---
title: "Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: B-Clear"
description: "Formulary evidence on Hibsago (bepirovirsen, GSK3228836) in Chronic hepatitis B virus infection in adults without cirrhosis: B-Clear. Covers Objective, Location and study date, Study design, Eligibility criteria, Treatment, Study outcomes, and 3 further headings. 83 evidence topics quoted from 13 sources."
canonical: "https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence/b-clear"
published: "2026-10-21T22:39:04-04:00"
modified: "2026-10-22T19:07:03-04:00"
---
# Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: B-Clear
## 3.1.3 B-Clear
### 3.1.3.1 Objective
#### Aim stated in the primary publication
> “We conducted a phase 2b trial (B-Clear) to investigate the efficacy and safety of 12- and 24-week bepirovirsen treatment in participants with chronic HBV infection either receiving stable NA therapy or not receiving NA therapy.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Primary objective stated in the design publication
> “The primary objective of the B-Clear study was to assess the efficacy of three dosing regimens of bepirovirsen: 24 weeks of treatment, 12 weeks of treatment with 12 weeks step-down dosing, and 12 weeks of treatment (with or without loading dose [LD]) in participants with chronic HBV infection on stable NA therapy or not currently receiving NA therapy.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Objective stated in the ClinicalTrials.gov record
> “This study is intended to evaluate if treatment with GSK3228836 can achieve sustained virologic response (SVR), that is hepatitis B virus surface antigen (HBsAg) less than (<) lower limit of quantitation (LLOQ) and HBV deoxyribonucleic acid (DNA) “This study will assess the efficacy and safety of treatment with GSK3228836 in two populations of participants with CHB; participants on stable nucleos(t)ide treatment (Cohort 1) and participants who are not currently on nucleos(t)ide therapy (Cohort 2).”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Primary objective in the protocol
> “Efficacy: To assess the efficacy of the three dosing regimens of GSK3228836 in participants with CHB”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
#### Aim stated in the company release of results
> “The B-Clear phase IIb trial investigated the efficacy and safety of 12 or 24 weeks of treatment with bepirovirsen in people with CHB on stable NA treatment or not-on-NA treatment at study start.”
Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)
### 3.1.3.2 Location and Study Date
#### Study dates and status in the ClinicalTrials.gov record
| Field | Registry value |
| --- | --- |
| Study start (actual) | “2020-07-27” |
| Primary completion (actual) | “2022-03-18” |
| Study completion (actual) | “2022-03-18” |
| First posted | “2020-06-26” |
| Results first posted | “2023-05-16” |
| Last update posted | “2023-05-16” |
| Status | “Completed” |
| Other study ID | “209668” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Number of locations in the ClinicalTrials.gov record
> “This study has 121 locations”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Trial dates, sites, and countries in the primary publication
> “B-Clear was a phase 2b, randomized, parallel-cohort trial conducted from July 27, 2020, to March 18, 2022, at 123 sites in 22 countries”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Sites enrolling both cohorts and last participant visit
> “Investigators were able to recruit both On-NA and Not-on-NA participants to the same study; 68% (47/69) of sites had participants in both cohorts.”
> “The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Presentation of end-of-study results
> “The end of study results will be presented today at the American Association for the Study of Liver Diseases’ Liver Meeting 2022 (AASLD) in Washington DC, and simultaneously published in the New England Journal of Medicine.”
Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)
### 3.1.3.3 Study Design
#### Phase 2b, randomized, investigator-unblinded parallel-cohort design
> “We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy.”
> “The trial sponsor and participants were unaware of the trial-group assignments, which were known to the investigators. Randomization was performed with the use of an interactive Web-response system, with stratification according to hepatitis B e antigen (HBeAg) status (positive or negative) and baseline HBsAg level (≤3 or >3 log10 IU per milliliter).”
> “Participants were followed for up to 55 weeks, with a 24-week treatment period and a 24-week follow-up period. Participants receiving NA therapy continued such therapy during the trial.”
> “An independent data monitoring committee reviewed unblinded data.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Design details in the ClinicalTrials.gov record
| Field | Registry value |
| --- | --- |
| Primary purpose | “Treatment” |
| Allocation | “Randomized” |
| Interventional model | “Parallel Assignment” |
| Interventional model description | “Participants with CHB will be divided into two different cohorts; participants on stable nucleos(t)ide treatment and participants not currently on nucleos(t)ide therapy. For each cohort, participants will be randomized into one of the 4 different parallel arms to receive treatment.” |
| Masking | “Single (Participant)” |
| Masking description | “Participants will be blinded to the study treatment.” |
| Phase | “Phase 2” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Partial-blind design and screening period in the design publication
> “B-Clear was a phase 2b, multicenter, randomized, partial blind (sponsor/participant-blinded, investigator-unblinded) parallel-cohort trial that enrolled people with chronic HBV infection receiving stable NA therapy (On-NA) and not currently receiving NA therapy (Not-on-NA).”
> “Participants were followed for up to 55 weeks, including a screening period of up to 45 days, a 24-week treatment period, and a 24-week follow-up period (Fig. 1).”
> “As the primary endpoint was based on objective laboratory measurements (HBsAg and HBV DNA), unblinding of site staff would not compromise the assessment of this endpoint, although initiation of rescue medication based on the investigator’s judgment would result in failure to meet the endpoint.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Two cohorts combined in one protocol
> “This trial administratively combined two studies in different HBV populations into one protocol, providing insight into the potential benefits of bepirovirsen for those on NA therapy and those not currently receiving NA therapy.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Placebo-first arm as a safety comparator
> “Although no full placebo arm was included, arm 4 was intended to serve as a comparator of safety in the first 12 weeks of treatment, including exploratory analyses such as inflammatory and immune activation biomarkers. In addition, arm 4 enables assessment of 12-week active treatment without LD.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Rationale for unblinding site staff in the protocol
> “A partial blind study (participant and sponsor blinded, site staff unblinded) was chosen because there is a high probability that the PI and site staff could infer treatment assignment due to:”
> “Differences in the injection force due to the viscosity of GSK3228836 versus placebo saline.”
