Chronic Hepatitis B
Conditions
Brief summary
A randomized, open-label multicentre clinical trial of daily Myrcludex B versus entecavir in patients with HBeAg negative chronic hepatitis B.
Detailed description
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.
Interventions
DRUGEntecavir
DRUGMyrcludex B
Sponsors
Hepatera Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With HBsAg Response at 12 Week of Therapy | 12 week | HBsAg response is defined as serum HBsAg decline of at least 0.5 logs IU/ml (or HBsAg negativation) at week 12 compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 12 weeks | HBV DNA response is defined as persistent reduction of HBV DNA by \>1 log IU/ml or negativation at week 12 compared to baseline. |
| Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 12 weeks | Biochemical response is defined as normalization of ALT level at week 12 compared to baseline. |
| Proportion of Patients With HBsAg Response at 24 Week of Therapy | 24 weeks | HBsAg response is defined as serum HBsAg decline of at least 0.5 logs IU/ml (or HBsAg negativation) at week 24 compared to baseline. |
| Proportion of Patients With HBV DNA Response at Week 24 of Therapy | 24 weeks | HBV DNA response is defined as persistent reduction of HBV DNA by \>1 log IU/ml or negativation at week 24 compared to baseline. |
| Proportion of Patients With Biochemical Response at 24 Weeks of Therapy | 24 weeks | Biochemical response is defined as normalization of ALT level at week 24 compared to baseline. |
| Proportion of Patients With cccDNA Response at 24 Week of Therapy | 24 weeks | Virological cccDNA response is defined as reduction of intrahepatic cccDNA by 0.5 logs in comparison to baseline at week 24. |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Myrcludex B 0.5 mg daily for 12 weeks, followed by 12 weeks follow-up period | 8 |
| Arm B Myrcludex B 1 mg daily for 12 weeks, followed by 12 weeks follow-up period | 8 |
| Arm C Myrcludex B 2 mg daily for 12 weeks, followed by 12 weeks follow-up period | 8 |
| Arm D Entecavir 0.5 mg daily for 24 weeks | 8 |
| Arm E Myrcludex B 5 mg daily for 12 weeks, followed by 12 weeks follow-up period | 8 |
| Arm F Myrcludex B 10 mg daily for 24 weeks, followed by 12 weeks follow-up period | 8 |
| Total | 48 |
Baseline characteristics
| Characteristic | Arm A | Total | Arm F | Arm E | Arm D | Arm C | Arm B |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 38.3 years STANDARD_DEVIATION 8.5 | 37.4 years STANDARD_DEVIATION 8.9 | 34.5 years STANDARD_DEVIATION 6.7 | 36.4 years STANDARD_DEVIATION 9.5 | 40.2 years STANDARD_DEVIATION 13 | 42.4 years STANDARD_DEVIATION 11.1 | 32.9 years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 46 Participants | 8 Participants | 7 Participants | 8 Participants | 8 Participants | 8 Participants |
| Region of Enrollment Russia | 8 participants | 48 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 16 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 32 Participants | 6 Participants | 5 Participants | 4 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 4 / 8 | 6 / 8 | 5 / 8 | 2 / 8 | 4 / 8 | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 8 | 1 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Proportion of Patients With HBsAg Response at 12 Week of Therapy
HBsAg response is defined as serum HBsAg decline of at least 0.5 logs IU/ml (or HBsAg negativation) at week 12 compared to baseline.
Time frame: 12 week
Population: For the efficacy assessments the main analysis set was Full analysis set (FAS): All patients of the Safety set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 0 Participants |
| Arm B | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 0 Participants |
| Arm C | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 1 Participants |
| Arm D | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 0 Participants |
| Arm E | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 0 Participants |
| Arm F | Proportion of Patients With HBsAg Response at 12 Week of Therapy | 0 Participants |
Secondary
Proportion of Patients With Biochemical Response at 12 Weeks of Therapy
Biochemical response is defined as normalization of ALT level at week 12 compared to baseline.
Time frame: 12 weeks
Population: Only patients with abnormal ALT levels at baseline were included in data analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 3 Participants |
| Arm B | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 4 Participants |
| Arm C | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 4 Participants |
| Arm D | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 4 Participants |
| Arm E | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 2 Participants |
| Arm F | Proportion of Patients With Biochemical Response at 12 Weeks of Therapy | 4 Participants |
Secondary
Proportion of Patients With Biochemical Response at 24 Weeks of Therapy
Biochemical response is defined as normalization of ALT level at week 24 compared to baseline.
Time frame: 24 weeks
Population: This variable was assessed in the patients administered 24-week treatment: patients of Arm F who received Myrcludex B 10 mg and patients of Arm D who received Entecavir 0.5 mg. Only patients with abnormal ALT levels at baseline were included in data analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With Biochemical Response at 24 Weeks of Therapy | 5 Participants |
| Arm B | Proportion of Patients With Biochemical Response at 24 Weeks of Therapy | 3 Participants |
Secondary
Proportion of Patients With cccDNA Response at 24 Week of Therapy
Virological cccDNA response is defined as reduction of intrahepatic cccDNA by 0.5 logs in comparison to baseline at week 24.
Time frame: 24 weeks
Population: Virological cccDNA response was to be estimated only for patients of group F administered 24-week therapy with Myrcludex B in the dose of 10 mg and to whom liver biopsy during screening period and at week 24 was performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With cccDNA Response at 24 Week of Therapy | 0 Participants |
Secondary
Proportion of Patients With HBsAg Response at 24 Week of Therapy
HBsAg response is defined as serum HBsAg decline of at least 0.5 logs IU/ml (or HBsAg negativation) at week 24 compared to baseline.
Time frame: 24 weeks
Population: This variable was assessed in the patients administered 24-week treatment: patients of Arm F who received Myrcludex B 10 mg and patients of Arm D who received Entecavir 0.5 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With HBsAg Response at 24 Week of Therapy | 0 Participants |
| Arm B | Proportion of Patients With HBsAg Response at 24 Week of Therapy | 0 Participants |
Secondary
Proportion of Patients With HBV DNA Response at Week 12 of Therapy
HBV DNA response is defined as persistent reduction of HBV DNA by \>1 log IU/ml or negativation at week 12 compared to baseline.
Time frame: 12 weeks
Population: For the efficacy assessments the main analysis set was Full analysis set (FAS): All patients of the Safety set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 2 Participants |
| Arm B | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 0 Participants |
| Arm C | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 2 Participants |
| Arm D | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 8 Participants |
| Arm E | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 1 Participants |
| Arm F | Proportion of Patients With HBV DNA Response at Week 12 of Therapy | 6 Participants |
Secondary
Proportion of Patients With HBV DNA Response at Week 24 of Therapy
HBV DNA response is defined as persistent reduction of HBV DNA by \>1 log IU/ml or negativation at week 24 compared to baseline.
Time frame: 24 weeks
Population: This variable was assessed in the patients administered 24-week treatment: patients of Arm F who received Myrcludex B 10 mg and patients of Arm D who received Entecavir 0.5 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Proportion of Patients With HBV DNA Response at Week 24 of Therapy | 7 Participants |
| Arm B | Proportion of Patients With HBV DNA Response at Week 24 of Therapy | 6 Participants |