Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate for Treatment of Hepatitis B e Antigen-Positive Hepatitis B (China)

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02836249
• Collaborator: (none)
• Enrollment: 181
• Locations: 25
• Arms: 3
• Anticipated Duration (Months): 100.4
• Patients Per Site: 7.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in treatment-naive and treatment-experienced adults with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (HBV) infection in China.

Condition or Disease	Intervention/Treatment	Phase
HBV; Chronic HBV Infections	Drug: TAF; Drug: TDF; Drug: TAF Placebo; Drug: TDF Placebo	Phase 3

Detailed Description

This study GS-US-320-0110 is an international study planned to enroll participants in global countries, including China. However, due to the review timeline difference in China, full enrollment was reached in the main study (NCT01940471) before China was able to participate. Therefore, this registration only includes the China cohorts as they were not part of the main study analysis. Data for China cohorts were analyzed separately after the main study analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 181 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD Versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment of HBeAg Positive, Chronic Hepatitis B
• Actual Study Start Date: Jun 19, 2015
• Actual Primary Completion Date: Dec 15, 2016
• Anticipated Study Completion Date: Nov 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAF TAF + TDF placebo for up to 144 weeks	Drug: TAF; TAF 25 mg tablet administered orally once daily; Other Names: GS-7340 Vemlidy® ; Drug: TDF Placebo; TDF placebo tablet administered orally once daily
Active Comparator: TDF TDF + TAF placebo for up to 144 weeks	Drug: TDF; TDF 300 mg tablet administered orally once daily; Other Names: Viread® ; Drug: TAF Placebo; TAF placebo tablet administered orally once daily
Experimental: Open-label TAF All participants who complete the double-blind period will be eligible to receive open-label TAF until Week 384 of the study.	Drug: TAF; TAF 25 mg tablet administered orally once daily; Other Names: GS-7340 Vemlidy®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 [Week 48]

Secondary Outcome Measures

1. Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48 [Week 48]

2. Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 [Baseline; Week 48]

3. Percent Change From Baseline in Spine BMD at Week 48 [Baseline; Week 48]

4. Change From Baseline at Week 48 in Serum Creatinine [Baseline; Week 48]

Other Outcome Measures

1. Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 [Up to 48 weeks]

   Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures

• Adult males and non-pregnant, non-lactating females

• Documented evidence of chronic HBV infection

• HBeAg-positive, chronic hepatitis B with all of the following:

• HBeAg-positive at screening

• Screening HBV DNA ≥ 2 x 10^4 IU/mL

• Screening serum alanine aminotransferase (ALT) level > 60 U/L (males) or > 38 U/L (females) and ≤ 10 x the upper limit of the normal range (ULN)

• Treatment-naive participants (defined as < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue) OR treatment-experienced participants (defined as participants meeting all entry criteria [including HBV DNA and serum ALT criteria] and with ≥ 12 weeks of previous treatment with any nucleoside or nucleotide analogue)

• Previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit

• Adequate renal function

• Normal ECG

Key Exclusion Criteria:

• Females who are breastfeeding

• Males and females of reproductive potential who are unwilling to use an "effective", protocol specified method(s) of contraception during the study

• Co-infection with hepatitis C virus, HIV, or hepatitis D virus

• Evidence of hepatocellular carcinoma

• Any history of, or current evidence of, clinical hepatic decompensation

• Abnormal hematological and biochemical parameters, including aspartate aminotransferase (AST) > 10 x ULN

• Received solid organ or bone marrow transplant

• History of malignancy within the past 5 years, with the exception of specific cancers that are cured by surgical resection; individuals under evaluation for possible malignancy are not eligible

• Currently receiving therapy with immunomodulators (eg, corticosteroids), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion

• Individuals receiving ongoing therapy with drugs not to be used with tenofovir alafenamide or tenofovir disoproxil fumarate or individuals with a known hypersensitivity to study drugs, metabolites, or formulation excipients

• Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance

• Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Ditan Hospital	Beijing		China	100015
2	PLA 302 Hospital	Beijing		China	100039
3	Beijing Friendship Hospital, Capital Medical University	Beijing		China	100050
4	Beijing Youan Hospital, Capital Medical University	Beijing		China	100069
5	Xianya Hospital, Central South University	Changsha		China	410008
6	Guangzhou Eighth People's Hospital	Guangzhou		China	510060
7	Nanfang Medical University, Nanfang Hospital	Guangzhou		China	510515
8	No. 3 Hospital, Zhongshan Medical University	Guangzhou		China	510630
9	The Affiliated Hospital of Guiyang Medical College	Guiyang		China	550004
10	The People's Hospital of Hainan Province	Haikou		China	570311
11	The Second Xiangya Hospital of Central South University	Hunan		China	410011
12	Jiangsu Province People's Hospital	Jiangsu		China	210029
13	The First Affiliated Hospital of Nanchang University	Jiangxi		China	330006
14	1st Hospital Jilin University	Jilin		China	130021
15	Jinan Infectious Disease Hospital	Jinan		China	250021
16	2nd Hospital of Nanjing City	Nanjing		China	210003
17	Ruijin Hospital, JiaoTong University School of Medicine	Shanghai		China	200025
18	Shanghai Public Health Clinical Center	Shanghai		China	200083
19	85 Hospital of People's Liberation Army	Shanghai		China	200235
20	Shengjing Hospital of China Medical University	Shenyang		China	110004
21	The Sixth People's Hospital of Shenyang	Shenyang		China	110006
22	3rd Hospital of Hebei Medical University	Shijiazhuang		China	050051
23	West China Hospital, Sichuan University	Sichuan		China	610041
24	First Affiliated Hospital of Xi'an Jiaotong University	Xi'an		China	710061
25	1st Affiliated Hospital Kunming Medical College	Yunnan		China	650032

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Gilead Clinical Trials Website

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT02836249
• Other Study ID Numbers: GS-US-320-0110 (China); 2013-000636-10
• First Posted: Jul 18, 2016
• Last Update Posted: Mar 21, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gilead Sciences: Hepatitis; Tenofovir; Viread
• Additional relevant MeSH terms: Hepatitis B; Hepatitis

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in China. The first participant was screened on 25 August 2013 for the main study and the first participant screened in China was on 19 June 2015. The last Week 48 visit for the primary endpoint in China occurred on 15 December 2016.
Pre-assignment Detail	227 participants were screened in China.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	Tenofovir alafenamide (TAF) 25 mg tablet + tenofovir disoproxil fumarate (TDF) placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Period Title: Overall Study
STARTED	123	58
COMPLETED	0	0
NOT COMPLETED	123	58

Baseline Characteristics

Arm/Group Title	TAF 25 mg	TDF 300 mg	Total
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks	Total of all reporting groups
Overall Participants	123	57	180
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34 (9.4)	36 (9.5)	34 (9.4)
Sex: Female, Male (Count of Participants)
Female	35 28.5%	13 22.8%	48 26.7%
Male	88 71.5%	44 77.2%	132 73.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	123 100%	57 100%	180 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	123 100%	57 100%	180 100%
HBV DNA (log10 IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 IU/mL]	7.2 (1.65)	7.2 (1.48)	7.2 (1.59)
Plasma HBV DNA Level (Count of Participants)
< 8 log10 IU/mL	74 60.2%	36 63.2%	110 61.1%
≥ 8 log10 IU/mL	49 39.8%	21 36.8%	70 38.9%
IL28b Status (Count of Participants)
CC	109 88.6%	52 91.2%	161 89.4%
CT	12 9.8%	5 8.8%	17 9.4%
TT	2 1.6%	0 0%	2 1.1%
Oral antiviral (OAV) Treatment Status (Count of Participants)
Treatment Experienced	45 36.6%	18 31.6%	63 35%
Treatment Naive	78 63.4%	39 68.4%	117 65%
Proteinuria by Urinalysis (dipstick) (Count of Participants)
Grade 0	117 95.1%	54 94.7%	171 95%
Grade 1	6 4.9%	2 3.5%	8 4.4%
Grade 2	0 0%	1 1.8%	1 0.6%
Grade 3	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set: participants who were randomized into the study and received at least 1 dose of study drugs. Participants were analyzed according to the treatment to which they were randomized.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	123	57
Number [percentage of participants]	61.0 49.6%	68.4 120%

