A Study of Pegylated Interferon Alfa-2A in Combination With Lamivudine or Entecavir Compared With Untreated Control Group in Children With Hepatitis B Envelope Antigen (HBeAg)-Positive Chronic Hepatitis B (CHB) in the Immune-Tolerant Phase

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02263079
• Collaborator: (none)
• Enrollment: 62
• Locations: 25
• Arms: 3
• Actual Duration (Months): 67.4
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized, controlled, parallel group, open-label multicenter study will evaluate the efficacy and safety of a combination of pegylated interferon alfa-2A (Pegasys) plus lamivudine or entecavir compared with an untreated control group in participants with HBeAg positive CHB in the immune tolerant phase. NOTE: STUDY RECRUITMENT HAS BEEN TERMINATED

Condition or Disease	Intervention/Treatment	Phase
Pediatric Immuno-Tolerant Chronic Hepatitis B	Drug: Entecavir; Drug: Lamivudine; Drug: Pegylated Interferon Alfa-2A	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIIb, Randomized, Open-Label Study of Pegylated Interferon Alfa-2A in Combination With Lamivudine or Entecavir Compared With Untreated Control Patients in Children With HBeAg Positive Chronic Hepatitis B in the Immune-Tolerant Phase
• Actual Study Start Date: Jun 16, 2014
• Actual Primary Completion Date: Jan 29, 2020
• Actual Study Completion Date: Jan 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Peg-IFN-Alfa-2A + Lamivudine or Entecavir Participants will receive lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Drug: Entecavir; Participants will receive entecavir, either as a film-coated tablet or oral solution, once daily at a dose of 0.015 milligrams per kilogram (mg/kg) (maximum daily dose of 0.5 mg).; Drug: Lamivudine; Participants will receive lamivudine, either as a film-coated tablet or oral solution, once daily at a dose of 3 mg/kg (maximum daily dose of 100 mg).; Drug: Pegylated Interferon Alfa-2A; Participants will receive pegylated interferon-alfa-2A at a body surface area (BSA) based dose of 180 micrograms per 1.73 square meter (mcg/1.73m^2) BSA.; Other Names: Pegasys, Peg-IFN-Alfa-2A
No Intervention: Untreated Control Participants Untreated control participants will be observed up to 80 weeks.
Experimental: Peg-INF-Alfa-2A Monotherapy Participants will receive Peginterferon Alfa 2A subcutaneously once weekly with dosing based on body surface area (BSA) categories for 48 weeks.	Drug: Pegylated Interferon Alfa-2A; Participants will receive pegylated interferon-alfa-2A at a body surface area (BSA) based dose of 180 micrograms per 1.73 square meter (mcg/1.73m^2) BSA.; Other Names: Pegasys, Peg-IFN-Alfa-2A

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Loss of Hepatitis B Surface Antigen (HBsAg) at 24 Weeks Post-End of Treatment/End of Untreated Observation [24 weeks post-treatment/at the end of untreated observation (Week 80)]

   This endpoint is defined as loss of HBsAg at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80). The percentage of responders (response rate) and 95% CI (using the Clopper-Pearson method) for the response rate are presented for each group.

Secondary Outcome Measures

1. Percentage of Participants With Loss of HBsAg [1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint is defined as loss of HBsAg at 1 year post-treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

2. Percentage of Participants With Loss of Hepatitis B Virus Envelope Antigen (HBeAg) [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint is defined as loss of HBeAg at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

3. Percentage of Participants With Seroconversion to Hepatitis B Surface Antibody (Anti-HBs), Defined as Loss of HBsAg and Presence of Anti-HBs [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint measures the seroconversion to anti-HBs defined as loss of HBsAg and presence of anti-HBs at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

4. Percentage of Participants With Seroconversion to Hepatitis B Envelope Antibody (Anti-HBe), Defined as Loss of HBeAg and Presence of Anti-HBe [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint measures the seroconversion to anti-HBe defined as loss of HBeAg and presence of anti-HBe at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

5. Percentage of Participants With Different Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels (Less Than [<] 20,000 International Units Per Milliliter [IU/mL], < 2000 IU/mL, or Undetectable HBV DNA) [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint measures different HBV DNA levels (<20000 IU/mL, <2000 IU/mL and undetectable) measured by PCR or hybridization at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-treatment in the treated group. HBV-DNA undetectable is defined as <29 IU/mL. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

6. Change From Baseline in HBV DNA Levels in the Peg-INF-Alfa-2A (Treated) Arm [Baseline, Week 8, 20, 32, 44, 56, Follow up Week 4 and 24]

   This outcome measure presents HBV DNA levels measured at defined time points from baseline in the Peg-INF-Alfa-2A + Lamivudine or Entecavir arm.

