Efficacy: To describe long-term durability of sustained virologic response (SVR) as measured by time to loss of SVR in treatment naïve participants who achieved a complete responseEfficacy: To describe long-term durability of sustained virologic…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time from achieving SVR in the previous GSK3228836 treatment study to the loss
of SVR (first occurrence of either HBsAg or HBV DNA reversion, or first use of
any rescue medication)
Time from NA cessation to the loss of SVR (first occurrence of either HBsAg or
HBV DNA reversion or first use of any rescue medication)
Secondary outcome
* Time from NA cessation to the first occurrence of HBsAg reversion or first
use of any rescue medication
* Time from NA cessation to the first occurrence of virologic relapse or first
use of any rescue medication
* Time from NA cessation to the first occurrence of clinical relapse or first
use of any rescue medication
* Time from NA cessation to NA retreatment
*
Time from achieving SVR in the previous GSK3228836 treatment study to the loss
of SVR (first occurrence of either HBsAg or HBV DNA reversion, or first use of
any rescue medication)
Time from end of treatment in the previous GSK2338836 treatment study to
delayed SVR in the absence of rescue medication
* In the subset of participants who go on to achieve a delayed SVR: Time to the
loss of SVR from time of achieving delayed SVR
* In NA controlled participants who are continuing NA treatment:
* Time from end of treatment in the previous GSK2338836 treatment study to
delayed SVR in the absence of any rescue medication
* In the subset of participants who go on to achieve a delayed SVR: Time to the
loss of SVR from time of achieving delayed SVR
* In NA controlled participants who have discontinued NA treatment:
* Time from NA cessation to delayed SVR, in the absence of NA retreatment
* In the subset of participants who go on to achieve a delayed SVR after NA
cessation: Time to the loss of SVR from time of achieving SVR
* Time from NA cessation to HBsAg loss in the absence of any rescue medication
* Time from NA cessation to the first occurrence of virologic relapse or first
use of any rescue medication
* Time from NA cessation to the first occurrence of clinical relapse or first
use of any rescue medication
* Time from NA cessation to the first occurrence of NA retreatment
* Occurrence of anti-HBs (antibody to HBsAg)
* Occurrence of anti-HBe (antibody to HBeAg)
* Actual values and changes from Baseline (EoS visit in the parent study) at
each study visit in HBsAg, HBV DNA, HBeAg, HBcrAg, HBV RNA levels
* Occurrence of mutations prior to GSK3228836 in the parent study and at the
time of virologic breakthrough
Background summary
HBV infection, especially chronic infection, is a significant worldwide medical
problem. Globally, in 2015, an estimated 257 million people were living with
CHB, with only 9% of patients being treated. Worldwide, it is estimated that
around 650 000 people die each year from the complications of CHB.
It has been proposed that the continued production of hepatitis B viral
antigens by infected hepatocytes interferes with immune clearance of both the
infected cells and circulating virus particles. In vitro studies with human
PBMCs have shown HBsAg impairs the functioning of dendritic cells and inhibits
the activation of monocytes. Further, data suggest the production of vast
excess of HBsAg (so called non infectious *sub-viral particles*) likely
functions as a decoy for host antibody responses. Most chronically infected
patients produce antibodies to HBsAg, but these can only be detected as immune
complexes due to the vast excess of circulating antigen. HBeAg is also thought
to have a role in immune response evasion through down regulation of the innate
immune system. Since loss of HBsAg expression is rarely achieved while loss of
HBeAg expression occurs in a higher proportion of the patient population, HBsAg
appears to be the main antagonist of immune clearance.
The goal of therapy for CHB is to improve quality of life and survival by
preventing progression of the disease to cirrhosis, decompensated liver
disease, HCC, or death. In both HBeAg-positive and HBeAg-negative CHB, the
ultimate treatment endpoint is loss of detectable serum HBsAg and serum HBV
DNA. Recently, a functional cure of CHB infection has been endorsed as the
endpoint for new HBV therapies. Functional cure of CHB infection is defined as
sustained suppression of serum HBsAg to seroconversion,) and undetectable HBV DNA in serum, after completion of a
finite course of treatment.