> “The comparisons/assessments for the placebo-first arm are not statistically powered.”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
#### Protocol amendment 2: nucleos(t)ide analogue initiation during suspected flares
> “The primary driver for this amendment was a request from a regulatory agency to include nucleos(t)ide analogue (NA) therapy initiation until hepatitis B flare could be ruled out (specifically for the patients who are not receiving NA therapy at baseline).”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
### 3.1.3.4 Eligibility Criteria
#### Key eligibility criteria in the primary publication
> “Participants were 18 years of age or older with documented chronic HBV infection for at least 6 months and an HBsAg level of more than 100 IU per milliliter. Participants who were receiving NA therapy were on a stable NA regimen and had an HBV DNA level of less than 90 IU per milliliter and an alanine aminotransferase (ALT) level less than or equal to 2 times the upper limit of the normal range. Participants who were not receiving NA therapy had never received such therapy or had ended NA therapy at least 6 months before screening and had an HBV DNA level of more than 2000 IU per milliliter and an ALT level of less than 3 times the upper limit of the normal range.”
> “Key exclusion criteria were the presence of hepatitis C, human immunodeficiency, or hepatitis D virus infection; cirrhosis; hepatocellular carcinoma; and interferon-containing therapy within 12 months before screening”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Cohort definitions in the design publication
> “Participants were included in the On-NA population if they had no changes in their NA regimen for ≥ 6 months before screening, with no planned changes to the regimen for the duration of the study, and had a HBsAg concentration > 100 IU/mL, HBV DNA concentration < 90 IU/mL, and ALT ≤ 2 × ULN.”
> “Participants were included in the Not-on-NA population if they had either never received HBV treatment or ended NA therapy ≥ 6 months before screening or interferon-containing therapy ≥ 12 months before screening, and had a HBsAg concentration > 100 IU/mL, HBV DNA concentration > 2000 IU/mL, and ALT < 3 × ULN.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Inclusion criteria in the ClinicalTrials.gov record: HBsAg, HBV DNA, and ALT
> “Plasma or serum HBsAg concentration >100 international units per milliliter (IU/mL).”
> “Plasma or serum HBV DNA concentration: Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 IU/mL; Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA <90 IU/mL.”
> “ALT for treatment naive participants and for participants who are not currently receiving treatment: ALT <3 times ULN will be included initially if agreed by the independent data monitoring committee (IDMC) after review of safety data, the ALT inclusion criteria may be expanded to include participants with ALT <5 times ULN; ALT less than equal to (<=2) times ULN for participants who are receiving stable nucleos(t)ide analogue therapy.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Exclusion criteria in the ClinicalTrials.gov record: coinfection, cirrhosis, and hepatocellular carcinoma
> “Co-infection with Current or past history of Hepatitis C virus (HCV), Human immunodeficiency virus (HIV), Hepatitis D virus (HDV).”
> “History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7.”
> “Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following criteria, they will be excluded from the study: Liver biopsy (i.e., Metavir Score F4); Liver stiffness >12 kilopascals (kPa).”
> “Diagnosed or suspected hepatocellular carcinoma as evidenced by the following: Alpha-fetoprotein concentration >=200 nanogram per milliliter (ng/mL)”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Exclusion criteria in the ClinicalTrials.gov record: vasculitis, immune conditions, and prior therapy
> “History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause) or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).”
> “History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).”
> “Currently taking, or took within 12 months of screening, any interferon-containing therapy.”
> “Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or anti-platelet agents like clopidogrel).”
> “Prior treatment with any oligonucleotide or small interfering ribonucleic acid (RNA) (Small interfering RNA [siRNA]) within 12 months prior to the first dosing day.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Exclusion criteria in the ClinicalTrials.gov record: laboratory values and QTc
> “Fridericia's QT correction formula (QTcF) >=450 milliseconds (msec)”
> “Laboratory results as follows: Serum albumin <3.5 grams per deciliter (g/dL), Glomerular filtration rate (GFR) <60 milliliter per minute per 1.73 square meter (mL/min /1.73 m^2) as calculated by the Chronic Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula”
> “International normalized ratio (INR) >1.25. Platelet count <140 times 10^9 cells/L, Total bilirubin >1.25 times ULN.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Age, sex, and healthy volunteers in the ClinicalTrials.gov record
| Field | Registry value |
| --- | --- |
| Ages eligible for study | “18 Years and older (Adult, Older Adult )” |
| Sexes eligible for study | “All” |
| Accepts healthy volunteers | “No” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
### 3.1.3.5 Treatment
#### Four regimens randomized 3:3:3:1
> “Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4)”
> “Loading doses of bepirovirsen (300 mg, in groups 1, 2, and 3) or placebo (in group 4) were administered on days 4 and 11.”
> “Doses were administered once weekly as two subcutaneous injections (two syringes total; one syringe contained either bepirovirsen at a dose of 150 mg or placebo).”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Injections per arm in the design publication
> “Participants in arm 1 received bepirovirsen 300 mg (administered as two 150 mg injections) for 24 weeks, with a bepirovirsen 300 mg LD. In arm 2, participants received bepirovirsen 300 mg for 12 weeks, with a bepirovirsen 300 mg LD, then a step-down in dose to a single injection of 150 mg and a placebo injection for 12 weeks. In arm 3, participants received 12 weeks of bepirovirsen 300 mg, with a bepirovirsen 300 mg LD, then placebo (administered as two injections) for 12 weeks to maintain blinded treatment.”
> “In arm 4, participants received placebo (administered as two injections) for 12 weeks (with a placebo LD) then bepirovirsen 300 mg without LD for 12 weeks.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Background nucleos(t)ide analogue therapy and criteria for initiating it
> “Participants On-NA therapy at baseline were expected to continue their NA therapy without changes for the study duration. Participants not receiving NA therapy at baseline were expected to remain off NA throughout the study.”
> “For these participants, NA therapy initiation was permitted if they had alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN; 40 IU/L [male participants] or 33 IU/L [female participants]) and bilirubin > 1.5 × ULN (18.81 µmol/L), and until other tests (e.g., HBV DNA, HBsAg) ruled out hepatitis B flare.”
> “NA therapy initiation was also permitted in arms 1–3 in case of virological breakthrough (defined as ≥ 1 log increase from nadir of HBV DNA or HBV DNA becoming quantifiable after being below the lower limit of quantification [LLOQ] at two sequential visits), virological non-response (< 1 log reduction in HBsAg by week 12) or partial response (> 1 log decline in HBV DNA, but subsequent plateau of HBV DNA levels such that achievement of HBV DNA below LLOQ was considered unlikely) to prevent development of resistance.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Study drug formulation in the ClinicalTrials.gov record
> “GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly.”
> “Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
#### Rationale for the loading doses and the step-down regimen in the protocol
> “The loading schedule (i.e., loading doses) in Week 1 (Day 4) and Week 2 (Day 11) were included in order to accelerate the achievement of steady state concentration in the liver to increase the likelihood of observing anti-HBV activity during a short treatment duration.”
