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Clinical Trial Results:
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B

Summary
EudraCT number	2004-005120-41
Trial protocol	GB DE CZ ES IT
Global end of trial date	28 Jan 2016

Results information
Results version number	v1(current)
This version publication date	11 Feb 2017
First version publication date	11 Feb 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

GS-US-174-0103

ISRCTN number

US NCT number

NCT00116805

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com

Scientific contact

Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Jan 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Jan 2016

Was the trial ended prematurely?

Main objective of the trial

This primary objectives of this study were to compare the efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-positive chronic hepatitis B. Participants will receive TDF or ADV for 48 weeks (double-blind). After 48 weeks, eligible participants switched to open-label TDF for up to 480 weeks.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Jun 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 45

Country: Number of subjects enrolled

Australia: 30

Country: Number of subjects enrolled

Canada: 26

Country: Number of subjects enrolled

Poland: 24

Country: Number of subjects enrolled

New Zealand: 19

Country: Number of subjects enrolled

Turkey: 14

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Greece: 3

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Bulgaria: 28

Country: Number of subjects enrolled

Czech Republic: 8

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 29

Country: Number of subjects enrolled

Italy: 1

Worldwide total number of subjects

271

EEA total number of subjects

137

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

271

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Participants were enrolled at study sites in North America, Europe, and Australia/New Zealand. The first participant was screened on 09 June 2005. The last study visit occurred on 28 January 2016.

Screening details

603 participants were screened.

Period 1 title

Double-blind Period Through Week 48

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Tenofovir disoproxil fumarate (TDF) 300 mg plus placebo to match adefovir dipivoxil (ADV) (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added emtricitabine (FTC) to their treatment regimen (as part of FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet) in the open-label period.

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

ADV-TDF

Arm description

ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Number of subjects in period 1 ^[1]	TDF-TDF	ADV-TDF
Started	176	90
Completed	165	85
Not completed	11	5
Withdrew Consent	4	2
Protocol Violation	1	1
Lost to follow-up	6	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 6 participants who were randomized but not treated are not included in the subject disposition table. 1 subject who was randomized into the study but was not included in the worldwide number enrolled because that subject's country of enrollment and age was not documented.

Period 2 title

Open-label Period Weeks 49 - 96

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 2 ^[2]	TDF-TDF	ADV-TDF
Started	154	84
Completed	144	83
Not completed	10	1
Seroconversion	2	-
Withdrew Consent	2	1
Investigator's Discretion	1	-
Protocol Violation	2	-
Lost to follow-up	2	-
Safety, Tolerability, or Efficacy Reason	1	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 12 participants (11 TDF-TDF; 1 ADV-TDF) completed 48 weeks but did not continue on study.

Period 3 title

Open-label Period Weeks 97 - 144

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 3	TDF-TDF	ADV-TDF
Started	144	83
Completed	133	74
Not completed	11	9
Seroconversion	2	3
Withdrew Consent	1	3
Investigator's Discretion	2	-
Protocol Violation	-	1
Lost to follow-up	5	2
Completed Study	1	-

Period 4 title

Open-label Period Weeks 145 - 192

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 4	TDF-TDF	ADV-TDF
Started	133	74
Completed	123	68
Not completed	10	6
Withdrew Consent	3	2
Seroconversion	-	1
Investigator's Discretion	2	-
Protocol Violation	1	-
Lost to follow-up	3	1
Completed Study	1	1
Safety, Tolerability, or Efficacy Reason	-	1

Period 5 title

Open-label Period Weeks 193 - 240

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 5	TDF-TDF	ADV-TDF
Started	123	68
Completed	110	64
Not completed	13	4
Withdrew Consent	7	1
Investigator's Discretion	1	-
Lost to follow-up	3	-
Safety, Tolerability, or Efficacy Reason	2	2
Completed Study	-	1

Period 6 title

Open-label Period Weeks 241 - 288

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 6	TDF-TDF	ADV-TDF
Started	110	64
Completed	104	64
Not completed	6	0
Withdrew Consent	4	-
Safety, Tolerability, or Efficacy Reason	2	-

Period 7 title

Open-label Period Weeks 289 - 336

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 7	TDF-TDF	ADV-TDF
Started	104	64
Completed	98	57
Not completed	6	7
Withdrew Consent	2	-
Investigator's Discretion	3	2
Study Site Discontinued	-	1
Protocol Violation	-	1
Lost to follow-up	1	1
Completed Study	-	1
Safety, Tolerability, or Efficacy Reason	-	1

Period 8 title

Open-label Period Weeks 337 - 384

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 8	TDF-TDF	ADV-TDF
Started	98	57
Completed	90	56
Not completed	8	1
Withdrew Consent	3	1
Investigator's Discretion	1	-
Protocol Violation	1	-
Lost to follow-up	2	-
Completed Study	1	-

Period 9 title

Open-label Period Weeks 385 - 432

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 9 ^[3]	TDF-TDF	ADV-TDF
Started	59	30
Completed	57	30
Not completed	2	0
Withdrew Consent	1	-
Investigator's Discretion	1	-

Notes
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 57 participants (31 TDF-TDF; 26 ADV-TDF) completed 384 weeks but did not continue on study.

Period 10 title

Open-label Period Weeks 433 - 480

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

TDF-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Adefovir dipivoxil placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

ADV-TDF

Arm description

Arm type

Experimental

Investigational medicinal product name

Adefovir dipivoxil

Investigational medicinal product code

Other name

ADV, Hepsera®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered once daily

Investigational medicinal product name

Tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

TDF, Viread®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

300 mg administered once daily

Investigational medicinal product name

Emtricitabine/tenofovir disoproxil fumarate

Investigational medicinal product code

Other name

FTC/TDF, Truvada®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200/300 mg FDC tablet administered once daily

Number of subjects in period 10 ^[4]	TDF-TDF	ADV-TDF
Started	57	29
Completed	53	29
Not completed	4	0
Withdrew Consent	3	-
Investigator's Discretion	1	-

Notes
[4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 1 participant (ADV-TDF) completed 432 weeks but did not continue on study.

Baseline characteristics

Top of page

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group values	TDF-TDF	ADV-TDF	Total
Number of subjects	176	90	266
Age categorical
Units: Subjects
≤ 18 years	3	1	4
Between 18 and 65 years	173	89	262
≥ 65 years	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	34 ± 11.3	34 ± 12.2	-
Gender categorical
Units: Subjects
Female	57	26	83
Male	119	64	183
Baseline Alanine Aminotransferase (ALT) above the Upper Limit of the Normal (ULN) Range
The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.
Units: Subjects
Yes	169	90	259
No	7	0	7
Prior Lamivudine or FTC Treatment
Units: Subjects
Yes	8	1	9
No	168	89	257
Baseline Hepatitis B Deoxyribonucleic Acid (HBV DNA)
Units: log10 copies/mL
arithmetic mean (standard deviation)	8.64 ± 1.076	8.88 ± 0.93	-
Baseline Knodell Necroinflammatory Score
Based on Knodell numerical scoring of liver biopsy specimens. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges 0 (best) to 14 (worst).
Units: units on a scale
arithmetic mean (standard deviation)	8.3 ± 2.11	8.5 ± 2.07	-

End points

Top of page

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Reporting group title

TDF-TDF

Reporting group description

Reporting group title

ADV-TDF

Reporting group description

Subject analysis set title

TDF-TDF With No Addition of FTC

Subject analysis set type

Sub-group analysis

Subject analysis set description

TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants in this reporting group did not add FTC to their study regimen in the open-label period.

Subject analysis set title

TDF-TDF With Addition of FTC

Subject analysis set type

Sub-group analysis

Subject analysis set description

TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants in this reporting group added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their study regimen in the open-label period.

Subject analysis set title

ADV-TDF With No Addition of FTC

Subject analysis set type

Sub-group analysis

Subject analysis set description

ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants in this reporting group did not add FTC to their study regimen in the open-label period.

Subject analysis set title

ADV-TDF With Addition of FTC

Subject analysis set type

Sub-group analysis

Subject analysis set description

ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants in this reporting group added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their study regimen in the open-label period.

Primary: Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48

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End point title

Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48

End point description

Complete response was a composite endpoint defined as histological response and HBV DNA < 400 copies/mL. Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4. A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40. Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study medication; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

End point type

Primary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	176	90
Units: percentage of participants
number (not applicable)	66.5	12.2

Statistical Analysis - TDF-TDF vs ADV-TDF

Statistical analysis description

2-sided 95% confidence interval (CI), stratified by baseline ALT was used to evaluate difference between groups in proportion of complete responders.

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

< 0.001 ^[2]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

54.1

Confidence interval

level

95%

sides

2-sided

lower limit

44.6

upper limit

63.6

Variability estimate

Standard error of the mean

Dispersion value

4.8

Notes
[1] - With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than -0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[2] - P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted (baseline ALT ≤ 4 x upper limit of the normal range [ULN] or > 4 x ULN) difference is 0.

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

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End point title

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

End point description

Randomized and Treated Analysis Set; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	176	90
Units: percentage of participants
number (not applicable)	76.1	13.3

Statistical Analysis - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001 ^[3]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

63.1

Confidence interval

level

95%

sides

2-sided

lower limit

53.8

upper limit

72.3

Variability estimate

Standard error of the mean

Dispersion value

4.7

Notes
[3] - P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference in zero. Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

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End point title

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

End point description

Participants in the Randomized and Treated Analysis Set with available data were analyzed. Data included for participants who discontinued study unless the discontinuation was unrelated to protocol criteria.

End point type

Secondary

End point timeframe

Week 96

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	165	86
Units: percentage of participants
number (not applicable)	77.6	77.9

Statistical Analysis - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.801 ^[4]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12

upper limit

9.3

Variability estimate

Standard error of the mean

Dispersion value

5.4

Notes
[4] - P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero. Two-sided 95% CIs, stratified by baseline ALT (baseline ALT ≤ 4 x ULN or > 4 x ULN), were used to evaluate treatment group differences.

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384

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End point title

Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384

End point description

Randomized and Treated Analysis Set. Data included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria. Participants with missing values related to protocol criteria or who added FTC to their open-label TDF regimen were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Weeks 144, 192, 240, 288, 336, and 384

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	166	88
Units: percentage of participants
number (not applicable)
Week 144 (TDF-TDF: N = 166; ADV-TDF: N = 88)	71.7	70.5
Week 192 (TDF-TDF: N = 165; ADV-TDF: N = 88)	67.9	71.6
Week 240 (TDF-TDF: N = 164; ADV-TDF: N = 86)	63.4	66.3
Week 288 (TDF-TDF: N = 163; ADV-TDF: N = 88)	61.3	64.8
Week 336 (TDF-TDF: N = 160; ADV-TDF: N = 87)	59.4	62.1
Week 384 (TDF-TDF: N = 155; ADV-TDF: N = 86)	56.1	60.5

No statistical analyses for this end point

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

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End point title

Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

End point description

Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added emtricitabine to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Weeks 432 and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	57	29
Units: percentage of participants
number (not applicable)
Week 432 (TDF-TDF: N = 57; ADV-TDF: N = 28)	93	100
Week 480 (TDF-TDF: N = 51; ADV-TDF: N = 29)	98	96.6

