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Trial registered on ANZCTR


Registration number
ACTRN12616000898459
Ethics application status
Approved
Date submitted
23/06/2016
Date registered
7/07/2016
Date last updated
9/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Tenofovir Alafenamide (TAF) versus Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in
Subjects with Chronic Hepatitis B (HBV) Infection and Stage 2 or Greater Chronic Kidney Disease Who Have Received a Liver Transplant
Scientific title
A Phase 2, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Tenofovir Alafenamide (TAF) versus Tenofovir Disoproxil Fumarate (TDF)–containing Regimens in
Subjects with Chronic HBV Infection and Stage 2 or Greater Chronic Kidney Disease Who Have Received a Liver Transplant
Secondary ID [1] 289419 0
GS-US-320-3912
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis B 299091 0
Chronic Kidney Disease 299326 0
Condition category
Condition code
Infection 299125 299125 0 0
Other infectious diseases
Oral and Gastrointestinal 299314 299314 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Renal and Urogenital 299316 299316 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Approximately 60 subjects with chronic hepatitis B and Stage 2 or greater chronic kidney disease and have received a liver transplant will be assigned to one of the two treatment arms (A:B) for 48 weeks. Randomization will be stratified by baseline renal function.
- Treatment Arm A: approximately 30 subjects administered Tenofovir Alafenamide (TAF) 25 mg oral daily
- Treatment Arm B: approximately 30 subjects to continue administration of Tenofovir Disoproxil Fumarate (TDF) alone or in combination with other approved antivirals per local practice;
After Week 48, during the optional treatment extension phase, subjects in treatment arms A and B will be eligible to receive TAF 25 mg daily and will be followed for an additional 96 weeks.
An accountability check at each visit, Drug tablet return and lab tests are all part of the protocol to manage and monitor adherence.
Intervention code [1] 295008 0
Treatment: Drugs
Comparator / control treatment
Tenofovir Disoproxil Furmarate (TDF) alone or in combination with other approved antivirals as per local practice
Control group
Active

Outcomes
Primary outcome [1] 298595 0
Change from baseline in renal function of TAF 25 mg daily versus TDF-containing regimens at Week 24.
eGFR is calculated by assessing Cystatin C and estimated serum creatinine clearance.
Timepoint [1] 298595 0
Assessment timepoints:
Creatinine Clearance: Baseline, Week 4, Week 8, Week 12, Week 20, and Week 24.
Cystatin C: Baseline, Week 4, Week 12, and Week 24.
Primary outcome [2] 298596 0
Proportion of subjects with HBV DNA < 20 IU/mL at Week 24.
The subject's HBV DNA will be assessed using a plasma assay.
Timepoint [2] 298596 0
Assessment timepoints: Baseline, Week 4, Week 8, Week 12, Week 20 and Week 24
Secondary outcome [1] 324675 0
Percent change from baseline in hip and spine bone mineral density (BMD) of TAF 25 mg daily versus TDF-containing regimens at Weeks 24 and 48. The outcome is assessed using a DEXA scan.
Timepoint [1] 324675 0
Assessment timepoints: Screening, Week 24, and Week 48.
For participants who opt in to the treatment extension phase, additional assessments performed at Week 96 and Week 144.
Secondary outcome [2] 324676 0
Change from baseline in serum creatinine of TAF 25 mg daily versus TDF-containing regimens at Weeks 24 and 48
Timepoint [2] 324676 0
Assessment timepoints: Baseline, Week 4, Week 8, Week 12, Week 20, Week 24, Week 36, and Week 48.
For participants who opt in to the treatment extension phase, additional assessments performed at Week 60, Week 72, Week 96, Week 120, and Week 144.
Secondary outcome [3] 324677 0
Change from baseline in renal function of TAF 25 mg daily versus TDF-containing regimens at Week 48.
eGFR is calculated by assessing Cystatin C and estimated serum creatinine clearance.
Timepoint [3] 324677 0
Assessment timepoints:
Creatinine Clearance: Baseline, Week 4, Week 8, Week 12, Week 20, Week 24, Week 36, and Week 48.
For participants who opt in to the treatment extension phase, additional assessments performed at Week 60, Week 72, Week 96, Week 120, and Week 144.
Cystatin C: Baseline, Week 4, Week 12, Week 24, and Week 48.
For participants who opt in to the treatment extension phase, additional assessments performed at Week 72, Week 96, Week 120, and Week 144.
Secondary outcome [4] 324678 0
Proportion of subjects with HBV DNA < 20 IU/mL at Week 48.
The subject's HBV DNA will be assessed using a plasma assay.
Timepoint [4] 324678 0
Assessment timepoints: Baseline, Week 4, Week 8, Week 12, Week 20, Week 24, Week 36, and Week 48.
For participants who opt in to the treatment extension phase, additional assessments performed at Week 60, Week 72, Week 96, Week 120, and Week 144.

Eligibility
Key inclusion criteria
1) Must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2) Adult male or non-pregnant female subjects, over 18 years of age based on the date of the screening visit
3) Documented evidence of chronic HBV infection prior to transplantation
4) Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from deceased or living donor
5) Liver Transplant =>12 weeks prior to screening
6) Maintained on TDF alone or in combination with other approved antivirals for HBV
prophylaxis or treatment
7) Have been on approved HBV OAV treatment for at least 12 weeks post-transplant prior to screening, with HBV DNA < LLOQ at screening
8) Screening renal function < 90 ml/min/1.73m^2
9) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
10) Women considered of child bearing potential must have a negative serum
pregnancy test at Screening and a negative urine test at Baseline before dosing
11) Must be willing and able to comply with all study requirements
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Multi-organ transplant that includes heart or lung recipient (subjects who have their liver transplant as part of a liver-kidney dual transplant are eligible to enroll)
2) Subjects with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant and at screening
3) Histological evidence of unresolved transplant rejection
4) Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis
5) Subjects meeting any of the following laboratory parameters at screening:
a) ALT > 10× the upper limit of normal (ULN)
b) INR > 1.5 × ULN unless the subject is stable on anticoagulant regimen affecting INR
c) Albumin < 3.0 g/dL
d) Direct bilirubin => 4 × ULN
e) Platelet count < 50,000/mL
6) Co-infection with HIV or HCV
7) Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics
8) Use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents, cyclosporine > 300 mg/day, or use of any prohibited medications within 28 days of the Baseline/Day 1 visit
9) Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (e.g., basal cell skin cancer, etc) or hepatocellular carcinoma. Subjects under evaluation for possible malignancy are not eligible
10) Significant cardiovascular, pulmonary, or neurological disease
11) Use of investigational agents within 3 months of screening, unless allowed by the Sponsor
12) Use of any prohibited concomitant medications
13) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
14) Known hypersensitivity to study drugs, metabolites or formulation excipients
15) Lactating females or those who may wish to become pregnant during the course of the study

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation was employed in the study, The factor used for stratification is the subject's baseline renal function.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary analysis set for efficacy analysis is the Full Analysis Set (FAS), defined as all
randomized subjects who receive at least one dose of study drug. Subjects will be analyzed according to the randomized treatment assignment.

The primary analysis set for safety analyses is the Safety Analysis Set (SAS), defined as all randomized subjects who receive at least one dose of study drug. Subjects will be analyzed according to the treatment actually received. All data collected during treatment will be included in the safety summaries.

Please note that this is an exploratory study, so there was no sample size calculation performed.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 7949 0
New Zealand
State/province [1] 7949 0

Funding & Sponsors
Funding source category [1] 293792 0
Commercial sector/Industry
Name [1] 293792 0
Gilead Sciences, Inc.
Address [1] 293792 0
333 Lakeside Drive
Foster City, CA 94404
Country [1] 293792 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences, Inc.
Address
333 Lakeside Drive
Foster City, CA 94404
Country
United States of America
Secondary sponsor category [1] 292626 0
None
Name [1] 292626 0
Address [1] 292626 0
Country [1] 292626 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295227 0
Health and Disability Ethics Committee (HDEC), NZ
Ethics committee address [1] 295227 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street, Wellington 6011
Ethics committee country [1] 295227 0
New Zealand
Date submitted for ethics approval [1] 295227 0
18/07/2016
Approval date [1] 295227 0
09/08/2016
Ethics approval number [1] 295227 0

Summary
Brief summary
This is a randomized, open-label, single center Phase 2 study to evaluate the safety and efficacy of TAF 25 mg daily versus TDF in adult chronic hepatitis B infection (CHB) subjects with Stage 2 or greater chronic kidney disease and have received a liver transplant.
Approximately 60 subjects will be randomized in a 1:1 ratio to either continue current treatment regimen with TDF alone or in combination with other approved antivirals or to receive TAF 25 mg oral daily. At least 50 subjects will be enrolled with renal function < 50 ml/min/1.73m^2.
- Treatment Arm A: approximately 30 subjects administered TAF 25 mg oral daily
- Treatment Arm B: approximately 30 subjects to continue administration of TDF alone or in combination with other approved antivirals as per local practice.
After Week 48, all subjects will be eligible to continue in the optional treatment extension phase, wherein they will receive TAF 25 mg daily and will be followed for an additional 96 weeks.
The primary analysis will occur at Week 24 with the primary efficacy endpoint being the maintenance of viral suppression (HBV DNA < 20 IU/mL).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66618 0
Prof Edward Gane
Address 66618 0
Auckland City Hospital
Park Road, Grafton 1142
New Zealand
Country 66618 0
New Zealand
Phone 66618 0
+64 9 373 3474
Fax 66618 0
Email 66618 0
edgane@adhb.govt.nz
Contact person for public queries
Name 66619 0
Ms Ansy Mathews
Address 66619 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 66619 0
United States of America
Phone 66619 0
+1 6505243912
Fax 66619 0
Email 66619 0
ansy.mathews@gilead.com
Contact person for scientific queries
Name 66620 0
Ms Ansy Mathews
Address 66620 0
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Country 66620 0
United States of America
Phone 66620 0
+1 6505243912
Fax 66620 0
Email 66620 0
ansy.mathews@gilead.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary