Download PDF

Clinical Trial Results:
A Phase II, Randomised, Adaptive, Open-Label Platform Trial to Evaluate Efficacy and Safety of Multiple Combination Therapies in Participants With Chronic Hepatitis B

Summary
EudraCT number	2019-002086-35
Trial protocol	GB FR NL BE BG
Global end of trial date	19 Jul 2024

Results information
Results version number	v1(current)
This version publication date	02 Aug 2025
First version publication date	02 Aug 2025
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

WV41073

ISRCTN number

US NCT number

NCT04225715

WHO universal trial number (UTN)

Sponsor organisation name

Hoffmann-La Roche

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4058

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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

19 Jul 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Jul 2024

Was the trial ended prematurely?

Yes

Main objective of the trial

The main purpose of this study is to compare the efficacy of new molecular entity (NME) combination regimens against a control arm in participants with chronic hepatitis B (CHB).

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form

Background therapy

Participants received background nucleos(t)ide (NUC) therapy in accordance with the local prescribing information.

Evidence for comparator

Actual start date of recruitment

05 Jul 2020

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

11 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 7

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

Chile: 1

Country: Number of subjects enrolled

China: 152

Country: Number of subjects enrolled

Spain: 14

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Hong Kong: 5

Country: Number of subjects enrolled

Korea, Republic of: 17

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Romania: 2

Country: Number of subjects enrolled

Thailand: 15

Country: Number of subjects enrolled

Taiwan: 41

Worldwide total number of subjects

281

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)

277

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

A total of 281 participants with CHB who had virologic suppression with NUC therapy took part in the study across 13 countries from 05 July 2020 to 19 July 2024.

Screening details

The study consisted of a screening phase, followed by up to 48 weeks of treatment and up to 48 weeks of post-treatment follow-up. Multiple new combination therapies were compared against a common control. Combos 1, 5, 7 and 8 were prematurely terminated by the Sponsor.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

NUC Control Arm

Arm description

Participants continued their background NUC therapy for 48 weeks. Thereafter, in line with current CHB treatment guidelines, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Active comparator

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Combo 1: CpAM + TLR7 Agonist + NUC

Arm description

Participants received core protein allosteric modulator (CpAM), 600 milligrams (mg) tablets, orally, once daily (QD) for 48 weeks and toll-like receptor 7 (TLR7) agonist, 150 mg, orally, once every other day (QOD) during Weeks 1-12 and Weeks 25-36 in addition to their background NUC therapy. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

CpAM

Investigational medicinal product code

RO7049389

Other name

Linvencorvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

CpAM, 600 mg tablets, orally, QD up to Week 48.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

TLR7

Investigational medicinal product code

RO7020531

Other name

Ruzotolimod

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

TLR7, 150 mg tablets, orally, QOD during Weeks 1-12 and Weeks 25-36.

Combo 2: siRNA (100 mg) + NUC

Arm description

Participants received short interfering ribonucleic acid (siRNA), 100 mg, as a subcutaneous (SC) injection, every 4 weeks (Q4W) in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 100 mg, as a SC injection, Q4W up to Week 48.

Combo 3: siRNA (200 mg) + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as a SC injection, Q4W up to Week 48.

Combo 4: siRNA + PEG-IFN + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W and pegylated interferon (PEG-IFN), 180 micrograms (µg), as a SC injection, every week (QW) in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as a SC injection, Q4W up to Week 48.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

PEG-IFN

Investigational medicinal product code

RO0258310

Other name

Pegasys

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PEG-IFN, 180 µg, as a SC injection, QW up to Week 48.

Combo 5: siRNA + CpAM + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W and CpAM, 600 mg tablets, orally, QD in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as a SC injection, Q4W up to Week 48.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

CpAM

Investigational medicinal product code

RO7049389

Other name

Linvencorvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

CpAM, 600 mg tablets, orally, QD up to Week 48.

Combo 6: siRNA + TLR7 Agonist + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W for 48 weeks and TLR7 agonist, 150 mg tablets, orally, QOD during Weeks 13-24 and Weeks 37-48 in addition to their background NUC therapy. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as an SC injection, Q4W during Weeks 13-24 and Weeks 37-48.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 48.

Investigational medicinal product name

TLR7

Investigational medicinal product code

RO7020531

Other name

Ruzotolimod

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

TLR7, 150 mg tablets, orally, QOD during Weeks 13-24 and Weeks 37-48.

Combo 7: siRNA + PD-L1 LNA + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W up to Week 24 and programmed death ligand-1 locked nucleic acid (PD-L1 LNA), 2 milligrams/kilograms (mg/kg), as a SC injection, QW during Weeks 13-24 in addition to their background NUC therapy for 24 weeks. After Week 24, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as an SC injection, Q4W up to Week 24.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 24.

Investigational medicinal product name

PD-L1 LNA

Investigational medicinal product code

RO7191863

Other name

Cadapersen

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PD-L1 LNA, 2 mg/kg, as a SC injection, QW during Weeks 13-24.

Combo 8: siRNA + PD-L1 LNA + NUC

Arm description

Participants received siRNA, 200 mg, as a SC injection, Q4W up to Week 24 and PD-L1 LNA, 2 mg/kg, as a SC injection, QW during Weeks 25-36 in addition to their background NUC therapy for 36 weeks. After Week 36, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Arm type

Experimental

Investigational medicinal product name

siRNA

Investigational medicinal product code

RO7445482

Other name

Xalnesiran, DCR-HBVS

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

siRNA, 200 mg, as an SC injection, Q4W up to Week 24.

Investigational medicinal product name

NUC

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

NUC tablets, orally up to follow up Week 36.

Investigational medicinal product name

PD-L1 LNA

Investigational medicinal product code

RO7191863

Other name

Cadapersen

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PD-L1 LNA, 2 mg/kg, as a SC injection, QW during Weeks 25-36.

Number of subjects in period 1	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Started	36	38	30	30	30	19	34	33	31
Completed	30	37	29	30	27	9	33	15	12
Not completed	6	1	1	0	3	10	1	18	19
Consent withdrawn by subject	4	1	1	-	3	1	1	1	-
Adverse event, non-fatal	-	-	-	-	-	-	-	-	1
Arm Terminated By Sponsor	-	-	-	-	-	-	-	17	18
Reason not Specified	1	-	-	-	-	-	-	-	-
Protocol deviation	1	-	-	-	-	9	-	-	-

Baseline characteristics

Top of page

Reporting group title

NUC Control Arm

Reporting group description

Reporting group title

Combo 1: CpAM + TLR7 Agonist + NUC

Reporting group description

Reporting group title

Combo 2: siRNA (100 mg) + NUC

Reporting group description

Reporting group title

Combo 3: siRNA (200 mg) + NUC

Reporting group description

Reporting group title

Combo 4: siRNA + PEG-IFN + NUC

Reporting group description

Reporting group title

Combo 5: siRNA + CpAM + NUC

Reporting group description

Reporting group title

Combo 6: siRNA + TLR7 Agonist + NUC

Reporting group description

Reporting group title

Combo 7: siRNA + PD-L1 LNA + NUC

Reporting group description

Reporting group title

Combo 8: siRNA + PD-L1 LNA + NUC

Reporting group description

Reporting group values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC	Total
Number of subjects	36	38	30	30	30	19	34	33	31	281
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	43.64 ( 9.2 )	46.03 ( 9.84 )	42.83 ( 10.69 )	39.97 ( 11.03 )	38.07 ( 9.54 )	38.95 ( 9.77 )	42.59 ( 8.46 )	49.7 ( 8.87 )	48.84 ( 8.36 )	-
Sex: Female, Male
Units: participants
Female	8	9	1	10	5	5	4	10	6	58
Male	28	29	29	20	25	14	30	23	25	223
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0
Asian	33	34	26	29	30	19	32	22	22	247
Native Hawaiian or Other Pacific Islander	1	1	1	0	0	0	0	0	0	3
Black or African American	0	0	0	0	0	0	2	2	1	5
White	2	3	3	1	0	0	0	9	8	26
More than one race	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	1	0	0	0	0	0	0	0	2
Not Hispanic or Latino	35	37	30	30	30	19	34	33	30	278
Unknown or Not Reported	0	0	0	0	0	0	0	0	1	1