No statistical analyses for this end point

Secondary: Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

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End point title

Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point description

Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	160	85
Units: log10 IU/mL
arithmetic mean (standard deviation)
Week 48 (TDF-TDF: N = 160; ADV-TDF: N = 85)	-6.17 ± 1.067	-3.93 ± 1.728
Week 96 (TDF-TDF: N = 144; ADV-TDF: N = 80)	-6.26 ± 1.137	-6.38 ± 1.184
Week 144 (TDF-TDF: N = 131; ADV-TDF: N = 72)	-6.32 ± 1.098	-6.31 ± 1.407
Week 192 (TDF-TDF: N = 117; ADV-TDF: N = 67)	-6.3 ± 1.203	-6.49 ± 1.028
Week 240 (TDF-TDF: N = 105; ADV-TDF: N = 60)	-6.22 ± 1.217	-6.45 ± 0.986
Week 288 (TDF-TDF: N = 101; ADV-TDF: N = 62)	-6.27 ± 1.248	-6.49 ± 1.003
Week 336 (TDF-TDF: N = 94; ADV-TDF: N = 57)	-6.35 ± 1.208	-6.46 ± 1.017
Week 384 (TDF-TDF: N = 83; ADV-TDF: N = 55)	-6.38 ± 1.167	-6.28 ± 1.45
Week 432 (TDF-TDF: N = 57; ADV-TDF: N = 28)	-6.13 ± 1.306	-6.45 ± 1.008
Week 480 (TDF-TDF: N = 51; ADV-TDF: N = 29)	-6.18 ± 1.3	-6.37 ± 1.159

No statistical analyses for this end point

Secondary: Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

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End point title

Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point description

Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	144	80
Units: log10 IU/mL
arithmetic mean (standard deviation)
Week 96 (TDF-TDF: N = 144; ADV-TDF: N = 80)	-0.1 ± 0.422	-2.43 ± 1.724
Week 144 (TDF-TDF: N = 131; ADV-TDF: N = 72)	-0.19 ± 0.475	-2.27 ± 1.866
Week 192 (TDF-TDF: N = 117; ADV-TDF: N = 67)	-0.2 ± 0.565	-2.41 ± 1.662
Week 240 (TDF-TDF: N = 105; ADV-TDF: N = 60)	-0.14 ± 0.706	-2.49 ± 1.599
Week 288 (TDF-TDF: N = 101; ADV-TDF: N = 62)	-0.18 ± 0.762	-2.62 ± 1.679
Week 336 (TDF-TDF: N = 94; ADV-TDF: N = 57)	-0.25 ± 0.618	-2.59 ± 1.622
Week 384 (TDF-TDF: N = 83; ADV-TDF: N = 55)	-0.29 ± 0.643	-2.34 ± 1.821
Week 432 (TDF-TDF: N = 57; ADV-TDF: N = 28)	-0.13 ± 0.854	-2.32 ± 1.694
Week 480 (TDF-TDF: N = 51; ADV-TDF: N = 29)	-0.24 ± 0.63	-2.16 ± 1.882

No statistical analyses for this end point

Secondary: Percentage of Participants With Histological Response at Week 48

Top of page

End point title

Percentage of Participants With Histological Response at Week 48

End point description

Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4. Randomized and Treated Analysis Set; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	176	90
Units: percentage of participants
number (not applicable)
Yes	74.4	67.8
No	25.6	32.2

Statistical Analysis - TDF-TDF vs ADV-TDF

Comparison groups

ADV-TDF v TDF-TDF

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.32 ^[5]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.6

upper limit

17.2

Variability estimate

Standard error of the mean

Dispersion value

5.8

Notes
[5] - P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference in zero. Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With Histological Response at Week 240

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End point title

Percentage of Participants With Histological Response at Week 240

End point description

Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4. Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 240

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	76	48
Units: percentage of participants
number (not applicable)
Yes	88.2	89.6
No	11.8	10.4

No statistical analyses for this end point

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48

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End point title

Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48

End point description

The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst). Participants in the Randomized and Treated Analysis Set with measurements at Baseline and Week 48 were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	157	79
Units: units on a scale
arithmetic mean (standard deviation)
Knodell Necroinflammatory Score	-3.6 ± 2.3	-3.2 ± 2.35
Ishak Necroinflammatory Score	-2.7 ± 1.7	-2.6 ± 1.94

No statistical analyses for this end point

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240

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End point title

Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240

End point description

The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, and ranges from 0 (best) to 14 (worst). The Ishak score measures the degree of liver fibrosis (scarring) caused by chronic necroinflammation (inflammation leading to cell death) and ranges from 0 (best) to 6 (worst). Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 240

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	76	48
Units: units on a scale
arithmetic mean (standard deviation)
Knodell Necroinflammatory Score	-4.8 ± 2.34	-5.1 ± 2.43
Ishak Necroinflammatory Score	-4.1 ± 2.14	-4.5 ± 2.32

No statistical analyses for this end point

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 48

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End point title

Ranked Assessment of Necroinflammation and Fibrosis at Week 48

End point description

Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening. Randomized and Treated Analysis Set; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	176	90
Units: percentage of participants
number (not applicable)
Improvement - Necroinflammation	81.3	78.9
No Change - Necroinflammation	4.5	3.3
Worsening - Necroinflammation	3.4	5.6
Missing Data - Necroinflammation	10.8	12.2
Improvement - Fibrosis	19.9	20
No Change - Fibrosis	63.6	61.1
Worsening - Fibrosis	5.1	6.7
Missing Data - Fibrosis	11.4	12.2

