This study has been transitioned to CTIS with ID 2024-514888-25-00 check the CTIS register for the current data. Objective: to provide proof of concept for the inhibition of HBx mediated cccDNA transcription by terbinafine, both as monotherapy and…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objective: provide proof of concept for the inhibition of HBx mediated
cccDNA transcription by terbinafine by means of:
- Decline in level of serum HBsAg >0.32 log10 IU/mL at the end of study
treatment (week 10 vs baseline).
- Decline in serum HBV DNA >0.86 log10 in group A (monotherapy) at the end of
study treatment (week 10 vs baseline).
Secondary outcome
Secondary Objective(s): safety and tolerability of terbinafine and changes in
alternative virology markers:
- Level of serum HBsAg and HBV DNA at 3 months follow-up, all HBV RNA, large
HBsAg (LHBs) HBcrAg levels, and HBeAg status (at baseline and end of study).
- Safety and tolerability of terbinafine as mono- or combination therapy, based
on serum markers including among others: ALT, AST, total bilirubin (if >17 µmol/
L, add conjugated bilirubin), ALP, GGT, albumin, thrombocytes, prothrombin time
(PT); Fibroscan measurements, clinical significant changes in physical
examination and/or reported physical complaints as assessed by the
investigator.
Background summary
There are approximately 50,000 CHB patients in the Netherlands and more than
290 million worldwide. These patients are carriers of the hepatitis B virus.
The virus infects the liver cells and can cause cirrhosis, liver failure and
liver cancer. Every year 887,000 patients die from these complications. There
are currently some drugs available, but treatment rarely leads to a cure. All
patients remain under medical control throughout their lives and patients with
a high viral load must take virus supressive medication for life. The
expectation is that most patients can only find cure if they are treated with a
combination of drugs that inhibit the virus from different angles. There is
therefore a great need for new drugs against CHB. Especially the presence of a
viral reservoir of stable episomal, covalently closed circular DNA (cccDNA) in
the nucleus of infected hepatocytes poses a great challenge for the development
of curative therapies. HBV cccDNA acts as the template for production of viral
proteins and HBV genomes. In a preclinical study, terbinafine (an antifungal
agent) was identified as a potent and specific suppressor of HBx-mediated
cccDNA transcription. HBx is an accessory viral protein of HBV which has been
proven to be essential for HBV replication and enhances replication at the
transcriptional level in vivo. The suppression of cccDNA transcription results
in a strong reduction of the production of viral genomes (RNA and DNA) as well
as viral proteins. This will allow recovery of the immune system, increase
viral clearance and prevent replenishment of the cccDNA pool in the hepatocyte,
all contributing to cure CHB.
Study objective
This study has been transitioned to CTIS with ID 2024-514888-25-00 check the CTIS register for the current data.
Objective: to provide proof of concept for the inhibition of HBx mediated
cccDNA transcription by terbinafine, both as monotherapy and add-on therapy
next to tenofovir. Secondary outcomes will be the safety and tolerability of
terbinafine in this specific group.
Study design
This pilot study is a stratified, single center, randomized, double-blinded,
placebo-controlled, dose-ascending proof of concept clinical trial.
Intervention
This study will be conducted in 2 groups of 16 CHB patients each. One group is
not treated with virus-suppressive drugs before participating in the study and
in this study receives monotherapy terbinafine. The other group is already
treated with tenofovir before start of the study and these patients will
receive terbinafine in combination with tenofovir. In both groups, 2 patients
will also receive a placebo (a total of 4 patients), patient selection for
placebo is based on randomisation.
All patients in this study will be treated with 1 tablet of terbinafine /
placebo per day orally for 4 weeks, followed by 2 weeks of medication stop and
then 4 weeks of treatment with 2 tablets of terbinafine / placebo once daily
(double dose).
Study burden and risks
Patients participating in this study will be asked to attend 13 visits within 7
months. Most visits will take place during the treatment period: 2 times 4
weeks. The weekly visits in this period will be short in duration: 15-30
minutes and an attempt will be made to match these visits to the personal
schedule of the patients where possible. The screening and last visit will be
more extensive with 40-60 minutes in duration. During this study, patients will
be asked to use medication on a daily basis and to keep a medication diary.
Furthermore, all measurements are linked to the visits: in every visit blood
will be taken, a questionnaire in 5 visits, a (shortened) physical examination
in 7 visits and a fibroscan measurement during screening and last visit. As
previously discussed under section E, patients may experience side effects and
there is a very low risk of liver damage. In the event that this rare side
effect occurs, it will be detected early due to the weekly monitoring of liver
function during medication use and the study medication can be discontinued.
The dose escalation model will also contribute to patient safety because the
safety of the study medication in normal dose is investigated for each
individual patient before proceeding to a higher dose. By selecting patients
with normal liver function, the adverse event profile/risk for participating
patients can be expected to be no different from that of patients who have been
treated for years for the registered indication: a fungal nail.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
1) Age 18 - 60 years
2) Proven chronic hepatitis B (CHB) for more than 6 months, based on serology
(HBsAg positivity) and at screening a viral load of:
i) Group A: HBV DNA >=200 IU/mL and <20,000 IU/mL
ii) Group B: HBV DNA < 20 IU/mL
3) HBeAg-positive and -negative CHB patients
4) No current use of any antiviral medication (group A) or currently treated
with tenofovir only.
5) Normal liver function, assessed by:
i) Fibroscan of <= 7.0 kiloPascal (kPa)
ii) Alanine aminotransferase (ALT) and/or aspirate aminotransferase (AST) at
screening <= 1.25 x upper limit of normal (ULN)
iii) Thrombocytes 150-400 10E9/L
iv) Total bilirubin 0-17 µmol/L (elevated levels may be accepted if
unconjugated portion is elevated in patients with Gilbert syndrome)
v) Albumin within normal value (35 - 50 g/L)
vi) Prothrombin Time (PT) within normal value (9,5 - 12.5 sec)
vii) Alkaline phosphatase (ALP) and Gamma-glutamyltransferase (GGT) within
normal values (40-120 U/L and 0-40 U/L respectively)
6) Body mass index (BMI): 17.0-35.0 kg/m2
7) Clinical chemistry, hematologic and coagulation tests at screening must be
within normal limits or clinically non-significant, as by the investigators
assessment.
8) At screening, women of child bearing potential must be non-pregnant and
non-lactating proven by negative urine or serum pregnancy test at screening.
9) Female patients of child-bearing potential (with a fertile male sexual
partner) and male patients (if not surgically sterilized) must be willing to
use adequate contraception from screening until last study visit.
10) At screening, has no recent (<3 months) history of any clinically
significant conditions, which, in the opinion of the investigator, would
jeopardize the safety of the subject or impact the validity of the study
results.
11) Voluntary written informed consent must be obtained before any study
related interventions (including screening and enrollment) can be conducted.
Exclusion criteria
1) Currently active, or a history of liver cirrhosis determined by one or more
of the following:
i) Liver biopsy;
ii) Elastography (e.g. Fibroscan);
iii) Combination of usual radiological and biochemical criteria
2) Currently active, liver disease other than CHB
3) Co-infection with HCV, HDV, HEV and/or HIV
4) Acute HAV at screening
5) Renal impairment (estimated glomerular filtration rate (eGRF) < 60ml/min)
6) Currently active, or a history of: psoriasis or lupus erythematodes
7) Use of oral medication that interacts with the liver metabolism enzyme
CYP2D6, or which is known to be hepatotoxic or otherwise known to interact with
terbinafine (such as rifampicine).
8) Usage or plans to receive systemic immunosuppressive or immunomodulating
medications (e.g. IFN) during the study or <= 4 months prior to the first
investigational product administration.
9) Clinical diagnosis of substance abuse <= 12 months prior to screening with
narcotics or cocaine or with alcohol (regular consumption > 14 units/week [men]
and > 7 units/week [women])
10) Inability to understand the patient information and make an informed
decision to participate
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 |
|---|---|
| EU-CTR | CTIS2024-514888-25-00 |
| EudraCT | EUCTR2019-003419-68-NL |
| CCMO | NL72439.018.19 |