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Entecavir Plus Tenofovir Combination Therapy Versus Entecavir Monotherapy in Naive Subjects With Chronic Hepatitis B

Primary Purpose

Hepatitis B, Chronic

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Entecavir

Entecavir + Tenofovir

About this trial

This is an interventional treatment trial for Hepatitis B, Chronic

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Chronic hepatitis B virus (HBV) infection (hepatitis B e antigen [HbeAg]-positive or negative) disease
Nucleoside- and nucleotide-naive
Males or females ≥16 years of age (or minimum age of consent in a given country)
Compensated liver function
HBV DNA >1.72*10*5*IU/mL (approximately 10*6*copies/mL) for HbeAg-positive participants
HBV DNA >1.72*10*4*IU/mL (approximately 10*5*copies/mL) for Hbe-Ag-negative participants
Alanine aminotransferase level ≥*upper limit of normal (ULN) and ≤10*ULN

Exclusion Criteria:

Evidence of decompensated cirrhosis
Coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus
Laboratory values out of protocol-specified range

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

TDF 0.5 mg

ETV 0.5 mg +TDF 300 mg

Arm Description

TDF=tenofovir

ETV=entecavir; TDF=tenofovir

Outcomes

Primary Outcome Measures

Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96

HBV DNA levels <50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Secondary Outcome Measures

Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status

Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96

LOQ=lower limit of quantitation. LOQ=29 IU/mL, or approximately 169 copies/mL. LOQ is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96

LOD=Lower limit of detection. LOD) LOD=10 IU/mL, or approximately 58 copies/mL. LOD is the lowest concentration level that can be determined to be statistically different from a blank (99% confidence). The LOD is typically determined to be in the region where the signal to noise ratio is greater than 5. Limits of detection are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Mean Log 10 HBV DNA at Weeks 48 and 96

HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load.

Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96

ALT normalization= ≤1*upper limit of normal (ULN). Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96

HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96

HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication.

Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96

HBsAg = A part of the hepatitis B virus. When found in the blood, HBsAg is an early marker of infection. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints.

Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96

HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection.

Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96

Using the Roche COBAS TaqMan - HPS assay. Lower limit of Quantitation (LOQ) is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.

Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities

AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded.

Number of Participants With HBV Resistance Through Week 48

ETVr=entecavir resistance; TDFr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used.

Number of Participants With HBV Resistance at Week 96

ETVr=entecavir resistance; TFDr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used.

Number of Participants With Virologic Breakthrough at Week 48

ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed >= 1 log10 increase in HBV DNA from the on-treatment nadir

Number of Participants With Virologic Breakthrough at Week 96

ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed >=1 log10 increase in HBV DNA from moving nadir

Full Information

NCT ID

NCT00410072

First Posted

December 11, 2006

Last Updated

March 13, 2013

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT00410072

Brief Title

Entecavir Plus Tenofovir Combination Therapy Versus Entecavir Monotherapy in Naive Subjects With Chronic Hepatitis B

Official Title

A Comparative Study of Chronic Hepatitis B Subjects Treated With Entecavir Plus Tenofovir Combination Therapy vs. Entecavir Monotherapy in Adults Who Are Treatment-Naive to Nucleosides and Nucleotides: The BE-LOW Study

Study Type

Interventional

2. Study Status

Record Verification Date

March 2013

Overall Recruitment Status

Completed

Study Start Date

April 2007 (undefined)

Primary Completion Date

October 2010 (Actual)

Study Completion Date

October 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to compare the effectiveness of entecavir plus tenofovir combination therapy with that of entecavir monotherapy. Safety will also be studied.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis B, Chronic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

669 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TDF 0.5 mg

Arm Type

Experimental

Arm Description

TDF=tenofovir

Arm Title

ETV 0.5 mg +TDF 300 mg

Arm Type

Experimental

Arm Description

ETV=entecavir; TDF=tenofovir

Intervention Type

Drug

Intervention Name(s)

Entecavir

Other Intervention Name(s)

Baraclude, BMS-200475

Intervention Description

Tablets, Oral, ETV = 0.5 mg, once daily, 100 weeks

Intervention Type

Drug

Intervention Name(s)

Entecavir + Tenofovir

Other Intervention Name(s)

Baraclude, BMS-200475

Intervention Description

Tablets, Oral, ETV = 0.5 mg + TFV = 300 mg, once daily, 100 weeks

Primary Outcome Measure Information:

Title

Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96

Description

Time Frame

At Week 96

Secondary Outcome Measure Information:

Title

Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status

Description

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Mean Log 10 HBV DNA at Weeks 48 and 96

Description

HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load.

Time Frame

Baseline, Weeks 48 and 96

Title

Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96

Description

HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication.

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96

Description

HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection.