No statistical analyses for this end point

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 240

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End point title

Ranked Assessment of Necroinflammation and Fibrosis at Week 240

End point description

Participants were ranked as having improvement, no change, worsening, or missing data (compared to Baseline) based on the Knodell scoring system, and results are presented as the percentage of participants in each category. The Knodell necroinflammatory score is the combined score for necrosis and inflammation domains of the Knodell scoring system, which ranges from 0 (best) to 14 (worst). The Knodell fibrosis domain score ranges from 0 (best) to 4 (worst). A decrease of 1 point or more indicated improvement, and an increase of 1 point or more indicated worsening. Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 240

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	76	48
Units: percentage of participants
number (not applicable)
Improvement - Necroinflammation	96.1	97.9
No Change - Necroinflammation	3.9	2.1
Worsening - Necroinflammation	0	0
Improvement - Fibrosis	56.6	58.3
No Change - Fibrosis	39.5	39.6
Worsening - Fibrosis	3.9	2.1

No statistical analyses for this end point

Secondary: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48

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End point title

Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48

End point description

ALT normalization was defined as ALT > upper limit of normal (ULN) at baseline and within the normal range at the end of blinded treatment. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69. Participants in the Randomized and Treated Analysis Set with ALT > ULN at baseline were analyzed; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	169	90
Units: percentage of participants
number (not applicable)	68	54.4

Statistical Analysis - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

259

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.032 ^[6]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

13.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

26.1

Variability estimate

Standard error of the mean

Dispersion value

6.4

Notes
[6] - P-value corresponds to a Z-test. Statistical tests were not adjusted for baseline ALT stratum. Difference, standard error of the difference, and CI are stratum adjusted (baseline ALT ≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With ALT Normalization at Week 96

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End point title

Percentage of Participants With ALT Normalization at Week 96

End point description

ALT normalization was defined as ALT > ULN at baseline and within the normal range at Week 96. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69. Participants in the Randomized and Treated Analysis Set with ALT > ULN at baseline. Data included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria; data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	158	86
Units: percentage of participants
number (not applicable)	65.2	74.4

Statistical Analysis - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1 ^[7]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

-9.8

Confidence interval

level

95%

sides

2-sided

lower limit

-21.5

upper limit

1.9

Variability estimate

Standard error of the mean

Dispersion value

Notes
[7] - P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted (baseline ALT ≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384

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End point title

Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384

End point description

ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69. Participants in the Randomized and Treated Analysis Set with ALT > ULN at baseline and available data were analyzed. Data included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria; data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Weeks 144, 192, 240, 288, 336, and 384

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	161	87
Units: percentage of participants
number (not applicable)
Week 144 (TDF-TDF: N = 161; ADV-TDF: N = 87)	60.2	67.8
Week 192 (TDF-TDF: N = 161; ADV-TDF: N = 85)	59.6	69.4
Week 240 (TDF-TDF: N = 156; ADV-TDF: N = 85)	50	65.9
Week 288 (TDF-TDF: N = 158; ADV-TDF: N = 87)	51.3	70.1
Week 336 (TDF-TDF: N = 156; ADV-TDF: N = 84)	46.2	67.9
Week 384 (TDF-TDF: N = 154; ADV-TDF: N = 82)	52.6	67.1

No statistical analyses for this end point

Secondary: Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

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End point title

Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point description

Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	160	84
Units: U/L
arithmetic mean (standard deviation)
Week 48 (TDF-TDF: N = 160; ADV-TDF: N = 84)	-107.2 ± 109.44	-106.1 ± 118.9
Week 96 (TDF-TDF: N = 141; ADV-TDF: N = 81)	-107.8 ± 108.07	-120.4 ± 138.03
Week 144 (TDF-TDF: N = 131; ADV-TDF: N = 72)	-100.7 ± 105.96	-126.2 ± 150.46
Week 192 (TDF-TDF: N = 119; ADV-TDF: N = 67)	-101.4 ± 108.63	-139.6 ± 137.95
Week 240 (TDF-TDF: N = 102; ADV-TDF: N = 62)	-95.9 ± 117.03	-134.8 ± 135.59
Week 288 (TDF-TDF: N = 100; ADV-TDF: N = 62)	-102.3 ± 111.68	-130.9 ± 123.08
Week 336 (TDF-TDF: N = 95; ADV-TDF: N = 57)	-101.9 ± 112.72	-132.3 ± 125.81
Week 384 (TDF-TDF: N = 85; ADV-TDF: N = 54)	-108.1 ± 118.05	-133.7 ± 128.57
Week 432 (TDF-TDF: N = 57; ADV-TDF: N = 28)	-105 ± 139.61	-162.1 ± 157.83
Week 480 (TDF-TDF: N = 51; ADV-TDF: N = 29)	-92.3 ± 83.56	-157.5 ± 159.96

No statistical analyses for this end point

Secondary: Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

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End point title

Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point description

Participants in the Randomized and Treated Analysis Set with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	141	81
Units: U/L
arithmetic mean (standard deviation)
Week 96 (TDF-TDF: N = 141; ADV-TDF: N = 81)	-2 ± 17.94	-6.9 ± 59.64
Week 144 (TDF-TDF: N = 131; ADV-TDF: N = 72)	-0.4 ± 21.94	-0.7 ± 82.7
Week 192 (TDF-TDF: N = 119; ADV-TDF: N = 67)	-1.3 ± 19.57	-7.8 ± 27.07
Week 240 (TDF-TDF: N = 102; ADV-TDF: N = 62)	3.7 ± 32.48	-8.1 ± 22.92
Week 288 (TDF-TDF: N = 100; ADV-TDF: N = 62)	-1.6 ± 19.91	-10.3 ± 25.26
Week 336 (TDF-TDF: N = 95; ADV-TDF: N = 57)	-1.2 ± 19.72	-9.3 ± 22.69
Week 384 (TDF-TDF: N = 85; ADV-TDF: N = 54)	-4.4 ± 24.87	-6.9 ± 31.76
Week 432 (TDF-TDF: N = 57; ADV-TDF: N = 28)	-4.3 ± 24.27	-11.6 ± 27.09
Week 480 (TDF-TDF: N = 51; ADV-TDF: N = 29)	-5.5 ± 19.28	-7.1 ± 39.76

