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Clinical Trial Results:
A prospective, randomised, open-label phase IIb clinical trial assessing the effect of pegylated Interferon alfa-2a (Pegasys®) 180 µg once weekly for 48 weeks in addition to an ongoing nucelos(t)ide based treatment on quantitative HBsAg levels in patients with chronic HBeAg-negative hepatitis B

Summary
EudraCT number	2011-002812-10
Trial protocol	DE
Global end of trial date	29 Mar 2018

Results information
Results version number	v1(current)
This version publication date	25 Apr 2022
First version publication date	25 Apr 2022
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

PADD-ON

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University Medical Center of the Johannes Gutenberg-University Mainz

Sponsor organisation address

Langenbeckstraße 1, Mainz, Germany, 55131

Public contact

Peter Galle, University Medical Center of the Johannes Gutenberg University Mainz, 0049 06131177275, peter.galle@unimedizin-mainz.de

Scientific contact

Peter Galle, University Medical Center of the Johannes Gutenberg University Mainz, 0049 06131177275, peter.galle@unimedizin-mainz.de

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

29 Mar 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Mar 2018

Global end of trial reached?

Yes

Global end of trial date

29 Mar 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the trial is to investigate whether the add-on of pegylated interferon alfa-2a to a continued treatment with nucleos(t)ide analogues increases the percentage of patients who have significant decrease (≥1log10) of HBs-antigen after 48 weeks.

Protection of trial subjects

All patients were insured according to §40 AMG requirements. Assessment of safety and tolerability by documentation of adverse events and serious adverse events. The study fulfills all ethical standards according to the independent ethics committee (IEC), such as GCP, Federal Data Protection Law and the Declaration of Helsinki (DoH). To evaluate safety and tolerability of pegylated interferon alfa-2a when combined with tenofovir, entecavir, lamivudine, adefovir, or a combination of lamivudine or entecavir with adefovir or tenofovir the following data was collected: adverse events, vital signs, physical examination, laboratory test abnormalities, laboratory test value changes over time.

Background therapy

Treatment with nucleos(t)ides.

Evidence for comparator

Treatment with nucleos(t)ide analogues partly restores HBV directed immune responses and reduces HBsAg levels during long-term administration, with the newer drugs being more potent. Therefore the nucleos(t)ides analogues lamivudine, adefovir, entecavir, tenofovir or a combination thereof were chosen as active comparator. Due to the increased neurotoxicity of pegylated interferon alfa-2a when combined with telbivudine in a previous study, use of telbivudine was not allowed. Recent data further support that interferon treatment is even more effective in preventing HBV associated complications than high potent nucleos(t)ide analogues. This included a better prevention of cirrhosis and hepatocellular carcinoma following interferon treatment compared to an ongoing entecavir therapy. We may speculate that interferon induces a sustaining immunological surveillance of HBV infection, which positively affects long-term prognosis. Other studies have investigated an add-on interferon approach in the setting of HBeAg positive hepatitis B and provide additional evidence for this novel approach. However, stopping stable nucleos(t)ide therapy has emerged as simple and safe alternative to promote HBsAg clearance by an endogenous inflammatory flare during therapy discontinuation.

Actual start date of recruitment

03 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 201

Worldwide total number of subjects

201

EEA total number of subjects

201

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)

199

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment and treatment of subjects were performed in 24 trial sites in Germany. Originally it was planned to replace patients who dropped out of the study before receiving any trial treatment, but further recruitment was not possible. Therefore not all randomized 170 patients could be included in the mITT population and the primary analysis.

Screening details

There was an individual screening period of approximately 4 weeks. After randomisation, the treatment period took 48 weeks. Follow-up continued for another 24 weeks (72 weeks in total).

Number of subjects started

201

Number of subjects completed

170

Reason: Number of subjects

Meeting any eclusion criterion: 15

Reason: Number of subjects

Violation of inclusion criteria: 16

Period 1 title

Treatment

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Intervention Group (Pegasys®)

Arm description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Arm type

Experimental

Investigational medicinal product name

pegylated interferon alfa-2a

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

In this trial the dosage and duration of Pegasys® is 180 micrograms once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh which is consistent with the recommended dosage and duration for both HBeAg-positive and –negative chronic hepatitis B. Temporary interruptions of study drug(s) administration are discouraged; patients are to remain on treatment for the entire duration of the trial; and the dose of peg-IFN should not be changed during the trial, unless dose reduction is indicated because of laboratory abnormalities/adverse events (c.f. Section 4.1.8 for instructions for dose reduction). The patients must be counselled regarding the importance of not missing doses of peg-IFN.

Control Group

Arm description

Group receiving the standard nucleos(t)ide treatment without the add-on drug [pegylated Interferon alfa-2a (Pegasys®)].

Arm type

Active comparator

Investigational medicinal product name

nucleos(t)ides

Investigational medicinal product code

Other name

amivudine, adefovir, entecavir, tenofovir or one of the following combinations: lamivudine/adefovir, lamivudine/tenofovir, entecavir/adefovir or entecavir/tenof

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dose and administration according to individual summary of product characteristics.

Number of subjects in period 1 ^[1]	Intervention Group (Pegasys®)	Control Group
Started	112	58
Completed	89	49
Not completed	23	9
Consent withdrawn by subject	4	4
Other(unknown)	6	1
Adverse event, non-fatal	9	-
Other (Unallowed concomitant medication indicated)	1	-
Lost to follow-up	1	4
Other(significant change of medical condition))	2	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline values were collected before randomization after a screening procedure.

Period 2 title

Follow Up

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Intervention Group (Pegasys®)

Arm description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Arm type

Experimental

Investigational medicinal product name

pegylated interferon alfa-2a

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 2 ^[2]	Intervention Group (Pegasys®)
Started	112
Completed	103
Not completed	9
Administrative/regulatory reasons	2
Consent withdrawn by subject	1
Adverse event, non-fatal	5
other reasons (unspecified)	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: The numbers from the safety population were used for reporting.

Baseline characteristics

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Reporting group title

Intervention Group (Pegasys®)

Reporting group description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Reporting group title

Control Group

Reporting group description

Group receiving the standard nucleos(t)ide treatment without the add-on drug [pegylated Interferon alfa-2a (Pegasys®)].

Reporting group values	Intervention Group (Pegasys®)	Control Group	Total
Number of subjects	112	58	170
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	43.8 ± 9.6	45.1 ± 9.7	-
Gender categorical
Units: Subjects
Female	26	16	42
Male	86	42	128
Ethnicity
Units: Subjects
European	85	39	124
Asian	15	6	21
African	7	6	13
Others	3	4	7
Missing	2	3	5
HBV DNA quant. negative ?
Units: Subjects
Yes	109	54	163
No	1	1	2
Missing	2	3	5
Anti-HBs
Units: Subjects
Positive	7	2	9
Negative	103	53	156
Missings	2	3	5
HBeAg
Units: Subjects
Negative	110	55	165
Missing	2	3	5
Anti-HBe
Units: Subjects
Positive	96	45	141
Negative	11	10	21
Missing	5	3	8
Anti-HBc
Units: Subjects
Positive	94	48	142
Negative	15	7	22
Missing	3	3	6
HCV
Units: Subjects
Negative	110	55	165
Missing	2	3	5
HDV
Units: Subjects
Negative	110	55	165
Missings	2	3	5
HIV
Units: Subjects
Negative	109	55	164
Missing	3	3	6
Is the HBV Genotype known?
Units: Subjects
Yes	22	12	34
No	88	43	131
Missing	2	3	5
HBV Genotype
Units: Subjects
Genotype A	2	1	3
Genotype C	1	0	1
Genotype D	16	11	27
Genotype E	1	0	1
Wildtyp	1	0	1
Missing	91	46	137
HBs antigen concentration
Units: IU/ ml
arithmetic mean (standard deviation)	6547.5 ± 10326.2	8434.9 ± 12660.1	-
ALT
(liver function)
Units: U/ l
arithmetic mean (standard deviation)	32.4 ± 15.7	34.8 ± 19.2	-
AST (GOT)
Units: U/ l
arithmetic mean (standard deviation)	26.6 ± 8.7	28.2 ± 12.3	-
Alkaline phosphatase
Units: U/ l
arithmetic mean (standard deviation)	65.6 ± 18.3	70.7 ± 20.2	-
GGT
Units: U/l
arithmetic mean (standard deviation)	26.7 ± 20.7	30.3 ± 22.1	-
Elastography
Fibroscan
Units: kPa
arithmetic mean (standard deviation)	6.5 ± 8.3	6.9 ± 9.2	-
Total bilirubin
Units: mg/ dl
arithmetic mean (standard deviation)	0.6 ± 0.5	0.6 ± 0.3	-
Thrombocytes
Units: /nl
arithmetic mean (standard deviation)	213.8 ± 56.2	223.1 ± 51.1	-
Albumin
Units: g/dl
arithmetic mean (standard deviation)	4.3 ± 0.6	4.4 ± 0.4	-
PT (quick)
clinical chemistry
Units: percent
arithmetic mean (standard deviation)	96.5 ± 12.5	101.2 ± 12.1	-