> “Study 209668 will also explore the impact on efficacy and safety of decreasing overall exposure to GSK3228836 by administrating a step-down dose of 150 mg GSK3228836 for 12 weeks after an initial 12 weeks of 300 mg GSK3228836 dose.”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
### 3.1.3.6 Study Outcomes
#### 3.1.3.6.1 Rationale for Using Sustained HBsAg and HBV DNA Loss as the Primary Endpoint
##### Primary outcome definition and its purpose in the primary publication
> “To assess durability of response, the primary efficacy outcome was HBsAg and HBV DNA loss for 24 weeks after the discontinuation of bepirovirsen treatment in the absence of newly initiated antiviral treatment.”
> “The primary composite efficacy outcome was an HBsAg level below the lower limit of detection (0.05 IU per milliliter) and an HBV DNA level below the lower limit of quantification (20 IU per milliliter) maintained for 24 weeks after the planned end of bepirovirsen treatment in the absence of any medication initiated for the purpose of suppressing HBV replication (groups 1, 2, and 3)”
> “Group 4 (placebo-first group) was included to allow evaluation of the effect of a loading dose and evaluation of safety in the first 12 weeks, but the trial was not powered to assess the primary outcome in this group.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Functional cure as the goal of therapy and its rarity with nucleos(t)ide analogues
> “The goal of therapy is to achieve functional cure”
> “fewer than 5% of patients have HBsAg loss after 12 months of treatment”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Functional cure as the optimal endpoint: design publication
> “While functional cure (durable undetectable hepatitis B virus [HBV] DNA and hepatitis B surface antigen [HBsAg] loss with or without HBsAg seroconversion) is the optimal endpoint for new chronic HBV therapies, this is rarely achieved with current standard of care despite long-term, sometimes often life-long, treatment.”
> “While the optimal goal for new HBV therapies is both HBsAg and HBV DNA loss, most previous HBV studies have focused on assessment of HBV DNA levels only [12].”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
##### Rescue medication and visit requirements for the primary endpoint
> “Rescue medication was defined as any medication initiated for the purpose of suppressing HBV replication, including administration of NA in the Not-on-NA population. The response should be maintained at every visit (at least every 8 weeks) until 24 weeks after the end of bepirovirsen treatment.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
##### Interpretation of the endpoint in each cohort
> “While this response cannot be considered equivalent to functional cure, as a result of the continuation of background NA therapy, it allowed determination of whether administration of bepirovirsen as an adjunct to NA therapy can increase the likelihood of functional cure.”
> “Treatment outcomes for the Not-on-NA participants, who receive bepirovirsen monotherapy, established the potential for bepirovirsen to achieve functional cure and to become an additional option for standard of care treatment of people living with hepatitis B.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
##### Clinically meaningful sustained virologic response with a finite course: protocol
> “The proposed Phase 2b study (209668) will evaluate whether up to 24 weeks treatment with GSK3228836 results in a clinically meaningful rate of sustained virologic response (SVR, HBsAg “Taken together, the data suggest that a longer duration of GSK3228836 therapy may be required to both increase the rate of seroclearance and to achieve sustained seroclearance.”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
##### Primary outcome measure in the ClinicalTrials.gov record
| Field | Registry value |
| --- | --- |
| Outcome measure | “Number of Participants Achieving Sustained Virologic Response (SVR)” |
| Measure description | “The SVR was a composite endpoint defined as Hepatitis B surface antigen (HBsAg) and Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) levels were less than (<) Lower limit of quantitation (LLOQ) at the planned end of GSK3228836 treatment which is sustained for 24 weeks post-GSK3228836 treatment in the absence of rescue medication.” |
| Time frame | “Up to Week 48” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029)
##### Modified primary outcome permitting blips
> “An additional prespecified analysis used a modified version of the primary outcome that permitted “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in the response”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Secondary efficacy and safety outcomes
> “Secondary efficacy outcomes included the difference between groups 1 and 2, groups 1 and 3, and groups 2 and 3 in the proportion of participants having a primary-outcome event; the proportion of participants having an HBsAg level below the lower limit of detection and an HBV DNA level below the lower limit of quantification at the end of treatment; log changes from baseline in HBsAg and HBV DNA levels (according to category of HBsAg or HBV DNA level); actual values and change from baseline in HBsAg, HBV DNA, HBeAg, and anti-HBs levels; and ALT normalization (ALT level less than or equal to the upper limit of the normal range) in the absence of newly initiated antiviral treatment in participants with an ALT level above the upper limit of the normal range at baseline.”
> “Increases in ALT levels, as well as class effects of antisense oligonucleotides (renal injury, injection-site reactions, thrombocytopenia, and vascular inflammation and complement activation), were evaluated as adverse events of special interest”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
### 3.1.3.7 Statistical Analysis Description
#### 3.1.3.7.1 Number of Participants (Planned and Analyzed)
##### Planned sample size and its Bayesian basis
> “We planned to enroll approximately 440 participants: approximately 66 participants receiving NA therapy and 66 not receiving NA therapy in each of groups 1, 2, and 3 and approximately 22 participants receiving NA therapy and 22 not receiving NA therapy in group 4. This sample size was chosen on the basis of a Bayesian model and selected to provide at least a 75% posterior probability of the true response rate exceeding a fixed threshold under a range of assumed values for the threshold of interest and true response rate”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Operating characteristics of the planned sample size
> “For example, with a true response rate of 20%, the proposed sample size of n = 66 for arms 1–3 has approximately 70% probability of confirming a true response of at least 15%, and if the true rate is 30%, there is an 88% chance of confirming a true response of at least 20%. The lower bounds of 95% credible intervals excluded the historical placebo response of 3% if the observed response is ≥ 14% in arms 1–3 or 18% in arm 4.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
##### Prior distribution in the protocol sample size determination
> “It is assumed that the number of responders follows a Binomial distribution, with a weakly informative prior (Beta (0.5, 0.5)) for the true response rate.”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
##### Participants analyzed in the primary publication
> “The intention-to-treat population included 457 participants (227 receiving NA therapy and 230 not receiving NA therapy)”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Enrollment in the ClinicalTrials.gov record
> “A total of 457 participants were enrolled in the study. These 457 participants were from 2 different set of populations (referred here after as on nucleos(t)ide [NA] and not on NA therapy). Participants from these subpopulations were randomized in a ratio of 3:3:3:1 into 4 treatment arms for each population (total of 8 arms).”