No statistical analyses for this end point

Secondary: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48

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End point title

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48

End point description

HBeAg loss was defined as HBeAg positive at baseline and HBeAg negative at Week 48. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative at baseline to positive at Week 48. Participants in the Randomized and Treated Analysis Set who were HBeAg-positive at baseline and with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	153	80
Units: percentage of participants
number (not applicable)
HBeAg Loss	22.2	17.5
HBeAg Seroconversion	20.9	17.5

HBeAg Loss - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

233

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.245 ^[8]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

6.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

16.4

Variability estimate

Standard error of the mean

Dispersion value

5.3

Notes
[8] - P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and Cl are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

HBeAg Seroconversion - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

233

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.363 ^[9]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

4.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

14.9

Variability estimate

Standard error of the mean

Dispersion value

5.2

Notes
[9] - P-value for HBeAg seroconversion corresponds to Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of difference, and Cl are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96

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End point title

Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96

End point description

HBeAg loss was defined as HBeAg positive at baseline and HBeAg negative at Week 96. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative at baseline to positive at Week 96. Participants in the Randomized and Treated Analysis Set who were HBeAg-positive at baseline and with available data were analyzed. Data included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	158	82
Units: percentage of participants
number (not applicable)
HBeAg Loss	25.9	25.6
Seroconversion to Anti-HBe	22.8	22

HBeAg Loss - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.963 ^[10]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-11.9

upper limit

11.9

Variability estimate

Standard error of the mean

Dispersion value

5.9

Notes
[10] - P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and Cl are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Seroconversion to Anti-HBe - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.904 ^[11]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.4

upper limit

11.7

Variability estimate

Standard error of the mean

Dispersion value

5.6

Notes
[11] - P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and Cl are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48

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End point title

Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48

End point description

HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at Week 48. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at Week 48. Participants in the Randomized and Treated Analysis Set with available data were analyzed.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	158	82
Units: percentage of participants
number (not applicable)
HBsAg Loss	3.2	0
HBsAg Seroconversion	1.3	0

HBsAg Loss - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.018 ^[12]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

19.9

Variability estimate

Standard error of the mean

Dispersion value

4.6

Notes
[12] - P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero. Difference, standard error of the difference, and confidence interval (CI) are stratum adjusted (baseline ALT ≤ 4 x ULN or > 4 x ULN).

HBsAg Seroconversion - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

240

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.148 ^[13]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

10.2

Variability estimate

Standard error of the mean

Dispersion value

Notes
[13] - P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero. Difference, standard error of the difference, and confidence interval (CI) are stratum adjusted (baseline ALT ≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96

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End point title

Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96

End point description

HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at the subsequent time point. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at the subsequent time point. Participants in the Randomized and Treated Analysis Set with available data were analyzed. Data is included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria.

End point type

Secondary

End point timeframe

Baseline; Week 96

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	171	86
Units: percentage of participants
number (not applicable)
HBsAg Loss	5.3	5.8
Anti-HBs Seroconversion	4.1	4.7

HBsAg Loss - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.757 ^[14]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

6.5

Variability estimate

Standard error of the mean

Dispersion value

2.9

Notes
[14] - P-value above for HBsAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Seroconversion to Anti-HBs - TDF-TDF vs ADV-TDF

Comparison groups

TDF-TDF v ADV-TDF

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.733 ^[15]

Method

Z-test

Parameter type

Difference in proportions

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

5.9

Variability estimate

Standard error of the mean

Dispersion value

2.6

Notes
[15] - P-value above corresponds to Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (≤ 4 x ULN or > 4 x ULN).

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480

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End point title

Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480

End point description

HBsAg loss was defined as HBsAg positive at baseline and HBsAg negative at the subsequent time point. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative at baseline to positive at the subsequent time point. Randomized and Treated Analysis Set. Data is included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria. Participants with missing values related to protocol criteria or who added FTC to their open-label TDF regimen were considered to have failed to reach the endpoint.

End point type

Secondary

End point timeframe

Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	174	89
Units: percentage of participants
number (not applicable)
Loss-Wk 144 (TDF: N = 173; ADV: N = 88)	7.5	8
Seroconversion-Wk 144 (TDF: N = 173; ADV: N = 88)	5.2	6.8
Loss-Wk 192 (TDF: N = 171; ADV: N = 89)	9.4	7.9
Seroconversion-Wk 192 (TDF: N = 171; ADV: N = 89)	6.4	6.7
Loss-Wk 240 (TDF: N = 174; ADV: N = 88)	9.2	8
Seroconversion-Wk 240 (TDF: N = 174; ADV: N = 88)	6.3	8
Loss-Wk 288 (TDF: N = 173; ADV: N = 88)	9.2	8
Seroconversion-Wk 288 (TDF: N = 173; ADV: N = 88)	6.4	8
Loss-Wk 336 (TDF: N = 174; ADV: N = 89)	10.3	7.9
Seroconversion-Wk 336 (TDF: N = 174; ADV: N = 89)	7.5	7.9
Loss-Wk 384 (TDF: N = 173; ADV: N = 89)	11	9
Seroconversion-Wk 384 (TDF: N = 173; ADV: N = 89)	8.1	7.9
Loss-Wk 432 (TDF: N = 174; ADV: N = 88)	10.9	10.2
Seroconversion-Wk 432 (TDF: N = 172; ADV: N = 87)	7.6	8
Loss-Wk 480 (TDF: N = 174; ADV: N = 89)	10.9	10.1
Seroconversion-Wk 480 (TDF: N = 174; ADV: N = 89)	8	7.9

