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Clinical Trial Results:
LIRA-B - Dose-Ranging Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Pegylated Interferon Lambda (BMS-914143) Monotherapy in Interferon-Naive Patients with Chronic Hepatitis B Virus Infection who are HBeAg-positive.

Summary
EudraCT number	2010-020387-38
Trial protocol	DE IT NL
Global end of trial date	13 Dec 2013

Results information
Results version number	v1(current)
This version publication date	31 Jul 2016
First version publication date	31 Jul 2016
Other versions

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

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Trial information

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Sponsor protocol code

AI452-005

ISRCTN number

US NCT number

NCT01204762

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Bristol-Myers Squibb International Corporation, Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

13 Dec 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Dec 2013

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objectives of the trial were to evaluate the safety and tolerability of Pegylated Interferon Lambda as measured by the frequency of serious adverse events and discontinuations due to adverse events and to assess the hepatitis B e antigen seroconversion rate at 24 weeks (Week 72) off treatment.

Protection of trial subjects

The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all international Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Nov 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

30 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Australia: 20

Country: Number of subjects enrolled

Canada: 35

Country: Number of subjects enrolled

Hong Kong: 35

Country: Number of subjects enrolled

Korea, Republic of: 62

Country: Number of subjects enrolled

Singapore: 14

Country: Number of subjects enrolled

Taiwan: 65

Country: Number of subjects enrolled

United States: 57

Worldwide total number of subjects

333

EEA total number of subjects

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)

332

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at 52 sites in 11 countries.

Screening details

A total of 333 subjects were enrolled in this study. Part A: Out of 298 subjects enrolled, 177 subjects were randomised and 176 were treated. Reasons for 121 subjects not randomised were: subject withdrew consent (7), subjects no longer met study criteria (107), and other reasons (7). Part B: A total of 21 subjects were treated.

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

Part B of the study was open-label.

Are arms mutually exclusive

Yes

Part A: Peginterferon Lambda 240 μg

Arm description

Subjects were administered Peginterferon Lambda 240 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks. All 13 subjects who were initially assigned to 240 μg Lambda subsequently had their dose dropped to 180 μg following a decision by the sponsor to discontinue development of this Lambda dose due to safety reasons.

Arm type

Experimental

Investigational medicinal product name

Pegylated Interferon Lambda

Investigational medicinal product code

BMS-914143

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Part A: Peginterferon Lambda 180 μg

Arm description

Subjects were administered Peginterferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Pegylated Interferon Lambda

Investigational medicinal product code

BMS-914143

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects were administered Pegylated Interferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Part A: Peginterferon alfa-2a 180 μg

Arm description

Subjects were administered Peginterferon alfa-2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Arm type

Active comparator

Investigational medicinal product name

Peginterferon alfa- 2a

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects were administered Peginterferon alfa- 2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Part B: Peginterferon Lambda + Entecavir

Arm description

Subjects with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B virus (HBV) infection received HBV treatment for a planned duration of 60 weeks: Entecavir 0.5 mg tablets administered orally, once daily, for 12 weeks followed by Peginterferon Lambda 180 μg, administered subcutaneously, once weekly, along with Entecavir 0.5 mg, tablets, administered orally, once daily for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Pegylated Interferon Lambda

Investigational medicinal product code

BMS-914143

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects were administered Pegylated Interferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Investigational medicinal product name

Entecavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were administered Entecavir 0.5 mg film-coated tablets, orally, once daily for 60 weeks (12 weeks as monotherapy and 48 weeks in combination with peginterferon lambda).

Number of subjects in period 1 ^[1]	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir
Started	13	80	83	21
Completed	9	74	68	6
Not completed	4	6	15	15
Consent withdrawn by subject	-	-	3	-
Adverse event, non-fatal	3	6	8	-
Subject request to discontinue study treatment	1	-	1	-
Pregnancy	-	-	-	1
Other reasons	-	-	-	3
Lost to follow-up	-	-	1	1
Lack of efficacy	-	-	2	-
Administrative reason by sponsor	-	-	-	10

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: Part A: Out of 298 subjects enrolled, 177 subjects were randomised and 176 were treated. Part B: A total of 21 subjects were treated.

Period 2 title

Follow-up Period (24 weeks)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A: Peginterferon Lambda 240 μg

Arm description

Subjects were followed up for 24 weeks after receiving Peginterferon Lambda 240 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks. All subjects who were initially assigned to 240 μg Lambda subsequently had their dose dropped to 180 μg.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A: Peginterferon Lambda 180 μg

Arm description

Subjects were followed up for 24 weeks after receiving Peginterferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A: Peginterferon alfa-2a 180 μg

Arm description

Subjects were followed up for 24 weeks after receiving Peginterferon alfa-2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part B: Peginterferon Lambda + Entecavir

Arm description

Subjects with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B virus (HBV) infection were to be followed up for 24 weeks after receiving HBV treatment for a planned duration of 60 weeks: Entecavir 0.5 mg tablets administered orally, once daily for 12 weeks followed by Peginterferon Lambda 180 μg, administered subcutaneously, once weekly along with Entecavir 0.5 mg, tablets, administered orally, once daily for 48 weeks

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir
Started	9	74	68	6
Completed	11	70	72	0
Not completed	1	8	6	9
Consent withdrawn by subject	1	3	4	-
Other reason	-	1	-	-
Lost to follow-up	-	2	1	-
Subject no longer meets study criteria	-	1	1	-
Lack of efficacy	-	1	-	-
Administrative reason by sponsor	-	-	-	9
Joined	3	4	10	3
Re-joined for follow-up	3	4	10	3

Period 3 title

Long-Term Follow-up

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A: Peginterferon Lambda 240 μg

Arm description

Subjects were to be followed up for 36 months after completion of 24 weeks post follow-up after receiving Peginterferon Lambda 240 μg, subcutaneously, once weekly for a planned duration of 48 weeks during the treatment period. All 13 subjects who were initially assigned to 240 μg Lambda subsequently had their dose dropped to 180 μg following a decision by the sponsor to discontinue development of this Lambda dose due to safety reasons.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A: Peginterferon Lambda 180 μg

Arm description

Subjects were to be followed up for 36 months after completion of 24 weeks post follow-up after receiving Peginterferon Lambda 180 μg, subcutaneously, once weekly for a planned duration of 48 weeks during the treatment period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part A: Peginterferon alfa-2a 180 μg

Arm description

Subjects were to be followed up for 36 months after completion of 24 weeks post follow-up after receiving Peginterferon alfa-2a 180 μg, subcutaneously, once weekly for a planned duration of 48 weeks during the treatment period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[2]	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Started	3	28	39
Completed	0	2	3
Not completed	3	26	36
Consent withdrawn by subject	-	3	-
Other reasons	3	21	35
Lost to follow-up	-	2	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: Out of 153 subjects who completed the 24 weeks follow-up period, only 70 subjects entered the long-term follow-up period.

