REP 2139-Mg and REP 2165-Mg Combination Therapy in Chronic Hepatitis B Infection

NCT02565719 | Completed Phase 2

• 1 other identifier: REP 401
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

NAPs have been previously shown to clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV infected ducks) and in human patients. REP 2139-Ca mediated HBsAg clearance acts synergistically with immunotherapeutic agent pegylated interferon-alpha 2a to restore host immunological control of HBV infection. REP 2165 is a version of REP 2139 which has been shown preclinically to retain antiviral activity with lower accumulation in the liver. Both REP 2139 and REP 2165 used in this protocol are formulated as magnesium chelate complexes, which improve their administration tolerability. This open label, randomized and controlled study will examine the safety and efficacy of REP 2139-Mg and REP 2165-Mg therapy in patients with HBeAg negative chronic hepatitis B when used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha-2a.

Conditions

Chronic Hepatitis B

Outcome Measures

Primary Outcomes (1)

• Number of patients with adverse events

  Patients will be assessed weekly for adverse events including symptoms and laboratory abnormalities

  48 or 72 weeks (treatment duration) + 48 weeks (follow-up)

Secondary Outcomes (2)

• Number of patients with reduction of serum HBsAg

  Every two weeks for 48 or 72 weeks (treatment duration) + 48 weeks (follow-up)

• Number of patients with controlled HBV infection following treatment

  48 weeks follow-up (after completion of 48 or 72 weeks of treatment)

Study Arms (4)

REP 2139-Mg with Viread and Pegasys

EXPERIMENTAL

REP 2139-Mg in combination with tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys).

Drug: REP 2139-Mg; Drug: Pegasys; Drug: Viread

REP 2165-Mg with Viread and Pegasys

EXPERIMENTAL

REP 2165-Mg in combination with tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys).

Drug: Pegasys; Drug: Viread; Drug: REP 2165-Mg

Viread and Pegasys with crossover to REP 2139-Mg and Pegasys

ACTIVE COMPARATOR

Tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys) - crossover into add-on REP 2139-Mg therapy (triple combination) in patients with \< 3 log reduction in serum HBsAg from baseline after 24 weeks of Pegasys exposure.

Drug: REP 2139-Mg; Drug: Pegasys; Drug: Viread

Viread and Pegasys with crossover to REP 2165-Mg and Pegasys

ACTIVE COMPARATOR

Tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys) - crossover into add-on REP 2165-Mg therapy (triple combination) in patients with \< 3 log reduction in serum HBsAg from baseline after 24 weeks of Pegasys exposure.

Drug: Pegasys; Drug: Viread; Drug: REP 2165-Mg

Interventions

REP 2139-Mg DRUG

REP 2139-Mg = magnesium chelate complex of REP 2139

Also known as: not availalble

REP 2139-Mg with Viread and Pegasys; Viread and Pegasys with crossover to REP 2139-Mg and Pegasys

Pegasys DRUG

immunotherapy

Also known as: pegylated interferon alpha-2a

REP 2139-Mg with Viread and Pegasys; REP 2165-Mg with Viread and Pegasys; Viread and Pegasys with crossover to REP 2139-Mg and Pegasys; Viread and Pegasys with crossover to REP 2165-Mg and Pegasys

Viread DRUG

HBV RT polymerase inhibitor

Also known as: tenofovir disoproxil fumarate

REP 2139-Mg with Viread and Pegasys; REP 2165-Mg with Viread and Pegasys; Viread and Pegasys with crossover to REP 2139-Mg and Pegasys; Viread and Pegasys with crossover to REP 2165-Mg and Pegasys

REP 2165-Mg DRUG

REP 2165-Mg = magnesium chelate complex of REP 2165

Also known as: unaivalable

REP 2165-Mg with Viread and Pegasys; Viread and Pegasys with crossover to REP 2165-Mg and Pegasys

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Signed Written Informed Consent
• Males or females 18-55 years of age
• HBsAg\> 1000 IU / ml at screening
• HBV DNA \> 10000 copies / ml at screening
• Seronegative for HIV, HCV, CMV (IgM) and HDV (anti-HDAg) as determined at screening visit
• HBeAg negative, anti-HBe positive
• Evidence of liver fibrosis at screening
• Non cirrhotic: absence of advanced cirrhosis based on fibroscan evaluation at screening.
• Willingness to utilize adequate contraception while being treated with REP 2139-Mg or REP 2165-Mg and for 6 months following the end of the treatment in the study
• Any woman of childbearing potential (WOCBP) who agrees to use an effective methods of birth control for the entire duration of the study.
• Sexually active men who agree to use an effective method of birth control if their partners are WOCBP for the entire duration of the study for 6 months following the end of treatment.
• Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 30kg/m2 at screening (http://www.nhlbisupport.com/bmi/bmicalc.htm)
• Adequate venous access allowing weekly intravenous therapies and blood tests

You may not qualify if:

• Women with positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
• Breast-feeding women.
• HBeAg positive as determined at screening visit
• Positive HCV antibody, or HIV-1/HIV-2 or CMV antibody (IgM) or anti-HDV antibody test at screening
• Evidence of chronic liver disease caused by diseases other than chronic HBV infection (such as but not limited to: severe NAFLD, Wilson's disease, hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, significant biliary disease, nonalcoholic hepatic steatosis and toxin exposure).
• Medical History and Concurrent Diseases
• Current evidence of or history of variceal hemorrhage, hepatic encephalopathy, or ascites requiring diuretics or paracentesis or evidence of any of these findings on physical examination performed at screening
• Documented or suspected HCC as evidenced by previously obtained imaging studies or liver biopsy.
• Current evidence of or history of pancreatitis
• Current evidence of or history of renal dialysis, including hemodialysis or peritoneal dialysis
• History of bone marrow or organ transplant (other than cornea or hair), including liver transplant, or therapy with an immunomodulatory agent, cytotoxic agent, or systemic corticosteroids within 2 months of screening
• Current or known history of cancer (except adequately treated in situ carcinoma of the cervix, or basal or squamous cell carcinoma of the skin) within 5 years prior to screening
• Subjects with clinically significant ECG abnormalities (indicative of arrhythmia, myocardial ischemia or other serious cardiovascular disorder) at the time of screening in the opinion of the investigator
• Active substance abuse, such as alcohol, or inhaled or injected drugs, as defined by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV), Diagnostic Criteria for Drug and Alcohol Abuse (see Appendix 1) within 12 months prior to screening.
• The use of illicit drugs within the past two years prior to screening.

Sponsors & Collaborators

• Replicor Inc.: lead

Study Sites (3)

Infectious Clinical Hospital (n.a. Toma Ciorba) Department 5

Chisinau, 2004, Moldova

Location

Infectious Clinical Hospital (n.a. Toma Ciorba), Department 4

Chisinau, 2004, Moldova

Location

Repiblican Clinical Hospital (ARENSIA unit)

Chisinau, 2025, Moldova

Location

Related Publications (4)

• Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers inhibit duck hepatitis B virus infection in vitro. Antimicrob Agents Chemother. 2013 Nov;57(11):5291-8. doi: 10.1128/AAC.01003-13. Epub 2013 Aug 12.

  PMID: 23939902 BACKGROUND

• Noordeen F, Vaillant A, Jilbert AR. Nucleic acid polymers prevent the establishment of duck hepatitis B virus infection in vivo. Antimicrob Agents Chemother. 2013 Nov;57(11):5299-306. doi: 10.1128/AAC.01005-13. Epub 2013 Aug 12.

  PMID: 23939904 BACKGROUND

• Bazinet M, Anderson M, Pantea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Gersch J, Holzmayer V, Kuhns M, Cloherty G, Vaillant A. Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP-Based Therapy. Hepatol Commun. 2021 Nov;5(11):1873-1887. doi: 10.1002/hep4.1767. Epub 2021 Jul 10.

  PMID: 34558823 DERIVED

• Bazinet M, Pantea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, Jimbei P, Iarovoi L, Smesnoi V, Musteata T, Jucov A, Dittmer U, Krawczyk A, Vaillant A. Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy. Gastroenterology. 2020 Jun;158(8):2180-2194. doi: 10.1053/j.gastro.2020.02.058. Epub 2020 Mar 6.

  PMID: 32147484 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

peginterferon alfa-2a; Tenofovir

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Victor Pantea, M.D.

  Infectious Diseases Department, State University of Medicine and Pharmacy, Infectious Clinical Hospital (n.a. Toma Clorba), Chisinau, Moldova, Republic of 2004

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2015
• First Posted: October 1, 2015
• Study Start: March 1, 2016
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: September 10, 2019

Record last verified: 2019-09

Locations

MO (3)