> “The safety population was comprised of 455 participants, 2 participants excluded from arms GSK3228836 300mg for 12 weeks in both on NA and not on NA therapy population, respectively.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
#### 3.1.3.7.2 Description of Analysis Sets
##### Efficacy and safety populations in the primary publication
> “Efficacy analyses were conducted in the intention-to-treat population, which included all randomly assigned participants, on the basis of the trial-group assignment. Safety analyses were conducted in all the participants who had undergone randomization and received at least one dose of bepirovirsen or placebo and were based on the trial agent received. As prespecified, analyses of all outcomes were conducted separately for participants receiving NA therapy and those not receiving NA therapy.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Analysis sets defined in the statistical analysis plan
| Analysis set | Definition |
| --- | --- |
| Enrolled | “All participants who passed screening and entered the study.” |
| Intention-to-treat | “All randomized participants” |
| Safety | “All participants who received at least one dose of study treatment.” |
| Pharmacokinetic | “All participants in the Safety population who received an active study treatment and had at least 1 non-missing PK assessment” |
| Pharmacodynamic | “All participants in the Safety population for whom a Pharmacodynamic sample was obtained and analysed.” |
Source: [GSK 209668 statistical analysis plan (2022)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/SAP_001.pdf)
##### Primary estimand and handling of intercurrent events
> “The primary estimand was the proportion of participants in groups 1, 2, and 3 who had a primary-outcome event, regardless of completion of treatment, interruptions in treatment, or adherence to treatment had they not been affected by wide disruptive events (e.g., the coronavirus disease 2019 pandemic).”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Intercurrent event strategies in the protocol
> “The use of rescue medication has been incorporated into the definition of variable (composite strategy). Discontinuation of, interruption of, and adherence to IP will be ignored (treatment policy).”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
##### Estimation approach and Bayesian model
> “An estimation approach with no hypothesis testing was used to analyze the primary outcome. A Bayesian hierarchical model (including baseline stratification factors) was used to calculate the point estimate of the primary outcome and 95% credible interval. If the Bayesian hierarchical model did not converge, a post hoc unstratified Bayesian analysis was performed”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Cohorts analyzed separately without multiplicity adjustment
> “All analyses were conducted separately for the two populations (On-NA and Not-on-NA). No adjustments were made for multiplicity.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
##### Analysis populations in the ClinicalTrials.gov results
> “The analysis was performed on the Intent to Treat (ITT) Set that includes all randomized participants who received a treatment randomization number. This population was based on the treatment the participant was randomized to. The analysis was conducted separately for the on NA treatment and not currently on NA treatment populations.”
> “The safety population included participants who received at least one dose of study treatment.”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
### 3.1.3.8 Results
#### 3.1.3.8.1 Participant Disposition
##### Discontinuation of the trial agent
> “13 participants (6%) receiving NA therapy and 23 (10%) not receiving NA therapy prematurely discontinued bepirovirsen or placebo, of whom 5 participants (2%) and 8 (3%), respectively, discontinued owing to adverse events”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Participant flow in the ClinicalTrials.gov results: groups 1 to 4 numbered as in the primary publication
| Participants | On NA, group 1 | On NA, group 2 | On NA, group 3 | On NA, group 4 | Not on NA, group 1 | Not on NA, group 2 | Not on NA, group 3 | Not on NA, group 4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Started | “68” | “68” | “68” | “23” | “70” | “68” | “68” | “24” |
| Completed | “65” | “65” | “66” | “22” | “64” | “66” | “63” | “24” |
| Not completed | “3” | “3” | “2” | “1” | “6” | “2” | “5” | “0” |
| Adverse event | “0” | “1” | “1” | “0” | “1” | “0” | “1” | “0” |
| Lost to follow-up | “0” | “1” | “0” | “0” | “0” | “0” | “0” | “0” |
| Protocol violation | “0” | “1” | “0” | “0” | “0” | “0” | “0” | “0” |
| Physician decision | “0” | “0” | “0” | “0” | “0” | “1” | “0” | “0” |
| Withdrawal by participant | “3” | “0” | “1” | “1” | “5” | “1” | “4” | “0” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Randomized participants who received no study treatment
> “Both participants did not receive study treatment, one due to randomization error (on NA therapy) and other due to the participant decision due to concern of potential side effects (not on NA therapy).”
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
#### 3.1.3.8.2 Baseline Characteristics
##### Demographic and clinical characteristics at baseline: intention-to-treat population, means ± SD
| Characteristic | On NA, group 1 (N=68) | On NA, group 2 (N=68) | On NA, group 3 (N=68) | On NA, group 4 (N=23) | Not on NA, group 1 (N=70) | Not on NA, group 2 (N=68) | Not on NA, group 3 (N=68) | Not on NA, group 4 (N=24) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age, years | “49.0±11.5” | “46.1±12.6” | “47.4±11.2” | “49.8±11.2” | “44.5±11.1” | “43.8±9.9” | “40.7±11.1” | “42.4±12.0” |
| Male sex, no. (%) | “48 (71)” | “49 (72)” | “51 (75)” | “17 (74)” | “33 (47)” | “41 (60)” | “39 (57)” | “11 (46)” |
| Body-mass index | “24.66±4.07” | “24.30±4.14” | “24.92±2.90” | “23.67±2.48” | “25.25±4.77” | “25.26±4.30” | “24.52±3.65” | “23.70±4.42” |
| Asian, no. (%) | “36 (53)” | “35 (51)” | “36 (53)” | “12 (52)” | “37 (53)” | “44 (65)” | “38 (56)” | “12 (50)” |
| White, no. (%) | “30 (44)” | “32 (47)” | “26 (38)” | “11 (48)” | “24 (34)” | “20 (29)” | “24 (35)” | “11 (46)” |
| Black, no. (%) | “2 (3)” | “1 (1)” | “4 (6)” | “0” | “9 (13)” | “4 (6)” | “6 (9)” | “1 (4)” |
| ALT at or below ULN, no. (%) | “62 (91)” | “60 (90)” | “62 (91)” | “21 (91)” | “50 (71)” | “48 (71)” | “47 (69)” | “15 (62)” |
| HBsAg 3 log10 IU/ml or less, no. (%) | “19 (28)” | “23 (34)” | “19 (28)” | “3 (13)” | “12 (17)” | “15 (22)” | “11 (16)” | “5 (21)” |
| HBsAg, log10 IU/ml | “3.29±0.62” | “3.26±0.61” | “3.33±0.59” | “3.43±0.43” | “3.72±0.77” | “3.65±0.72” | “3.66±0.67” | “3.76±0.79” |
| HBV DNA, log10 IU/ml | “0.48±0.64” | “0.39±0.60” | “0.55±0.66” | “0.40±0.62” | “5.02±1.53” | “5.14±1.56” | “5.57±1.65” | “5.00±1.55” |
| Negative HBeAg status, no. (%) | “50 (74)” | “47 (70)” | “44 (65)” | “16 (70)” | “49 (70)” | “52 (76)” | “52 (76)” | “17 (71)” |
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Nucleos(t)ide analogue therapy at baseline: participants receiving NA therapy
| Characteristic | Group 1 (N=68) | Group 2 (N=68) | Group 3 (N=68) | Group 4 (N=23) |
| --- | --- | --- | --- | --- |
| Current NA therapy for 3 years or more, no. (%) | “47 (69)” | “45 (67)” | “43 (63)” | “20 (87)” |
| Entecavir, no. (%) | “38 (56)” | “25 (37)” | “20 (29)” | “10 (43)” |
| Tenofovir disoproxil, no. (%) | “24 (35)” | “36 (54)” | “33 (49)” | “11 (48)” |
| Tenofovir alafenamide, no. (%) | “9 (13)” | “6 (9)” | “17 (25)” | “2 (9)” |
| Lamivudine, no. (%) | “1 (1)” | “1 (1)” | “1 (1)” | “0” |
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Comparability of trial groups and upper limit of normal for ALT
> “The demographic and clinical characteristics of the participants at baseline were similar across trial groups (Table 1).”
> “The upper limit of the normal range (ULN) for alanine aminotransferase (ALT) is 40 IU per liter for men and 33 IU per liter for women.”
> “Data were missing for 1 participant in group 2 who was receiving NA therapy, so the denominator is 67 rather than 68.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### 3.1.3.8.3 Efficacy Results
##### Primary outcome by group and cohort (intention-to-treat population)
| Result | On NA, group 1 (N=68) | On NA, group 2 (N=68) | On NA, group 3 (N=68) | On NA, group 4 (N=23) | Not on NA, group 1 (N=70) | Not on NA, group 2 (N=68) | Not on NA, group 3 (N=68) | Not on NA, group 4 (N=24) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Primary-outcome event, no. of participants (%) | “6 (9)” | “6 (9)” | “2 (3)” | “0” | “7 (10)” | “4 (6)” | “1 (1)” | “0” |
| Point estimate of response, % (95% credible interval) | “9 (0–31)” | “9 (0–43)” | “3 (0–16)” | “2 (0–8)” | “10 (0–38)” | “6 (0–25)” | “2 (0–6)” | “2 (0–8)” |
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Primary outcome in the text of the primary publication
> “In group 1, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) receiving NA therapy and in 7 (10%; 95% credible interval, 0 to 38) not receiving NA therapy. In group 2, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 43) receiving NA therapy and in 4 (6%; 95% credible interval, 0 to 25) not receiving NA therapy. In group 3, a primary-outcome event occurred in 2 participants (3%; 95% credible interval, 0 to 16) receiving NA therapy and in 1 (1%; post hoc credible interval, 0 to 6) not receiving NA therapy”
> “Shown are point estimates and credible intervals from post hoc unstratified Bayesian analysis owing to nonconvergence of the prespecified stratified Bayesian hierarchical model.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Modified primary outcome permitting blips: group 1
> “When we used the modified primary-outcome definition that allowed for “blips” (single-time-point increases in the HBsAg level to greater than or equal to the lower limit of detection or in the HBV DNA level to greater than or equal to the lower limit of quantification) in response, in group 1, a total of 7 participants (10%; 95% credible interval, 0 to 36) receiving NA therapy and 10 (14%; 95% credible interval, 0 to 64) not receiving NA therapy had a response.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Primary outcome by baseline HBsAg level: group 1
> “In group 1, a total of 16% of the participants receiving NA therapy and 25% of those not receiving NA therapy with a low HBsAg level (≤3 log10 IU per milliliter) at baseline had a primary-outcome event, as compared with 6% and 7% of participants, respectively, with a high HBsAg level (>3 log10 IU per milliliter) at baseline (Fig. S3).”
> “A receiver-operating-characteristic analysis in group 1 indicated that an HBsAg level of approximately 3000 IU per milliliter (3.5 log10 IU per milliliter) at baseline may be an appropriate cutoff point for predicting response (Fig. S4). At the cutoff point of 3000 IU or less per milliliter in group 1, a total of 5 of 43 participants (12%) receiving NA therapy and 6 of 24 (25%) not receiving NA therapy had a primary-outcome event.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Primary outcome by baseline HBeAg status: group 1
> “Among HBeAg-negative participants, a primary-outcome event occurred in those receiving NA therapy and in those not receiving NA therapy (in group 1, 10% of participants receiving NA therapy and 14% of those not receiving NA therapy). Among HBeAg-positive participants, a primary-outcome event occurred only in those receiving NA therapy (in group 1, 6% of participants receiving NA therapy and 0% of those not receiving NA therapy)”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### HBsAg levels at the end of treatment and 24 weeks after: group 1
> “In group 1, 43 participants (63%) receiving NA therapy and 41 (59%) not receiving NA therapy had an HBsAg level of less than 100 IU per milliliter by the end of treatment; the values were 26 (38%) and 20 (29%), respectively, at 24 weeks after the end of treatment (Figure 2).”
> “By the end of treatment in group 1, a total of 18 participants (26%) receiving NA therapy and 20 (29%) not receiving NA therapy had an HBsAg level below the lower limit of detection; at 24 weeks after the end of treatment, the values were 8 (12%) and 10 (14%), respectively”
> “In group 1, a total of 34 participants (50%) receiving NA therapy and 35 (50%) not receiving NA therapy had a decrease of at least 3 log10 IU per milliliter in the HBsAg level at the end of treatment; the incidence of relapse at the end of the trial was lowest in group 1 (Fig. S11).”
> “For many participants, HBsAg and HBV DNA levels increased after treatment discontinuation (Figs. S7 and S8).”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### HBV DNA below the lower limit of quantification: participants not receiving NA therapy
> “Among participants not receiving NA therapy, the number in group 1 who had an HBV DNA level below the lower limit of quantification was 26 (37%) at the end of treatment and 19 (27%) at 24 weeks after the end of treatment, as compared with 20 (29%) and 15 (22%), respectively, in group 2; 18 (26%) and 9 (13%), respectively, in group 3; and 4 (17%) at both time points in group 4.”