Baseline characteristics

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Reporting group title

Part A: Peginterferon Lambda 240 μg

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 180 μg

Reporting group description

Subjects were administered Peginterferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part A: Peginterferon alfa-2a 180 μg

Reporting group description

Subjects were administered Peginterferon alfa-2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part B: Peginterferon Lambda + Entecavir

Reporting group description

Reporting group values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir	Total
Number of subjects	13	80	83	21	197
Age categorical
Units: Subjects
<21 years	0	0	1	0	1
21 - <65 years	13	80	82	21	196
>=65 years	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	33.1 ( 7.17 )	36.5 ( 10.19 )	34.9 ( 8.9 )	34 ( 7.86 )	-
Gender categorical
Units: Subjects
Female	1	21	20	6	48
Male	12	59	63	15	149

End points

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Reporting group title

Part A: Peginterferon Lambda 240 μg

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 180 μg

Reporting group description

Subjects were administered Peginterferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part A: Peginterferon alfa-2a 180 μg

Reporting group description

Subjects were administered Peginterferon alfa-2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part B: Peginterferon Lambda + Entecavir

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 240 μg

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 180 μg

Reporting group description

Subjects were followed up for 24 weeks after receiving Peginterferon Lambda 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part A: Peginterferon alfa-2a 180 μg

Reporting group description

Subjects were followed up for 24 weeks after receiving Peginterferon alfa-2a 180 μg via subcutaneous injection, once weekly, for a planned duration of 48 weeks.

Reporting group title

Part B: Peginterferon Lambda + Entecavir

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 240 μg

Reporting group description

Reporting group title

Part A: Peginterferon Lambda 180 μg

Reporting group description

Reporting group title

Part A: Peginterferon alfa-2a 180 μg

Reporting group description

Primary: Percentage of Subjects Who Achieved Hepatitis B e Antigen (HBeAg) Seroconversion at Follow-up Week 24 - Part A

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End point title

Percentage of Subjects Who Achieved Hepatitis B e Antigen (HBeAg) Seroconversion at Follow-up Week 24 - Part A ^[1]

End point description

HBeAg seroconversion was defined as having a post-baseline negative serum HBeAg and simultaneous positive Hepatitis B e antibody (HBeAb) for subjects with positive serum HBeAg and negative HBeAb at screening. HBeAG levels were measured using commercially available qualitative HBeAg (qHBeAg) assays. The analysis was performed in all treated subjects using modified intent-to-treat algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure).

End point type

Primary

End point timeframe

Follow-up Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Percentage of subjects
number (confidence interval 80%)	7.7 (0 to 17.2)	13.8 (8.8 to 18.7)	30.1 (23.7 to 36.6)

HBeAG seroconversion rate

Comparison groups

Part A: Peginterferon Lambda 180 μg v Part A: Peginterferon alfa-2a 180 μg

Number of subjects included in analysis

163

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-0.1635

Confidence interval

level

80%

sides

2-sided

lower limit

-0.2425

upper limit

-0.0845

Notes
[2] - A 2-stage testing procedure was planned. In the first stage, non-inferiority of Lambda to alfa would be tested. Provided non-inferiority was met, superiority of Lambda to alfa would be tested. Non-inferiority of Lambda to alfa was not met because the lower bound of the 80% confidence limit was < -15%, the pre-specified non-inferiority margin. Thus, superiority was not tested."

Primary: Number of Subjects With Serious Adverse Events (SAEs) and Discontinuation Due to Adverse Events (AEs)

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End point title

Number of Subjects With Serious Adverse Events (SAEs) and Discontinuation Due to Adverse Events (AEs) ^[3]

End point description

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Analysis population included all treated subjects.

End point type

Primary

End point timeframe

Day 1 to end of treatment plus 10 days

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive summary statistics were planned for this outcome measure.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13	80	83	21
Units: Subjects
SAEs	3	7	5	0
Discontinuation due to AEs	3	6	8	0

No statistical analyses for this end point

Secondary: Percentage of Subjects With Hepatitis B Virus (HBV) DNA <50 IU/mL - Part A

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End point title

Percentage of Subjects With Hepatitis B Virus (HBV) DNA <50 IU/mL - Part A ^[4]

End point description

HBV DNA was measured by polymerase chain reaction (PCR) using the Roche COBAS TaqMan - High Pure System (HPS) assay with lower limit of quantification (LOQ) = 29 IU/mL and limit of detection (LOD) = 10 IU/mL. The analysis was performed in all treated subjects using modified intent-to-treat (ITT) algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure). Here, ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 72, 96, 120, 144, 168, and 192

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Percentage of subjects
number (confidence interval 80%)
Week 12	99999 (99999 to 99999)	5 (1.9 to 8.1)	0 (0 to 0)
Week 24	7.7 (0 to 17.2)	10 (5.7 to 14.3)	1.2 (0 to 2.7)
Week 48	0 (0 to 0)	13.8 (8.8 to 18.7)	10.8 (6.5 to 15.2)
Week 72	0 (0 to 0)	6.3 (2.8 to 9.7)	1.2 (0 to 2.7)
Week 96	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 120	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 144	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 168	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 192	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part A

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End point title

Mean Change From Baseline in Log10 HBV DNA levels - Part A ^[5]