Time Frame

At Weeks 48 and 96

Title

Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96

Description

Time Frame

At Weeks 48 and 96

Title

Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities

Description

Time Frame

From enrollment through Week 100 + 24-week follow-up

Title

Number of Participants With HBV Resistance Through Week 48

Description

Time Frame

Week 48

Title

Number of Participants With HBV Resistance at Week 96

Description

Time Frame

Week 96

Title

Number of Participants With Virologic Breakthrough at Week 48

Description

ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed >= 1 log10 increase in HBV DNA from the on-treatment nadir

Time Frame

Week 48

Title

Number of Participants With Virologic Breakthrough at Week 96

Description

ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed >=1 log10 increase in HBV DNA from moving nadir

Time Frame

Week 96

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Chronic hepatitis B virus (HBV) infection (hepatitis B e antigen [HbeAg]-positive or negative) disease Nucleoside- and nucleotide-naive Males or females ≥16 years of age (or minimum age of consent in a given country) Compensated liver function HBV DNA >1.72*10*5*IU/mL (approximately 10*6*copies/mL) for HbeAg-positive participants HBV DNA >1.72*10*4*IU/mL (approximately 10*5*copies/mL) for Hbe-Ag-negative participants Alanine aminotransferase level ≥*upper limit of normal (ULN) and ≤10*ULN Exclusion Criteria: Evidence of decompensated cirrhosis Coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus Laboratory values out of protocol-specified range

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bristol-Myers Squibb

Organizational Affiliation

Bristol-Myers Squibb

Official's Role

Study Director

Facility Information:

Facility Name

Sergio E. Rojter

City

Los Angeles

State/Province

California

ZIP/Postal Code

90017

Country

United States

Facility Name

Tuan Nguyen, Md

City

San Diego

State/Province

California

ZIP/Postal Code

92105

Country

United States

Facility Name

San Jose Gastroenterology

City

San Jose

State/Province

California

ZIP/Postal Code

95128

Country

United States

Facility Name

Yale University School Of Medicine

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06510

Country

United States

Facility Name

University Of Miami

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

Atlanta Gastroenterology Associates

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30308

Country

United States

Facility Name

Digestive Healthcare Of Georgia

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30309

Country

United States

Facility Name

Digestive Disease Associates, P.A.

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21229

Country

United States

Facility Name

Maryland Digestive Disease Research, Llc

City

Laurel

State/Province

Maryland

ZIP/Postal Code

20707

Country

United States

Facility Name

Beth Israel Deaconess Medical Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

University Of Michigan Health System

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Sing Chan, Md

City

Flushing

State/Province

New York

ZIP/Postal Code

11355

Country

United States

Facility Name

North Shore University

City

Manhasset

State/Province

New York

ZIP/Postal Code

11030

Country

United States

Facility Name

Beth Israel Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10003

Country

United States

Facility Name

Concorde Medical Group

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

Facility Name

Mount Sinai School Of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Local Institution

