Official Title

A Multicenter, Open-label, Randomized Clinical Study to Assess Efficacy and Safety of 3 Doses of Myrcludex B for 24 Weeks in Combination With Tenofovir Compared to Tenofovir Alone to Suppress HBV Replication in Patients With Chronic Hepatitis D
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Study Participants

    120
This is a multicenter, open-label, randomized clinical trial to Assess Efficacy and Safety of 3 Doses of Myrcludex B for 24 Weeks in Combination with Tenofovir Compared to Tenofovir Alone to Suppress HBV Replication in Patients with Chronic Hepatitis D
This is a multicenter, open-label, randomised, phase II study.

The study will be conducted in Russia and Germany. The study is designed to evaluate the benefit of 3 MXB doses versus observation in patients on background therapy with tenofovir, suffering from hepatitis delta with very limited therapeutic options; the patients will be randomized 1:1:1:1 into 3 treatment arms and an observation arm. Patients with compensated cirrhosis at screening will be stratified to allow similar distribution into each treatment arm. If patients were not receiving treatment with nucleoside/nucelotide analogue, the comparator/background drug will be initiated after the eligibility confirmation, for 12 weeks prior to randomization visit; patients who previously received tenofovir will continue the dosing; patients on different nucleoside/nucleotide analogue will be switched to tenofovir. Observation is considered an adequate control group, as daily placebo injections for 24 weeks are regarded not feasible and ethically questionable.

It is planned to screen 200 patients, and 120 patients will be randomised into four treatment arms in the 1:1:1:1 ratio.

Arm A (30 patients): Myrcludex B, 2 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
Arm B (30 patients): Myrcludex B, 5 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
Arm C (30 patients): Myrcludex B, 10 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.
Arm D (30 patients): tenofovir treatment for 48 weeks.
Study Started
Feb 16
2016
Primary Completion
Jan 31
2018
Study Completion
Jan 31
2018
Results Posted
Dec 30
2019
Last Update
May 10
2021

Drug Myrcludex B

2 mg, once daily, subcutaneously

Drug Myrcludex-B

5 mg, once daily, subcutaneously

Drug Myrcludex-B

10 mg, once daily, subcutaneously

Drug Tenofovir

tenofovir disoproxil 245 mg, equivalent to tenofovir disoproxil fumarate 300 mg

  • Other names: Viread

Arm A Experimental

Myrcludex B, 2 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.

Arm B Experimental

Myrcludex B, 5 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.

Arm C Experimental

Myrcludex B, 10 mg/day subcutaneously (s.c.) for 24 weeks + tenofovir with a further follow-up period of 24 weeks of continued tenofovir therapy.

Arm D Active Comparator

tenofovir treatment for 48 weeks

Criteria

Inclusion Criteria:

Age from 18 to 65 years inclusively at the time of signing Informed Consent Form.
Positive serum HBsAg for at least 6 months before Screening.
Positive serum anti-HDV antibody for at least 6 months before screening.
Positive PCR results for serum HDV RNA at Screening.
Patients with liver cirrhosis, irrespective of previous interferon treatment .
Patients without liver cirrhosis, who failed prior interferon treatment or for whom, in the opinion of the Investigator, such treatment is currently contraindicated (including history of interferon intolerance) .
Alanine aminotransferase level >1 x ULN, but less than 10 x ULN.
Previous nucleotide/nucleoside analogue treatment within at least 12 weeks prior to the planned start of study treatment or subject's willingness to take tenofovir for at least 12 weeks prior to the planned start of study treatment.
Negative urine pregnancy test for females of childbearing potential.

Inclusion criteria for female subjects:

Postmenopausal for at least 2 years, or
Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, staples, or another type of sterilization), or
Abstinence from heterosexual intercourse throughout the study, or
Willingness to use highly effective contraception throughout the study and for 3 months after the last dose of the study medication.
Male and female subjects must agree to use a highly effective contraception throughout the study and for 3 months after the last dose of the study medication.
Male subjects must agree not to donate sperm throughout the study and for 3 months after the last dose of the study medication.