End point description

HBV DNA was measured by PCR using the Roche COBAS TaqMan - HPS assay with LOQ = 29 IU/mL and LOD = 10 IU/mL. Values below LOQ were set to LOQ-1. HBV DNA levels were converted to the log10 scale. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 8, 12, 16, 24, 48, 72, 96, 120, 144, 168, 192

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	80	83
Units: IU/mL
arithmetic mean (standard error)
Week 2 (n=75, 78)	-0.93 ( 0.0883 )	-0.475 ( 0.0562 )
Week 4 (n=76, 81)	-1.515 ( 0.095 )	-0.876 ( 0.0864 )
Week 8 (n=30, 35)	-2.288 ( 0.261 )	-1.51 ( 0.2207 )
Week 12 (n=73, 75)	-2.602 ( 0.1808 )	-1.778 ( 0.1743 )
Week 16 (n=72, 74)	-2.692 ( 0.2109 )	-2.027 ( 0.1991 )
Week 24 (n=73, 72)	-2.782 ( 0.233 )	-2.276 ( 0.2124 )
Week 48 (n=69, 65)	-2.667 ( 3.402 )	-2.876 ( 3.469 )
Week 72 (n=55, 61)	-1.295 ( 3.856 )	-2.093 ( 4.173 )
Week 96 (n=24, 32)	-2.571 ( 0.5387 )	-2.412 ( 0.4353 )
Week 120 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 144 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 168 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 192 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Percentage of Subjects with Alanine Aminotransferase (ALT) Normalization - Part A

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End point title

Percentage of Subjects with Alanine Aminotransferase (ALT) Normalization - Part A ^[6]

End point description

ALT normalization was defined as having ALT values <=1*Upper Limit of Normal (ULN) in subjects who have values >ULN at screening. The analysis was performed in all treated subjects using modified ITT algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure). Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 24, 48, 72, 96, 120, 144, 168, and 192

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	80	83
Units: Percentage of subjects
number (confidence interval 80%)
Week 24 (n=80, 83)	23.8 (17.7 to 29.8)	33.7 (27.1 to 40.4)
Week 48 (n=80, 83)	32.5 (25.8 to 39.2)	32.5 (25.9 to 39.1)
Week 72 (n=80, 83)	43.8 (36.6 to 50.9)	51.8 (44.8 to 58.8)
Week 96 (n=0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 120 (n=0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 144 (n=0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 168 (n=0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 192 (n=0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HBeAg Loss - Part A

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End point title

Percentage of Subjects With HBeAg Loss - Part A ^[7]

End point description

HBeAg loss was defined as having negative post-baseline serum HBeAg for subjects with positive serum HBeAg at screening. HBeAG levels were measured using commercially available quantitative HBeAg (qHBeAg) assays. The analysis was performed in all treated subjects using modified ITT algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure). Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 72, 96, 120, 144, 168, and 192

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Percentage of subjects
number (confidence interval 80%)
Week 12 (n=13, 80, 83)	99999 (99999 to 99999)	7.5 (3.7 to 11.3)	7.2 (3.6 to 10.9)
Week 24 (n=13, 80, 83)	0 (0 to 0)	8.8 (4.7 to 12.8)	8.4 (4.5 to 12.3)
Week 48 (n=13, 80, 83)	7.7 (0 to 17.2)	18.8 (13.2 to 24.3)	18.1 (12.7 to 23.5)
Week 72 (n=13, 80, 83)	7.7 (0 to 17.2)	15 (9.9 to 20.1)	32.5 (25.9 to 39.1)
Week 96 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 120 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 144 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 168 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 192 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part A

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End point title

Percentage of Subjects With HBeAg Seroconversion - Part A ^[8]

End point description

HBeAG seroconversion was defined as having a post-baseline negative serum HBeAg and simultaneous positive HBeAb for subjects with positive serum HBeAg and negative HBeAb at screening. HBeAG levels were measured using commercially available quantitative HBeAg (qHBeAg) assays (ARCHITECT [Abbott]). The analysis was performed in all treated subjects using modified ITT algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure). Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 72, 96, 120, 144, 168, and 192

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Percentage of subjects
number (confidence interval 80%)
Week 12 (n=13, 80, 83)	99999 (99999 to 99999)	6.3 (2.8 to 9.7)	6 (2.7 to 9.4)
Week 24 (n=13, 80, 83)	0 (0 to 0)	6.3 (2.8 to 9.7)	8.4 (4.5 to 12.3)
Week 48 (n=13, 80, 83)	7.7 (0 to 17.2)	17.5 (12.1 to 22.9)	16.9 (11.6 to 22.1)
Week 72 (n=13, 80, 83)	7.7 (0 to 17.2)	13.8 (8.8 to 18.7)	30.1 (23.7 to 36.6)
Week 96 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 120 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 144 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 168 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Week 192 (n=0, 0, 0)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part A

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End point title

Mean Change From Baseline in Log10 Quantitative HBeAg - Part A ^[9]

End point description

HBeAG levels were measured using commercially available quantitative HBeAg (qHBeAg) assays (ARCHITECT [Abbott]). The dynamic range of the qHBeAg assay is 0.22-56.70 Paul Erhlich Institute (PEI) U/mL and the assay is currently validated to dilute samples with a concentration of up to 567 PEI U/mL. Values below the lower LOQ were set to lower LOQ/2. Values above the upper LOQ were set to upper LOQ+1. qHBeAg values were converted to the log 10 scale. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 48, 72, 96, 120, 144, 168, and 192

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	80	83
Units: IU/mL
arithmetic mean (standard error)
Week 12 (n=71, 74)	-0.954 ( 0.107 )	-0.719 ( 0.1114 )
Week 24 (n=71, 70)	-1.067 ( 0.1212 )	-0.965 ( 0.1301 )
Week 48 (n=68, 62)	-1.191 ( 2.239 )	-1.347 ( 1.974 )
Week 72 (n=51, 58)	-0.869 ( 0.2024 )	-1.496 ( 0.2013 )
Week 96 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 120 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 144 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 168 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )
Week 192 (n=0, 0)	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, AEs Leading to Dose Reduction, Grade 1 to 4 AEs, Grade 3 to 4 AEs, and Discontinuations Due to Treatment-Limiting Toxicity (TLT)-Treatment Period (Part A)