End points

Top of page

Reporting group title

NUC Control Arm

Reporting group description

Reporting group title

Combo 1: CpAM + TLR7 Agonist + NUC

Reporting group description

Reporting group title

Combo 2: siRNA (100 mg) + NUC

Reporting group description

Reporting group title

Combo 3: siRNA (200 mg) + NUC

Reporting group description

Reporting group title

Combo 4: siRNA + PEG-IFN + NUC

Reporting group description

Reporting group title

Combo 5: siRNA + CpAM + NUC

Reporting group description

Reporting group title

Combo 6: siRNA + TLR7 Agonist + NUC

Reporting group description

Reporting group title

Combo 7: siRNA + PD-L1 LNA + NUC

Reporting group description

Reporting group title

Combo 8: siRNA + PD-L1 LNA + NUC

Reporting group description

Subject analysis set title

Combo 7 and 8: siRNA + PD-L1 LNA + NUC

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received siRNA, 200 mg, as a SC injection, Q4W up to Week 24 and PD-L1 LNA, 2 mg/kg, as a SC injection, QW during Weeks 13-24 (Combo 7)/ Weeks 25-36 (Combo 8) in addition to their background NUC therapy for 24 weeks (Combo 7)/ 36 weeks (Combo 8). After Week 24/36, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Primary: Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)

Top of page

End point title

Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)

End point description

HBsAg loss was defined as quantitative HBsAg <0.05 international units/milliliters (IU/mL). The percentage of participants with HBsAg loss was calculated as number of participants with HBsAg loss / total number of participants *100. 95% confidence interval (CI) was calculated using the Clopper-Pearson method. Modified Intent to Treat (mITT) population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. Percentages have been rounded off.

End point type

Primary

End point timeframe

Follow-up Week (FUW) 24

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	35	30	30	30	9	34	33	30
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 10)	0 (0 to 0)	6.7 (0.8 to 22.1)	3.3 (0.1 to 17.2)	23.3 (9.9 to 42.3)	0 (0 to 0)	11.8 (3.3 to 27.5)	0 (0 to 10.6)	6.7 (0.8 to 22.1)

NUC vs Combo 2

Statistical analysis description

95% CI for difference of two proportions was calculated using Cochran-Mantel-Haenszel (CMH) method.

Comparison groups

NUC Control Arm v Combo 2: siRNA (100 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

7.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

16.4

NUC vs Combo 8

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 8: siRNA + PD-L1 LNA + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

6.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

15.7

NUC vs Combo 6

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 6: siRNA + TLR7 Agonist + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

12.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

23.3

NUC vs Combo 5

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 7: siRNA + PD-L1 LNA + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

NUC vs Combo 3

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 3: siRNA (200 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

NUC vs Combo 4

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 4: siRNA + PEG-IFN + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

24.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

39.5

Secondary: Percentage of Participants With HBsAg loss

Top of page

End point title

Percentage of Participants With HBsAg loss

End point description

HBsAg loss was defined as quantitative HBsAg <0.05 IU/mL. The percentage of participants with HBsAg loss was calculated as number of participants with HBsAg loss / total number of participants *100. 95% CI was calculated using the Clopper-Pearson method. Percentages have been rounded off. mITT population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. n = participants with data available for analysis at that specified timepoint. 9999= No participants were analyzed for this timepoint.

End point type

Secondary

End point timeframe

Combos 2, 3, 4, 6 and NUC Arm: Week 48 and FUW 48; Combo 7: Week 24; Combo 8: Week 36

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	36	30	30	30	4	34	33	30
Units: percentage of participants
number (confidence interval 95%)
Week 24 (n=0,36,0,0,0,4,0,33,0)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	6.1 (0.7 to 20.2)	9999 (9999 to 9999)
Week 36 (n=0,23,0,0,0,1,0,0,30)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	13.3 (3.8 to 30.7)
Week 48 (n=35,20,30,30,30,4,30,0,0)	0 (0 to 10)	0 (0 to 0)	6.7 (0.8 to 22.1)	3.3 (0.1 to 17.2)	30 (14.7 to 49.4)	0 (0 to 0)	17.6 (6.8 to 34.5)	9999 (9999 to 9999)	9999 (9999 to 9999)
FUW 48 (n=35,28,30,30,30,1,34,0,0)	2.9 (0.1 to 14.9)	0 (0 to 0)	10 (2.1 to 26.5)	0 (0 to 11.6)	16.7 (5.6 to 34.7)	0 (0 to 0)	11.8 (3.3 to 27.5)	9999 (9999 to 9999)	9999 (9999 to 9999)

NUC vs Combo 7: Week 24

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 7: siRNA + PD-L1 LNA + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

6.2

Point estimate

6.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

14.5

NUC vs Combo 8: Week 36

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 8: siRNA + PD-L1 LNA + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

13.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

25.6

Combo 2: Week 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 2: siRNA (100 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

7.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

16.4

NUC vs Combo 3: Week 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 3: siRNA (200 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

NUC vs Combo 4: Week 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 4: siRNA + PEG-IFN + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

31.2

Confidence interval

level

95%

sides

2-sided

lower limit

14.7

upper limit

47.6

NUC vs Combo 3: FUW 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 3: siRNA (200 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

-2.7

Confidence interval

level

95%

sides

2-sided

lower limit

-8.1

upper limit

2.7

NUC vs Combo 6: Week 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 6: siRNA + TLR7 Agonist + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

18.4

Confidence interval

level

95%

sides

2-sided

lower limit

5.4

upper limit

31.4

NUC vs Combo 2: FUW 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 2: siRNA (100 mg) + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

8.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.9

upper limit

20.1

NUC vs Combo 4: FUW 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 4: siRNA + PEG-IFN + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

14.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

28.8

NUC vs Combo 6: FUW 48

Statistical analysis description

95% CI for difference of two proportions was calculated using CMH method.

Comparison groups

NUC Control Arm v Combo 6: siRNA + TLR7 Agonist + NUC

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Response Rate

Point estimate

9.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

21.5

Secondary: Percentage of Participants With HBsAg Seroconversion

Top of page

End point title

Percentage of Participants With HBsAg Seroconversion

End point description

HBsAg seroconversion was defined as a quantitative HBsAg < 0.05 IU/mL and a positive anti-HBs antibody (defined as per assay reactive threshold anti-HBs ≥10 IU/L). 95% CI was calculated using the Clopper-Pearson method. Percentages have been rounded off. mITT population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. Number analyzed included participants with data available for analysis at that specified timepoint. n = participants with data available for analysis at that specified timepoint. 9999= No participants were analyzed for this timepoint.

End point type

Secondary

End point timeframe

Combos 2, 3, 4, 6 and NUC Arm: Week 48, FUW 24 and FUW 48; Combo 7: Week 24 and FUW 24; Combo 8: Week 36 and FUW 24

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	36	30	30	30	9	34	33	30
Units: percentage of participants
number (confidence interval 95%)
Week 24 (n=0,36,0,0,0,9,0,33,0)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	0 (0 to 10.6)	9999 (9999 to 9999)
Week 36 (n=0,23,0,0,0,1,0,0,30)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)	0 (0 to 0)	9999 (9999 to 9999)	9999 (9999 to 9999)	0 (0 to 11.9)
Week 48 (n=35,20,30,30,30,4,34,0,0)	0 (0 to 10)	0 (0 to 0)	3.3 (0.1 to 17.2)	0 (0 to 11.6)	23.3 (9.9 to 42.3)	0 (0 to 0)	0 (0 to 10.3)	9999 (9999 to 9999)	9999 (9999 to 9999)
FUW 24 (n=35,35,30,30,30,9,34,33,30)	0 (0 to 10)	0 (0 to 0)	3.3 (0.1 to 17.2)	0 (0 to 11.6)	20 (7.7 to 38.6)	0 (0 to 0)	3.1 (0.1 to 16.2)	0 (0 to 10.9)	0 (0 to 11.6)
FUW 48 (n=35,28,30,30,30,1,34,0,0)	2.9 (0.1 to 14.9)	0 (0 to 0)	3.3 (0.1 to 17.2)	0 (0 to 11.6)	16.7 (5.6 to 34.7)	0 (0 to 0)	5.9 (0.7 to 19.7)	9999 (9999 to 9999)	9999 (9999 to 9999)

No statistical analyses for this end point

Secondary: Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants

Top of page

End point title

Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants

End point description

HBeAg loss was defined as negative /non-reactive HBeAg level. Percentages have been rounded off. mITT population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. Number analyzed included participants from the mITT population who were positive for HBeAg at baseline. n = participants with data available for analysis at that specified timepoint. 9999= No participants were analyzed for this timepoint.

