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Combination Entecavir and Peginterferon Therapy in HBeAg-Positive Immune-Tolerant Adults With Chronic Hepatitis B (HBRN)

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ClinicalTrials.gov Identifier: NCT01369199
Recruitment Status : Terminated
First Posted : June 8, 2011
Results First Posted : July 3, 2018
Last Update Posted : September 21, 2018
Sponsor:
Collaborators:
University of Pittsburgh
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hepatitis B
Intervention Drug: Entecavir and peginterferon
Enrollment 28

Recruitment Details Twenty-eight (28) adults were enrolled at 11 clinical sites in the United States and Canada between 12/18/12 and 04/29/15.
Pre-assignment Details  
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up for 48 weeks.
Period Title: Overall Study
Started 28
End of Treatment (EOT) 26 [1]
Completed [2] 25
Not Completed 3
Reason Not Completed
Withdrawal by Subject             1
Lost to Follow-up             2
[1]
1 withdrew consent before treatment,1 missed end of treatment (EOT) visit but completed follow-up.
[2]
End of follow-up
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Baseline Participants 28
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 28 participants
37.2
(22.2 to 61.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants
Female
13
  46.4%
Male
15
  53.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants
Asian
27
  96.4%
Black/African American
1
   3.6%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 28 participants
Canada
9
  32.1%
United States
19
  67.9%
Hepatitis B Virus (HBV) DNA  
Median (Full Range)
Unit of measure:  Log10 IU/mL
Number Analyzed 28 participants
8.2
(7.2 to 8.8)
1.Primary Outcome
Title Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL
Hide Description Lack of data was considered to be treatment failure.
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
2.Primary Outcome
Title Incidence of Adverse Events (AEs) Per Person-Year of Observation
Hide Description The number of AEs includes both AEs and Serious Adverse Events (SAEs). The incidence is calculated as the number of AEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Time Frame From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Events per person-year of observation
End of treatment (Up to 48 weeks)
1.60
(1.17 to 2.19)
End of follow-up (Up to 96) weeks
0.86
(0.64 to 1.17)
3.Primary Outcome
Title Incidence of Serious Adverse Events (SAEs) Per Person-Year
Hide Description The incidence is calculated as the number of SAEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Time Frame From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: SAEs per person-year of observation
End of treatment (Up to 48 weeks)
0 [1] 
(NA to NA)
End of follow-up (Up to 96 weeks)
.021
(.003 to .146)
[1]
95% Confidence Interval (CI) around 0 not calculated
4.Secondary Outcome
Title Proportion of Participants With HBeAg Loss
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.036
(.001 to .183)
5.Secondary Outcome
Title Proportion of Participants With HBeAg Loss
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.036
(.001 to .183)
6.Secondary Outcome
Title Proportion of Participants With HBeAg Seroconversion
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.036
(.001 to .183)
7.Secondary Outcome
Title Proportion of Participants With HBeAg Seroconversion
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.036
(.001 to .183)
8.Secondary Outcome
Title Proportion of Participants With HBsAg Loss
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
9.Secondary Outcome
Title Proportion of Participants With HBsAg Loss
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
10.Secondary Outcome
Title Proportion of Participants With HBsAg Seroconversion
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
11.Secondary Outcome
Title Proportion of Participants With HBsAg Seroconversion
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
12.Secondary Outcome
Title Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.571
(.245 to .628)
13.Secondary Outcome
Title Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.750
(.551 to .893)
14.Secondary Outcome
Title Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.393
(.215 to .594)
15.Secondary Outcome
Title Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.464
(.275 to .661)
16.Secondary Outcome
Title Proportion of Participants With HBV DNA ≤1000 IU/mL
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.929
(.765 to .991)
17.Secondary Outcome
Title Proportion of Participants With HBV DNA ≤1000 IU/mL
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
18.Secondary Outcome
Title Proportion of Participants With HBV DNA <20 IU/mL
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
.179
(.061 to .369)
19.Secondary Outcome
Title Proportion of Participants With HBV DNA <20 IU/mL
Hide Description [Not Specified]
Time Frame End of follow-up (up to 96 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description:
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks.
Overall Number of Participants Analyzed 28
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of participants
0
(0 to .123)
20.Secondary Outcome
Title Absence of Detectable Antiviral Drug-resistance HBV Mutations
Hide Description [Not Specified]
Time Frame End of treatment (up to 48 weeks)
Outcome Measure Data Not Reported
Time Frame Study entry (consent) to the end of follow-up (up to 96 weeks after treatment initiation).
Adverse Event Reporting Description

Asked at each visit. Expected symptoms/signs or common side effects of meds not reported (these are termed Adverse Effects). Below is a guide for recording adverse events which are at the discretion of the investigator.

  1. Symptom or event requiring discontinuation of study medication.
  2. New symptom or event requiring a written prescription for treatment.
  3. New symptom or event resulting in a referral to another provider.
  4. Grade 3 or 4 event per the NCI Common Toxicity Criteria.
 