End points

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Reporting group title

Intervention Group (Pegasys®)

Reporting group description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Reporting group title

Control Group

Reporting group description

Group receiving the standard nucleos(t)ide treatment without the add-on drug [pegylated Interferon alfa-2a (Pegasys®)].

Reporting group title

Intervention Group (Pegasys®)

Reporting group description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Primary: Objective response after 48 weeks

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End point title

Objective response after 48 weeks

End point description

The primary endpoint was the objective response after 48 weeks of combination therapy. The response is defined as a confirmed reduction of ≥ 1 log10 in HBsAg compared to baseline. Missing values of the primary variable were carried forward in the main Analysis and the first sensitivity analysis. In the second sensitivity analysis drop-outs before week 48 were considered as non-responders, includingpatients with missing baseline values.

End point type

Primary

End point timeframe

The primary endpoint was the objective response after 48 weeks of combination therapy. Objective response is defined as confirmed reduction of ≥ 1 log10 in HBsAg compared to baseline.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: Yes, No, Missing
confirmed reduction of ≥ 1 log10 in HBsAg	26	1
no reduction	80	53
missing	4	1

Response of HBs Antigen after 48 weeks

Comparison groups

Intervention Group (Pegasys®) v Control Group

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Fisher exact

Confidence interval

Secondary: Decline of HBs antigen at week 12 (mITT)

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End point title

Decline of HBs antigen at week 12 (mITT)

End point description

Differences between screening after 12 weeks compared to baseline. Modified Intention-to-treat (mITT) population was investigated.

End point type

Secondary

End point timeframe

12 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110 ^[1]	55 ^[2]
Units: IU/ml
geometric mean (confidence interval 95%)	0.7058 (0.5803 to 0.8585)	0.9380 (0.7154 to 1.2297)

Notes
[1] - modified Intention-to-treat (mITT) population.
[2] - modified Intention-to-treat (mITT) population.

No statistical analyses for this end point

Secondary: Decline of HBs antigen at week 24 (mITT)

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End point title

Decline of HBs antigen at week 24 (mITT)

End point description

Differences between screening after 24 weeks compared to baseline. Modified Intention-to-treat (mITT) population was investigated.

End point type

Secondary

End point timeframe

24 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: IU/ml
geometric mean (confidence interval 95%)	0.3694 (0.2872 to 0.4752)	0.7995 (0.5646 to 1.1322)

No statistical analyses for this end point

Secondary: Patients with minimum 10% HBsAg loss at week 24 (compared to baseline)

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End point title

Patients with minimum 10% HBsAg loss at week 24 (compared to baseline)

End point description

Decline of HBs antigen rate at week 24 at least 10% compared to baseline.

End point type

Secondary

End point timeframe

24 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: Yes, No, Missing
Yes	72	21
No	38	32
Missing	0	2

Fisher's Exact test

Comparison groups

Intervention Group (Pegasys®) v Control Group

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1799

Method

Fisher exact

Confidence interval

Secondary: HBsAg seroconversion detected

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End point title

HBsAg seroconversion detected

End point description

HBsAg seroconversion was defined as percentage of subjects who became HBsAg negative (<10 IU/ml) and anti-HBs positive (≥10 IU/l) at least once during the observation period (baseline - EoFU).

End point type

Secondary

End point timeframe

HBsAg seroconversion defined as percentage of subjects who became HBsAg negative and anti-HBs positive during the observation period

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: Subjects
Yes	6	0
No	104	55

No statistical analyses for this end point

Secondary: Visit when HBsAg seroconversion was detected

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End point title

Visit when HBsAg seroconversion was detected

End point description

Visit when HBs antigen seroconversion was first detected

End point type

Secondary

End point timeframe

During the whole study period.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: Visits
Visit 9	1	0
Visit 11	1	0
Visit 13	3	0
Visit 14	1	0
Missing	104	55

No statistical analyses for this end point

Secondary: Seroconversion at end of follow-up

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End point title

Seroconversion at end of follow-up

End point description

End point type

Secondary

End point timeframe

Week 48-72.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: Subjects
Yes	2	0
No	4	0
Missing	104	55

No statistical analyses for this end point

Secondary: HBsAg levels at all measurement times

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End point title

HBsAg levels at all measurement times

End point description

End point type

Secondary

End point timeframe

Week 12

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: IU/ml
arithmetic mean (standard deviation)	7001.3 ± 13903.8	9277.5 ± 17574.4

No statistical analyses for this end point

Secondary: Decline of HBs antigen at week 36 (mITT)

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End point title

Decline of HBs antigen at week 36 (mITT)

End point description

36 Weeks.

End point type

Secondary

End point timeframe

Differences between screening after 36 weeks compared to baseline. Modified Intention-to-treat (mITT) population was investigated.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: IU/ml
geometric mean (confidence interval 95%)	0.1931 (0.1304 to 0.2858)	0.7937 (0.4749 to 1.3266)

No statistical analyses for this end point

Secondary: Decline of HBs antigen at week 48 (mITT)

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End point title

Decline of HBs antigen at week 48 (mITT)

End point description

Differences between screening after 48 weeks compared to baseline. Modified Intention-to-treat (mITT) population was investigated.

End point type

Secondary

End point timeframe

48 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: IU/ml
geometric mean (confidence interval 95%)	0.1859 (0.1279 to 0.2701)	0.7372 (0.4350 to 1.2494)

No statistical analyses for this end point

Secondary: Decline of HBs antigen at week 72 (mITT)

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End point title

Decline of HBs antigen at week 72 (mITT)

End point description

Differences between screening after 72 weeks compared to baseline. Modified Intention-to-treat (mITT) population was investigated.

End point type

Secondary

End point timeframe

72 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: IU/ml
geometric mean (confidence interval 95%)	0.2535 (0.1849 to 0.3476)	0.6581 (0.4225 to 1.0250)

No statistical analyses for this end point

Secondary: Systolic Blood pressure week 24

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End point title

Systolic Blood pressure week 24

End point description

End point type

Secondary

End point timeframe

24 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: mmHg
arithmetic mean (standard deviation)	127.34 ± 14.29	129.85 ± 16.92

No statistical analyses for this end point

Secondary: Systolic Blood pressure week 36

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End point title

Systolic Blood pressure week 36

End point description

End point type

Secondary

End point timeframe

36 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: mmHg
arithmetic mean (standard deviation)	126.36 ± 14.43	131.00 ± 16.86

No statistical analyses for this end point

Secondary: Systolic Blood Pressure (EoT)

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End point title

Systolic Blood Pressure (EoT)

End point description

End point type

Secondary

End point timeframe

48 weeks/ end of study.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: mmHg
arithmetic mean (standard deviation)	124.75 ± 14.16	130.13 ± 15.67

No statistical analyses for this end point

Secondary: Pulse (EoT)

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End point title

Pulse (EoT)

End point description

End point type

Secondary

End point timeframe

End of trial. 48 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: bpm
arithmetic mean (standard deviation)	73.86 ± 9.48	72.30 ± 7.63

No statistical analyses for this end point

Secondary: body weight week 12

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End point title

body weight week 12

End point description

End point type

Secondary

End point timeframe

Week 12.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg
arithmetic mean (standard deviation)	79.64 ± 12.93	79.35 ± 15.49

No statistical analyses for this end point

Secondary: body weight week 24

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End point title

body weight week 24

End point description

End point type

Secondary

End point timeframe

24 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg
arithmetic mean (standard deviation)	78.77 ± 12.40	79.64 ± 15.61

No statistical analyses for this end point

Secondary: body weight week 36

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End point title

body weight week 36

End point description

End point type

Secondary

End point timeframe

36 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg
arithmetic mean (standard deviation)	79.02 ± 11.63	79.13 ± 15.44

No statistical analyses for this end point

Secondary: body weight (EoT)

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End point title

body weight (EoT)

End point description

End point type

Secondary

End point timeframe

End of Trial. 48 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg
arithmetic mean (standard deviation)	77.72 ± 12.33	79.79 ± 15.12

No statistical analyses for this end point

Secondary: BMI week 12

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End point title

BMI week 12

End point description

End point type

Secondary

End point timeframe

12 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg/m²
arithmetic mean (standard deviation)	26.19 ± 3.86	26.76 ± 4.31

No statistical analyses for this end point

Secondary: BMI week 24

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End point title

BMI week 24

End point description

End point type

Secondary

End point timeframe

24 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg/m²
arithmetic mean (standard deviation)	25.91 ± 3.61	26.85 ± 4.38

No statistical analyses for this end point

Secondary: BMI week 36

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End point title

BMI week 36

End point description

End point type

Secondary

End point timeframe

Week 36.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg/m²
arithmetic mean (standard deviation)	25.88 ± 3.56	26.75 ± 4.37

No statistical analyses for this end point

Secondary: BMI (EoT)

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End point title

BMI (EoT)

End point description

End point type

Secondary

End point timeframe

End of Trial. 48 weeks.

End point values	Intervention Group (Pegasys®)	Control Group
Number of subjects analysed	110	55
Units: kg/m²
arithmetic mean (standard deviation)	25.56 ± 3.60	26.88 ± 4.28

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

In this trial, the period of observation for adverse events extended from the time the subject had signed the informed consent document up to the end of follow up at week 72 (visit 15 of the treatment group or visit 7 of the control group).

Adverse event reporting additional description

If the investigator detected a serious adverse event after the period of observation, considering the event possibly related to this trial, he should contact the sponsor to determine how the adverse event should be documented & reported. Serious adverse events had to be immediately (within 24h of the investigator’s awareness) reported to IZKS Mainz

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Intervention Group (Pegasys®)

Reporting group description

The group received addiotional treatment with Pegasys in the following treatment period. After the treatment period, both groups were treated with the standard therapeutic use of Nucleos(t)ides.

Reporting group title

Control Group

Reporting group description

Group receiving the standard nucleos(t)ide treatment without the add-on drug [pegylated Interferon alfa-2a (Pegasys®)].

Serious adverse events	Intervention Group (Pegasys®)	Control Group
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 112 (11.61%)	4 / 58 (6.90%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Aortic valve replacement
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Internal fixation of fracture
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pain
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Postmenopausal haemorrhage
Additional description: recovering/resolving
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Nasal turbinate hypertrophy
Additional description: hypertrophy recovering/resolving
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Facial bones fracture
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Forearm fracture
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus injury
Additional description: recovering/resolving
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Coronary artery disease
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenitis
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal haemorrhage
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin hyperpigmentation
Additional description: recovered/resolved
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
Additional description: recovered/resolved
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
Additional description: recovered/resolved with sequel
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Foot deformity
Additional description: recovered/resolved
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pyelonephritis
Additional description: recovered/resolved
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
Additional description: recovered/resolved
subjects affected / exposed	0 / 112 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chlamydial infection
Additional description: recovering/resolving
subjects affected / exposed	1 / 112 (0.89%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Intervention Group (Pegasys®)	Control Group
Total subjects affected by non serious adverse events
subjects affected / exposed	106 / 112 (94.64%)	20 / 58 (34.48%)
Investigations
Transaminases increased
subjects affected / exposed	6 / 112 (5.36%)	0 / 58 (0.00%)
occurrences all number	9	0
Weight decreased
subjects affected / exposed	8 / 112 (7.14%)	1 / 58 (1.72%)
occurrences all number	8	1
Nervous system disorders
Dizziness
subjects affected / exposed	11 / 112 (9.82%)	0 / 58 (0.00%)
occurrences all number	18	0
Headache
subjects affected / exposed	40 / 112 (35.71%)	0 / 58 (0.00%)
occurrences all number	48	0
General disorders and administration site conditions
Chills
subjects affected / exposed	11 / 112 (9.82%)	0 / 58 (0.00%)
occurrences all number	19	0
Fatigue
subjects affected / exposed	48 / 112 (42.86%)	2 / 58 (3.45%)
occurrences all number	52	2
Influenza like illness
subjects affected / exposed	13 / 112 (11.61%)	2 / 58 (3.45%)
occurrences all number	21	2
Injection site erythema
subjects affected / exposed	11 / 112 (9.82%)	0 / 58 (0.00%)
occurrences all number	12	0
Pyrexia
subjects affected / exposed	25 / 112 (22.32%)	0 / 58 (0.00%)
occurrences all number	28	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	8 / 112 (7.14%)	0 / 58 (0.00%)
occurrences all number	11	0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	11 / 112 (9.82%)	6 / 58 (10.34%)
occurrences all number	11	10
Diarrhoea
subjects affected / exposed	9 / 112 (8.04%)	1 / 58 (1.72%)
occurrences all number	12	1
Nausea
subjects affected / exposed	12 / 112 (10.71%)	1 / 58 (1.72%)
occurrences all number	13	1
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	6 / 112 (5.36%)	0 / 58 (0.00%)
occurrences all number	6	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	9 / 112 (8.04%)	2 / 58 (3.45%)
occurrences all number	10	2
Oropharyngeal pain
subjects affected / exposed	7 / 112 (6.25%)	0 / 58 (0.00%)
occurrences all number	8	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	17 / 112 (15.18%)	0 / 58 (0.00%)
occurrences all number	17	0
Dry skin
subjects affected / exposed	7 / 112 (6.25%)	0 / 58 (0.00%)
occurrences all number	7	0
Pruritus
subjects affected / exposed	15 / 112 (13.39%)	0 / 58 (0.00%)
occurrences all number	17	0
Rash
subjects affected / exposed	8 / 112 (7.14%)	0 / 58 (0.00%)
occurrences all number	10	0
Psychiatric disorders
Insomnia
subjects affected / exposed	9 / 112 (8.04%)	0 / 58 (0.00%)
occurrences all number	10	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	31 / 112 (27.68%)	0 / 58 (0.00%)
occurrences all number	45	0
Back pain
subjects affected / exposed	15 / 112 (13.39%)	2 / 58 (3.45%)
occurrences all number	17	3
Myalgia
subjects affected / exposed	19 / 112 (16.96%)	0 / 58 (0.00%)
occurrences all number	21	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	28 / 112 (25.00%)	3 / 58 (5.17%)
occurrences all number	31	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	6 / 112 (5.36%)	0 / 58 (0.00%)
occurrences all number	9	0

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Were there any global substantial amendments to the protocol? Yes

22 Dec 2011

Added following inclusion criteria: -Treatment with a nucleos(t)ide regimen (lamivudine, adefovir, entecavir, tenofovir or one of the following combinations: lamivudine/adefovir, lamivudine/tenofovir, entecavir/adefovir or entecavir/tenofovir) and a fully suppressed viral load for at least 12 months (below limit of detection in conventional HBV-PCR assays, i.e. <116 copies/ml). Added following exclusion criteria: -Preexisting polyneuropathy -If polyneuropathy develops and is confirmed by a neurologist, withdrawal will be discussed according to severity of the symptoms Declared the following as secondary objectives: -To evaluate safety and tolerability of pegylated interferon alfa-2a when combined with tenofovir, entecavir, lamivudine, adefovir, or a combination of lamivudine or entecavir with adefovir or tenofovir. Added the following information to the basic treatment section: The known dosing instructions, contraindications, side effects and risks for each drug must be taken into account accoring to the maufacturers’ recommendations. Regular laboratory and clinical assessments throughout the course of this study are to provide adequate monitoring of potential toxicities. Added the following info on physical examination: As an increased incidence of polyneuropathy was observed during combination therapy with pegylated interferon alfa-2a and telbivudine, special attention should be paid to the development of polyneuropathy or other neurological symptoms in subjects on combination therapy. Investigators need to question patients about development of hyp- or dysesthesia, muscle weakness or any other neurological symptoms. If neurological symptoms occur, they need to be documented as adverse events, and the patients will then be referred to a neurologist for further examination.

19 Apr 2013

The amendment contains the change of: - the coordinating investigator - the inclusion criterion “HBsAg ≥1000 IU/ml” to “HBsAg ≥100 IU/ml” - the following exclusion criteria: - Decompensated liver disease, or history of decompensated liver disease, as evidenced by ascites, portal hypertension, jaundice or hepatic encephalopathy, coagulopathy, varices, history of varicose bleeding, or any othe clinical evidence of decompensation. (Patients with stable liver cirrhosis are eligible for this study, if a history of decompensated liver disease as outlined above has been excluded.) -Usage of any investigational drugs within 3 months before enrolment removed: Histologically proven liver cirrhosis (exclusion criteria). Earlier: Usage of any investigational drugs within 12 months before enrolment.

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.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective response after 48 weeks

Primary: Objective response after 48 weeks

Secondary: Decline of HBs antigen at week 12 (mITT)

Secondary: Decline of HBs antigen at week 12 (mITT)

Secondary: Decline of HBs antigen at week 24 (mITT)

Secondary: Decline of HBs antigen at week 24 (mITT)

Secondary: Patients with minimum 10% HBsAg loss at week 24 (compared to baseline)

Secondary: Patients with minimum 10% HBsAg loss at week 24 (compared to baseline)

Secondary: HBsAg seroconversion detected

Secondary: HBsAg seroconversion detected

Secondary: Visit when HBsAg seroconversion was detected

Secondary: Visit when HBsAg seroconversion was detected

Secondary: Seroconversion at end of follow-up

Secondary: Seroconversion at end of follow-up

Secondary: HBsAg levels at all measurement times

Secondary: HBsAg levels at all measurement times

Secondary: Decline of HBs antigen at week 36 (mITT)

Secondary: Decline of HBs antigen at week 36 (mITT)

Secondary: Decline of HBs antigen at week 48 (mITT)

Secondary: Decline of HBs antigen at week 48 (mITT)

Secondary: Decline of HBs antigen at week 72 (mITT)

Secondary: Decline of HBs antigen at week 72 (mITT)

Secondary: Systolic Blood pressure week 24

Secondary: Systolic Blood pressure week 24

Secondary: Systolic Blood pressure week 36

Secondary: Systolic Blood pressure week 36

Secondary: Systolic Blood Pressure (EoT)

Secondary: Systolic Blood Pressure (EoT)

Secondary: Pulse (EoT)

Secondary: Pulse (EoT)

Secondary: body weight week 12

Secondary: body weight week 12

Secondary: body weight week 24

Secondary: body weight week 24

Secondary: body weight week 36

Secondary: body weight week 36

Secondary: body weight (EoT)

Secondary: body weight (EoT)

Secondary: BMI week 12

Secondary: BMI week 12

Secondary: BMI week 24

Secondary: BMI week 24

Secondary: BMI week 36

Secondary: BMI week 36

Secondary: BMI (EoT)

Secondary: BMI (EoT)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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