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL, those with viral breakthrough, and those who discontinued after Week 24 with HBV DNA ≥ 400 copies/mL. Participants in the Randomized and Treated Analysis Set were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Week 48

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	176	90
Units: participants
Participants evaluated	31	75
Changes at conserved sites in HBV polymerase	2	8
Changes at polymorphic sites in HBV polymerase	13	17
No genotypic changes (wild-type virus)	7	43
Unable to be genotyped	9	7

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 96 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 48 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 48 (ie, entered the open-label phase) were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 49 to 96

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	154	15	84	13
Units: participants
Participants evaluated	18	13	16	10
Changes at conserved sites in HBV polymerase	2	0	2	3
Changes at polymorphic sites in HBV polymerase	3	1	1	2
No genotypic changes (wild-type virus)	10	5	12	3
Unable to be genotyped	3	7	1	2

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 144 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 96 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 96 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 96 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 97 to 144

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	126	17	69	13
Units: participants
Participants evaluated	2	7	5	5
Changes at conserved sites in HBV polymerase	1	2	2	0
Changes at polymorphic sites in HBV polymerase	0	3	3	0
No genotypic changes (wild-type virus)	1	2	0	3
Unable to be genotyped	0	0	0	1

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 192 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 144 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 144 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 144 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 145 to 192

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	115	15	61	10
Units: participants
Participants evaluated	2	5	1	1
Changes at conserved sites in HBV polymerase	0	0	0	0
Changes at polymorphic sites in HBV polymerase	1	0	1	1
No genotypic changes (wild-type virus)	0	1	0	0
Unable to be genotyped	1	3	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 240 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 192 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 192 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 192 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 193 to 240

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	103	13	55	12
Units: participants
Participants evaluated	3	3	0	1
Changes at conserved sites in HBV polymerase	0	0	0	1
Changes at polymorphic sites in HBV polymerase	2	0	0	0
No genotypic changes (wild-type virus)	1	2	0	0
Unable to be genotyped	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 288 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 240 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 240 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 240 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 241 to 288

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	92	11	52	12
Units: participants
Participants evaluated	3	0	0	0
Changes at conserved sites in HBV polymerase	0	0	0	0
Changes at polymorphic sites in HBV polymerase	0	0	0	0
No genotypic changes (wild-type virus)	2	0	0	0
Unable to be genotyped	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 336 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 288 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 288 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 288 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 289 to 336

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	93	12	53	12
Units: participants
Participants evaluated	1	0	1	0
Changes at conserved sites in HBV polymerase	0	0	0	0
Changes at polymorphic sites in HBV polymerase	0	0	0	0
No genotypic changes (wild-type virus)	0	0	1	0
Unable to be genotyped	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 384 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 336 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 336 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 336 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 337 to 384

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	87	12	50	10
Units: participants
Participants evaluated	1	0	2	2
Changes at conserved sites in HBV polymerase	0	0	1	0
Changes at polymorphic sites in HBV polymerase	0	0	1	1
No genotypic changes (wild-type virus)	0	0	0	1
Unable to be genotyped	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 432 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 384 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 384 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 384 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 385 to 432

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	49	10	26	4
Units: participants
Participants evaluated	1	3	0	1
Changes at conserved sites in HBV polymerase	0	0	0	0
Changes at polymorphic sites in HBV polymerase	1	0	0	0
No genotypic changes (wild-type virus)	0	3	0	1
Unable to be genotyped	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)

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End point title

Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)

End point description

Of the total number analyzed, participants evaluated for resistance included those with HBV DNA ≥ 400 copies/mL at Week 480 on TDF monotherapy, those with viral breakthrough, those who discontinued after Week 432 with HBV DNA ≥ 400 copies/mL, and those who added emtricitabine to the open-label TDF regimen after Week 432 and had HBV DNA ≥ 400 copies/mL at the time of the addition. Participants in the Randomized and Treated Analysis Set who continued on the study after Week 432 with available data were analyzed to determine if they qualified for protocol criteria for resistance surveillance, and those meeting the criteria were evaluated.

End point type

Secondary

End point timeframe

Baseline; Weeks 433 to 480

End point values	TDF-TDF With No Addition of FTC	TDF-TDF With Addition of FTC	ADV-TDF With No Addition of FTC	ADV-TDF With Addition of FTC
Number of subjects analysed	47	10	26	3
Units: participants
Participants evaluated	0	3	1	0
Changes at conserved sites in HBV polymerase	0	0	0	0
Changes at polymorphic sites in HBV polymerase	0	1	0	0
No genotypic changes (wild-type virus)	0	2	1	0
Unable to be genotyped	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With ALT Normalization at Weeks 432 and 480

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End point title

Percentage of Participants With ALT Normalization at Weeks 432 and 480

End point description

ALT normalization was defined as ALT > ULN at baseline and within the normal range at the subsequent time point. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69. Participants in the Randomized and Treated Analysis Set with ALT > ULN at baseline and with observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

End point type

Secondary

End point timeframe

Baseline; Weeks 432 and 480

End point values	TDF-TDF	ADV-TDF
Number of subjects analysed	54	29
Units: percentage of participants
number (not applicable)
Week 432 (TDF-TDF: N = 54; ADV-TDF: N = 28)	79.6	78.6
Week 480 (TDF-TDF: N = 48; ADV-TDF: N = 29)	75	82.8

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline to Week 480

Adverse event reporting additional description

Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Double-Blind TDF

Reporting group description

Adverse events this reporting group include those occurring in the TDF-TDF group during the double-blind period only (baseline to Week 48). TDF 300 mg plus placebo to match ADV (double-blind period).