> “Among participants in group 1 not receiving NA therapy, a decrease of at least 3 log10 IU per milliliter in the HBV DNA level was observed in 27 participants (39%) at the end of treatment and in 18 (26%) at 24 weeks after the end of treatment (Fig. S12).”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### HBeAg loss, seroconversion, and anti-HBs
> “Of the participants who were positive for HBeAg and negative for antibodies against hepatitis B e (anti-HBe) at baseline, 10 of 63 (16%) receiving NA therapy and 8 of 41 (20%) not receiving NA therapy had HBeAg loss at 24 weeks after the end of treatment; 7 participants (11%) receiving NA therapy and 8 (20%) not receiving NA therapy had seroconversion (HBeAg loss and positivity for anti-HBe). Of the participants who had a primary-outcome event, 7 (50%) receiving NA therapy and 6 (50%) not receiving NA therapy had anti-HBs at the end of the trial.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### HBsAg and HBV DNA below LLOQ at the end of treatment: ClinicalTrials.gov results
| Arm | Participants analyzed | Participants with response | Percentage |
| --- | --- | --- | --- |
| On NA, group 1 | “68” | “16” | “23.5%” |
| On NA, group 2 | “68” | “9” | “13.2%” |
| On NA, group 3 | “68” | “8” | “11.8%” |
| On NA, group 4 | “23” | “4” | “17.4%” |
| Not on NA, group 1 | “70” | “17” | “24.3%” |
| Not on NA, group 2 | “68” | “10” | “14.7%” |
| Not on NA, group 3 | “68” | “6” | “8.8%” |
| Not on NA, group 4 | “24” | “1” | “4.2%” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Median time to ALT normalization in participants with baseline ALT above ULN: ClinicalTrials.gov results
| Arm | Participants analyzed | Median, weeks | 95% confidence interval |
| --- | --- | --- | --- |
| On NA, group 1 | “6” | “16.6” | “(1.1 to NA)” |
| On NA, group 2 | “7” | “4.1” | “(1.0 to 11.9)” |
| On NA, group 3 | “6” | “1” | “(1.0 to 8.1)” |
| On NA, group 4 | “2” | “7” | “(1.1 to NA)” |
| Not on NA, group 1 | “20” | “13.4” | “(2.1 to NA)” |
| Not on NA, group 2 | “20” | “15.1” | “(4.3 to 18.1)” |
| Not on NA, group 3 | “21” | “10.7” | “(5.1 to 21.1)” |
| Not on NA, group 4 | “9” | “18.1” | “(1 to 32.1)” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Bepirovirsen pharmacokinetics in participants receiving NA therapy: ClinicalTrials.gov results
| Parameter | Bepirovirsen 150 mg (n=12) | Bepirovirsen 300 mg (n=12) |
| --- | --- | --- |
| AUC0-24h, h*ug/mL, mean (SD) | “55.214(22.9901)” | “140.312(37.3548)” |
| Cmax, ug/mL, mean (SD) | “6.112(2.8112)” | “14.956(5.6592)” |
| Tmax, hour, median | “3.008” | “3.017” |
| Tmax, hour, full range | “(2.00 to 4.02)” | “(2.00 to 5.00)” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Bepirovirsen terminal half-life: ClinicalTrials.gov results
| Arm | Participants analyzed | Median, days | Full range |
| --- | --- | --- | --- |
| On NA, group 1 | “68” | “28.897” | “(7.52 to 191.98)” |
| On NA, group 2 | “67” | “24.918” | “(8.84 to 216.43)” |
| Not on NA, group 1 | “70” | “27.846” | “(10.19 to 149.74)” |
| Not on NA, group 2 | “67” | “38.205” | “(6.87 to 161.83)” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Primary outcome and low-baseline-HBsAg subgroup in the company release
> “Bepirovirsen, with a loading dose at day 4 and 11, and at a dose of 300mg per week for 24 weeks (treatment arm 1) resulted in 9% of patients on-NA and 10% of patients not-on-NA achieving the primary outcome of HBsAg levels below the Lower Limit of Detection (LLOD) and HBV DNA levels below the Lower Limit of Quantification (LLOQ). Patients with low baseline hepatitis B surface antigen levels3 responded best to treatment with bepirovirsen in treatment arm 1 with 16% of patients on-NA and 25% of patients not-on-NA achieving the primary outcome.”
> “Prospectively defined as including patients with a baseline HBsAg ≤ 1000 IU/mL”
Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)
Additional sources: [Bouquet et al. (2026)](https://doi.org/10.1016/j.jhep.2025.12.025)
#### 3.1.3.8.4 Health-related Quality of Life and Patient-reported Outcomes
##### Patient-reported outcome objective and instruments planned in the protocol
> “Patient Reported Outcomes: To assess changes from baseline in patient reported outcomes following 12 weeks, 12 weeks + 12 weeks step-down, and 24 weeks of treatment with GSK3228836.”
> “Change from baseline of HBQOL and EQ-5D.”
> “The HBQOL has been designed to assess quality of life in patients with Hepatitis B. It consists of 31 items and 6 domains: psychological well-being, anticipation anxiety, vitality, stigma, transmissibility and vulnerability.”
Source: [GSK 209668 protocol (2021)](https://cdn.clinicaltrials.gov/large-docs/29/NCT04449029/Prot_000.pdf)
##### Patient-reported outcome results
No evidence found.