Exclusion Criteria:

Child-Pugh score of B-C or over 6 points.
HCV or HIV coinfection. Subjects with anti-HCV antibodies can be enrolled, if screening HCV RNA test is negative.
Creatinine clearance <60 mL/min.
Total bilirubin ≥ 2mg/dL. Patients with higher total bilirubin values may be included after the consultation with the Study's Medical Monitor, if such elevation can be clearly attributed to Gilbert's syndrome associated with low-grade hyperbilirubinemia.
Any previous or current malignant neoplasms, including hepatic carcinoma.

Summary

Arm A

Arm B

Arm C

Arm D

All Events

Event Type Organ System Event Term Arm A Arm B Arm C Arm D

HDV RNA Response at Week 24

HDV RNA negativation or decrease by ≥2 log10 from baseline to Week 24

Arm A

Arm B

Arm C

Arm D

Durability of HDV RNA Response

Durability of HDV RNA response to 24 weeks post treatment

Arm A

Response at Week 24 and 48

Response at Week 24 only

Arm B

Response at Week 24 and 48

Response at Week 24 only

Arm C

Response at Week 24 and 48

Response at Week 24 only

Arm D

Response at Week 24 and 48

Response at Week 24 only

Combined Response: HDV RNA Response and Normal ALT at Treatment Week 24

Combined response: HDV RNA negativation or ≥2 log decline and normal ALT at treatment week 24

Arm A

Week 24

Week 48

Arm B

Week 24

Week 48

Arm C

Week 24

Week 48

Arm D

Week 24

Week 48

Changes in ALT Values

Changes in ALT values at Week 24 and Week 48 compared to baseline.

Arm A

Change from Baseline to Week 24

-49.6
U/L (Mean)
Standard Deviation: 58.7

Change from Baseline to Week 48

-1.6
U/L (Mean)
Standard Deviation: 72.8

Arm B

Change from Baseline to Week 24

-79.4
U/L (Mean)
Standard Deviation: 84.2

Change from Baseline to Week 48

-18.2
U/L (Mean)
Standard Deviation: 94.4

Arm C

Change from Baseline to Week 24

-78.9
U/L (Mean)
Standard Deviation: 81.1

Change from Baseline to Week 48

1.4
U/L (Mean)
Standard Deviation: 76.0

Arm D

Change from Baseline to Week 24

-29.2
U/L (Mean)
Standard Deviation: 61.4

Change from Baseline to Week 48

-26.3
U/L (Mean)
Standard Deviation: 39.0

Change (Absence of Increase) in Fibrosis Marker

Change (absence of increase) in fibrosis marker: serum alpha-2-macroglobulin at Week 24 and Week 48 compared to baseline

Arm A

Change from Baseline to Week 24

-0.076
g/L (Mean)
Standard Deviation: 0.320

Change from Baseline to Week 48

-0.056
g/L (Mean)
Standard Deviation: 0.416

Arm B

Change from Baseline to Week 24

0.02
g/L (Mean)
Standard Deviation: 0.280

Change from Baseline to Week 48

0.075
g/L (Mean)
Standard Deviation: 0.360

Arm C

Change from Baseline to Week 24

0.024
g/L (Mean)
Standard Deviation: 0.257

Change from Baseline to Week 48

-0.008
g/L (Mean)
Standard Deviation: 0.265

Arm D

Change from Baseline to Week 24

-0.141
g/L (Mean)
Standard Deviation: 0.607

Change from Baseline to Week 48

-0.031
g/L (Mean)
Standard Deviation: 0.485

Change in Hepatitis B Surface Antigen

Changes in hepatitis B surface antigen (HBsAg) (defined as decline in HBsAg levels, disappearance of HBsAg and HBsAg seroconversion to anti-HBsAg) at week 24 and week 48 compared to baseline