Reporting group title

Double-Blind ADV

Reporting group description

Adverse events this reporting group include those occurring in the ADV-TDF group during the double-blind period only (baseline to Week 48). ADV 10 mg plus placebo to match TDF (double-blind period).

Reporting group title

Open-Label TDF

Reporting group description

Adverse events for this reporting group include those occurring during the open-label TDF 300 mg period (Week 49 up to Week 480), regardless of which group they were randomized to in the double-blind period. TDF 300 mg + ADV placebo or ADV 10 mg + TDF placebo (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.

Serious adverse events	Double-Blind TDF	Double-Blind ADV	Open-Label TDF
Total subjects affected by serious adverse events
subjects affected / exposed	15 / 176 (8.52%)	7 / 90 (7.78%)	41 / 238 (17.23%)
number of deaths (all causes)	0	0	4
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer metastatic
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hepatic neoplasm
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	2 / 238 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hodgkin's disease
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Lymphoma
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	2 / 238 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillar neoplasm
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Thrombosis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 176 (0.00%)	1 / 90 (1.11%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst ruptured
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Drug dependence
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	6 / 176 (3.41%)	4 / 90 (4.44%)	6 / 238 (2.52%)
occurrences causally related to treatment / all	4 / 6	4 / 4	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 176 (1.14%)	1 / 90 (1.11%)	2 / 238 (0.84%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glucose urine present
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	2 / 238 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 176 (0.00%)	1 / 90 (1.11%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural dizziness
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital anomaly in offspring
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Diabetic neuropathy
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial spasm
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	2 / 238 (0.84%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	0 / 176 (0.00%)	1 / 90 (1.11%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	3 / 238 (1.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 176 (0.00%)	1 / 90 (1.11%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess soft tissue
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 176 (0.57%)	0 / 90 (0.00%)	0 / 238 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 176 (0.00%)	0 / 90 (0.00%)	1 / 238 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-Blind TDF	Double-Blind ADV	Open-Label TDF
Total subjects affected by non serious adverse events
subjects affected / exposed	97 / 176 (55.11%)	49 / 90 (54.44%)	165 / 238 (69.33%)
Investigations
Creatinine renal clearance decreased
subjects affected / exposed	1 / 176 (0.57%)	1 / 90 (1.11%)	12 / 238 (5.04%)
occurrences all number	1	1	13
Vascular disorders
Hypertension
subjects affected / exposed	3 / 176 (1.70%)	1 / 90 (1.11%)	24 / 238 (10.08%)
occurrences all number	3	1	27
Nervous system disorders
Dizziness
subjects affected / exposed	12 / 176 (6.82%)	2 / 90 (2.22%)	11 / 238 (4.62%)
occurrences all number	13	2	11
Headache
subjects affected / exposed	31 / 176 (17.61%)	14 / 90 (15.56%)	30 / 238 (12.61%)
occurrences all number	50	27	36
General disorders and administration site conditions
Fatigue
subjects affected / exposed	22 / 176 (12.50%)	8 / 90 (8.89%)	20 / 238 (8.40%)
occurrences all number	24	8	21
Influenza like illness
subjects affected / exposed	9 / 176 (5.11%)	3 / 90 (3.33%)	14 / 238 (5.88%)
occurrences all number	10	5	20
Immune system disorders
Seasonal allergy
subjects affected / exposed	4 / 176 (2.27%)	1 / 90 (1.11%)	17 / 238 (7.14%)
occurrences all number	5	1	22
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	6 / 176 (3.41%)	3 / 90 (3.33%)	22 / 238 (9.24%)
occurrences all number	9	3	26
Abdominal pain upper
subjects affected / exposed	15 / 176 (8.52%)	4 / 90 (4.44%)	25 / 238 (10.50%)
occurrences all number	16	4	26
Diarrhoea
subjects affected / exposed	12 / 176 (6.82%)	3 / 90 (3.33%)	12 / 238 (5.04%)
occurrences all number	16	3	15
Nausea
subjects affected / exposed	26 / 176 (14.77%)	1 / 90 (1.11%)	9 / 238 (3.78%)
occurrences all number	30	1	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	10 / 176 (5.68%)	5 / 90 (5.56%)	30 / 238 (12.61%)
occurrences all number	10	5	45
Oropharyngeal pain
subjects affected / exposed	8 / 176 (4.55%)	5 / 90 (5.56%)	18 / 238 (7.56%)
occurrences all number	10	6	28
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 176 (2.84%)	6 / 90 (6.67%)	17 / 238 (7.14%)
occurrences all number	5	7	25
Back pain
subjects affected / exposed	13 / 176 (7.39%)	3 / 90 (3.33%)	18 / 238 (7.56%)
occurrences all number	13	4	20
Musculoskeletal pain
subjects affected / exposed	2 / 176 (1.14%)	3 / 90 (3.33%)	15 / 238 (6.30%)
occurrences all number	2	4	17
Myalgia
subjects affected / exposed	8 / 176 (4.55%)	5 / 90 (5.56%)	11 / 238 (4.62%)
occurrences all number	11	5	12
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 176 (1.14%)	4 / 90 (4.44%)	13 / 238 (5.46%)
occurrences all number	2	4	17
Influenza
subjects affected / exposed	8 / 176 (4.55%)	5 / 90 (5.56%)	25 / 238 (10.50%)
occurrences all number	8	5	36
Nasopharyngitis
subjects affected / exposed	22 / 176 (12.50%)	13 / 90 (14.44%)	43 / 238 (18.07%)
occurrences all number	31	13	76
Upper respiratory tract infection
subjects affected / exposed	7 / 176 (3.98%)	6 / 90 (6.67%)	21 / 238 (8.82%)
occurrences all number	7	8	42

More information

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Were there any global substantial amendments to the protocol? Yes

13 Sep 2005

— The treatment phase of the study was extended to 240 weeks to evaluate long-term virological, serological, and biochemical response, as well as the safety profile observed among subjects initiating double-blind treatment with tenofovir DF and maintained on tenofovir DF (early) versus subjects initiating double-blind treatment with adefovir dipivoxil and switching to tenofovir DF at the end of the first year (deferred). — Statistical analysis of the antiviral and safety parameters at Week 96 (and every 48 weeks thereafter) was added to evaluate continuous (early) tenofovir DF treatment versus secondary (deferred) tenofovir DF treatment based on randomization to double-blind tenofovir DF or adefovir dipivoxil, respectively, at study entry in the first year. The original treatment assignment is to remain blinded to the subject and the investigator for the entire 240 weeks of the study. — A final required liver biopsy was added at Week 240. — To help characterize a role for combination therapy in subjects with persistent viral replication or incomplete virologic response, a provision was added allowing subjects with HBV DNA ≥ 400 copies/mL at or after Week 72, confirmed on two consecutive visits, to be eligible to remain on tenofovir DF, switch to emtricitabine 200 mg/tenofovir DF 300 mg combination tablet taken QD, or initiate commercially available HBV therapy.

14 Sep 2005

— A substudy was planned for sites in France, Germany, and the Netherlands to measure hepatic covalently closed circular DNA (cccDNA) in approximately 45 subjects (approximately 15 adefovir dipivoxil subjects and 30 tenofovir DF subjects) at baseline, Week 144, and Week 240. The substudy required an additional liver biopsy at Year 3, during which additional tissue samples would be collected for analysis of intrahepatic HBV DNA levels and for immunostaining. a. Post-amendment note: No subjects enrolled in the substudy; thus, the substudy was not conducted.

22 Dec 2005

— Subjects were allowed to enroll with up to 10% variance from the stated eligibility criterion for ALT (> 2 × ULN and no more than 10 × ULN) and/or in time windows for study eligibility criteria, with approval of the medical monitor. — The primary efficacy and safety analysis sets were redefined as all randomized subjects who received at least one dose of study medication.

27 Jun 2008

— The study duration was extended to 384 weeks (8 years). — Annual dual energy x-ray absorptiometry (DEXA) scans of the hip and spine from Week 192 to Week 384 were added to monitor for changes in bone mineral density (BMD). — Added recommendation that subjects remain on study treatment until HBsAg loss or seroconversion to anti-HBs since seroconversion to anti-HBe does not preclude the development of precore mutations. — Strengthened the protocol language recommending intensification of TDF therapy with emtricitabine 200 mg after Week 72 in order to help minimize the risk of developing resistance mutations associated with persistent viremia and continued monotherapy treatment.

13 Sep 2011

— Instructions were added for the collection of an optional blood sample from subjects who provided a separate informed consent form for biomarker analysis (including pharmacogenomics). These samples may be used for exploration of appropriate markers that may be predictive of virologic response and/or the tolerability of HBV therapies. — Instructions were added for subjects with creatinine clearance (CLcr) between 30 to 49 mL/min to have a dose modification to every 48 hours dosing. — Clarification was added about management of subjects who HBsAg seroconvert. — Clarification was added about visit windows for protocol-specific visits.

24 Jan 2013

— Study was extended to 480 weeks for subjects who completed 384 weeks of study treatment under the original protocol. — Instructions were added for reporting events categorized as special situations. — Clarification was added that dual energy x-ray absorptiometry (DEXA) scans will not be performed beyond Week 384 due to unavailability of baseline values and the lack of decline in bone mineral density from results available for Year 4 through Year 6.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

There were no limitations affecting the analysis or results.

http://www.ncbi.nlm.nih.gov/pubmed/23939953
http://www.ncbi.nlm.nih.gov/pubmed/23234725
http://www.ncbi.nlm.nih.gov/pubmed/23364953
http://www.ncbi.nlm.nih.gov/pubmed/25179493
http://www.ncbi.nlm.nih.gov/pubmed/25277773
http://www.ncbi.nlm.nih.gov/pubmed/25046847
http://www.ncbi.nlm.nih.gov/pubmed/25788199
http://www.ncbi.nlm.nih.gov/pubmed/25532501
http://www.ncbi.nlm.nih.gov/pubmed/27658343

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48

Primary: Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480

Secondary: Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Percentage of Participants With Histological Response at Week 48

Secondary: Percentage of Participants With Histological Response at Week 48

Secondary: Percentage of Participants With Histological Response at Week 240

Secondary: Percentage of Participants With Histological Response at Week 240

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240

Secondary: Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 48

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 48

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 240

Secondary: Ranked Assessment of Necroinflammation and Fibrosis at Week 240

Secondary: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48

Secondary: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48

Secondary: Percentage of Participants With ALT Normalization at Week 96

Secondary: Percentage of Participants With ALT Normalization at Week 96

Secondary: Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384

Secondary: Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384

Secondary: Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48

Secondary: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48

Secondary: Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96

Secondary: Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96

Secondary: Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48

Secondary: Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)

Secondary: Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)

Secondary: Percentage of Participants With ALT Normalization at Weeks 432 and 480

Secondary: Percentage of Participants With ALT Normalization at Weeks 432 and 480

Adverse events

Adverse events

Clinical Trial Results:
A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B