Arm/Group Title Peginterferon and Entecavir
Hide Arm/Group Description Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously (sq) weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment will be for 48 weeks.
All-Cause Mortality
Peginterferon and Entecavir
Affected / at Risk (%)
Total   0/28 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Peginterferon and Entecavir
Affected / at Risk (%) # Events
Total   1/28 (3.57%)    
Infections and infestations   
Malaria   1/28 (3.57%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Peginterferon and Entecavir
Affected / at Risk (%) # Events
Total   14/28 (50.00%)    
Blood and lymphatic system disorders   
Low white blood cells, platelets, and absolute neutrophil count   1/28 (3.57%)  1
Neutropenia   1/28 (3.57%)  1
Endocrine disorders   
Altered thyroid function   1/28 (3.57%)  1
Graves disease   1/28 (3.57%)  1
Hypothyroidism   1/28 (3.57%)  1
Eye disorders   
Blurred vision   1/28 (3.57%)  1
Gastrointestinal disorders   
Heartburn   1/28 (3.57%)  1
Heartburn and diarrhea   1/28 (3.57%)  1
Poor appetite   1/28 (3.57%)  1
Upset stomach   1/28 (3.57%)  1
General disorders   
Decrease in appetite   1/28 (3.57%)  1
Fatigue   1/28 (3.57%)  1
Fever   2/28 (7.14%)  2
Head cold   1/28 (3.57%)  1
Sore throat   1/28 (3.57%)  1
Swollen lips   1/28 (3.57%)  1
Upper respiratory infection   1/28 (3.57%)  1
Infections and infestations   
Infection in right forefinger   1/28 (3.57%)  1
Musculoskeletal and connective tissue disorders   
Intermittent finger joint pain   1/28 (3.57%)  1
Myalgia   1/28 (3.57%)  1
Nervous system disorders   
Headache   2/28 (7.14%)  2
Shingles   1/28 (3.57%)  1
Vertigo   1/28 (3.57%)  1
Psychiatric disorders   
Depressive disorder   1/28 (3.57%)  1
Renal and urinary disorders   
Foul urine smell   1/28 (3.57%)  1
Frequent urination - prophylaxis   1/28 (3.57%)  1
Penile yeast infection   1/28 (3.57%)  1
Urinary tract infection   2/28 (7.14%)  4
Respiratory, thoracic and mediastinal disorders   
Pneumococcal pneumonia   1/28 (3.57%)  1
Skin and subcutaneous tissue disorders   
Alopecia (Hair loss)   3/28 (10.71%)  4
Bruising on legs   1/28 (3.57%)  1
Hives   1/28 (3.57%)  1
Itchiness at injection site (intermittent)   1/28 (3.57%)  1
Rash and itchiness on lower jaw   1/28 (3.57%)  1
Redness at injection site   2/28 (7.14%)  2
Indicates events were collected by systematic assessment

Early termination of recruitment per Data and Safety Monitoring Board.

1 case with multiple central and local lab discrepancies was not considered to have HBeAg loss since central lab was always negative.

Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Steven Belle
Organization: University of Pittsburgh
Phone: 412-624-5419
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01369199     History of Changes
Obsolete Identifiers: NCT01534611
Other Study ID Numbers: DK082864 HBRN IT Adult Trial
U01DK082916 ( U.S. NIH Grant/Contract )
U01DK082843 ( U.S. NIH Grant/Contract )
U01DK082863 ( U.S. NIH Grant/Contract )
U01DK082864 ( U.S. NIH Grant/Contract )
U01DK082866 ( U.S. NIH Grant/Contract )
U01DK082867 ( U.S. NIH Grant/Contract )
U01DK082871 ( U.S. NIH Grant/Contract )
U01DK082872 ( U.S. NIH Grant/Contract )
U01DK082874 ( U.S. NIH Grant/Contract )
U01DK082919 ( U.S. NIH Grant/Contract )
U01DK082923 ( U.S. NIH Grant/Contract )
U01DK082927 ( U.S. NIH Grant/Contract )
U01DK082943 ( U.S. NIH Grant/Contract )
U01DK082944 ( U.S. NIH Grant/Contract )
P30DK050306 ( U.S. NIH Grant/Contract )
A-DK-3002-001 ( Other Grant/Funding Number: Interagency agreement with NIDDK )
M01RR000040 ( U.S. NIH Grant/Contract )
UL1TR000058 ( U.S. NIH Grant/Contract )
UL1TR000004 ( U.S. NIH Grant/Contract )
UL1TR001111 ( U.S. NIH Grant/Contract )
UL1RR024986 ( U.S. NIH Grant/Contract )
First Submitted: June 6, 2011
First Posted: June 8, 2011
Results First Submitted: March 7, 2018
Results First Posted: July 3, 2018
Last Update Posted: September 21, 2018