End point type

Secondary

End point timeframe

Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	8	8	9	8	12	7	10	9	5
Units: percentage of participants
number (not applicable)
Week 12 (n=8,8,9,8,12,7,10,9,5)	0	0	22.2	50	33.3	28.6	30	11.1	40
Week 24 (n=7,8,8,8,12,2,7,9,5)	0	0	37.5	50	41.7	50	28.6	11.1	40
Week 36 (n=7,5,9,4,9,0,10,0,5)	14.3	0	44.4	25	55.6	9999	50	9999	40
Week 48 (n=8,5,9,8,11,2,10,0,0)	12.5	20	44.4	62.5	54.5	50	50	9999	9999
FUW 12 (n=6,8,7,8,11,3,9,9,5)	16.7	0	42.9	62.5	54.5	33.3	44.4	11.1	20
FUW 24 (n=7,8,8,8,11,3,9,9,5)	14.3	0	12.5	50	36.4	66.7	44.4	11.1	60
FUW 36 (n=8,8,8,8,11,0,9,6,3)	12.5	0	12.5	50	27.3	9999	33.3	0	66.7
FUW 48 (n=7,8,9,8,11,0,9,5,0)	14.3	25	33.3	50	27.3	9999	44.4	0	9999

No statistical analyses for this end point

Secondary: Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants

Top of page

End point title

Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants

End point description

HBeAg seroconversion was defined as a negative /non-reactive HBeAg level and a positive anti-HBe antibody. Percentages have been rounded off. Number analyzed included participants from the mITT population who were positive for HBeAg at baseline. n = participants with data available for analysis at that specified timepoint. 9999= No participants were analyzed for this timepoint.

End point type

Secondary

End point timeframe

Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	8	8	9	8	12	7	10	9	5
Units: percentage of participants
number (not applicable)
Week 12 (n=8,8,9,8,12,7,10,9,5)	0	0	11.1	0	8.3	14.3	0	0	0
Week 24 (n=7,8,8,8,12,2,7,9,5)	0	0	0	12.5	8.3	0	0	0	0
Week 36 (n=7,5,9,4,9,0,10,0,5)	0	0	11.1	0	11.1	9999	10	9999	0
Week 48 (n=8,5,9,8,11,2,10,0,0)	0	0	11.1	12.5	18.2	0	10	9999	9999
FUW 12 (n=6,8,7,8,11,3,9,9,5)	16.7	0	14.3	12.5	18.2	0	11.1	0	0
FUW 24 (n=7,8,8,8,11,3,9,9,5)	14.3	0	0	25	9.1	33.3	11.1	0	0
FUW 36 (n=8,8,8,8,11,0,9,6,3)	12.5	0	0	25	9.1	9999	11.1	0	0
FUW 48 (n=7,8,9,8,11,0,9,5,0)	14.3	25	11.1	37.5	9.1	9999	33.3	0	9999

No statistical analyses for this end point

Secondary: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL

Top of page

End point title

Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL

End point description

Chronic HBV infection is characterized by high levels of circulating HBV DNA. Therefore, HBV levels are indicative of virological response. At screening participants were on NUC therapy and had circulating HBV DNA levels below the assay LLOQ or below 20 IU/mL for at least 6 months. The emergence of a virological breakthrough (HBV DNA >100 IU/mL or >1 log increase from nadir) while on NUC therapy, or the emergence of a virological relapse (>2,000 IU/mL) in participants taken off NME combination and NUC therapy during follow-up, was monitored through the quantification of HBV DNA in plasma. mITT population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. n = participants with data available for analysis at that specified timepoint. Different participants may have contributed data for each timepoint. 9999= No participants were analyzed for this timepoint.

End point type

Secondary

End point timeframe

FUW 12, 24, 36, and 48

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	35	30	30	30	9	34	33	30
Units: participants
FUW12: OFFNUC(<LLOQ;n=1,0,5,6,5,0,10,3,5)	0	9999	3	4	4	9999	7	2	4
FUW12: OFFNUC(≥LLOQ-<20IU/mL;n=1,0,0,0,0,0,0,3,5)	1	9999	9999	9999	9999	9999	9999	1	0
FUW12: OFFNUC(≥20 -<200IU/mL;n=1,0,0,0,0,0,0,3,5)	0	9999	9999	9999	9999	9999	9999	0	1
FUW12:OFFNUC(≥LLOQ-<200IU/mL;n=1,0,5,6,5,0,10,0,0)	0	9999	1	1	0	9999	2	9999	9999
FUW12:OFFNUC(≥200-<2000IU/mL;n=1,0,5,6,5,0,10,3,5)	0	9999	1	1	1	9999	1	0	0
FUW12: OFFNUC(≥2000IU/mL;n=1,0,5,6,5,0,10,3,5)	0	9999	0	0	0	9999	0	0	0
FUW12: ON NUC(<LLOQ;n=28,32,19,23,21,8,20,30,25)	28	32	19	23	21	8	20	30	24
FUW12:ONNUC(≥LLOQ-<20IU/mL;n=28,32,0,0,0,0,8,30,25	0	0	9999	9999	9999	0	9999	0	0
FUW12:ONNUC(≥20-<200IU/mL;n=28,32,0,0,0,0,8,30,25	0	0	9999	9999	9999	0	9999	0	0
FUW12:ONNUC(≥LLOQ-<200IU/mL;n=28,0,0,0,0,0,0,30,25	0	9999	0	0	0	9999	0	9999	9999
FW12:ONNUC(≥200-< 2000;n=28,32,19,23,21,8,20,30,25	0	0	0	0	0	0	0	0	1
FUW12:ONNUC(≥2000IU/mL;n=28,32,19,23,21,8,20,30,25	0	0	0	0	0	0	0	0	0
FUW24:OFFNUC(<LLOQ;n=2,0,4,5,7,0,12,8,9)	0	9999	2	3	6	9999	5	5	6
FUW24:OFFNUC(≥LLOQ-<20IU/mL;n=2,0,0,0,0,0,0,8,9)	0	9999	9999	9999	9999	9999	9999	0	0
FUW24:OFFNUC(≥20-<200IU/mL;n=2,0,0,0,0,0,0,8,9)	1	9999	9999	9999	9999	9999	9999	2	1
FUW24:OFFNUC(≥LLOQ-<200IU/mL;n=2,0,4,5,7,0,12,0,0)	0	9999	2	0	0	9999	5	9999	9999
FUW24:OFFNUC(≥200-<2000IU/mL;n=2,0,4,5,7,0,12,8,9)	0	9999	0	2	1	9999	2	1	1
FUW24:OFFNUC(≥2000IU/mL;n=2,0,4,5,7,0,12,8,9)	1	9999	0	0	0	9999	0	0	1
FUW24:ON NUC(<LLOQ;n=27,35,24,24,20,9,21,24,21)	27	35	22	24	20	9	21	24	21
FUW24:ONNUC(≥LLOQ-<20IU/mL;n=27,35,0,0,0,9,0,24,21	0	0	9999	9999	9999	0	9999	0	0
FUW24:ONNUC(≥20-<200IU/mL;n=27,35,0,0,0,9,0,24,21	0	0	9999	9999	9999	0	9999	0	0
FUW24:ONNUC(≥LLOQ-<200;n=27,0,24,24,20,0,21,0,0	0	9999	1	0	0	9999	0	9999	9999
FUW24:ONNUC(≥200-<2000;n=27,35,24,24,20,9,21,24,21	0	0	0	0	0	0	0	0	0
FUW24:ONNUC(≥2000IU/mL;n=27,35,24,24,20,9,21,24,21	0	0	1	0	0	0	0	0	0
FUW36:OFFNUC(<LLOQ)(n=1,0,3,5,6,0,9,5,6)	0	9999	1	3	6	9999	1	5	3
FUW36:OFFNUC(≥LLOQ-<20IU/mL;n=1,0,0,0,0,0,0,5,6)	0	9999	9999	9999	9999	9999	9999	0	0
FUW36:OFFNUC(≥20-<200IU/mL;n=1,0,0,0,0,0,0,5,6)	0	9999	9999	9999	9999	9999	9999	0	2
FUW36:OFFNUC(≥LLOQ -<200IU/mL;n=1,0,3,5,6,0,9,0,0)	0	9999	1	0	0	9999	3	9999	9999
FUW36:OFFNUC(≥200-<2000IU/mL;n=1,0,3,5,6,0,9,5,6)	1	9999	0	2	0	9999	5	0	0
FUW36:OFFNUC(≥2000IU/mL;n=1,0,3,5,6,0,9,5,6)	0	9999	1	0	0	9999	0	0	1
FUW36:ON NUC(<LLOQ;n=29,31,25,25,21,1,24,17,13)	29	31	24	25	21	1	22	16	13
FUW36:ONNUC(≥LLOQ-<20IU/mL;n=29,31,0,0,0,1,0,17,13	0	0	9999	9999	9999	0	9999	0	0
FUW36:ONNUC(≥20-<200IU/mL;n=29,31,0,0,0,1,0,17,13)	0	0	9999	9999	9999	0	9999	1	0
FUW36:ONNUC(≥LLOQ-<200;n=29,0,25,25,21,0,24,0,0	0	9999	1	0	0	9999	2	9999	9999
FUW36:ONNUC(≥200-<2000;n=29,31,25,25,21,1,24,17,13	0	0	0	0	0	0	0	0	0
FUW36:ONNUC(≥2000IU/mL;n=29,31,25,25,21,1,24,17,13	0	0	0	0	0	0	0	0	0
FUW48:OFFNUC(<LLOQ)(n=0,0,2,7,6,0,9,5,4)	9999	9999	0	5	3	9999	3	4	1
FUW48:OFFNUC(≥LLOQ -<20IU/mL;n=0,0,0,0,0,0,0,5,4)	9999	9999	9999	9999	9999	9999	9999	0	1
FUW48:OFFNUC(≥20-<200IU/mL;n=0,0,0,0,0,0,0,5,4)	9999	9999	9999	9999	9999	9999	9999	1	0
FUW48:OFFNUC(≥LLOQ- <200IU/mL;n=0,0,2,7,6,0,9,5,4)	9999	9999	1	0	3	9999	4	9999	9999
FUW48:OFFNUC(≥200-<2000IU/mL;n=0,0,2,7,6,0,9,5,4)	9999	9999	1	2	0	9999	2	0	1
FUW48:OFFNUC(≥2000IU/mL;n=0,0,2,7,6,0,9,5,4)	9999	9999	0	0	0	9999	0	0	1
FUW48:ON NUC(<LLOQ;n=30,28,27,23,21,1,23,10,8)	30	28	27	23	21	1	23	10	7
FUW48:ON NUC(≥LLOQ -<20;n=30,28,0,0,0,1,0,10,8	0	0	9999	9999	9999	0	0	0	1
FUW48:ONNUC(≥20-<200IU/mL;n=30,28,0,0,0,1,0,10,8	0	0	9999	9999	9999	0	9999	0	0
FUW48:ON NUC(≥LLOQ-<200;n=30,0,27,23,21,0,23,0,0	0	9999	0	0	0	9999	0	9999	9999
FUW48:ONNUC(≥200-< 2000;n=30,28,27,23,21,1,23,10,8	0	0	0	0	0	0	0	0	0
FUW48:ON NUC(≥2000IU/mL;n=30,28,27,23,21,1,23,10,8	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time