Arm A

Change from Baseline to Week 24

-0.048
IU/mL (Mean)
Standard Deviation: 0.392

Change from Baseline to Week 48

-0.138
IU/mL (Mean)
Standard Deviation: 0.288

Arm B

Change from Baseline to Week 24

0.003
IU/mL (Mean)
Standard Deviation: 0.175

Change from Baseline to Week 48

-0.162
IU/mL (Mean)
Standard Deviation: 0.412

Arm C

Change from Baseline to Week 24

0.034
IU/mL (Mean)
Standard Deviation: 0.106

Change from Baseline to Week 48

-0.134
IU/mL (Mean)
Standard Deviation: 0.175

Arm D

Change from Baseline to Week 24

0.025
IU/mL (Mean)
Standard Deviation: 0.239

Change from Baseline to Week 48

-0.07
IU/mL (Mean)
Standard Deviation: 0.186

Change in HBV DNA Levels at Week 24 and Week 48 Compared to Baseline

Change in hepatitis B virus (HBV) DNA levels at Week 24 and Week 48 compared to baseline.

Arm A

Change from Baseline to Week 24

-0.314
IU/mL (Mean)
Standard Deviation: 0.956

Change from Baseline to Week 48

-0.244
IU/mL (Mean)
Standard Deviation: 0.828

Arm B

Change from Baseline to Week 24

-0.484
IU/mL (Mean)
Standard Deviation: 1.106

Change from Baseline to Week 48

-0.194
IU/mL (Mean)
Standard Deviation: 1.416

Arm C

Change from Baseline to Week 24

-0.173
IU/mL (Mean)
Standard Deviation: 1.144

Change from Baseline to Week 48

-0.267
IU/mL (Mean)
Standard Deviation: 1.275

Arm D

Change from Baseline to Week 24

-0.343
IU/mL (Mean)
Standard Deviation: 1.151

Change from Baseline to Week 48

-0.257
IU/mL (Mean)
Standard Deviation: 0.979

Absence of a Fibrosis Progression According to the Findings of Transient Elastometry

Decrease in liver stiffness and absence of a fibrosis progression according to the findings of transient elastometry (fibroscan) at week 24 compared to baseline

Arm A

Baseline

14.45
kPa (Mean)
Standard Deviation: 6.37

Change from Baseline to Week 24

-2.85
kPa (Mean)
Standard Deviation: 2.65

Arm B

Baseline

17.18
kPa (Mean)
Standard Deviation: 11.49

Change from Baseline to Week 24

-2.52
kPa (Mean)
Standard Deviation: 6.21

Arm C

Baseline

16.0
kPa (Mean)
Standard Deviation: 7.37

Change from Baseline to Week 24

-3.38
kPa (Mean)
Standard Deviation: 3.83

Arm D

Baseline

16.2
kPa (Mean)
Standard Deviation: 7.83

Change from Baseline to Week 24

-0.78
kPa (Mean)
Standard Deviation: 3.17

Number of Participants With Improvement of Histological Findings According to the Liver Biopsy Results

Change (improvement/ worsening) in fibrosis and histological activity stage according to the liver biopsy study results at week 24 compared to baseline. Liver fibrosis was evaluated by histological staging systems with stage 0 corresponding to absence of fibrosis and with the highest score (the last stage in all systems) corresponding to cirrhosis. Improvement is defined as a decrease of at least 1 point in histological staging systems; worsening is defined as an increase of at least 1 point. Data should be interpreted with caution due to low number of paired biopsies available.

Arm A

Histological activity index

Ishak fibrosis score

Knodell fibrosis score

Metavir activity grade

Metavir fibrosis stage

Arm B

Histological activity index

Ishak fibrosis score

Knodell fibrosis score

Metavir activity grade

Metavir fibrosis stage

Arm C

Histological activity index

Ishak fibrosis score

Knodell fibrosis score

Metavir activity grade

Metavir fibrosis stage

Arm D

Histological activity index

Ishak fibrosis score

Knodell fibrosis score

Metavir activity grade

Metavir fibrosis stage

Total

118
Participants

Age, Continuous

40.2
years (Mean)
Standard Deviation: 9.5

Body Weight (kg)

75.53
kg. (Mean)
Standard Deviation: 14.49

Height (cm)

172.0
cm. (Mean)
Standard Deviation: 8.9

Age, Categorical

Body Mass Index (kg/m²)

Race (NIH/OMB)

Sex: Female, Male

Overall Study

Arm A

Arm B

Arm C

Arm D

Drop/Withdrawal Reasons

Arm B

Arm C

Arm D