First-line therapy for CHB is treatment with an NA therapy. While these
antiviral agents are effective in suppressing HBV replication in both
HBeAg-positive and HBeAg-negative CHB, and improve the prognosis of CHB,
patients frequently relapse after treatment is discontinued, particularly if
HBsAg loss was not achieved. Pegylated interferons (PegIFNs) are also approved
for treatment of CHB and are dosed for a finite treatment duration (usually up
to 48 weeks). Because of the frequent and sometimes severe side effects
associated with PegIFN and high cost versus a small gain in treatment response,
PegIFNs are less frequently used than NAs. Rates of HBsAg loss following 12
months of treatment with either a NA and/or PegIFN generally range from 0 to 3%
in most studies with occasional studies reporting higher rates, for example an
approximately 10% functional cure after tenofovir disoproxil fumarate
(TDF)+PegIFN for 48 weeks (off-label) [Marcellin, 2016]. Thus, most patients on
treatment fail to achieve a sustained off-treatment virologic response and
require extended and often life-long therapy to suppress HBV DNA.
GSK3228836, an antisense oligonucleotide, was designed to inhibit the synthesis
of HBsAg without having a direct effect on cccDNA or integrated HBV DNA.
GSK3228836 directly targets all HBV messenger ribonucleic acids (mRNAs) via
ribonuclease H (RNAse H)-mediated degradation, resulting in the reduction of
viral proteins including HBsAg. GSK3228836 treatment permits examination of
whether reduction of HBsAg allows resumption of a host immune response against
HBV and infected cells and can suppress serum HBsAg to been designed and selected to minimise risk of proinflammatory response
associated as a class effect by methylating every cytosine in the antisense
oligonucleotide (ASO) sequence as well as avoiding the presence of CpG motifs
that can be recognised by pattern recognition receptors [Henry, 2008]. However,
it is expected that GSK3228836 may trigger marginal immune activation in the
local environment of the liver, which may not be readily detectable in
periphery. In turn, the intrinsic immunostimulatory activity of GSK3228836 may
contribute to the efficacy in addition to direct pharmacodynamic response of
HBsAg reduction . Complete and partial responders from previous studies of
GSK3228836 will enter this study to be observed for durability of, late
development of, and/or relapse from, their responder status, including
attempted NA cessation in participants likely to benefit.
Study objective
Efficacy: To describe long-term durability of sustained virologic response
(SVR) as measured by time to loss of SVR in treatment naïve participants who
achieved a complete response
Efficacy: To describe long-term durability of sustained virologic response
(SVR) after NA cessation as measured by time to loss of SVR in NA controlled
participants who achieved a complete response and discontinued NA treatment
Study design
This is a global, multi-centre, long term follow-up study designed to assess
durability of efficacy, as measured by SVR, in participants who have received
prior treatment with GSK3228836 and had achieved a complete or partial
response.
Intervention
No study medication will be administered in this study.
Study burden and risks
Risks associated with study procedures/tests:
Blood sample: patient may feel faint or experience mild pain, bruising,
irritation or redness from the needle. In rare cases, may get an infection
and/or swelling and redness along a vein.
Questionnaires
There is a risk or discomfort of possible loss of confidentiality and/or the
emotional discomfort answering some of the questions.
Great West Road 980
Brentford, Middlesex TW8 9GS
GB
Great West Road 980
Brentford, Middlesex TW8 9GS
GB
Listed location countries
Age
Inclusion criteria
1. Participants who have previously received at least one dose of GSK3228836 AND
a. Achieved SVR (defined as HBsAg the end of previous investigational treatment [GSK3228836 and/or with or
without pegylated interferon] in the absence of rescue medication) and who
maintained SVR until the EoS visit in their previous treatment study (defined
as complete responders to GSK3228836 from the parent study) OR
b. Participants who have previously received at least 1 dose of GSK3228836 and
demonstrated HBsAg reduction of >=1.0 log10 IU/mL from their treatment study
Baseline and also with HBsAg levels <100 IU/mL and HBV DNA after the end of previous investigational treatment [GSK3228836] until the EoS
visit in their previous treatment study in the absence of rescue medication
(defined as partial responders to GSK3228836 from the parent study).
2. Participants who enter the study on stable NA are willing and able to cease
their NA treatment in accordance with the NA cessation schedule.
3. Capable of giving signed informed consent as described in Section 10.1 which
includes compliance with the requirements and restrictions listed in the
informed consent form (ICF) and in this protocol.
Exclusion criteria
1. Participants who have/or are currently participating in another non-GSK
interventional clinical study exploring HBV treatment since completing their
treatment with GSK3228836.
2. Any condition which, in the opinion of the investigator or Medical Monitor,
contraindicates their participant in this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000554-26-NL |
| ClinicalTrials.gov | NCT04954859 |
| CCMO | NL79112.078.21 |