7. Change From Baseline in HBV DNA Levels in the Untreated Control Participants [Baseline, Week 32, 56 and end of untreated observation (Week 80)]

   This outcome measure presents HBV DNA levels measured at defined time points from baseline in the Untreated Control arm.

8. Percentage of Participants With Combined Response for HBeAg Seroconversion (Defined as Loss of HBeAg and Presence of Anti-HBe) and HBV DNA Levels <20,000 IU/mL [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint measures the combined response for HBeAg Seroconversion and HBV DNA Levels <20,000 IU/mL at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The HBeAg is defined as loss of HBeAg and presence of anti-HBe. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

9. Percentage of Participants With Combined Response for HBeAg Seroconversion (Defined as Loss of HBeAg and Presence of Anti-HBe) and HBV DNA Levels <2000 IU/mL [24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)]

   This endpoint measures the combined response for HBeAg Seroconversion and HBV DNA Levels <2000 IU/mL at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The HBeAg is defined as loss of HBeAg and presence of anti-HBe. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.

10. Percentage of Participants With Adverse Events (AEs) [Baseline up to 24 weeks post-treatment/end of untreated observation (Week 80)]

    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

11. Percentage of Participants With AEs Leading to Dose Modification or Interruption [Baseline up to 24 weeks post-end of treatment]

    This endpoint measures AEs and lab abnormalities leading to dose interruption or dose modification. Does modification included dose reduced, dose increased or drug interrupted. Adverse events included laboratory abnormalities reported as adverse events.

12. Serum Concentration of Peg-INF-Alfa-2A [At Weeks 12, 16, 20, 32, 44, 56]

    The serum concentration of Peg-INF-Alfa-2A was measured in picogram/milliliter.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Positive for HBsAg and HBeAg for more than 6 months prior to baseline

• Detectable HBV-DNA (>20,000 IU/mL) as measured by polymerization chain reaction (PCR) or hybridization on at least 2 occasions at least one month apart with the latest determination obtained less than or equal to (</=) 42 days prior to baseline

• Compensated liver disease (Child-Pugh Class A clinical classification)

• Either Liver biopsy performed within 2 years prior to baseline showing no or minimal fibrosis (Liver Biopsy Scores and stable normal ALT levels (less than or equal to upper limit of normal [ULN]) during the 6 months leading up to baseline (including two separate occasions at least 1 month apart over the 6 months prior to baseline). Screening ALT levels must be normal (</= ULN) OR Stable normal ALT levels (</= ULN), during the 1 year leading up to baseline (including three separate occasions at least 1 month apart over the 1 year prior to baseline) and no signs of hepatocellular carcinoma (HCC), advanced fibrosis/cirrhosis, or splenomegaly on liver abdominal ultrasound at screening. Screening ALT levels must be normal (</= ULN)

Exclusion Criteria:

• Participants who have received investigational drugs or licensed treatments with anti HBV activity (Exception: Participants who have had a limited [</= 7-day] course of acyclovir for herpetic lesions more than 1 month before the study baseline visit are not excluded)

• Participants who have participated in any other clinical trial or who have received any investigational drug within 6 months prior to baseline

• Known hypersensitivity to interferon (IFN), pegylated interferon-alfa-2a or lamivudine or entecavir

• Positive test results at screening for hepatitis A virus Immunoglobulin M (IgM) antibody (Ab), anti-hepatitis C virus (HCV) Ab, anti- hepatitis D (HDV) Ab or anti-human immunodeficiency virus (HIV) Ab

• Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification or clinical evidence such as ascites or varices)

• Advanced fibrosis or cirrhosis

• Suspicion of HCC on liver abdominal ultrasound (all patients to have liver abdominal ultrasound within 6 months prior to baseline)

• History or other evidence of a medical condition associated with chronic liver disease other than CHB including metabolic liver diseases such as hemochromatosis, Wilson's disease or alpha-1 anti-trypsin deficiency

• Active substance abuse within 6 months prior to screening

• Sexually active females of childbearing potential and sexually active males who are not willing to utilize reliable contraception during treatment and for 90 days following the end of treatment

• Females who are pregnant or who are breastfeeding (females of childbearing potential who have a positive urine or serum pregnancy test result within 24 hours of baseline are excluded)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Mercy Hosp Clinics	Kansas City	Missouri	United States	64108
2	Columbia University	New York	New York	United States	10032-3725
3	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
4	Womens and Childrens Hospital; Department of Gastroenterology	North Adelaide	South Australia	Australia	5006
5	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
6	UZ Gent	Gent		Belgium	9000
7	Universitätsklinikum Essen; Klinik für Kinder- und Jugendmedizin Pädiatrie II	Essen		Germany	45122
8	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin	Mainz		Germany	55131
9	Dr. von Haunerschen Kinderspital, Kinderchirurgische Klinik und Poliklinik	München		Germany	80337
10	HELIOS Klinikum Wuppertal, Zentrum für Kinder- und Jugendmedizin, Universität Witten-Herdecke	Wuppertal		Germany	42283
11	Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi; U.O. Malattie Infettive	Bologna	Emilia-Romagna	Italy	40138
12	University Malaya Medical Center; Department of Paediatrics	Kuala Lumpur		Malaysia	59100
13	Grigore Alexandrescu Emergency Clinical Hospital for Children	Bucharest		Romania	011743
14	FSI Scientific research Institute of children's infections	Saint Petersburg		Russian Federation	197022
15	MC Gepatolog	Samara		Russian Federation	443100
16	Chang-Gung Memorial Hospital-Linkou; Division of Pediatric Gastroenterology, Dept Pediatrics	Taoyuan County		Taiwan	333
17	Cukurova University Medical School Department of Pediatrics; Pediatric Infectious Diseases	Adana		Turkey	01330
18	Ankara University School of Medicine, Pediatrics Department; Pediatric Gastroenterology	Ankara		Turkey	06100
19	Hacettepe Uni , School of Medicine; Gastroenterology	Ankara		Turkey	06100
20	Gazi Universitesi Tip Fakultesi Pediyatri Anabilim Dalı; Pediyatrik Gastroenteroloji	Ankara		Turkey	06500
21	SI Institute of the pediatrics, obstetrics and gynecology	Kyiv		Ukraine	04050
22	Birmingham Children'S Hopsital; Liver Unit	Birmingham		United Kingdom	B4 6NH
23	Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom	LS9 7AU
24	Kings College Hospital NHS Foundation Trust	London		United Kingdom	SE5 9RS
25	North Manchester General Hospital	Manchester		United Kingdom	M8 5RB

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 26, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02263079
• Other Study ID Numbers: NV25361; 2006-000977-31
• First Posted: Oct 13, 2014
• Last Update Posted: Aug 24, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Interferons; Interferon-alpha; Lamivudine; Interferon alpha-2; Peginterferon alfa-2a; Entecavir

Study Results

Participant Flow

Recruitment Details	The study began as a single-site, three arm IST and was subsequently adapted as a multi-center, two arm study, conducted at 22 sites in Malaysia, Taiwan, Australia, Belgium, Germany, United Kingdom, Italy, Romania, Russian Federation, Turkey, Ukraine and the U.S. Enrolment was stopped prematurely, at which time 62 participants had been enrolled.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants	Peg-INF-Alfa-2A Monotherapy
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.	Participants received Peginterferon Alfa 2A subcutaneously once weekly with dosing based on body surface area (BSA) categories for 48 weeks.
Period Title: Overall Study
STARTED	26	33	3
COMPLETED	23	25	3
NOT COMPLETED	3	8	0

Baseline Characteristics

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants	Peg-INF-Alfa-2A Monotherapy	Total
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.	Participants received Peginterferon Alfa 2A subcutaneously once weekly with dosing based on body surface area (BSA) categories for 48 weeks.	Total of all reporting groups
Overall Participants	26	33	3	62
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	11.9 (3.2)	10.9 (3.7)	11.3 (3.5)
Sex: Female, Male (Count of Participants)
Female	16 61.5%	14 42.4%	30 1000%
Male	10 38.5%	19 57.6%	29 966.7%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 3.8%	0 0%	1 33.3%
Not Hispanic or Latino	25 96.2%	33 100%	58 1933.3%
Race/Ethnicity, Customized (Count of Participants)
Asian	11 42.3%	11 33.3%	22 733.3%
Black or African American	4 15.4%	2 6.1%	6 200%
Multiple	2 7.7%	0 0%	2 66.7%
Other	0 0%	3 9.1%	3 100%
White	9 34.6%	17 51.5%	26 866.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Loss of Hepatitis B Surface Antigen (HBsAg) at 24 Weeks Post-End of Treatment/End of Untreated Observation
Description	This endpoint is defined as loss of HBsAg at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80). The percentage of responders (response rate) and 95% CI (using the Clopper-Pearson method) for the response rate are presented for each group.
Time Frame	24 weeks post-treatment/at the end of untreated observation (Week 80)

Outcome Measure Data

Analysis Population Description

The Intent to treat (ITT) population was defined as all participants who received at least one dose of study medication of treated group. For untreated group, the ITT population included all randomized participants.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
Number (95% Confidence Interval) [Percentage of Participants]	3.8 14.6%	0 0%

2. Secondary Outcome

Title	Percentage of Participants With Loss of HBsAg
Description	This endpoint is defined as loss of HBsAg at 1 year post-treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

The analysis population included participants from the Peg-INF-Alfa-2A arm, who received at least one dose of study medication of treated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated participants).

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.
Measure Participants	26
Number (95% Confidence Interval) [Percentage of Participants]	3.8 14.6%

3. Secondary Outcome

Title	Percentage of Participants With Loss of Hepatitis B Virus Envelope Antigen (HBeAg)
Description	This endpoint is defined as loss of HBeAg at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
24 Weeks post-treatment/Week 80	3.8 14.6%	12.1 36.7%
1 year post-end of treatment	11.5 44.2%

4. Secondary Outcome

Title	Percentage of Participants With Seroconversion to Hepatitis B Surface Antibody (Anti-HBs), Defined as Loss of HBsAg and Presence of Anti-HBs
Description	This endpoint measures the seroconversion to anti-HBs defined as loss of HBsAg and presence of anti-HBs at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
24 Weeks post-treatment/Week 80	3.8 14.6%	0.0 0%
1 year post-end of treatment	3.8 14.6%

5. Secondary Outcome

Title	Percentage of Participants With Seroconversion to Hepatitis B Envelope Antibody (Anti-HBe), Defined as Loss of HBeAg and Presence of Anti-HBe
Description	This endpoint measures the seroconversion to anti-HBe defined as loss of HBeAg and presence of anti-HBe at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
24 Weeks post-treatment/Week 80	0.0 0%	9.1 27.6%
1 year post-end of treatment	7.7 29.6%

6. Secondary Outcome

Title	Percentage of Participants With Different Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels (Less Than [<] 20,000 International Units Per Milliliter [IU/mL], < 2000 IU/mL, or Undetectable HBV DNA)
Description	This endpoint measures different HBV DNA levels (<20000 IU/mL, <2000 IU/mL and undetectable) measured by PCR or hybridization at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-treatment in the treated group. HBV-DNA undetectable is defined as <29 IU/mL. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
HBV-DNA <20000 IU/mL at follow up Week 24/Week 80	7.7 29.6%	12.1 36.7%
HBV-DNA <2000 IU/mL at follow up Week 24/Week 80	7.7 29.6%	12.1 36.7%
HBV-DNA Undetectable at follow up Week 24/Week 80	0.0 0%	6.1 18.5%
HBV-DNA <20000 IU/mL 1 year post-end of treatment	15.4 59.2%
HBV-DNA <2000 IU/mL 1 year post-end of treatment	7.7 29.6%
HBV-DNA Undetectable 1 year post-end of treatment	0.0 0%

7. Secondary Outcome

Title	Change From Baseline in HBV DNA Levels in the Peg-INF-Alfa-2A (Treated) Arm
Description	This outcome measure presents HBV DNA levels measured at defined time points from baseline in the Peg-INF-Alfa-2A + Lamivudine or Entecavir arm.
Time Frame	Baseline, Week 8, 20, 32, 44, 56, Follow up Week 4 and 24

Outcome Measure Data

Analysis Population Description

The analysis population included participants from the Peg-INF-Alfa-2A arm, who received at least one dose of study medication of treated group. Only participants for whom data were collected are included in the analysis.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.
Measure Participants	26
Baseline	8.02 (0.93)
Week 8	4.74 (1.01)
Week 20	3.54 (0.81)
Week 32	2.56 (0.84)
Week 44	2.15 (0.70)
Week 56	2.21 (0.90)
Fu Week 4	4.34 (2.65)
Fu Week 24	7.31 (1.99)

8. Secondary Outcome

Title	Change From Baseline in HBV DNA Levels in the Untreated Control Participants
Description	This outcome measure presents HBV DNA levels measured at defined time points from baseline in the Untreated Control arm.
Time Frame	Baseline, Week 32, 56 and end of untreated observation (Week 80)

Outcome Measure Data

Analysis Population Description

The analysis population included participants from the Untreated Control arm. Only participants for whom data were collected are included in the analysis.