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End point title

Number of Subjects With SAEs, Discontinuations Due to AEs, AEs Leading to Dose Reduction, Grade 1 to 4 AEs, Grade 3 to 4 AEs, and Discontinuations Due to Treatment-Limiting Toxicity (TLT)-Treatment Period (Part A) ^[10]

End point description

End point type

Secondary

End point timeframe

Day 1 to end of treatment plus 10 days

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Subjects
SAEs	3	7	5
Discontinuations Due to AEs	3	6	8
AEs Leading to Dose Reduction	3	10	23
Grade 1 to 4 AEs	13	76	77
Grade 3 to 4 AEs	7	22	23
Discontinuations due to TLT	2	5	1

No statistical analyses for this end point

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part A

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End point title

Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part A ^[11]

End point description

Laboratory tests with Division of AIDS (DAIDS) Version 1.0 toxicity criteria were performed and assessed. Platelet count: <50,000/mm^3; Leukocytes: <1500/mm^3; Lymphocytes (Absolute):<500/mm^3; Neutrophils+band (Absolute): <750/mm^3; Alanine transaminase (ALT): >5*upper limit of normal (ULN); Aspartate aminotransferase (AST): >5*ULN; Bilirubin (Total): >2.5*ULN; Bilirubin (direct): >3*ULN; Lipase, total: >3*ULN. Subjects with any grade 3 or 4 laboratory abnormalities are summarised. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Day 1 to end of treatment plus 10 days

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13	80	83
Units: Subjects
Platelet count (n=13, 80, 82)	0	0	1
Leukocytes (n=13, 80, 82)	0	0	1
Lymphocytes (Absolute) (n=13, 80, 82)	0	1	1
Neutrophils + band (Absolute) (n=13, 80, 82)	0	2	17
ALT (n=13, 80, 82)	7	33	19
AST (n=13, 80, 82)	7	27	15
Bilirubin, total (n=13, 80, 82)	3	3	0
Bilurubin, direct (n=7, 20, 5)	3	4	0
Lipase, total (n=13, 80, 81)	0	0	1

No statistical analyses for this end point

Secondary: Maximum observed concentration (Cmax) - Part A

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End point title

Maximum observed concentration (Cmax) - Part A ^[12]

End point description

Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Day 1 and Day 85: pre-dose, 1, 2, 4, and 8 hours post-dose

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	4	4
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1 (n=4, 4)	1.48 ( 49.9 )	5.08 ( 68.9 )
Day 85 (n=3, 3)	2.38 ( 65.1 )	10.3 ( 26.2 )

No statistical analyses for this end point

Secondary: Time of maximum observed concentration (Tmax) - Part A

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End point title

Time of maximum observed concentration (Tmax) - Part A ^[13]

End point description

Tmax: Time to reach the maximum plasma concentration. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Day 1 and Day 85: pre-dose, 1, 2, 4, and 8 hours post-dose

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	4	4
Units: hour
median (full range (min-max))
Day 1 (n=4, 4)	8 (4.52 to 24)	96 (48 to 144)
Day 85 (n=3, 3)	24 (8 to 24)	72 (1.98 to 144)

No statistical analyses for this end point

Secondary: Minimal Observed Plasma Concentration (Cmin) - Part A

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End point title

Minimal Observed Plasma Concentration (Cmin) - Part A ^[14]

End point description

Cmin: Minimal observed serum/plasma concentration. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Day 85: pre-dose, 1, 2, 4, and 8 hours post-dose

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	4	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 85	0.243 ( 63 )	6.43 ( 65.8 )

No statistical analyses for this end point

Secondary: Area Under the Concentration Time Curve in one Dosing Interval [AUC(TAU)] - Part A

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End point title

Area Under the Concentration Time Curve in one Dosing Interval [AUC(TAU)] - Part A ^[15]

End point description

AUC(TAU): Area under the serum/plasma concentration-time curve during one dose interval. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms.

End point type

Secondary

End point timeframe

Day 1 and Day 85: pre-dose, 1, 2, 4, and 8 hours post-dose

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	4	4
Units: nanogramhour per mililitre (ngh/mL)
geometric mean (geometric coefficient of variation)
Day 1 (n=4, 4)	107 ( 38.5 )	99999 ( 99999 )
Day 85 (n=4, 3)	188 ( 72.8 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Accumulation Index (AI): Ratio of AUC(TAU) at Steady-State to AUC(TAU) - Part A

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End point title

Accumulation Index (AI): Ratio of AUC(TAU) at Steady-State to AUC(TAU) - Part A ^[16]

End point description

AI: ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Day 1 and Day 85: pre-dose, 1, 2, 4, and 8 hours post-dose

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	4	4
Units: Ratio
geometric mean (geometric coefficient of variation)
Day 85	1.52 ( 67.6 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Percentage of Subjects Who Achieved HBeAg Seroconversion at Follow-up Week 24 – Part B

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End point title

Percentage of Subjects Who Achieved HBeAg Seroconversion at Follow-up Week 24 – Part B ^[17]

End point description

End point type

Secondary

End point timeframe

Follow-up Week 24

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Percentage of subjects
number (confidence interval 95%)	0 (0 to 0)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HBV DNA <50 IU/mL - Part B

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End point title

Percentage of Subjects With HBV DNA <50 IU/mL - Part B ^[18]

End point description

HBV DNA was measured by PCR using the Roche COBAS TaqMan - HPS assay with LOQ = 29 IU/mL and LOD = 10 IU/mL. The analysis was performed in all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 36, 60, and 84

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Percentage of subjects
number (confidence interval 95%)
Week 4 (n=13)	0 (0 to 0)
Week 8 (n=13)	0 (0 to 0)
Week 12 (n=12)	0 (0 to 0)
Week 24 (n=8)	37.5 (8.5 to 75.5)
Week 36 (n=5)	60 (14.7 to 94.7)
Week 60 (n=0)	99999 (99999 to 99999)
Week 84 (n=0)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part B

