臨床研究等提出・公開システム

Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study to Assess the Efficacy and Safety of Treatment With GSK3228836 in Participants With Chronic Hepatitis B Virus (B-Clear)

A Study of GSK3228836 in Participants With Chronic Hepatitis B (CHB) (B-Clear)

457

１）on-NA group (n=227: 68 cases in Arm1, 68 cases in Arm2, 68 cases in Arm3, 23 cases in Arm4) Mean age(yrs): 49.0, 46.1,47.4, 49.8 Male sex no.(%):48(71), 49(72), 51(75), 17(74) Mean HBsAg levels(log10IU/mL):3.29, 3.26, 3.33, 3.45 2）Not-on-NA group (n=230: 70 cases in Arm1, 68 cases in Arm2, 68 cases in Arm3, 24 cases in Arm4) Mean age(yrs): 44.5, 43.8,40.7, 42.4 Male sex no.(%):33(47), 41(60), 39(57), 11(46) Mean HBsAg levels(log10IU/mL):3.72, 3.65, 3.66, 3.76

In On-NA group, 495 participants were screened, of which 227 participants were randomized and received the study drug. In Not-on NA group, 498 participants were screened, of which 230 participants were randomized and received the study drug. 13 participants (6%) in On-NA group and 23 (10%) in Not-on NA group prematurely discontinued bepirovirsen or placebo, of whom 5 participants (2%) and 8 (3%), respectively, discontinued owing to adverse events.

No deaths were reported in On-NA and Not-on NA group. The propotion of subjects with serious adverse events (SAE) in on-NA group was 1.47% (1/68 subjects) in Arm1, 1.49% (1/67 subjects) in Arm2, and 5.88% (4/68 subjects) in Arm3, and 0 subjects in Arm4, and 1 SAE (cryoglobulinemia) in Arm1 was related to study treatment. The proportion of subject with SAE was 8.57% (6/70 subjects) in Arm1, 2.99% (2/67 subjects) in Arm2, 4.41% (3/68 subjects) in Arm3, and 0 subject in Arm4. There were 3 SAEs (systemic inflammatory response syndrome, hepatitis B, abnormal hepatic function) in Arm1 were related to study treatment.The most common adverse events of special interest were injection-site reactions, reported in 48 to 74% of participants across trial groups and participants in on NA and not-on NA group.

1) Primary endpoint:Number of participants achieving sustained virologic response The number of subjects who achieved primary endpoint in On-NA group were 6 (9%), 6 (9%), 2 (3%) and 0 in each Arm1, 2, 3 and 4. In Not-on NA group, the number of subjects who achieved primary endpoint were 7 (10%), 4 (6%), 1 (1%) and 0) in each Arm1,2,3 and 4.

2) secondary endpoint： Number of participants achieving HBsAg and HBV DNA＜LLOQ In on-NA group, the number of subjects acheiving HBsAg and HBV DNA levels ＜LLOQ at the end of treatment (EOT) were 16, 9, 8, 4 subjects in Arm 1,2,3 and 4. In Not-on NA group, the number of subjects acheiving HBsAg and HBV DNA levels ＜LLOQ at EOT were 17, 10, 6, 1 subjectsin Arm1, 2, 3 and 4.

This IIb study demonstrated that bepirovirsen at a dose of 300 mg per week for 24 weeks (including loading doase) resulted in 9 to 10% of participants having HBsAg and HBV DNA loss for 24 weeks after the end of bepirovirsen treatment. Results were similar in participants in On-NA group and those in Not-on NA group. Among participants in On-NA group and those in Not-on NA group, bepirovirsen at a dose of 300 mg weekly for 24 weeks (including loading dose) did not show any marked difference in safety or side effect profile as compared with other regimens.

April. 03, 2023

Nov. 24, 2022

https://pubmed.ncbi.nlm.nih.gov/36346079/

Yes

[Plan Description] IPD for this study will be made available via the Clinical Study Data Request site. [URL] http://clinicalstudydatarequest.com

Okawa Yasutoshi

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

jp.gskjrct@gsk.com

Okawa Yasutoshi

GlaxoSmithKline K.K.

Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, Japan

+81-120-561-007

jp.gskjrct@gsk.com

completed

Sept. 11, 2020

Interventional

randomized controlled trial, single blind, placebocontrol, parallel assignment, treatment purpose

treatment purpose

2

Participants who have documented chronic HBV infection greater than equal to (>=6) months prior to screening and not currently on nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naive) or must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit; OR Currently receiving stable nucleos(t)ide analogue therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
※Other inclusion criteria specified in the protocol may also apply.

Clinically significant abnormalities, aside from chronic HBV infection in medical history (e.g., moderate-severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant/unstable cardiac disease, uncontrolled diabetes, bleeding diathesis or coagulopathy) or physical examination.
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. If only one parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted. 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); If the screening alpha fetoprotein concentration is >=50 ng/mL and <200 ng/mL, the absence of liver mass must be documented by imaging within 6 months before randomization.

Both

investigational material(s)
Generic name etc :
INN of investigational material : -
Therapeutic category code : 391 Agents for liver disease
Dosage and Administration for Investigational material :

control material(s)
Generic name etc :
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material :

efficacy
Percentage of participants achieving SVR [ Time Frame: Up to Week 48 ]
Sustained response is defined as a continuous 24 weeks from end of GSK3228836 treatment during which levels of HBsAg in serum remain <LLOQ and HBV DNA< LLOQ.

efficacy
pharmacokinetics
Percentage of Participants achieving HBsAg <LLOQ at the end of treatment
Percentage of participants achieving HBV DNA at the end of treatment
Participants with Baseline ALT greater than (>) upper limit of normal (ULN) will be assessed for ALT normalization in absence of rescue medication over time.
Change from Baseline and each level at indicated time pointes in HBsAg, HBV DNA, HBeAg, HBsAb and HBeAb
Time to ALT normalization in absence of rescue medication will be measured in participants with Baseline ALT>ULN.
Percentage of participants achieving SVR over time
PK parameters (area under the plasma concentration-time curve (AUC), end-of-dose concentration (Ctau), maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), and apparent clearance (after subcutaneous administration for GSK3228836 and oral administration for NA) of GSK3228836 and NA preparations in a subset of subjects from whom time-course pharmacokinetic (PK) samples were collected.
T1/2 and Ctau following administration of nucleos(t)ide therapy/GSK3228836- All participants

July. 21, 2020