Arm/Group Title	Untreated Control Participants
Arm/Group Description	Untreated control participants were observed up to 80 weeks.
Measure Participants	33
Baseline	8.22 (1.07)
Week 32	8.29 (0.97)
Week 56	7.57 (1.96)
Week 80	7.24 (2.58)

9. Secondary Outcome

Title	Percentage of Participants With Combined Response for HBeAg Seroconversion (Defined as Loss of HBeAg and Presence of Anti-HBe) and HBV DNA Levels <20,000 IU/mL
Description	This endpoint measures the combined response for HBeAg Seroconversion and HBV DNA Levels <20,000 IU/mL at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The HBeAg is defined as loss of HBeAg and presence of anti-HBe. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
24 Weeks post-treatment/Week 80	0.0 0%	9.1 27.6%
1 year post-end of treatment	7.7 29.6%

10. Secondary Outcome

Title	Percentage of Participants With Combined Response for HBeAg Seroconversion (Defined as Loss of HBeAg and Presence of Anti-HBe) and HBV DNA Levels <2000 IU/mL
Description	This endpoint measures the combined response for HBeAg Seroconversion and HBV DNA Levels <2000 IU/mL at 24 weeks post-treatment (follow-up Week 24)/end of untreated observation (Week 80) and at 1 year post-end of treatment in the treated group. The HBeAg is defined as loss of HBeAg and presence of anti-HBe. The 95% Confidence Interval of response rate is calculated by Clopper-Pearson method.
Time Frame	24 weeks post-treatment /end of untreated observation (Week 80), and 1 year post-end of treatment (End of treatment = Week 56)

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study medication of treated group, and all randomized participants in the untreated group. None of the participants from the untreated group were assessed at 1 year post-end of treatment as they were only observed up to 80 weeks (=24 weeks post-treatment for treated group)

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
24 Weeks post-treatment/Week 80	0.0 0%	9.1 27.6%
1 year post-end of treatment	7.7 29.6%

11. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs)
Description	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame	Baseline up to 24 weeks post-treatment/end of untreated observation (Week 80)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least one dose of study medication and had at least one post-baseline safety assessment. For untreated group, the safety population included all randomized participants who had at least one post-baseline safety assessment.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir	Untreated Control Participants
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.	Untreated control participants were observed up to 80 weeks.
Measure Participants	26	33
With at least one Non-Serious AE	92.3 355%	45.5 137.9%
With at least one Serious Adverse Event (SAE)	0 0%	3.0 9.1%

12. Secondary Outcome

Title	Percentage of Participants With AEs Leading to Dose Modification or Interruption
Description	This endpoint measures AEs and lab abnormalities leading to dose interruption or dose modification. Does modification included dose reduced, dose increased or drug interrupted. Adverse events included laboratory abnormalities reported as adverse events.
Time Frame	Baseline up to 24 weeks post-end of treatment

Outcome Measure Data

Analysis Population Description

The safety analysis population included all participants who received at least one dose of study medication and had at least one post-baseline safety assessment in the Peg-INF-Alfa-2A treated arm.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.
Measure Participants	26
Number [Percentage of Participants]	23.0 88.5%

13. Secondary Outcome

Title	Serum Concentration of Peg-INF-Alfa-2A
Description	The serum concentration of Peg-INF-Alfa-2A was measured in picogram/milliliter.
Time Frame	At Weeks 12, 16, 20, 32, 44, 56

Outcome Measure Data

Analysis Population Description

The analysis population was the Peg-IFN-Alfa-2A + Lamivudine or Entecavir arm. The untreated arm did not receive any study medication. Only participants for whom data were collected are included in the analysis.

Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.
Measure Participants	26
Week 12 Predose	8430 (6090)
Week 16 Predose	16300 (10100)
Week 20 Predose	13800 (8740)
Week 32 Predose	14900 (7710)
Week 32 24-48h Post-dose	22700 (6070)
Week 32 72-96h Post-dose	23000 (4900)
Week 32 168h Post-dose	19300 (5880)
Week 44 Predose	21900 (14200)
Week 56 Predose	25400 (13100)

Adverse Events

Time Frame	From Baseline up to 1 year post-end of treatment in the treated arm; From Baseline to end of untreated observation (Week 80) in the untreated group [up to clinical cut-off date 29 Jan 2020]
Adverse Event Reporting Description	The safety population included all participants who received at least one dose of study medication and had at least one post-baseline safety assessment. For untreated group, the safety population included all randomized participants who had at least one post-baseline safety assessment. Total # at Risk =0 in Other (Not Including Serious) Adverse Events section represents not reported data in consideration of participant re-identification.
Arm/Group Title	Peg-IFN-Alfa-2A + Lamivudine or Entecavir		Untreated Control Participants		Peg-INF-Alfa-2A Monotherapy
Arm/Group Description	Participants received lamivudine or entecavir alone for 8 weeks followed by peg-IFN-alfa-2A in combination with lamivudine or entecavir for 48 weeks.		Untreated control participants were observed up to 80 weeks.		Participants received Peginterferon Alfa 2A subcutaneously once weekly with dosing based on body surface area (BSA) categories for 48 weeks.
All Cause Mortality
	Peg-IFN-Alfa-2A + Lamivudine or Entecavir		Untreated Control Participants		Peg-INF-Alfa-2A Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/33 (0%)		0/3 (0%)
Serious Adverse Events
	Peg-IFN-Alfa-2A + Lamivudine or Entecavir		Untreated Control Participants		Peg-INF-Alfa-2A Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		1/33 (3%)		0/3 (0%)
Infections and infestations
PHARYNGITIS	0/26 (0%)	0	1/33 (3%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
DEHYDRATION	0/26 (0%)	0	1/33 (3%)	1	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Peg-IFN-Alfa-2A + Lamivudine or Entecavir		Untreated Control Participants		Peg-INF-Alfa-2A Monotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/26 (80.8%)		10/33 (30.3%)		0/0 (NaN)
Gastrointestinal disorders
ABDOMINAL PAIN	1/26 (3.8%)	1	2/33 (6.1%)	2	0/0 (NaN)	0
ABDOMINAL PAIN UPPER	3/26 (11.5%)	3	3/33 (9.1%)	3	0/0 (NaN)	0
NAUSEA	4/26 (15.4%)	5	1/33 (3%)	1	0/0 (NaN)	0
VOMITING	3/26 (11.5%)	4	1/33 (3%)	1	0/0 (NaN)	0
General disorders
ASTHENIA	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
FATIGUE	5/26 (19.2%)	11	0/33 (0%)	0	0/0 (NaN)	0
HYPERTHERMIA	2/26 (7.7%)	3	0/33 (0%)	0	0/0 (NaN)	0
INJECTION SITE BRUISING	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
PAIN	3/26 (11.5%)	5	0/33 (0%)	0	0/0 (NaN)	0
PYREXIA	11/26 (42.3%)	21	0/33 (0%)	0	0/0 (NaN)	0
Infections and infestations
GASTROENTERITIS	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
INFLUENZA	1/26 (3.8%)	1	2/33 (6.1%)	2	0/0 (NaN)	0
NASOPHARYNGITIS	3/26 (11.5%)	3	1/33 (3%)	1	0/0 (NaN)	0
UPPER RESPIRATORY TRACT INFECTION	2/26 (7.7%)	3	1/33 (3%)	1	0/0 (NaN)	0
Injury, poisoning and procedural complications
CONTUSION	2/26 (7.7%)	7	0/33 (0%)	0	0/0 (NaN)	0
LIMB INJURY	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
Metabolism and nutrition disorders
DECREASED APPETITE	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
MYALGIA	2/26 (7.7%)	5	0/33 (0%)	0	0/0 (NaN)	0
PAIN IN EXTREMITY	2/26 (7.7%)	4	1/33 (3%)	1	0/0 (NaN)	0
Nervous system disorders
DIZZINESS	3/26 (11.5%)	5	0/33 (0%)	0	0/0 (NaN)	0
HEADACHE	14/26 (53.8%)	91	0/33 (0%)	0	0/0 (NaN)	0
MIGRAINE	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
EPISTAXIS	3/26 (11.5%)	8	1/33 (3%)	1	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
ACNE	2/26 (7.7%)	2	1/33 (3%)	1	0/0 (NaN)	0
ALOPECIA	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0
ECZEMA	2/26 (7.7%)	2	0/33 (0%)	0	0/0 (NaN)	0

Limitations/Caveats

In accordance with the recommendation from the DSMB, enrollment was stopped due to low efficacy and a changed benefit risk assessment. Enrolled participants were allowed to complete treatment and were followed up for 1 year after the end of treatment

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.