: Treatment A & C
Cohort 3: Treatment A & D
Cohort 4: Treatment E & F

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] 297957 0
Treatment: Drugs
Comparator / control treatment
Cohorts 1-3: 1mg GS-9688 dose
Cohort 4: 2mg GS-9688 dose
Also comparing effect different drugs VORI, PBC, CIPRO and RIF on GS-9688
Control group
Active

Outcomes
Primary outcome [1] 301975 0
To evaluate the effect of UGT inhibition on the pharmacokinetics (PK) of GS-9688.
PK parameters AUCinf, AUClast, and Cmax
PK parameters are assessed by blood sample collection.
Timepoint [1] 301975 0
Intensive PK sampling will occur relative to the morning dosing of GS-9688 at the following timepoints:
Days 1 and 8: 0 predose (=< 5 min), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, and 24 hours postdose.
Primary outcome [2] 301976 0
To evaluate the effect of CYP1A2 and CYP3A inhibition on the PK of GS-9688
PK parameters AUCinf, AUClast, and Cmax
PK parameters are assessed by blood sample collection.
Timepoint [2] 301976 0
Intensive PK sampling will occur relative to the morning dosing of GS-9688 at the following timepoints:
Days 1 and 8: 0 predose (=< 5 min), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, and 24 hours postdose.
Primary outcome [3] 301977 0
To evaluate the effect of CYP450/UGT induction on the PK of GS-9688
PK parameters AUCinf, AUClast, and Cmax
PK parameters are assessed by blood sample collection.
Timepoint [3] 301977 0
Intensive PK sampling will occur relative to the morning dosing of GS-9688 at the following timepoints:
Days 1 and 8: 0 predose (=< 5 min), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, and 24 hours postdose.
Secondary outcome [1] 334419 0
To evaluate the safety of GS-9688 when administered with probe drugs.
Timepoint [1] 334419 0
Safety is continually assessed throughout the course of the study. Participants are reviewed at each visit and can contact the site at any time to report adverse events.
Safety assessments:
Physical examination: screening, Day -1, D1, 2, 3, 4, 5, 6, 7, 8, 9, 15, and end termination.
Vital signs: screening, Day -1, D1, 2, 3, 4, 5, 6, 7, 8, 9, 15, and end termination.
Bloods tests: screening, Day -1, D2, 5, 7, 9, 15, and end termination.
Urinalysis: screening, Day -1, D2, 5, 7, 9, 15, and end termination.
ECG: Day -1, D1, 7, 8, 15, and end termination. On days 1 and 8, ECGs will be performed at 4, 8, 12, and 24 hours postdose.
Patients can continually self-report AEs from screening until day 23.

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]) = 0.85 x CLcr (mL/min)
6. Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission (Day -1);
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 30 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 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,
HBsAg, or 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 and/or acetaminophen 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. 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 hepatotoxicity)
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;
9. 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 computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Randomised on a 1:1:1:1 ratio
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
7/06/2017
Actual
20/06/2017
Date of last participant enrolment
Anticipated
31/08/2017
Actual
10/08/2017
Date of last data collection
Anticipated
26/09/2017
Actual
31/08/2017
Sample size
Target
100
Accrual to date
Final
100
Recruitment outside Australia
Country [1] 8870 0
New Zealand
State/province [1] 8870 0

Funding & Sponsors
Funding source category [1] 296343 0
Commercial sector/Industry
Name [1] 296343 0
Gilead Sciences, Inc
Country [1] 296343 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] 295273 0
None
Name [1] 295273 0
Address [1] 295273 0
Country [1] 295273 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297575 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 297575 0
Ministry of Health Ethics Department Freyberg Building Reception – Ground Floor 20 Aitken Street, Wellington 6011
Ethics committee country [1] 297575 0
New Zealand
Date submitted for ethics approval [1] 297575 0
02/05/2017
Approval date [1] 297575 0
19/05/2017
Ethics approval number [1] 297575 0

Summary
Brief summary
Nonclinical data suggested GS-9688 human metabolism is mediated by a combination of glucuronidation by UGT2B7 and oxidation by multiple CYP enzymes including CYP1A2,
CYP3A, CYP2C19 and CYP2C9. GS-9688 was not found to be a substrate for P-gp, BCRP or OATP and is unlikely to be a clinically relevant inhibitor of these transporters in vivo. As such, the objective of this study is to increase understanding of in vivo disposition of GS-9688 in humans.

The probe inhibitors and inducers selected for the study are based on the recommendations of the FDA guidance entitled “In Vivo Drug Metabolism/Drug Interaction Studies — Study Design, Data Analysis, and Recommendations for Dosing and Labeling” (2011). Data from this study will inform the potential need for conducting additional drug interaction studies and/or on whether potential interactions are of the magnitude to be clinically meaningful and thus, necessitate a dosage adjustment and/or monitoring of GS-9688.

Healthy volunteers are selected for this study to remove the confounding effects of background therapies and to avoid the need to make multiple, short-term changes in treatment regimens of HBV-infected patients for the purpose of examining pharmacokinetics.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74490 0
Prof Edward Gane
Address 74490 0
Auckland Clinical Studies Limited 3 Ferncroft Street, Auckland 1042
Country 74490 0
New Zealand
Phone 74490 0
+64 9 373 3474
Fax 74490 0
Email 74490 0
[email protected]
Contact person for public queries
Name 74491 0
Ms Lorraine Ampaw
Address 74491 0
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City CA 94404
Country 74491 0
United States of America
Phone 74491 0
+1 (650) 389 8793
Fax 74491 0
Email 74491 0
[email protected]
Contact person for scientific queries
Name 74492 0
Ms Lorraine Ampaw
Address 74492 0
Gilead Sciences, Inc.
333 Lakeside Drive,
Foster City CA 94404
Country 74492 0
United States of America
Phone 74492 0
+1 (650) 389 8793
Fax 74492 0
Email 74492 0
[email protected]

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