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End point title

Mean Change From Baseline in Log10 HBV DNA levels - Part B ^[19]

End point description

End point type

Secondary

End point timeframe

Baseline and at Weeks 4, 8, 12, 24, 36, 60, 84

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	0 ^[20]
Units: Log 10 IU/mL
arithmetic mean (standard deviation)	( )

Notes
[20] - This endpoint was planned but not analyzed due to early study termination

No statistical analyses for this end point

Secondary: Percentage of Subjects with ALT Normalization – Part B

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End point title

Percentage of Subjects with ALT Normalization – Part B ^[21]

End point description

ALT normalization was defined as having ALT values <=1*ULN for subjects who have values >ULN at screening. Values below LOQ were set to LOQ-1. The analysis was performed in all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 24, 36, 60, 84

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Percentage of subjects
number (confidence interval 95%)
Week 4 (n=13)	7.7 (0.2 to 36)
Week 8 (n=13)	23.1 (5 to 53.8)
Week 12 (n=13)	38.5 (13.9 to 68.4)
Week 24 (n=9)	33.3 (7.5 to 70.1)
Week 36 (n=5)	60 (14.7 to 94.7)
Week 60 (n=0)	99999 (99999 to 99999)
Week 84 (n=0)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HBeAg Loss - Part B

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End point title

Percentage of Subjects With HBeAg Loss - Part B ^[22]

End point description

HBeAg loss was defined as having negative post-baseline serum HBeAg for subjects with positive serum HBeAg at screening. Values below LOQ were set to LOQ-1. HBeAG levels were measured using commercially available quantitative HBeAg (qHBeAg) assays (ARCHITECT [Abbott]). The analysis was performed in all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 36, 60, and 84

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Percentage of subjects
number (confidence interval 95%)
Week 12 (n=13)	0 (0 to 0)
Week 24 (n=8)	0 (0 to 0)
Week 36 (n=5)	0 (0 to 0)
Week 60 (n=0)	99999 (99999 to 99999)
Week 84 (n=0)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part B

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End point title

Percentage of Subjects With HBeAg Seroconversion - Part B ^[23]

End point description

HBeAG seroconversion was defined as having a post-baseline negative serum HBeAg and simultaneous positive HBeAb for subjects with positive serum HBeAg and negative HBeAb at screening. The analysis was performed in all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 36, 60, and 84

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Percentage of subjects
number (confidence interval 95%)
Week 12 (n=13)	0 (0 to 0)
Week 24 (n=8)	0 (0 to 0)
Week 36 (n=5)	0 (0 to 0)
Week 60 (n=0)	99999 (99999 to 99999)
Week 84 (n=0)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part B

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End point title

Mean Change From Baseline in Log10 Quantitative HBeAg - Part B ^[24]

End point description

HBeAG levels were measured using commercially available quantitative HBeAg (qHBeAg) assays (ARCHITECT [Abbott]). The dynamic range of the qHBeAg assay is 0.22-56.70 PEI U/mL and the assay is currently validated to dilute samples with a concentration of up to 567 PEI U/mL. Values below the lower LOQ were set to lower LOQ/2. Values above the upper LOQ were set to upper LOQ+1. qHBeAg values were converted to the log 10 scale. Analysis population included all treated subjects. Here, 'n' signifies evaluable subjects for specified categories in respective treatment arms and ‘99999’ represents not estimable data for specified categories in respective arms.

End point type

Secondary

End point timeframe

Weeks 12, 24, 36, 60, and 84

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Log 10 IU/mL
arithmetic mean (standard deviation)
Week 12 (n=13)	-0.0465 ( 0.47483 )
Week 24 (n=8)	-0.8293 ( 0.87189 )
Week 36 (n=4)	-0.87 ( 1.16781 )
Week 60 (n=0)	99999 ( 99999 )
Week 84 (n=0)	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part B

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End point title

Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part B ^[25]

End point description

Laboratory tests with DAIDS Version 1.0 toxicity criteria were performed and assessed. ALT: >5*ULN; AST: >5*ULN. Analysis population included all treated subjects.

End point type

Secondary

End point timeframe

Day 1 to end of treatment plus 10 days

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Subjects
ALT	3
AST	3

No statistical analyses for this end point

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, Grade 1 to 4 AEs, Grade 3 to 4 AEs and who Died - Part B

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End point title

Number of Subjects With SAEs, Discontinuations Due to AEs, Grade 1 to 4 AEs, Grade 3 to 4 AEs and who Died - Part B ^[26]

End point description

End point type

Secondary

End point timeframe

Day 1 to end of treatment plus 10 days

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part B: Peginterferon Lambda + Entecavir
Number of subjects analysed	13
Units: Subjects
SAEs	0
Discontinuations due to AEs	0
Grade 1 to 4 AEs	8
Grade 3 to 4 AEs	1
Deaths	0

No statistical analyses for this end point

Secondary: Number of Subjects with SAEs - Follow-up Period (Part A)

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End point title

Number of Subjects with SAEs - Follow-up Period (Part A)

End point description

SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

End point type

Secondary

End point timeframe

From start of study treatment to 24-week post-dosing follow-up visit (up to Week 72)

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	12	78	78
Units: subjects	1	7	1

No statistical analyses for this end point

Secondary: Number of subjects experiencing anti-drug antibody (ADA) seroconversion or boosted ADA response on treatment

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End point title

Number of subjects experiencing anti-drug antibody (ADA) seroconversion or boosted ADA response on treatment ^[27]

End point description

Subjects were assessed for the presence of anti-drug (interferon) antibodies at baseline and during the course of study therapy. Subjects who had detectable antibodies at baseline were assessed for change (increase or boosting) of antibody titer during treatment.

End point type

Secondary

End point timeframe

Day 1 to Week 24 Follow-up visit

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was planned to evaluate only the specified arms.

End point values	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg
Number of subjects analysed	13 ^[28]	80 ^[29]	83 ^[30]
Units: subjects
Subjects who seroconverted	6	45	27
Subjects with a boosted response	1	2	0

Notes
[28] - Subjects with anti-drug antibodies tested at baseline
[29] - Subjects with anti-drug antibodies tested at baseline
[30] - Subjects with anti-drug antibodies tested at baseline

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 through the end of treatment plus 10 days

Adverse event reporting additional description

On-treatment period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Part A: Peginterferon Lambda 240 μg

Reporting group description

Subjects received Peginterferon Lambda 240 μg, subcutaneous, once weekly for 48 weeks.

Reporting group title

Part A: Peginterferon Lambda 180 μg

Reporting group description

Subjects received Peginterferon Lambda 180 μg, subcutaneous, once weekly for 48 weeks.

Reporting group title

Part A: Peginterferon alfa-2a 180 μg

Reporting group description

Subjects received Peginterferon alfa-2a 180 μg, subcutaneous, once weekly for 48 weeks.

Reporting group title

Part B: Peginterferon Lambda + Entecavir

Reporting group description

Subjects with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B virus (HBV) infection received Entecavir 0.5 mg, tablets, orally, once daily for 12 weeks; Peginterferon Lambda 180 µg, subcutaneous, once weekly along with Entecavir 0.5 mg, tablets, orally, once daily for 48 weeks.

Reporting group title

Part B: Entecavir

Reporting group description

Subjects with hepatitis E antigen-positive (HBeAg-positive) chronic hepatitis B virus (HBV) infection received Entecavir 0.5 mg, tablets, orally, once daily for up to 12 weeks.

Serious adverse events	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir	Part B: Entecavir
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 13 (23.08%)	7 / 80 (8.75%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 13 (7.69%)	2 / 80 (2.50%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Coronary artery stenosis
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastric ulcer
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal hypertension
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part A: Peginterferon Lambda 240 μg	Part A: Peginterferon Lambda 180 μg	Part A: Peginterferon alfa-2a 180 μg	Part B: Peginterferon Lambda + Entecavir	Part B: Entecavir
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 13 (100.00%)	72 / 80 (90.00%)	74 / 83 (89.16%)	8 / 13 (61.54%)	2 / 8 (25.00%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 13 (7.69%)	2 / 80 (2.50%)	2 / 83 (2.41%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	3	2	0	0
Chills
subjects affected / exposed	0 / 13 (0.00%)	2 / 80 (2.50%)	8 / 83 (9.64%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	9	0	0
Fatigue
subjects affected / exposed	4 / 13 (30.77%)	26 / 80 (32.50%)	24 / 83 (28.92%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	4	30	26	0	0
Influenza like illness
subjects affected / exposed	1 / 13 (7.69%)	4 / 80 (5.00%)	8 / 83 (9.64%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	7	11	0	0
Injection site erythema
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	7 / 83 (8.43%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	7	0	0
Injection site pruritus
subjects affected / exposed	1 / 13 (7.69%)	3 / 80 (3.75%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	3	0	0	0
Injection site rash
subjects affected / exposed	2 / 13 (15.38%)	7 / 80 (8.75%)	2 / 83 (2.41%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	7	2	0	0
Injection site reaction
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	5	0	0
Injection site swelling
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	0 / 83 (0.00%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Irritability
subjects affected / exposed	2 / 13 (15.38%)	0 / 80 (0.00%)	3 / 83 (3.61%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	3	0	0
Malaise
subjects affected / exposed	0 / 13 (0.00%)	10 / 80 (12.50%)	3 / 83 (3.61%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	17	9	0	0
Pyrexia
subjects affected / exposed	2 / 13 (15.38%)	8 / 80 (10.00%)	37 / 83 (44.58%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	4	21	49	0	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 13 (0.00%)	6 / 80 (7.50%)	8 / 83 (9.64%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	9	13	0	0
Dyspnoea
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	5	0	0
Oropharyngeal pain
subjects affected / exposed	2 / 13 (15.38%)	5 / 80 (6.25%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	5	6	0	0
Rhinitis allergic
subjects affected / exposed	2 / 13 (15.38%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	1	0	0
Throat tightness
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Wheezing
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 13 (7.69%)	3 / 80 (3.75%)	3 / 83 (3.61%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	3	4	0	0
Insomnia
subjects affected / exposed	1 / 13 (7.69%)	8 / 80 (10.00%)	10 / 83 (12.05%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	9	10	0	0
Sleep disorder
subjects affected / exposed	0 / 13 (0.00%)	2 / 80 (2.50%)	2 / 83 (2.41%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	2	2	1	0
Somnambulism
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 13 (30.77%)	14 / 80 (17.50%)	8 / 83 (9.64%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	6	21	8	0	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 13 (15.38%)	7 / 80 (8.75%)	6 / 83 (7.23%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	3	8	6	0	0
Blood bilirubin increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0
Blood glucose increased
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Hepatic enzyme increased
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	9 / 83 (10.84%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	11	0	0
Transaminases increased
subjects affected / exposed	1 / 13 (7.69%)	3 / 80 (3.75%)	2 / 83 (2.41%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	2	4	3	1	0
Injury, poisoning and procedural complications
Limb crushing injury
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Cardiac disorders
Gastrocardiac syndrome
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Palpitations
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	2 / 83 (2.41%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	2	0	0
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	2 / 83 (2.41%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	0	3	1	0
Dizziness
subjects affected / exposed	0 / 13 (0.00%)	5 / 80 (6.25%)	13 / 83 (15.66%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	6	23	1	0
Headache
subjects affected / exposed	4 / 13 (30.77%)	11 / 80 (13.75%)	24 / 83 (28.92%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	5	21	50	1	0
Lethargy
subjects affected / exposed	1 / 13 (7.69%)	2 / 80 (2.50%)	2 / 83 (2.41%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	2	3	0	0
Myoclonus
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Somnolence
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	7 / 83 (8.43%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	8	0	0
Lymphadenopathy
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	20 / 83 (24.10%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	25	0	0
Thrombocytopenia
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	6	0	0
Eye disorders
Blindness transient
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Eye pain
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0
Visual acuity reduced
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0
Gastrointestinal disorders
Dry mouth
subjects affected / exposed	0 / 13 (0.00%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1
Abdominal discomfort
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0
Abdominal distension
subjects affected / exposed	2 / 13 (15.38%)	4 / 80 (5.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	3	4	1	0	0
Abdominal pain
subjects affected / exposed	1 / 13 (7.69%)	4 / 80 (5.00%)	4 / 83 (4.82%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	4	4	0	0
Abdominal pain upper
subjects affected / exposed	1 / 13 (7.69%)	8 / 80 (10.00%)	7 / 83 (8.43%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	12	10	0	0
Constipation
subjects affected / exposed	0 / 13 (0.00%)	4 / 80 (5.00%)	4 / 83 (4.82%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	4	4	0	0
Diarrhoea
subjects affected / exposed	2 / 13 (15.38%)	5 / 80 (6.25%)	8 / 83 (9.64%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	2	5	20	1	0
Flatulence
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Gingival polyp
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	0 / 83 (0.00%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Mouth ulceration
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	8 / 83 (9.64%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	9	0	0
Nausea
subjects affected / exposed	3 / 13 (23.08%)	12 / 80 (15.00%)	7 / 83 (8.43%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	8	14	11	1	0
Vomiting
subjects affected / exposed	0 / 13 (0.00%)	7 / 80 (8.75%)	4 / 83 (4.82%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	9	5	0	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 13 (0.00%)	9 / 80 (11.25%)	25 / 83 (30.12%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	9	27	0	0
Dry skin
subjects affected / exposed	1 / 13 (7.69%)	3 / 80 (3.75%)	2 / 83 (2.41%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	3	2	0	0
Eczema
subjects affected / exposed	0 / 13 (0.00%)	0 / 80 (0.00%)	4 / 83 (4.82%)	2 / 13 (15.38%)	0 / 8 (0.00%)
occurrences all number	0	0	4	2	0
Night sweats
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	2	0	0
Pruritus
subjects affected / exposed	0 / 13 (0.00%)	7 / 80 (8.75%)	13 / 83 (15.66%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	12	14	0	0
Rash
subjects affected / exposed	0 / 13 (0.00%)	4 / 80 (5.00%)	12 / 83 (14.46%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	4	13	0	0
Skin reaction
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 13 (15.38%)	0 / 80 (0.00%)	10 / 83 (12.05%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	2	0	12	1	0
Back pain
subjects affected / exposed	0 / 13 (0.00%)	5 / 80 (6.25%)	4 / 83 (4.82%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	0	6	7	1	0
Musculoskeletal pain
subjects affected / exposed	1 / 13 (7.69%)	2 / 80 (2.50%)	1 / 83 (1.20%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	2	1	0	0
Myalgia
subjects affected / exposed	2 / 13 (15.38%)	3 / 80 (3.75%)	18 / 83 (21.69%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	3	23	0	0
Tenosynovitis
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	1 / 83 (1.20%)	1 / 13 (7.69%)	0 / 8 (0.00%)
occurrences all number	1	0	1	1	0
Influenza
subjects affected / exposed	0 / 13 (0.00%)	5 / 80 (6.25%)	5 / 83 (6.02%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	14	6	0	0
Nasopharyngitis
subjects affected / exposed	0 / 13 (0.00%)	4 / 80 (5.00%)	2 / 83 (2.41%)	2 / 13 (15.38%)	0 / 8 (0.00%)
occurrences all number	0	7	4	2	0
Periodontitis
subjects affected / exposed	1 / 13 (7.69%)	1 / 80 (1.25%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 13 (7.69%)	4 / 80 (5.00%)	6 / 83 (7.23%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	8	12	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 13 (23.08%)	3 / 80 (3.75%)	9 / 83 (10.84%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	3	4	10	0	0
Hypophagia
subjects affected / exposed	1 / 13 (7.69%)	0 / 80 (0.00%)	0 / 83 (0.00%)	0 / 13 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

15 Feb 2011

The purpose of this amendment was to: • Add clarification on all subjects who discontinue from study therapy early to receive 24 week follow-up, • Update Overall Risk/Benefit Assessment which outlines significant level hyperbilirubinemia as a potential safety signal for pegIFN λ,

18 Apr 2011

• Dropped the 240 μg arm and modified hypothesis and study design to eliminate dose ranging, and changed the number of subjects from 180 to 170, • Changed study rationale to reflect outcome from the Week 12 interim analysis of the 2b phase of the ongoing study AI452-004 (EMERGE), • Added sections to describe the AI452-004 (EMERGE) study, and the safety and efficacy of the 240 μg vs 180 μg doses, • Made changes in regards to safety and management of lab abnormalities, • Changed design to reflect a 1:1 arm randomisation instead of 1:1:1, and dropped the 240 μg arm,

23 May 2011

• Added language pertaining to the ALT inclusion criteria for study, • Addition of Netherlands as a participating country, • Inserted additional risks associated with IFN α, • Inserted language pertaining to ALT flares for patients with chronic HBV infection, • Updated ALT criteria to >47 U/L to <10*ULN, • Added contraception be used for 24 weeks during post dosing for women of childbearing potential (WOCBP), • Changed weekly pregnancy testing to “at least monthly” to be consistent with requirements for pegIFN monotherapy, • Modified to exclude subjects only with severe psychiatric disease and allow subjects with either mild or moderate depression , • Replaced serum albumin <LLN with <=3.5 g/dl, • Removed fibrinogen as an eligibility criterion; maintained as an on study laboratory assessment, • Changed prior investigational product usage from 60 to 30 days prior to randomisation, • Changed prior hematologic growth factors use from 60 to 30 days prior to randomisation, • Language modified in selection and timing of dose of each subject and to specify the criteria for treatment interruption, dose reduction and discontinuation due to hepatobiliary events; in addition guidelines were provided on laboratory monitoring, • Added a Week 8 HBV DNA assessment, • Updated the dual lab testing at local and central lab to occur only at Weeks 1, 2, 3, 4, and 8, • Provided criteria for the definition and reporting of potential drug-induced liver injury (DILI).

06 Sep 2011

• Added FibroTest assessment at screening as an option to determine baseline liver status when historical liver biopsy data is not available, • Edited ALT/AST criteria requiring immediate discontinuation, • Included immediate discontinuation criteria (if Creatinine Clearance is < 50 mL/min), • Added FibroTest as means of evaluating for presence/absence of cirrhosis, • Edited screening period for this study from 28 days to 28 days (± 3 days) and subsequent dosing of randomised subjects within 28 days (± 3 days) of the day they are screened.

05 Apr 2012

• Added a potential of five additional long term follow-up visits to the post dosing follow-up, • Added criteria for which subjects would be eligible for long term follow-up, • Edited the Study Schema, • Added criteria when the medical monitor should be contacted for dose modifications due to adverse events and laboratory abnormalities, • Clarified in the short term procedures that serum samples should be provided for interferon antibody and pharmacokinetic trough samples, • Added weeks 96, 120, 144, 168, and 192 to the long term procedures table, • Updated adverse event reporting to include up to Week 192 post dosing.

08 Jan 2013

• Clarified post dosing follow-up requirements for subjects and site staff.

24 May 2013

• Removed incorrect Branding name for study (removed incorrect study name and inserted correct, LIRA-B), • Clarified Clinical Outcomes reporting.

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.

The study treatment failed to meet the pre-specified non-inferiority criteria for the primary endpoint and several key secondary efficacy endpoints. Hence, the sponsor decided to terminate the ongoing long-term follow-up phase and Part B sub-study.

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Clinical trials

Clinical Trial Results: LIRA-B - Dose-Ranging Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Pegylated Interferon Lambda (BMS-914143) Monotherapy in Interferon-Naive Patients with Chronic Hepatitis B Virus Infection who are HBeAg-positive.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects Who Achieved Hepatitis B e Antigen (HBeAg) Seroconversion at Follow-up Week 24 - Part A

Primary: Percentage of Subjects Who Achieved Hepatitis B e Antigen (HBeAg) Seroconversion at Follow-up Week 24 - Part A

Primary: Number of Subjects With Serious Adverse Events (SAEs) and Discontinuation Due to Adverse Events (AEs)

Primary: Number of Subjects With Serious Adverse Events (SAEs) and Discontinuation Due to Adverse Events (AEs)

Secondary: Percentage of Subjects With Hepatitis B Virus (HBV) DNA <50 IU/mL - Part A

Secondary: Percentage of Subjects With Hepatitis B Virus (HBV) DNA <50 IU/mL - Part A

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part A

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part A

Secondary: Percentage of Subjects with Alanine Aminotransferase (ALT) Normalization - Part A

Secondary: Percentage of Subjects with Alanine Aminotransferase (ALT) Normalization - Part A

Secondary: Percentage of Subjects With HBeAg Loss - Part A

Secondary: Percentage of Subjects With HBeAg Loss - Part A

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part A

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part A

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part A

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part A

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, AEs Leading to Dose Reduction, Grade 1 to 4 AEs, Grade 3 to 4 AEs, and Discontinuations Due to Treatment-Limiting Toxicity (TLT)-Treatment Period (Part A)

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, AEs Leading to Dose Reduction, Grade 1 to 4 AEs, Grade 3 to 4 AEs, and Discontinuations Due to Treatment-Limiting Toxicity (TLT)-Treatment Period (Part A)

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part A

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part A

Secondary: Maximum observed concentration (Cmax) - Part A

Secondary: Maximum observed concentration (Cmax) - Part A

Secondary: Time of maximum observed concentration (Tmax) - Part A

Secondary: Time of maximum observed concentration (Tmax) - Part A

Secondary: Minimal Observed Plasma Concentration (Cmin) - Part A

Secondary: Minimal Observed Plasma Concentration (Cmin) - Part A

Secondary: Area Under the Concentration Time Curve in one Dosing Interval [AUC(TAU)] - Part A

Secondary: Area Under the Concentration Time Curve in one Dosing Interval [AUC(TAU)] - Part A

Secondary: Accumulation Index (AI): Ratio of AUC(TAU) at Steady-State to AUC(TAU) - Part A

Secondary: Accumulation Index (AI): Ratio of AUC(TAU) at Steady-State to AUC(TAU) - Part A

Secondary: Percentage of Subjects Who Achieved HBeAg Seroconversion at Follow-up Week 24 – Part B

Secondary: Percentage of Subjects Who Achieved HBeAg Seroconversion at Follow-up Week 24 – Part B

Secondary: Percentage of Subjects With HBV DNA <50 IU/mL - Part B

Secondary: Percentage of Subjects With HBV DNA <50 IU/mL - Part B

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part B

Secondary: Mean Change From Baseline in Log10 HBV DNA levels - Part B

Secondary: Percentage of Subjects with ALT Normalization – Part B

Secondary: Percentage of Subjects with ALT Normalization – Part B

Secondary: Percentage of Subjects With HBeAg Loss - Part B

Secondary: Percentage of Subjects With HBeAg Loss - Part B

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part B

Secondary: Percentage of Subjects With HBeAg Seroconversion - Part B

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part B

Secondary: Mean Change From Baseline in Log10 Quantitative HBeAg - Part B

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part B

Secondary: Number of Subjects With Grade 3 or 4 On-Treatment Emergent Laboratory Abnormalities - Part B

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, Grade 1 to 4 AEs, Grade 3 to 4 AEs and who Died - Part B

Secondary: Number of Subjects With SAEs, Discontinuations Due to AEs, Grade 1 to 4 AEs, Grade 3 to 4 AEs and who Died - Part B

Secondary: Number of Subjects with SAEs - Follow-up Period (Part A)

Secondary: Number of Subjects with SAEs - Follow-up Period (Part A)

Secondary: Number of subjects experiencing anti-drug antibody (ADA) seroconversion or boosted ADA response on treatment

Secondary: Number of subjects experiencing anti-drug antibody (ADA) seroconversion or boosted ADA response on treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
LIRA-B - Dose-Ranging Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Pegylated Interferon Lambda (BMS-914143) Monotherapy in Interferon-Naive Patients with Chronic Hepatitis B Virus Infection who are HBeAg-positive.