#### 3.1.3.8.5 Safety Results
##### Safety summary by group and cohort: safety population, number of participants (percent)
| Adverse event | On NA, group 1 (N=68) | On NA, group 2 (N=67) | On NA, group 3 (N=68) | On NA, group 4 (N=23) | Not on NA, group 1 (N=70) | Not on NA, group 2 (N=67) | Not on NA, group 3 (N=68) | Not on NA, group 4 (N=24) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Weeks 1 to 12: any adverse event | “53 (78)” | “57 (85)” | “52 (76)” | “10 (43)” | “63 (90)” | “55 (82)” | “59 (87)” | “13 (54)” |
| Weeks 1 to 12: any grade 3 or 4 adverse event | “5 (7)” | “9 (13)” | “5 (7)” | “0” | “10 (14)” | “9 (13)” | “7 (10)” | “0” |
| Weeks 1 to 12: any serious adverse event | “1 (1)” | “1 (1)” | “3 (4)” | “0” | “3 (4)” | “0” | “0” | “0” |
| Weeks 1 to 12: injection-site reaction | “38 (56)” | “47 (70)” | “43 (63)” | “3 (13)” | “50 (71)” | “41 (61)” | “46 (68)” | “3 (12)” |
| Weeks 1 to 12: vascular inflammation and complement activation | “24 (35)” | “31 (46)” | “30 (44)” | “1 (4)” | “45 (64)” | “38 (57)” | “42 (62)” | “6 (25)” |
| Weeks 1 to 12: thrombocytopenia | “12 (18)” | “9 (13)” | “11 (16)” | “3 (13)” | “21 (30)” | “17 (25)” | “19 (28)” | “4 (17)” |
| Weeks 1 to 12: increased ALT level | “7 (10)” | “10 (15)” | “6 (9)” | “0” | “15 (21)” | “12 (18)” | “11 (16)” | “1 (4)” |
| Weeks 1 to 12: renal injury | “2 (3)” | “6 (9)” | “6 (9)” | “0” | “5 (7)” | “3 (4)” | “9 (13)” | “1 (4)” |
| All visits: any adverse event | “56 (82)” | “59 (88)” | “53 (78)” | “16 (70)” | “65 (93)” | “60 (90)” | “62 (91)” | “19 (79)” |
| All visits: adverse event leading to discontinuation of trial agent | “2 (3)” | “3 (4)” | “3 (4)” | “0” | “3 (4)” | “1 (1)” | “5 (7)” | “0” |
| All visits: any grade 3 or 4 adverse event | “7 (10)” | “11 (16)” | “8 (12)” | “0” | “16 (23)” | “15 (22)” | “13 (19)” | “4 (17)” |
| All visits: any serious adverse event | “1 (1)” | “1 (1)” | “4 (6)” | “0” | “6 (9)” | “2 (3)” | “3 (4)” | “0” |
| All visits: injection-site reaction | “41 (60)” | “49 (73)” | “43 (63)” | “11 (48)” | “52 (74)” | “41 (61)” | “49 (72)” | “12 (50)” |
| All visits: vascular inflammation and complement activation | “30 (44)” | “34 (51)” | “31 (46)” | “10 (43)” | “49 (70)” | “40 (60)” | “46 (68)” | “12 (50)” |
| All visits: thrombocytopenia | “19 (28)” | “16 (24)” | “12 (18)” | “6 (26)” | “32 (46)” | “21 (31)” | “21 (31)” | “6 (25)” |
| All visits: increased ALT level | “7 (10)” | “10 (15)” | “6 (9)” | “6 (26)” | “20 (29)” | “19 (28)” | “16 (24)” | “5 (21)” |
| All visits: renal injury | “4 (6)” | “9 (13)” | “6 (9)” | “2 (9)” | “7 (10)” | “6 (9)” | “9 (13)” | “3 (12)” |
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Adverse events during weeks 1 through 12, when a placebo comparison was possible
> “During weeks 1 through 12, when comparison between bepirovirsen and placebo was possible, adverse events were more common during bepirovirsen treatment in groups 1, 2, and 3 (in 78%, 85%, and 76%, respectively, of participants receiving NA therapy and in 90%, 82%, and 87%, respectively, of those not receiving NA therapy) than during receipt of placebo in group 4 (in 43% of those receiving NA therapy and 54% of those not receiving NA therapy) (Table 3). For example, injection-site reactions, pyrexia, fatigue, and increased ALT levels were reported more frequently with bepirovirsen than with placebo (Tables S13 and S14).”
> “During weeks 1 through 12, no participants in group 4 (placebo) had serious adverse events; five participants receiving NA therapy (one in group 1, one in group 2, and three in group 3) and three participants not receiving NA therapy (all in group 1) had serious adverse events. Grade 3 or 4 adverse events occurred in 7 to 13% of participants receiving NA therapy and in 10 to 14% of those not receiving NA therapy in groups 1, 2, and 3, as compared with 0 in group 4.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Adverse events during weeks 1 through 48
> “During weeks 1 through 48, the proportion of participants who reported adverse events was higher among those not receiving NA therapy than among those receiving NA therapy (Table 3), with a higher incidence of increased ALT level, increased aspartate aminotransferase level, decreased platelet count, decreased complement factor C3 level, and decreased complement factor C4 level (Tables S17 and S18). In patients receiving NA therapy and in those not receiving NA therapy, the most common adverse events were injection-site reactions (erythema, pain, and pruritus).”
> “Overall, 17 participants had adverse events leading to discontinuation of bepirovirsen or placebo, with 0 to 4% frequency among participants receiving NA therapy and 0 to 7% frequency among those not receiving NA therapy (Table 3).”
> “Grade 3 or 4 adverse events occurred in 74 participants overall, with 0 to 16% frequency among those receiving NA therapy and 17 to 23% frequency among those not receiving NA therapy. Serious adverse events were reported in 6 participants (3%) receiving NA therapy and 11 (5%) not receiving NA therapy; 1 serious adverse event in participants receiving NA therapy and 3 in those not receiving NA therapy were considered by the investigator to be related to bepirovirsen treatment (Table 3 and Tables S19 and S20). No deaths were reported.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### ALT increases of 3 times ULN or more
> “Overall, 39 of 225 participants receiving NA therapy (17%) and 93 of 227 not receiving NA therapy (41%) had a transient increase in the ALT level to at least 3 times the upper limit of the normal range between randomization and the end of follow-up (Table S6).”