2. Secondary Outcome

Title	Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Serologically Evaluable Full Analysis Set: participants who were randomized, had received at least 1 dose of study drug, and were HBeAg positive and anti-HBe negative or had a value missing value at baseline. Participants were analyzed according to their randomized treatment group. All missing data were treated as no HBeAg seroconversion.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	118	57
Number [percentage of participants]	11.0 8.9%	8.8 15.4%

3. Secondary Outcome

Title	Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
Time Frame	Baseline; Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Hip Dual-Energy X-ray Absorptiometry (DXA) Analysis Set (participants who were randomized, received at least 1 dose of study drugs, and had nonmissing baseline hip BMD values) with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data were excluded from analysis.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	53	31
Mean (Standard Deviation) [percent change]	0.624 (2.2731)	-1.507 (2.4193)

4. Secondary Outcome

Title	Percent Change From Baseline in Spine BMD at Week 48
Time Frame	Baseline; Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Spine DXA Analysis Set (participants who were randomized, received at least 1 dose of study drugs, and had nonmissing baseline spine BMD values) with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data were excluded from analysis.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	54	31
Mean (Standard Deviation) [percent change]	0.683 (3.3281)	-2.169 (3.4503)

5. Secondary Outcome

Title	Change From Baseline at Week 48 in Serum Creatinine
Time Frame	Baseline; Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data were excluded from analysis.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	121	55
Mean (Standard Deviation) [mg/dL]	-0.003 (0.0701)	0.016 (0.0920)

6. Other Pre-specified Outcome

Title	Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48
Description	Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method.
Time Frame	Up to 48 weeks

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set with at least 1 postbaseline urine protein value were analyzed.

Arm/Group Title	TAF 25 mg	TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks	TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
Measure Participants	123	57
Grade 1	24.4 19.8%	22.8 40%
Grade 2	0.8 0.7%	3.5 6.1%
Grade 3	0 0%	0 0%

Adverse Events

Time Frame	Up to the Week 48 Data Cut
Adverse Event Reporting Description	Safety Analysis Set: participants who were randomized into the study and received at least 1 dose of study drug. Participants were analyzed according to the treatment they actually received during the double-blinded phase.
Arm/Group Title	TAF 25 mg		TDF 300 mg
Arm/Group Description	TAF 25 mg tablet + TDF placebo tablet once daily for up to 144 weeks		TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks
All Cause Mortality
	TAF 25 mg		TDF 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/123 (0%)		0/57 (0%)
Serious Adverse Events
	TAF 25 mg		TDF 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/123 (4.1%)		2/57 (3.5%)
Infections and infestations
Appendicitis	1/123 (0.8%)		0/57 (0%)
Injury, poisoning and procedural complications
Subarachnoid haemorrhage	0/123 (0%)		1/57 (1.8%)
Investigations
Alanine aminotransferase increased	1/123 (0.8%)		1/57 (1.8%)
Renal and urinary disorders
Nephrolithiasis	1/123 (0.8%)		0/57 (0%)
Reproductive system and breast disorders
Dysfunctional uterine bleeding	1/123 (0.8%)		0/57 (0%)
Surgical and medical procedures
Abortion induced	1/123 (0.8%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	TAF 25 mg		TDF 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/123 (37.4%)		24/57 (42.1%)
Gastrointestinal disorders
Nausea	2/123 (1.6%)		3/57 (5.3%)
Infections and infestations
Nasopharyngitis	27/123 (22%)		7/57 (12.3%)
Upper respiratory tract infection	17/123 (13.8%)		5/57 (8.8%)
Urinary tract infection	4/123 (3.3%)		4/57 (7%)
Investigations
Blood parathyroid hormone increased	6/123 (4.9%)		4/57 (7%)
Creatinine renal clearance decreased	2/123 (1.6%)		3/57 (5.3%)
Musculoskeletal and connective tissue disorders
Osteopenia	0/123 (0%)		3/57 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years