A Trial To Evaluate The Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B

Phase 2

Completed

Conditions: Hepatitis B, Chronic

Interventions: Drug: Nucleos(t)ide (NUC)
Drug: CpAM (RO7049389)
Drug: siRNA (RO7445482)
Drug: TLR7 (RO7020531)
Drug: PEG-IFN
Drug: PD-L1 LNA (RO7191863)

Registration Number: NCT04225715

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This is a study designed to evaluate the safety, tolerability and efficacy of New Molecular Entity (NME) combination therapies in Chronic Hepatitis B (CHB) participants with preserved liver function and without significant fibrosis/cirrhosis. The platform design allows comparison of multiple NME combination therapies against a common control, and introduction of additional treatment arms at later study time points. Each arm will consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks) and post-treatment follow-up phase (48 weeks). The safety and efficacy will be monitored throughout the study.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 281

Inclusion Criteria

Body mass index between 18 and 32 kg/m2 inclusive.
Participants with Chronic Hepatitis B (CHB) infection (HBsAg positive for >=6 months) who are on established NUC (entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy for >=12 months, having received the same NUC therapy for >=3 months prior to screening.
HBV DNA below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and confirmed at screening.
Alanine transaminase (ALT) <=1.5 x upper limit of normal (ULN) for > 6 months prior to screening and confirmed at screening.
Female Participants: Eligible to participate if she is not pregnant, not breastfeeding and agrees to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods.
Male Participants: During the treatment period and for at least 6 months after the final dose of study treatment, agrees to remain abstinent (refrain from heterosexual intercourse), use contraceptive measures and refrain from donating sperm.

Exclusion Criteria

Pregnant or lactating women.
Co-infection with other pathogens such as Hepatitis A, C, D and E or Human Immunodeficiency Virus (HIV).
History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis or decompensated liver disease.
History of or suspicion of Hepatocellular Carcinoma (HCC).
Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests.
Clinically significant disease other than CHB that, in the opinion of the Investigator, makes the participant unsuitable for the study.
Pre-existing cardiac disease that in the opinion of the investigator would increase the risk for the participant to take part in the study.
History of alcohol abuse and/or drug abuse within one year of randomization.
History of having received (in the last 6 months) or currently receiving any systemic antineoplastic (including radiation) or immunosuppressive (including biologic immunosuppressors) or immune modulating treatment.
Currently taking, or have received within 3 months of Day 1, systemic corticosteroids.
Electrocardiogram (ECG) with clinically significant abnormalities.
Previous treatment with an investigational agent for Hepatitis B (HBV) within 6 months prior to screening.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Nucleos(t)ide (NUC) Control Arm	Nucleos(t)ide (NUC)	Participants will continue their background NUC therapy for the 48-week treatment period. At the end of the treatment period, in line with current CHB treatment guidelines, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC	CpAM (RO7049389)	Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC	TLR7 (RO7020531)	Participants will receive RO7049389 (600 mg once daily \[QD\]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day \[QOD\]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) (Dose 2) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) (Dose 2) + NUC	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC	PEG-IFN	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + CpAM (RO7049389) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + CpAM (RO7049389) + NUC	CpAM (RO7049389)	Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + CpAM (RO7049389) + NUC	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + TLR7 (RO7020531) + NUC	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + TLR7 (RO7020531) + NUC	TLR7 (RO7020531)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + TLR7 (RO7020531) + NUC	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]	PD-L1 LNA (RO7191863)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]	Nucleos(t)ide (NUC)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]	siRNA (RO7445482)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]	PD-L1 LNA (RO7191863)	Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)	Follow-up Week (FUW) 24	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. Percentages have been rounded off.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With HBsAg Loss	Combos 1 and 5: Weeks 24, 36, 48 and FUW 48; Combos 2, 3, 4, 6 and NUC Arm: Week 48 and FUW 48; Combo 7: Week 24; Combo 8: Week 36	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.
Percentage of Participants With HBsAg Seroconversion	Combos 1 and 5: Weeks 24, 36, 48, FUW 24 and FUW 48; 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	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.
Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants	Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48	HBeAg loss was defined as negative /non-reactive HBeAg level. Percentages have been rounded off.
Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants	Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48	HBeAg seroconversion was defined as a negative /non-reactive HBeAg level and a positive anti-HBe antibody. Percentages have been rounded off.
Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL	FUW 12, 24, 36, and 48	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.
Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time	HBsAg, Anti-HBs, HBeAg & HBV RNA: Combo 1 to 6 and NUC arm: Weeks 24, 36, 48, FUW 24 and FUW 48; Combo 7: Week 24, FUW 24 & FUW 48; Combo 8: Weeks 24, 36, FUW 24 & FUW 48; HBV DNA: FUW 24 and FUW 48	The serological markers of HBV infection include viral antigens (HBsAg \& HBeAg) and antibody (anti-HBs). Changes in serological markers and efficacy biomarkers (HBV RNA) from baseline are reported. Change from baseline for HBV DNA was assessed in 'ON NUC' participants.
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	Predose on Day 1 and up to 168 hours post dose (Week 1)	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.
Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA	Predose on Day 1 and up to 168 hours post dose (Week 1)	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.
Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA	Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)	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.
Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA	Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12)	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.
Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA	Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28	The AUC was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA	From Day 29 up to Day 56	The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. Simulations for the dosing interval between Day 29 and Day 56 was done using population PK modeling informed by sparse PK samples collected on Days 1, 85, 169, 253, and 337 at predose, 1-3 hours, and 4-6 hours post dose.
Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA	Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28	The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
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	From Day 29 up to Day 56	The AUC tau was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples. Simulations for the dosing interval between Day 29 and Day 56 was done using population PK modeling informed by sparse PK samples collected on Days 1, 85, 169, 253, and 337 at predose, 1-3 hours, and 4-6 hours post dose.
Combos 1 and 6: AUC of TLR7	Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36	The AUC was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Combos 1 and 6: Cmax of TLR7	Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36	The Cmax was predicted and summarized by modelling \& simulation via the PopPK method based on pre and post dose samples.
Number of Participants With Adverse Events (AEs)	From Day 1 up to end of 48 weeks of follow up (up to approximately 1.8 years)	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.
Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants With Anti-siRNA Antibodies	From Day 1 up to end of follow up (up to approximately 4 years)	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).
Combos 7 and 8: Number of Participants With Anti-PD-L1 Antibodies	From Day 1 for Combo 7 and 8 up to end of follow up (Up to approximately 2 years)	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).

Trial Locations

Locations (33): Tokuda Hospital Sofia
🇧🇬
Sofia, Bulgaria
University Multiprofile Hospital For Active Treatment "Sveti Ivan Rilski" EAD
🇧🇬
Sofia, Bulgaria
University of Calgary
🇨🇦
Calgary, Alberta, Canada
Hopital Beaujon
🇫🇷
Clichy, France
Hospital Alvaro Cunqueiro
🇪🇸
Vigo, Pontevedra, Spain
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳
Kaohsiung City, Taiwan
China Medical University Hospital
🇨🇳
Taichung, Taiwan
HIVNAT
🇹🇭
Bangkok, Thailand
Uni of Alberta Hospital
🇨🇦
Edmonton, Alberta, Canada
Toronto Liver Centre
🇨🇦
Toronto, Ontario, Canada
Scroll for more (23 remaining)
Tokuda Hospital Sofia
🇧🇬Sofia, Bulgaria