> “There were two serious adverse events related to ALT changes, which are discussed further in the Results section in the Supplementary Appendix, and one case of Gilbert’s syndrome. Otherwise, increases in ALT levels were asymptomatic and resolved without increases in bilirubin or alkaline phosphatase levels and without evidence of liver dysfunction.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Injection-site reactions leading to withdrawal
> “Overall, injection-site reactions were the most common adverse events; two participants (one receiving NA therapy and one not receiving NA therapy) withdrew owing to an injection-site reaction.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
##### Serious adverse events, other adverse events, and deaths: ClinicalTrials.gov results, affected participants at risk up to week 48
| Event | On NA, group 1 | On NA, group 2 | On NA, group 3 | On NA, group 4 | Not on NA, group 1 | Not on NA, group 2 | Not on NA, group 3 | Not on NA, group 4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All-cause mortality | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Serious adverse events, total | “1/68 (1.47%)” | “1/67 (1.49%)” | “4/68 (5.88%)” | “0/23 (0.00%)” | “6/70 (8.57%)” | “2/67 (2.99%)” | “3/68 (4.41%)” | “0/24 (0.00%)” |
| Other (not serious) adverse events, total | “56/68 (82.35%)” | “59/67 (88.06%)” | “53/68 (77.94%)” | “16/23 (69.57%)” | “65/70 (92.86%)” | “60/67 (89.55%)” | “61/68 (89.71%)” | “19/24 (79.17%)” |
| Thrombocytopenia (not serious) | “4/68 (5.88%)” | “2/67 (2.99%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “5/70 (7.14%)” | “2/67 (2.99%)” | “3/68 (4.41%)” | “0/24 (0.00%)” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Individual serious adverse events: ClinicalTrials.gov results
| Serious adverse event | On NA, group 1 | On NA, group 2 | On NA, group 3 | On NA, group 4 | Not on NA, group 1 | Not on NA, group 2 | Not on NA, group 3 | Not on NA, group 4 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Cryoglobulinaemia | “1/68 (1.47%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Hepatic function abnormal | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Hepatitis B | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Systemic inflammatory response syndrome | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Hepatocellular carcinoma | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/24 (0.00%)” |
| Bile duct cancer | “0/68 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/23 (0.00%)” | “1/70 (1.43%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Interstitial lung disease | “0/68 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
| Cerebral infarction | “0/68 (0.00%)” | “0/67 (0.00%)” | “1/68 (1.47%)” | “0/23 (0.00%)” | “0/70 (0.00%)” | “0/67 (0.00%)” | “0/68 (0.00%)” | “0/24 (0.00%)” |
Source: [ClinicalTrials.gov NCT04449029](https://clinicaltrials.gov/study/NCT04449029?tab=results)
##### Safety statement in the company release
> “There were no safety signals to preclude further development. AEs leading to treatment discontinuation occurred in 17 participants overall, with 0–4% frequency in participants on-NA, and 0–7% frequency in participants not-on-NA. Serious AEs (SAEs) were reported in 6 (3%) participants on-NA and 11 (5%) participants not-on-NA; 1 SAE in the on-NA and 3 in the not-on-NA population were considered related to treatment.”
Source: [GSK press release, B-Clear results (2022)](https://www.gsk.com/en-gb/media/press-releases/positive-data-for-bepirovirsen-from-b-clear-phase-iib-trial/)
### 3.1.3.9 Study Limitations
#### Summary: study limitations
B-Clear had no full placebo arm: group 4 received placebo only during weeks 1 through 12, enrolled 23 participants receiving NA therapy and 24 not receiving it, and was not powered for the primary outcome. The primary outcome was analyzed by estimation without hypothesis testing or adjustment for multiplicity, the 95% credible intervals in group 1 spanned 0 to 31 in participants receiving NA therapy and 0 to 38 in those not receiving it, and some estimates came from a post hoc unstratified analysis because the prespecified Bayesian model did not converge. Investigators knew the trial-group assignments, while the sponsor and participants were blinded. Response was assessed for 24 weeks after the end of treatment, and in the cohort that continued NA therapy the response “cannot be considered equivalent to functional cure”. Generalizability is limited by the inclusion criteria, which excluded participants with cirrhosis, hepatocellular carcinoma, or hepatitis C, HIV, or hepatitis D coinfection.
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027); [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### No full placebo arm and small placebo-first arm
> “A full placebo arm was not included in the study on the basis of feedback from external experts and a focus group of patients with chronic HBV infection, who expressed concerns owing to the study burden. Therefore, all participants received active treatment with bepirovirsen. The absence of a full placebo arm limits interpretation of the results, preventing direct comparison with a group that received no treatment”
> “The size of arm 4 does limit interpretation of the LD requirement. This arm was originally planned to be a placebo-only arm and hence had a lower sample size; following the change in treatment regimen that occurred on the basis of protocol feedback, the sample size was not increased. Hence further investigations may be required to assess the need for a LD.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Limited off-treatment follow-up and generalizability
> “Although conclusions from the B-Clear study were limited to the 24-week off-treatment period for most treatment arms, except for arm 3 which includes a 36-week off-treatment follow-up period, longer-term open-label data will be collected in the B-Sure extension study mentioned above, to evaluate the durability of response. Generalizability of the data to the wider population of people living with chronic HBV infection is limited to the requirements for study inclusion.”
Source: [Cremer et al. (2023)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10427703/)
#### Authors' statements on the size of the effect and the need for larger trials
> “Although this is a relatively low percentage of participants overall, it indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both.”
> “Larger trials and longer follow-up are needed to assess the safety and efficacy of bepirovirsen.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
#### Sponsor role in design, analysis, and drafting
> “The sponsor, GSK, designed and oversaw the trial conduct and data collection and analysis. Professional writers paid by the sponsor prepared the first draft of the manuscript under the authors’ direction.”
Source: [Yuen et al. (2022)](https://www.nejm.org/doi/full/10.1056/NEJMoa2210027)
Additional sources: [Hoofnagle (2022)](https://pubmed.ncbi.nlm.nih.gov/36346068/); [Vaillant (2023)](https://pubmed.ncbi.nlm.nih.gov/36947477/); [Yuen et al. (2023a)](https://pubmed.ncbi.nlm.nih.gov/36947478/); [Lens (2023)](https://pubmed.ncbi.nlm.nih.gov/36801391/); [Mak et al. (2023)](https://pubmed.ncbi.nlm.nih.gov/37902953/)
## Related pages
- [Hibsago (bepirovirsen): Chronic hepatitis B virus infection in adults without cirrhosis](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Terms and abbreviations](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/terms-and-abbreviations) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/terms-and-abbreviations.md)
- [Hibsago (bepirovirsen): Chronic hepatitis B virus infection in adults without cirrhosis](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/executive-summary) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/executive-summary.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Product information and disease description](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/product-information-and-disease-description.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Clinical evidence](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/clinical-evidence.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: Economic information and modeling report](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/economics) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/economics.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: References](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/references) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/references.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: new drug review](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/monograph/review) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/monograph/review.md)
- [Hibsago (bepirovirsen) in Chronic hepatitis B virus infection in adults without cirrhosis: cost-effectiveness analyses and utility weights](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/cost-effectiveness-analyses) · [Markdown](https://www.evicenter.com/drugs/hibsago--chronic-hepatitis-b-virus-infection-in-adults-without-cirrhosis/cost-effectiveness-analyses.md)