Top of page

End point title

Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time

End point description

The serological markers of HBV infection include viral antigens (HBsAg & HBeAg) and antibody (anti-HBs ). Changes in serological markers and efficacy biomarkers (HBV DNA & HBV RNA) from baseline are reported. mITT population included participants who were randomized and received at least one dose of each drug for their assigned treatment regimen. n = participants with data available for analysis at that specified timepoint. 999=Since only 1 participant was analyzed, standard deviation (SD) could not be calculated. 9999= No participants were analyzed for this timepoint. 99999= Mean and SD were not estimable due to majority of samples being below LLOQ.

End point type

Secondary

End point timeframe

Combo 2, 3, 4, 6 and NUC arm: Weeks 24, 36, 48, FUW 24 and FUW 48; Combo 7: Week 24, FUW 24 and FUW 48; Combo 8: Weeks 24, 36, FUW 24 and FUW 48

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	36	30	30	30	9	34	33	30
Units: log10 IU/mL
arithmetic mean (standard deviation)
HBsAg: Week 24(n=34,36,28,29,28,4,18,33,30)	-0.08 ( 0.16 )	-0.11 ( 0.26 )	-1.49 ( 0.56 )	-1.78 ( 0.59 )	-1.89 ( 1.05 )	-1.38 ( 0.41 )	-1.74 ( 0.62 )	-2.12 ( 0.73 )	-1.8 ( 0.49 )
HBsAg: Week 36(n=33,23,24,19,22,1,34,0,30)	-0.08 ( 0.13 )	-0.13 ( 0.23 )	-1.52 ( 0.67 )	-1.93 ( 0.47 )	-2.14 ( 1.27 )	-1.51 ( 999 )	-1.71 ( 0.69 )	9999 ( 9999 )	-2.08 ( 0.63 )
HBsAg: Week 48(n=34,20,29,30,28,4,34,0,0)	-0.2 ( 0.52 )	-0.09 ( 0.12 )	-1.58 ( 0.63 )	-1.93 ( 0.6 )	-2.22 ( 1.16 )	-1.3 ( 0.45 )	-2.18 ( 0.86 )	9999 ( 9999 )	9999 ( 9999 )
HBsAg: FUW 24(n=29,35,28,30,27,9,31,32,30)	-0.19 ( 0.35 )	-0.18 ( 0.31 )	-1.19 ( 0.76 )	-1.71 ( 0.75 )	-1.71 ( 1.24 )	-1.5 ( 0.89 )	-1.47 ( 0.81 )	-1.3 ( 0.7 )	-1.46 ( 0.74 )
HBsAg: FUW 48(n=30,28,29,30,27,1,32,15,12)	-0.25 ( 0.43 )	-0.25 ( 0.36 )	-0.89 ( 0.76 )	-1.2 ( 0.84 )	-1.28 ( 1.12 )	-2.02 ( 999 )	-1.01 ( 0.8 )	-0.91 ( 0.69 )	-1.14 ( 0.83 )
Anti-HBs: Week 24(n=34,36,28,29,28,4,18,33,30)	-0.01 ( 0.04 )	-0.01 ( 0.08 )	0.06 ( 0.32 )	0 ( 0 )	0.03 ( 0.2 )	0.06 ( 0.13 )	-0.01 ( 0.04 )	0.01 ( 0.12 )	-0.03 ( 0.1 )
Anti-HBs: Week 36(n=34,23,24,19,22,1,34,0,30)	-0.01 ( 0.02 )	-0.02 ( 0.09 )	0.06 ( 0.34 )	0 ( 0 )	0.3 ( 0.69 )	0 ( 999 )	-0.07 ( 0.27 )	9999 ( 9999 )	-0.03 ( 0.11 )
Anti-HBs: Week 48(n=34,20,29,30,28,4,34,0,0)	0 ( 0.01 )	-0.04 ( 0.11 )	0.06 ( 0.35 )	0 ( 0 )	0.55 ( 0.96 )	0.01 ( 0.02 )	-0.05 ( 0.27 )	9999 ( 9999 )	9999 ( 9999 )
Anti-HBs: FUW 24(n=29,35,28,30,27,9,31,32,25)	-0.02 ( 0.08 )	-0.01 ( 0.06 )	0.05 ( 0.31 )	0.01 ( 0.05 )	0.63 ( 1.04 )	0.09 ( 0.2 )	-0.02 ( 0.41 )	0.01 ( 0.1 )	-0.06 ( 0.2 )
Anti-HBs: FUW 48(n=30,28,29,30,27,1,32,9,9)	0.04 ( 0.33 )	-0.01 ( 0.04 )	0.01 ( 0.28 )	0.02 ( 0.12 )	0.41 ( 0.93 )	0 ( 999 )	0.04 ( 0.49 )	0.09 ( 0.26 )	0.02 ( 0.07 )
HBeAg: Week 24(n=7,8,8,8,12,2,7,9,5)	-0.08 ( 0.1 )	-0.04 ( 0.13 )	-0.39 ( 0.16 )	-0.4 ( 0.21 )	-0.37 ( 0.19 )	-0.19 ( 0.32 )	-0.53 ( 0.3 )	-0.47 ( 0.32 )	-0.46 ( 0.15 )
HBeAg: Week 36(n=7,5,9,4,9,0,10,0,5)	-0.08 ( 0.14 )	-0.05 ( 0.04 )	-0.45 ( 0.2 )	-0.53 ( 0.15 )	-0.43 ( 0.2 )	9999 ( 9999 )	-0.65 ( 0.44 )	9999 ( 9999 )	-0.46 ( 0.26 )
HBeAg: Week 48(n=8,5,9,8,11,2,10,0,0)	-0.06 ( 0.15 )	-0.06 ( 0.06 )	-0.48 ( 0.18 )	-0.48 ( 0.2 )	-0.44 ( 0.19 )	-0.28 ( 0.42 )	-0.69 ( 0.44 )	9999 ( 9999 )	9999 ( 9999 )
HBeAg: FUW 24(n=7,8,8,8,11,3,9,9,5)	-0.19 ( 0.15 )	-0.09 ( 0.12 )	-0.02 ( 1.37 )	-0.42 ( 0.22 )	-0.33 ( 0.19 )	-0.68 ( 0.73 )	-0.56 ( 0.33 )	-0.4 ( 0.37 )	-0.51 ( 0.31 )
HBeAg: FUW 48(n=7,8,9,8,11,0,9,5,0)	-0.36 ( 0.31 )	-0.22 ( 0.11 )	-0.14 ( 1.06 )	-0.38 ( 0.19 )	-0.3 ( 0.16 )	9999 ( 9999 )	-0.5 ( 0.38 )	-0.42 ( 0.47 )	9999 ( 9999 )
HBV RNA: Week 24(n=9,11,10,14,14,2,10,33,6)	0.09 ( 0.43 )	-1.19 ( 1.19 )	-0.7 ( 0.34 )	-0.95 ( 0.6 )	-1.43 ( 0.89 )	-1.34 ( 0.65 )	-0.92 ( 0.92 )	-1.17 ( 1.26 )	-0.81 ( 0.55 )
HBV RNA: Week 36(n=9,6,9,9,9,0,15,0,6)	0.05 ( 0.3 )	-1.66 ( 1.4 )	-0.74 ( 0.41 )	-0.73 ( 0.57 )	-1.67 ( 0.9 )	9999 ( 9999 )	-0.76 ( 0.76 )	9999 ( 9999 )	-0.76 ( 0.56 )
HBV RNA: Week 48(n=10,6,11,15,14,2,15,0,0)	-0.04 ( 0.32 )	-1.66 ( 1.4 )	-0.8 ( 0.48 )	-0.94 ( 0.6 )	-1.43 ( 0.95 )	-1.32 ( 0.68 )	-0.9 ( 0.81 )	9999 ( 9999 )	9999 ( 9999 )
HBV RNA: FUW 24(n=9,11,11,15,14,4,13,10,6)	-0.25 ( 0.28 )	-0.13 ( 0.12 )	-0.68 ( 0.49 )	-0.87 ( 0.59 )	-0.64 ( 0.82 )	-1.04 ( 0.63 )	-0.51 ( 0.63 )	-0.82 ( 0.75 )	-0.81 ( 0.55 )
HBV RNA: FUW 48(n=8,8,11,15,14,0,14,4,2)	-0.43 ( 0.6 )	-0.11 ( 0.19 )	-0.6 ( 0.48 )	-0.78 ( 0.55 )	-0.85 ( 0.75 )	9999 ( 9999 )	-0.37 ( 0.52 )	-0.98 ( 0.8 )	-0.49 ( 0.57 )
HBV DNA: Week 24 (n=0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 9999 )	99999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
HBV DNA: Week 36 (n=0,0,0,0,0,0,0,0,0)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
HBV DNA: Week 48 (n=0,0,0,0,0,0,0,0,0)	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
HBV DNA: FUW 24 (n=27,35,24,24,20,9,21,24,21)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
HBV DNA: FUW 48(n=30,28,2,7,6,1,9,10,8)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Combos 7 and 8:  Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA

Top of page

End point title

Combos 7 and 8:  Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA

End point description

The Cmax was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8. PK population included participants who received at least one dose of the PD-L1 LNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)

End point values	Combo 7 and 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	63
Units: nmol/L
arithmetic mean (standard deviation)	165 ( 60.9 )

No statistical analyses for this end point

Secondary: Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA

Top of page

End point title

Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA

End point description

The AUC was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8. PK population included participants who received at least one dose of the PD-L1 LNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)

End point values	Combo 7 and 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	63
Units: hr*nmol/L
arithmetic mean (standard deviation)	1143 ( 286 )

No statistical analyses for this end point

Secondary: Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA

Top of page

End point title

Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA

End point description

The AUC was predicted and summarized by modelling & simulation via the population pharmacokinetics (PopPK) method based on pre and post dose samples. As per planned analysis data was collected and reported in a pooled manner for Combos 7 and 8. PK population included participants who received at least one dose of the PD-L1 LNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose on Day 1 and up to 168 hours post dose (Week 1)

End point values	Combo 7 and 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	63
Units: hoursnanomoles/liters (hrnmol/L)
arithmetic mean (standard deviation)	1047 ( 273 )

No statistical analyses for this end point

Secondary: Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA

Top of page

End point title

Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA

End point description

End point type

Secondary

End point timeframe

Predose on Day 1 and up to 168 hours post dose (Week 1)

End point values	Combo 7 and 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	63
Units: nanomoles/liters (nmol/L)
arithmetic mean (standard deviation)	163 ( 60.8 )

No statistical analyses for this end point

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA

Top of page

End point title

Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA ^[1]

End point description

The AUC was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. PK population included participants who received at least one dose of the siRNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28

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: This endpoint is assessing PK parameter for Combos 2, 3, 4, 6, 7 and 8 only.

End point values	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	30	30	30	34	33	31
Units: hoursnanograms/millilitres (hrng/mL)
arithmetic mean (standard deviation)	4670 ( 1112 )	11098 ( 2499 )	11073 ( 2272 )	9831 ( 2215 )	9780 ( 1942 )	9110 ( 1418 )

No statistical analyses for this end point

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA

Top of page

End point title

Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA ^[2]

End point description

The Cmax was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. PK population included participants who received at least one dose of the siRNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28

Notes
[2] - 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: This endpoint is assessing PK parameter for Combos 2, 3, 4, 6, 7 and 8 only.

End point values	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	30	30	30	34	33	31
Units: nanograms/millilitres (ng/mL)
arithmetic mean (standard deviation)	190 ( 116 )	463 ( 203 )	450 ( 168 )	408 ( 168 )	373 ( 149 )	311 ( 97 )

No statistical analyses for this end point

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA

Top of page

End point title

Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA ^[3]

End point description

End point type

Secondary

End point timeframe

From predose on Day 29 and multiple timepoints post dose up to Day 56

Notes
[3] - 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: This endpoint is assessing PK parameter for Combos 2, 3, 4, 6, 7 and 8 only.

End point values	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	30	30	30	34	33	31
Units: ng/mL
arithmetic mean (standard deviation)	192 ( 116 )	468 ( 204 )	454 ( 169 )	411 ( 169 )	376 ( 150 )	315 ( 98 )

No statistical analyses for this end point

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA

Top of page

End point title

Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA ^[4]

End point description

The AUC tau was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. PK population included participants who received at least one dose of the siRNA and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

From predose on Day 29 and multiple timepoints post dose up to Day 56

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: This endpoint is assessing PK parameter for Combos 2, 3, 4, 6, 7 and 8 only.

End point values	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	30	30	30	34	33	31
Units: hr*ng/mL
arithmetic mean (standard deviation)	5401 ( 1245 )	12591 ( 2659 )	12623 ( 2428 )	11207 ( 2371 )	11216 ( 2068 )	10513 ( 1511 )

No statistical analyses for this end point

Secondary: Combos 1 and 6: Cmax of TLR7

Top of page

End point title

Combos 1 and 6: Cmax of TLR7 ^[5]

End point description

The Cmax was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. PK population included participants who received at least one dose of the TLR7 and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36

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: This endpoint is assessing PK parameter for Combos 1 and 6 only.

End point values	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 6: siRNA + TLR7 Agonist + NUC
Number of subjects analysed	38	34
Units: ng/mL
arithmetic mean (standard deviation)	1548 ( 419.7 )	1491 ( 334.8 )

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs)

Top of page

End point title

Number of Participants with Adverse Events (AEs)

End point description

An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Safety population included participants randomized to a treatment regimen who received at least one dose of any drug for their assigned treatment regimen, whether prematurely withdrawn from the study or not.

End point type

Secondary

End point timeframe

From Day 1 up to end of 48 weeks of follow up (up to approximately 1.8 years)

End point values	NUC Control Arm	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	35	38	30	30	30	19	34	33	31
Units: participants	27	34	30	29	30	18	33	26	27

No statistical analyses for this end point

Secondary: Combos 1 and 6: AUC of TLR7

Top of page

End point title

Combos 1 and 6: AUC of TLR7 ^[6]

End point description

The AUC was predicted and summarized by modelling & simulation via the PopPK method based on pre and post dose samples. PK population included participants who received at least one dose of the TLR7 and had at least one evaluable post-baseline PK sample.

End point type

Secondary

End point timeframe

Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36

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: This endpoint is assessing PK parameter for Combos 1 and 6 only.

End point values	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 6: siRNA + TLR7 Agonist + NUC
Number of subjects analysed	38	34
Units: ng*hr/mL
arithmetic mean (standard deviation)	3139 ( 938.8 )	2813 ( 75.33 )

No statistical analyses for this end point

Secondary: Combos 7 and 8: Number of Participants with Anti-PD-L1 Antibodies

Top of page

End point title

Combos 7 and 8: Number of Participants with Anti-PD-L1 Antibodies ^[7]

End point description

Treatment-emergent ADA was defined as participants who seroconverted or experienced a boost in preexisting ADA during the study. Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but develop an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples were greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response). Immunogenicity population included participants who had at least one pre-dose (baseline) or at least one post-dose assessment will be included and analyzed according to the treatment they actually received or were allocated to receive.

End point type

Secondary

End point timeframe

From Day 1 for Combo 7 and 8 up to end of follow up (Up to approximately 2 years)

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: This endpoint is assessing PK parameter for Combos 7 and 8 only.

End point values	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	33	31
Units: participants	16	15

No statistical analyses for this end point

Secondary: Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants with Anti-siRNA Antibodies

Top of page

End point title

Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants with Anti-siRNA Antibodies ^[8]

End point description

Treatment-emergent anti drug antibody (ADA) was defined as participants who seroconverted or experienced a boost in preexisting ADA during the study. Participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but develop an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples were greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 4-fold (treatment-enhanced ADA response). Immunogenicity population included participants who had at least one pre-dose (baseline) or at least one post-dose assessment will be included and analyzed according to the treatment they actually received or were allocated to receive.

End point type

Secondary

End point timeframe

From Day 1 up to end of follow up (up to approximately 4 years)

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: This endpoint is assessing PK parameter for Combos 2, 3, 4, 6, 7 and 8 only.

End point values	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC
Number of subjects analysed	30	30	30	19	34	33	31
Units: participants	3	2	12	1	3	10	14

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Day 1 up to end of 48 week follow up (up to approximately 1.8 years)

Adverse event reporting additional description

Safety population included participants randomized to a treatment regimen who received at least one dose of any drug for their assigned treatment regimen, whether prematurely withdrawn from the study or not.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Combo 1: CpAM + TLR7 Agonist + NUC

Reporting group description

Participants received CpAM, 600 mg tablets, orally, QD for 48 weeks and TLR7 agonist, 150 mg, orally, QOD during Weeks 1-12 and Weeks 25-36 in addition to their background NUC therapy. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Reporting group title

Combo 2: siRNA (100 mg) + NUC

Reporting group description

Participants received siRNA, 100 mg, as a SC injection, Q4W in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Reporting group title

Combo 3: siRNA (200 mg) + NUC

Reporting group description

Reporting group title

Combo 4: siRNA + PEG-IFN + NUC

Reporting group description

Participants received siRNA, 200 mg, as a SC injection, Q4W and PEG-IFN, 180 µg, as a SC injection, QW in addition to their background NUC therapy for 48 weeks. After Week 48, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Reporting group title

Combo 5: siRNA + CpAM + NUC

Reporting group description

Reporting group title

Combo 6: siRNA + TLR7 Agonist + NUC

Reporting group description

Reporting group title

Combo 7: siRNA + PD-L1 LNA + NUC

Reporting group description

Participants received siRNA, 200 mg, as a SC injection, Q4W up to Week 24 and PD-L1 LNA, 2 mg/kg, as a SC injection, QW during Weeks 13-24 in addition to their background NUC therapy for 24 weeks. After Week 24, participants continued NUC treatment during follow-up unless the NUC discontinuation criteria were met.

Reporting group title

Combo 8: siRNA + PD-L1 LNA + NUC

Reporting group description

Reporting group title

NUC Control Arm

Reporting group description

Serious adverse events	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC	NUC Control Arm
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 38 (7.89%)	3 / 30 (10.00%)	4 / 30 (13.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic neuroendocrine tumour
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign hepatic neoplasm
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Large intestine polyp
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Panic reaction
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Vertebral osteophyte
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Fascioliasis
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Combo 1: CpAM + TLR7 Agonist + NUC	Combo 2: siRNA (100 mg) + NUC	Combo 3: siRNA (200 mg) + NUC	Combo 4: siRNA + PEG-IFN + NUC	Combo 5: siRNA + CpAM + NUC	Combo 6: siRNA + TLR7 Agonist + NUC	Combo 7: siRNA + PD-L1 LNA + NUC	Combo 8: siRNA + PD-L1 LNA + NUC	NUC Control Arm
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 38 (86.84%)	27 / 30 (90.00%)	29 / 30 (96.67%)	29 / 30 (96.67%)	18 / 19 (94.74%)	33 / 34 (97.06%)	23 / 33 (69.70%)	25 / 31 (80.65%)	25 / 35 (71.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of liver
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	1	0	0	0	0	0	0
Skin papilloma
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	2 / 30 (6.67%)	1 / 30 (3.33%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	2	1	0	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	2 / 34 (5.88%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	3	0	0	1	1	2	0	1	0
Asthenia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	0	1	0	0	0	1
Pain
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	1	0	0	3	0	0	1
Vessel puncture site bruise
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	1	0	0	0	0
Injection site reaction
subjects affected / exposed	1 / 38 (2.63%)	2 / 30 (6.67%)	9 / 30 (30.00%)	15 / 30 (50.00%)	3 / 19 (15.79%)	7 / 34 (20.59%)	5 / 33 (15.15%)	7 / 31 (22.58%)	1 / 35 (2.86%)
occurrences all number	1	2	16	39	4	10	9	37	1
Fatigue
subjects affected / exposed	5 / 38 (13.16%)	1 / 30 (3.33%)	2 / 30 (6.67%)	7 / 30 (23.33%)	1 / 19 (5.26%)	3 / 34 (8.82%)	3 / 33 (9.09%)	3 / 31 (9.68%)	0 / 35 (0.00%)
occurrences all number	5	1	2	12	1	3	8	3	0
Pyrexia
subjects affected / exposed	6 / 38 (15.79%)	0 / 30 (0.00%)	3 / 30 (10.00%)	7 / 30 (23.33%)	4 / 19 (21.05%)	7 / 34 (20.59%)	1 / 33 (3.03%)	2 / 31 (6.45%)	1 / 35 (2.86%)
occurrences all number	9	0	3	7	4	10	1	2	1
Chest pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	0	1	2	0	0	0	2	2	0
Influenza like illness
subjects affected / exposed	14 / 38 (36.84%)	0 / 30 (0.00%)	0 / 30 (0.00%)	8 / 30 (26.67%)	1 / 19 (5.26%)	16 / 34 (47.06%)	0 / 33 (0.00%)	4 / 31 (12.90%)	0 / 35 (0.00%)
occurrences all number	62	0	0	12	1	38	0	6	0
Thirst
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Sensation of foreign body
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Reproductive system and breast disorders
Prostatic calcification
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	3 / 30 (10.00%)	5 / 30 (16.67%)	0 / 19 (0.00%)	3 / 34 (8.82%)	1 / 33 (3.03%)	4 / 31 (12.90%)	1 / 35 (2.86%)
occurrences all number	0	0	3	5	0	3	1	4	1
Rhinorrhoea
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	3 / 33 (9.09%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	0	0	0	0	0	3	1	1
Oropharyngeal pain
subjects affected / exposed	0 / 38 (0.00%)	4 / 30 (13.33%)	1 / 30 (3.33%)	2 / 30 (6.67%)	3 / 19 (15.79%)	1 / 34 (2.94%)	2 / 33 (6.06%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	0	5	1	2	3	1	2	1	1
Epistaxis
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	0	1	1	6	0	0	0	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	3 / 30 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	0	0	1	3	0	0	1	1	0
Depression
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	1	1	0	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	4 / 38 (10.53%)	1 / 30 (3.33%)	1 / 30 (3.33%)	12 / 30 (40.00%)	0 / 19 (0.00%)	6 / 34 (17.65%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	4	2	3	24	0	11	0	0	1
Thyroxine free decreased
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Blood uric acid increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	2 / 35 (5.71%)
occurrences all number	0	1	0	2	0	0	0	0	3
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	7 / 30 (23.33%)	1 / 19 (5.26%)	1 / 34 (2.94%)	2 / 33 (6.06%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	9	1	1	2	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	0	8	0	1	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 38 (7.89%)	6 / 30 (20.00%)	10 / 30 (33.33%)	21 / 30 (70.00%)	7 / 19 (36.84%)	11 / 34 (32.35%)	4 / 33 (12.12%)	2 / 31 (6.45%)	1 / 35 (2.86%)
occurrences all number	4	11	17	32	7	21	4	3	1
Amylase increased
subjects affected / exposed	0 / 38 (0.00%)	5 / 30 (16.67%)	5 / 30 (16.67%)	6 / 30 (20.00%)	1 / 19 (5.26%)	5 / 34 (14.71%)	3 / 33 (9.09%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	0	6	5	14	1	6	3	1	1
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	1 / 30 (3.33%)	5 / 30 (16.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	2	0	1	7	0	0	0	2	0
White blood cell count decreased
subjects affected / exposed	4 / 38 (10.53%)	1 / 30 (3.33%)	1 / 30 (3.33%)	8 / 30 (26.67%)	0 / 19 (0.00%)	5 / 34 (14.71%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	4	2	4	14	0	11	0	0	1
Electrocardiogram PR shortened
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Cystatin C increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	5	0	1	0	0	0
Lipase increased
subjects affected / exposed	0 / 38 (0.00%)	3 / 30 (10.00%)	3 / 30 (10.00%)	2 / 30 (6.67%)	3 / 19 (15.79%)	2 / 34 (5.88%)	4 / 33 (12.12%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	0	4	5	4	5	4	4	1	0
Blood bilirubin increased
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	3 / 30 (10.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	5	4	0	1	0	1	0	0
Weight decreased
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	2 / 35 (5.71%)
occurrences all number	1	1	0	3	0	0	0	0	2
Alanine aminotransferase increased
subjects affected / exposed	4 / 38 (10.53%)	13 / 30 (43.33%)	13 / 30 (43.33%)	25 / 30 (83.33%)	10 / 19 (52.63%)	15 / 34 (44.12%)	6 / 33 (18.18%)	6 / 31 (19.35%)	3 / 35 (8.57%)
occurrences all number	5	22	21	39	16	25	6	8	3
Blood phosphorus decreased
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Glutamate dehydrogenase increased
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	3 / 30 (10.00%)	5 / 30 (16.67%)	1 / 19 (5.26%)	2 / 34 (5.88%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	0	3	12	1	2	0	1	1
Platelet count decreased
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	17 / 30 (56.67%)	1 / 19 (5.26%)	3 / 34 (8.82%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	0	0	26	1	3	0	0	1
Protein urine present
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	8 / 30 (26.67%)	2 / 19 (10.53%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	12	2	1	0	0	0
Injury, poisoning and procedural complications
Product dose omission issue
subjects affected / exposed	2 / 38 (5.26%)	13 / 30 (43.33%)	14 / 30 (46.67%)	19 / 30 (63.33%)	2 / 19 (10.53%)	15 / 34 (44.12%)	0 / 33 (0.00%)	0 / 31 (0.00%)	13 / 35 (37.14%)
occurrences all number	3	14	14	23	7	33	0	0	13
Overdose
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 30 (3.33%)	3 / 19 (15.79%)	1 / 34 (2.94%)	4 / 33 (12.12%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	0	1	1	3	1	4	1	1
Muscle strain
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Accidental overdose
subjects affected / exposed	8 / 38 (21.05%)	5 / 30 (16.67%)	6 / 30 (20.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	4 / 34 (11.76%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	10	5	6	0	1	6	0	0	1
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Ventricular extrasystoles
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	5	0	0	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	1	1	0	1	0	0	0	1
Sinus arrhythmia
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	3 / 30 (10.00%)	1 / 30 (3.33%)	2 / 19 (10.53%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	3	4	1	2	0	0	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	5 / 34 (14.71%)	1 / 33 (3.03%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	4	0	1	2	0	12	1	1	0
Headache
subjects affected / exposed	5 / 38 (13.16%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	3 / 34 (8.82%)	2 / 33 (6.06%)	3 / 31 (9.68%)	0 / 35 (0.00%)
occurrences all number	24	0	0	1	1	6	3	4	0
Hypoaesthesia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	2 / 34 (5.88%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	2	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 19 (10.53%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	0	2	0	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	4 / 30 (13.33%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	6	0	1	0	0	0
Lymphopenia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	3	0	1	1	0	0
Monocytopenia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 19 (10.53%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Neutropenia
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	5 / 30 (16.67%)	2 / 19 (10.53%)	2 / 34 (5.88%)	2 / 33 (6.06%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	1	2	0	5	2	2	2	2	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	1	1	0	0	0	0
Ear discomfort
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	2	1	0	0	0	0
Gastrointestinal disorders
Chronic gastritis
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	1	0	0	3	0	0	0
Gingival bleeding
subjects affected / exposed	2 / 38 (5.26%)	0 / 30 (0.00%)	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	3	0	0	3	0	1	0	0	0
Abdominal discomfort
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0	0
Abdominal pain
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 33 (3.03%)	3 / 31 (9.68%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	1	2	4	0
Periodontal disease
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	2 / 30 (6.67%)	4 / 30 (13.33%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	2	6	0	1	0	0	0
Dental caries
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 38 (5.26%)	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	3 / 34 (8.82%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	1	0	1	0	4	2	0	0
Nausea
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 30 (6.67%)	1 / 19 (5.26%)	1 / 34 (2.94%)	2 / 33 (6.06%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	2	1	0	2	1	3	8	1	1
Abdominal pain upper
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 30 (6.67%)	4 / 19 (21.05%)	4 / 34 (11.76%)	1 / 33 (3.03%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	0	1	4	5	4	2	1	1
Dyspepsia
subjects affected / exposed	2 / 38 (5.26%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	0	0	0	0	0	0	1
Diarrhoea
subjects affected / exposed	1 / 38 (2.63%)	2 / 30 (6.67%)	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 19 (10.53%)	2 / 34 (5.88%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	3	0	1	2	2	0	1	1
Flatulence
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Mouth ulceration
subjects affected / exposed	2 / 38 (5.26%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 19 (10.53%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0	1	2	2	0	0	0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0
Hepatic steatosis
subjects affected / exposed	1 / 38 (2.63%)	7 / 30 (23.33%)	3 / 30 (10.00%)	6 / 30 (20.00%)	1 / 19 (5.26%)	2 / 34 (5.88%)	3 / 33 (9.09%)	0 / 31 (0.00%)	4 / 35 (11.43%)
occurrences all number	1	8	3	6	1	2	3	0	4
Cholelithiasis
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	2 / 34 (5.88%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	1	0	2	1	0	0
Hepatic cyst
subjects affected / exposed	2 / 38 (5.26%)	2 / 30 (6.67%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	2	1	2	0	1	0	0	1
Liver disorder
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Hepatic mass
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	2	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 38 (5.26%)	1 / 30 (3.33%)	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	1	1	1	0	0	0	0	0
Alopecia
subjects affected / exposed	1 / 38 (2.63%)	2 / 30 (6.67%)	1 / 30 (3.33%)	5 / 30 (16.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	2	1	5	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0	0
Pruritus
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	3 / 30 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	1 / 31 (3.23%)	0 / 35 (0.00%)
occurrences all number	1	0	0	3	0	0	1	2	0
Ecchymosis
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome
subjects affected / exposed	2 / 38 (5.26%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Back pain
subjects affected / exposed	2 / 38 (5.26%)	1 / 30 (3.33%)	3 / 30 (10.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	0 / 34 (0.00%)	2 / 33 (6.06%)	3 / 31 (9.68%)	0 / 35 (0.00%)
occurrences all number	2	2	3	1	1	0	2	3	0
Pain in extremity
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	2 / 30 (6.67%)	2 / 30 (6.67%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	1	0	3	4	0	1	0	1	2
Arthralgia
subjects affected / exposed	2 / 38 (5.26%)	3 / 30 (10.00%)	3 / 30 (10.00%)	1 / 30 (3.33%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 33 (0.00%)	2 / 31 (6.45%)	1 / 35 (2.86%)
occurrences all number	2	3	4	1	0	3	0	3	1
Intervertebral disc protrusion
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 19 (10.53%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1	0	3	0	0	0	1
Myalgia
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	3 / 30 (10.00%)	1 / 19 (5.26%)	3 / 34 (8.82%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 35 (0.00%)
occurrences all number	1	1	0	4	1	4	0	2	0
Infections and infestations
Herpes virus infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
COVID-19
subjects affected / exposed	6 / 38 (15.79%)	10 / 30 (33.33%)	16 / 30 (53.33%)	17 / 30 (56.67%)	3 / 19 (15.79%)	17 / 34 (50.00%)	3 / 33 (9.09%)	4 / 31 (12.90%)	8 / 35 (22.86%)
occurrences all number	6	10	17	17	3	18	3	4	8
Hepatitis B reactivation
subjects affected / exposed	0 / 38 (0.00%)	6 / 30 (20.00%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	10 / 34 (29.41%)	4 / 33 (12.12%)	7 / 31 (22.58%)	3 / 35 (8.57%)
occurrences all number	0	6	1	2	0	10	4	7	3
Gingivitis
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	1 / 30 (3.33%)	0 / 30 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	3	1	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	0	2	0	2	0	0	0	0	1
Conjunctivitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	4 / 30 (13.33%)	1 / 30 (3.33%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	5	1	0	2	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	2	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	4 / 38 (10.53%)	14 / 30 (46.67%)	11 / 30 (36.67%)	13 / 30 (43.33%)	5 / 19 (26.32%)	4 / 34 (11.76%)	1 / 33 (3.03%)	2 / 31 (6.45%)	4 / 35 (11.43%)
occurrences all number	5	24	16	16	6	6	1	4	4
Nasopharyngitis
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	0 / 30 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	2 / 33 (6.06%)	4 / 31 (12.90%)	0 / 35 (0.00%)
occurrences all number	1	1	0	0	0	0	2	5	0
Sinusitis
subjects affected / exposed	1 / 38 (2.63%)	1 / 30 (3.33%)	0 / 30 (0.00%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	1	0	2	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 38 (2.63%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	2 / 19 (10.53%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	1	0	0	1	2	0	0	0	0
Hyperuricaemia
subjects affected / exposed	1 / 38 (2.63%)	6 / 30 (20.00%)	6 / 30 (20.00%)	3 / 30 (10.00%)	1 / 19 (5.26%)	2 / 34 (5.88%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	9	9	5	1	3	0	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	1 / 30 (3.33%)	2 / 30 (6.67%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	2	4	3	0	0	0	0	0
Hyperphosphataemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 30 (3.33%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	1	1	1	0	0	0	0
Dyslipidaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 30 (3.33%)	0 / 30 (0.00%)	3 / 30 (10.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	1	0	3	1	0	1	0	0
Hyperlipidaemia
subjects affected / exposed	0 / 38 (0.00%)	6 / 30 (20.00%)	7 / 30 (23.33%)	1 / 30 (3.33%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 35 (2.86%)
occurrences all number	0	10	15	1	0	11	0	1	1
Hypocalcaemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 30 (0.00%)	0 / 30 (0.00%)	1 / 30 (3.33%)	1 / 19 (5.26%)	0 / 34 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 38 (0.00%)	2 / 30 (6.67%)	1 / 30 (3.33%)	1 / 30 (3.33%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 35 (0.00%)
occurrences all number	0	3	2	1	0	1	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

25 Nov 2019

- Enhance the safety monitoring for flu-like symptoms. - NUC analogue stopping criteria were introduced which applied to all arms to increase participants’ safety and reduce the chances of Alanine aminotransferase (ALT) flares after discontinuation. - The follow-up period was extended from 24 to 48 weeks, to comply with American Association for the Study of Liver Diseases (AASLD) guidelines that recommend monitoring for recurrent viremia, ALT flares, seroconversion, and clinical decompensation up to 48 weeks. - History of orthostatic hypotension was added in the exclusion criteria for the CpAM (RO7049389) + TLR7 (RO7020531) + NUC arm as a precautionary measure and to be able to distinguish any potential study drug driven hypotension from pre-existing propensity for hypotension.

20 Jul 2020

- Introduction of an option for RO7020531 dose reduction to 100 mg once every other day (QOD) and to a dosing regimen of 100 mg QW for participants who experience recurrent/repetitive flu-like symptoms to improve tolerablity. - Updated the inclusion criteria for women of childbearing potential (WOCBP) to ”Have a negative pregnancy test at screening (Day -14 to -7)". - An event that leads to hospitalization for administrative reasons, e.g., participant lives far way and is kept in the clinic/hospital for participant and/or site convenience was updated to not considered as serious adverse event (SAE).

14 Oct 2020

Five additional combination treatment arms were added. These new combination treatment arms included a direct-acting antiviral (DAA), which was a siRNA that targets HBV RNA transcripts, thus inhibiting HBV gene expression. These 5 treatment arms were: siRNA + NUC (2 treatment arms), siRNA + PEG-IFN + NUC, siRNA + CpAM + NUC, and siRNA + TLR7 + NUC.

25 Aug 2021

- NUC stopping criteria had been amended - Minor clarifications and updates on the general study exclusion criteria - Addition of tables to summarize existing information on dose interruption, modification, and discontinuation - Exclusion criterion related to systemic use of anti-neoplastic, immunosuppressive, immune modulator, and systemic steroids has been added. - Exclusion criterion related to prohibited medications and prohibited foods has been added.

16 Dec 2021

- Two additional treatment arms had been added with the same treatment combinations siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC but with different treatment durations. - 2D-shear wave elastography [2D-SWE] was added as an acceptable procedure to assess significant liver fibrosis, cirrhosis, or decompensated liver disease. - Hypersensitivity to study drug excipients was added as an exclusion criterion.

18 Jul 2022

- NUC re-starting criteria was amended to enable early detection and prompt management of virological relapse to prevent participants potentially developing liver decompensation. NUC discontinuation criteria was amended to take into account participants with very low HBsAg levels at baseline. - Appendix 13 has been updated to confirm dose selected and provide dose justification for 2.0 mg/kg once a week (QW), including preliminary pre-clinical AAV-HBV data supporting the rationale for combining PD-L1 LNA and siRNA; PD-L1 LNA dosing regimens that are no longer applicable removed

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase II, Randomised, Adaptive, Open-Label Platform Trial to Evaluate Efficacy and Safety of Multiple Combination Therapies in Participants With Chronic Hepatitis B

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)

Primary: Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)

Secondary: Percentage of Participants With HBsAg loss

Secondary: Percentage of Participants With HBsAg loss

Secondary: Percentage of Participants With HBsAg Seroconversion

Secondary: Percentage of Participants With HBsAg Seroconversion

Secondary: Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants

Secondary: Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants

Secondary: Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants

Secondary: Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants

Secondary: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL

Secondary: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL

Secondary: Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time

Secondary: Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time

Secondary: Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA

Secondary: Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA

Secondary: Combos 1 and 6: Cmax of TLR7

Secondary: Combos 1 and 6: Cmax of TLR7

Secondary: Number of Participants with Adverse Events (AEs)

Secondary: Number of Participants with Adverse Events (AEs)

Secondary: Combos 1 and 6: AUC of TLR7

Secondary: Combos 1 and 6: AUC of TLR7

Secondary: Combos 7 and 8: Number of Participants with Anti-PD-L1 Antibodies

Secondary: Combos 7 and 8: Number of Participants with Anti-PD-L1 Antibodies

Secondary: Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants with Anti-siRNA Antibodies

Secondary: Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants with Anti-siRNA Antibodies

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase II, Randomised, Adaptive, Open-Label Platform Trial to Evaluate Efficacy and Safety of Multiple Combination Therapies in Participants With Chronic Hepatitis B

Secondary: Combos 7 and 8:  Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA

Secondary: Combos 7 and 8:  Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA