A randomized, open-label multicentre clinical trial of daily Myrcludex B versus entecavir in patients with HBeAg negative chronic hepatitis B.

This is a randomized, open-label multicentre clinical trial of daily Myrcludex B versus entecavir in patients with HBeAg negative chronic hepatitis B. Accounting for screen-outs about 76 patients will be screened and 48 of them will be randomized into 6 treatment groups:

Arm A (8 patients): Myrcludex B 0.5 mg / day / sc / 12 weeks Arm B (8 patients): Myrcludex B 1 mg / day / sc / 12 weeks Arm C (8 patients): Myrcludex B 2 mg / day / sc / 12 weeks Arm D (8 patients): Entecavir 0.5 mg / day / orally / 24 weeks Arm E (8 patients): Myrcludex B 5 mg / day / sc / 12 weeks Arm F (8 patients): Myrcludex B 10 mg / day / sc / 24 weeks

The study consists of screening period up to 28 days (Day -28 -1); baseline visit (Day 0), treatment period up to 12 weeks for groups A-C, E and 24 weeks for groups D, F; follow-up period up to 12 weeks for groups A-C, E, F.

Inclusion Criteria:

1. Age 18-65 years inclusive at the time of giving of written informed consent for study participation.

2. Chronic hepatitis B defined by the presence of HBsAg for at least 6 months prior to screening period.

3. Liver biopsy performed within one year prior to screening or during screening period.

4. Alanine aminotransferase (ALT) ≥1.5 x ULN and ≤ 6 x ULN. If ALT level during screening period is ≥1 ULN the patient can be included in the study after obtaining the sponsor's approval and if the following conditions are met :

   • evidence of inflammation such as lymphocyte infiltration confirmed by liver biopsy performed within the 6 months prior to the inclusion in the study,
   • and/or the patient has a history of elevated ALT levels of ≥1.5 ULN during the 12 months prior to screening period.

5. HBeAg negative and anti-HBeAg positive.

6. HBV DNA ≥ 104 copies/mL.

7. All women of childbearing potential must have a negative urine pregnancy test prior to enrolment.

8. Women must:

   • Be menopausal for at least 2 years, or
   • Be surgically sterile (total hysterectomy or bilateral ovariectomy or bilateral tubal ligation/clips or otherwise be incapable of pregnancy), or
   • Not be heterosexually active during the study, or
   • Agree to use a highly effective method of birth control (double barrier method or combination of barrier method with hormonal or intrauterine device) during the study and for 3 month after the last dosing of the investigational medicinal product.

9. Men must agree to use a highly effective method of birth control (double barrier methods or combination of barrier method with hormonal or intrauterine device in their women-partner) and not to donate a sperm during the study and for 3 month after the last dosing of the investigational medicinal product.

10. An understanding, ability and willingness to fully comply with study procedures and restrictions.

11. An ability to provide the written informed consent to participate in the study.

Exclusion Criteria:

1. Decompensated liver disease (Child-Pugh-Score >6).
2. Any sign of liver cirrhosis (histological, ultra sound, biochemical).
3. Co-infected with hepatitis C virus (HCV), hepatitis D virus (HDV), or HIV.
4. ALT > 6 ULN.
5. Creatinine clearance < 60 mL/min.
6. Total bilirubin > 2 mg/dL.
7. Pre-treatment with nucleoside-analogues (lamivudine, telbivudine, entecavir) less than 6 months prior to the first dosing of the investigational medicinal products. Pre-treatment with nucleotide-analogues and interferons is allowed.
8. History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies or elevated serum alpha-fetoprotein (AFP) levels. In patients with such findings, HCC will be ruled-out prior to screening for the present study.
9. One or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, e.g. congestive heart failure or other severe cardiopulmonary disease). Patients with Gilbert's syndrome and Dubin-Johnson syndrome, two benign disorders associated with low-grade hyperbilirubinemia can be enrolled into the trial.
10. History of clinically evident pancreatitis.
11. History of alcohol or drug abuse within the preceding two years. For the purposes of the present study, alcohol abuse is arbitrarily defined as frequent consumption of alcoholic beverages with an average daily intake of more than 40 g of ethanol.
12. Participation in another study with an investigational drug within less than one month prior to this study or simultaneously to this study.
13. Patients who are unable or unwilling to follow the protocol requirements.
14. Patients with a history of seizures, central nervous system disorders or psychiatric disability thought to be clinically significant in the opinion of the investigator.
15. Patients with limited mental capacity to the extent that she/he cannot provide informed consent or information regarding adverse events of the study drug.
16. Clinically significant renal, respiratory or cardiovascular disease.
17. Pregnancy and lactation.
18. Patients who have previously participated in this study.

Safety population - all randomized patients who were administered at least one dose of the study drugs.