City

Ciudad De Buenos Aires

State/Province

Buenos Aires

ZIP/Postal Code

C1121ABE

Country

Argentina

Facility Name

Local Institution

City

Ciudad De Buenos Aires

State/Province

Buenos Aires

ZIP/Postal Code

C1181ACH

Country

Argentina

Facility Name

Local Institution

City

Ciudad De Buenos Aires

State/Province

Buenos Aires

ZIP/Postal Code

C1282AEN

Country

Argentina

Facility Name

Local Institution

City

Rosario

State/Province

Prov De Santa

ZIP/Postal Code

S2000PBJ

Country

Argentina

Facility Name

Local Institution

City

Westmead Nsw

State/Province

New South Wales

ZIP/Postal Code

2145

Country

Australia

Facility Name

Local Institution

City

Clayton Vic

State/Province

Victoria

ZIP/Postal Code

3168

Country

Australia

Facility Name

Local Institution

City

Fitzroy

State/Province

Victoria

ZIP/Postal Code

3065

Country

Australia

Facility Name

Local Institution

City

Heidelberg

State/Province

Victoria

ZIP/Postal Code

3084

Country

Australia

Facility Name

Local Institution

City

Prahan

State/Province

Victoria

ZIP/Postal Code

3004

Country

Australia

Facility Name

Local Institution

City

Belo Horizonte

State/Province

Minas Gerais

ZIP/Postal Code

30150

Country

Brazil

Facility Name

Local Institution

City

Porto Alegre Rs

State/Province

Rio Grande Do Sul

ZIP/Postal Code

90035

Country

Brazil

Facility Name

Local Institution

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T2N 4Z6

Country

Canada

Facility Name

Local Institution

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Z 1H2

Country

Canada

Facility Name

Local Institution

City

Winnipeg

State/Province

Manitoba

ZIP/Postal Code

R3E 3P4

Country

Canada

Facility Name

Local Institution

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M3N 2V7

Country

Canada

Facility Name

Local Institution

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2N2

Country

Canada

Facility Name

Local Institution

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5T 2S8

Country

Canada

Facility Name

Local Institution

City

Grenoble Cedex 09

ZIP/Postal Code

38043

Country

France

Facility Name

Local Institution

City

Marseille Cedex 08

ZIP/Postal Code

13285

Country

France

Facility Name

Local Institution

City

Paris Cedex 12

ZIP/Postal Code

75571

Country

France

Facility Name

Local Institution

City

Paris Cedex 13

ZIP/Postal Code

75013

Country

France

Facility Name

Local Institution

City

Paris

ZIP/Postal Code

75014

Country

France

Facility Name

Local Institution

City

Strasbourg

ZIP/Postal Code

67090

Country

France

Facility Name

Local Institution

City

Hyderabad

State/Province

Andhra Pradesh

ZIP/Postal Code

500082

Country

India

Facility Name

Local Institution

City

Lucknow

ZIP/Postal Code

226014

Country

India

Facility Name

Local Institution

City

Ludhiana

ZIP/Postal Code

141001

Country

India

Facility Name

Local Institution

City

Vellore

ZIP/Postal Code

632004

Country

India

Facility Name

Local Institution

City

Antella Firenze

ZIP/Postal Code

50012

Country

Italy

Facility Name

Local Institution

City

Brescia

ZIP/Postal Code

25123

Country

Italy

Facility Name

Local Institution

City

Pisa

ZIP/Postal Code

56124

Country

Italy

Facility Name

Local Institution

City

Roma

ZIP/Postal Code

00149

Country

Italy

Facility Name

Local Institution

City

Durango

ZIP/Postal Code

34229

Country

Mexico

Facility Name

Local Institution

City

Bialystok

ZIP/Postal Code

15-540

Country

Poland

Facility Name

Local Institution

City

Chorzow

ZIP/Postal Code

41-500

Country

Poland

Facility Name

Local Institution

City

Krakow

ZIP/Postal Code

31-531

Country

Poland

Facility Name

Local Institution

City

Lublin

ZIP/Postal Code

20-081

Country

Poland

Facility Name

Local Institution

City

Warszawa

ZIP/Postal Code

01-201

Country

Poland

Facility Name

Local Institution

City

Moscow

ZIP/Postal Code

105275

Country

Russian Federation

Facility Name

Local Institution

City

Moscow

ZIP/Postal Code

115446

Country

Russian Federation

Facility Name

Local Institution

City

Moscow

ZIP/Postal Code

117593

Country

Russian Federation

Facility Name

Local Institution

City

Smolensk

ZIP/Postal Code

214018

Country

Russian Federation

Facility Name

Local Institution

City

St. Petersburg

ZIP/Postal Code

190103

Country

Russian Federation

Facility Name

Local Institution

City

St. Petersburg

ZIP/Postal Code

191163

Country

Russian Federation

Facility Name

Local Institution

City

St. Petersburg

ZIP/Postal Code

191167

Country

Russian Federation

Facility Name

Local Institution

City

St. Petersburg

ZIP/Postal Code

194044

Country

Russian Federation

Facility Name

Local Institution

City

Pretoria

State/Province

Gauteng

ZIP/Postal Code

0001

Country

South Africa

Facility Name

Local Institution

City

Bellville

State/Province

Western Cape

ZIP/Postal Code

7530

Country

South Africa

Facility Name

Local Institution

City

N1 City Goodwood

State/Province

Western Cape

ZIP/Postal Code

7463

Country

South Africa

Facility Name

Local Institution

City

Bornova Izmir

ZIP/Postal Code

35100

Country

Turkey

Facility Name

Local Institution

City

Cebeci Ankara

ZIP/Postal Code

06620

Country

Turkey

Facility Name

Local Institution

City

Sihhiye Ankara

ZIP/Postal Code

06100

Country

Turkey

Facility Name

Local Institution

City

Trabzon

ZIP/Postal Code

61080

Country

Turkey

12. IPD Sharing Statement

Citations:

PubMed Identifier

22643350

Citation

Lok AS, Trinh H, Carosi G, Akarca US, Gadano A, Habersetzer F, Sievert W, Wong D, Lovegren M, Cohen D, Llamoso C. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naive patients with chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):619-628.e1. doi: 10.1053/j.gastro.2012.05.037. Epub 2012 May 27.

Results Reference

derived

Learn more about this trial

Entecavir Plus Tenofovir Combination Therapy Versus Entecavir Monotherapy in Naive Subjects With Chronic Hepatitis B

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Entecavir Plus Tenofovir Combination Therapy Versus Entecavir Monotherapy in Naive Subjects With Chronic Hepatitis B

Hepatitis B, Chronic

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial