Myrcludex B Plus Pegylated Interferon-alpha-2a in Patients With HBeAg Negative HBV/HDV Co-infection

Study Overview
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Brief Summary
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Randomized open-label substudy of daily Myrcludex B (MXB) plus pegylated interferon-alpha-2a (PEG-INF-a) in patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B virus (HBV) co-infected with hepatitis delta virus (HDV).

Detailed Description
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The study is designed to evaluate safety and efficacy of MXB in a subset of HBV infected patients who are co-infected with HDV. Hepatitis delta represents the most severe form of chronic viral hepatitis and there is no approved treatment option available for patients infected with both HBV and HDV. 24 patients will be randomised into 3 arms: pre-treatment with MXB followed by PEG-INF-a treatment versus a combination of both drugs versus PEG-INF-a. Prolonged blockade of HBV entry into hepatocytes should also block infection with HDV particles (which uses hepatitis B surface antigen (HBsAg) as its envelope) and thus provide a therapeutic option for this otherwise hardly treatable disease. PEG-INF-a is used for the treatment of chronic hepatitis delta. The study endpoints are virological response (HBsAg, hepatitis delta virus ribonucleic acid (HDV RNA), hepatitis B virus deoxyribonucleic acid (HBV DNA)), as well as safety and tolerability and drug immunogenicity.

Official Title
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Randomized Open-label Substudy of Daily Myrcludex B Plus Pegylated Interferon-alpha-2a in Patients With HBeAg Negative Chronic Hepatitis B Co-infected With Hepatitis Delta

Conditions
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Chronic Hepatitis D Infection

Intervention / Treatment
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* Drug: PEG IFN alfa-2a
* Drug: Myrcludex B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis B defined by the presence of HBsAg for at least 6 months prior to screening period. Co-infection with hepatitis D virus defined as positive anti-HDV antibodies for at least 3 months and positive for HDV-RNA within the screening period. Liver biopsy performed within one year prior to screening or during screening period. HBeAg negative All women of childbearing potential must have a negative urine pregnancy test prior to enrolment. 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. 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. An understanding, ability and willingness to fully comply with study procedures and restrictions. An ability to provide the written informed consent to participate in the study Exclusion Criteria: Decompensated liver disease (Child-Pugh-Score >6). Co-infected with hepatitis C virus (HCV), or HIV. Patients with presence of anti-HCV antibody and negative HCV RNA in two separate occasions within 12 months prior to screening could be enrolled into the study after sponsor written permission. ALT > 6 ULN. Creatinine clearance < 60 mL/min. Total bilirubin > 2 mg/dL. Confirmed contraindication for treatment with PEG-INF-a. 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. 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. History of clinically evident pancreatitis. 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. Participation in another study with an investigational drug within less than one month prior to this study or simultaneously to this study. Patients who are unable or unwilling to follow the protocol requirements. Patients with a history of seizures, central nervous system disorders or psychiatric disability thought to be clinically significant in the opinion of the investigator. Patients with limited mental capacity to the extent that she/he cannot provide informed consent or information regarding adverse events of the study drug. Clinically significant renal, respiratory or cardiovascular disease. Pregnancy and lactation. Patients who have previously participated in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MXB then PEG IFN<br>Myrcludex B 2mg daily for 24 weeks, followed by PEG IFN alfa-2a 180 µg/0.5 mL weekly for 48 weeks | Drug: PEG IFN alfa-2a<br> <br> * Other names: Pegasys;Drug: Myrcludex B<br> <br> * Other names: Myrcludex;|
| Experimental: MXB + PEG IFN then PEG IFN<br>Myrcludex B 2mg daily and PEG IFN alfa-2a 180 µg/0.5 mL weekly for 24 weeks, followed by PEG IFN alfa-2a 180 µg/0.5 mL weekly for 24 weeks | Drug: PEG IFN alfa-2a<br> <br> * Other names: Pegasys;Drug: Myrcludex B<br> <br> * Other names: Myrcludex;|
| Active Comparator: PEG IFN<br>PEG IFN alfa-2a 180 µg/0.5 mL once weekly for 48 weeks | Drug: PEG IFN alfa-2a<br> <br> * Other names: Pegasys;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hepatitis B Surface Antigen (HBsAg) Response at Week 12 of Therapy | HBsAg response was defined as serum HBsAg decline of at least 0.5 log IU/mL (or HBsAg negativation) at week 12 compared to baseline (including the patient with negative baseline level) | Baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hepatitis B Surface Antigen (HBsAg) Response at Week 24 of Therapy | HBsAg response was defined as serum HBsAg decline of at least 0.5 log IU/mL (or HBsAg negativation) at week 24 compared to baseline (including the patient with negative baseline level) | Baseline and 24 weeks | 
| Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Response at Week 24 of Therapy | HBV DNA response was defined as persistent reduction of HBV DNA by > 1 log IU/mL or negativation (including the patient with negative baseline level) | Baseline and 24 weeks | 
| Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Response at Week 12 of Therapy | HBV DNA response was defined as persistent reduction of HBV DNA by > 1 log IU/mL or negativation (including the patient with negative baseline level) | Baseline and 12 weeks | 
| Number of Participants With Hepatitis D Virus Ribonucleic Acid (HDV RNA) Response at Week 12 of Therapy | HDV RNA response was defined as persistent reduction of HDV RNA by > 1 log IU/mL or negativation (including the patient with negative baseline level) | Baseline and 12 weeks | 
| Number of Participants With Hepatitis D Virus Ribonucleic Acid (HDV RNA) Response at Week 24 of Therapy | HDV RNA response was defined as persistent reduction of HDV RNA by > 1 log IU/mL or negativation (including the patient with negative baseline level) | Baseline and 24 weeks | 
| Number of Participants With Biochemical Response at Week 12 of Therapy | Biochemical response was defined as normalization of ALT level as compared to baseline. | Baseline and 12 weeks | 
| Number of Participants With Biochemical Response at Week 24 of Therapy | Biochemical response was defined as normalization of ALT level as compared to baseline. | Baseline and 24 weeks | 
| Number of Participants With Covalently Closed Circular Deoxyribonucleic Acid (cccDNA) Response at Week 72 of Therapy | Virological cccDNA response was defined as reduction of intrahepatic cccDNA by 0.5 log in comparison to baseline at the end of follow up. | Baseline and 72 weeks for arm A and 48 weeks for arms B and C |