Rationale: Currently, there is no curative therapy available for patients that are chronically infected with the hepatitis B virus (HBV). 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 chronic hepatitis B (CHB). 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. Study population: patients chronically infected with the hepatitis B virus with a normal liver function and no signs of liver damage, who do not use any antiviral medication (group A, n=16) or are treated with tenofovir \> 6 months (group B, n=16). Intervention: Patients will be randomly allocated to daily oral treatment with terbinafine or a matched placebo, either as monotherapy (group A) or as add-on therapy to tenofovir (group B). Main study parameters/endpoints: Primary outcomes: decline in level of serum HBsAg \>0.32log10 IU/mL in both groups A and B and decline in serum HBV DNA \>0.86log10 in group A at the end of study treatment (week 10 vs baseline). Secondary outcomes: 1) Safety and tolerability of terbinafine as mono- or combination therapy; 2) level of serum HBsAg and HBV DNA at 3 months follow-up; 3) decline of HBsAg levels over time (all visits); 4) HBV RNA, large HBsAg (LHBs) HBcrAg levels, and HBeAg status at baseline and end of study 4). Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients participating in this study will undergo physical examinations and blood sample collections (13 samples and in total 467.5 mL). They will also be asked to fill in the HBQOL and EQ5D5L quality of life questionnaires and a medicine diary. In total there will be 13 visits in the hospital of which 7 will be for blood collection only. Terbinafine can induce liver damage 1 of 50,000 to 120,000 prescriptions (LiverTox), a weekly safety laboratory control is implemented in the visits to detect possible liver toxicity in an early stage and prevent liver damage.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
36
terbinafine 250mg once daily for 4 weeks, followed by 2 weeks washout, followed by 4 weeks bid.
Placebo 250mg once daily for 4 weeks, followed by 2 weeks washout, followed by 4 weeks bid.
Tenofovir 245mg standard of care
Amsterdam UMC
Amsterdam, North Holland, Netherlands
RECRUITINGChange in level of serum HBsAG
\- Change in level of serum HBsAg \>0.32 log10 IU/mL at the end of study treatment (week 10 vs baseline).
Time frame: 10 weeks
Change in serum HBV DNA
\- Change in serum HBV DNA \>0.86 log10 in group A (monotherapy) at the end of study treatment (week 10 vs baseline).
Time frame: 10 weeks
Safety of terbinafine
\- Safety of terbinafine as mono- or combination therapy, as defined by the number of patients with treatment-related laboratory adverse events as assessed by CTCAE v4.0.
Time frame: 10 weeks
Tolerability of terbinafine
\- Tolerability of terbinafine as mono- or combination therapy, as defined by the number of patients with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 10 weeks
Serum levels of HBsAG
\- Level of serum (large) HBsAg at 3 months follow-up.
Time frame: 3 months
Serum levels of HBV DNA
\- Level of serum HBV DNA at 3 months follow-up.
Time frame: 3 months
Serum levels of HBV RNA
\- Level of serum HBV RNA at 3 months follow-up.
Time frame: 3 months
Serum levels of HBcrAg
\- Level of serum HBcrAg at 3 months follow-up.
Time frame: 3 months
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