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Chronic Hepatitis BPhase 2NCT02565719

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

A Phase 2 study testing REP 2139-Mg, Pegasys and Viread in people with Chronic Hepatitis B, run by Replicor Inc. at 3 sites in Moldova.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 to 55 years
Conditions the study is for
Chronic Hepatitis B
What is being tested?
REP 2139-Mg, Pegasys and Viread
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
3 sitesMoldova
Study dates
Mar 2016to May 2019
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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

Who cannot join

  • 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
Show all 60Show fewer
  • 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.
  • Prior or current history of cardiomyopathy or significant ischemic cardiac or cerebrovascular disease, including history of angina, myocardial infarction, or interventional procedure for coronary artery disease (including angioplasty, stent procedure, or cardiac bypass surgery)
  • Confirmed uncontrolled hypertension (patients with screening systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg should be excluded unless discussed with Replicor Inc.)
  • Presence of diabetes (controlled or uncontrolled).
  • Prior or current history of clinically significant hemoglobinopathy or hemolytic anemia
  • History of or evidence of hyperthyroidism at screening.
  • Subjects with pre-existing ophthalmologic disorders considered clinically significant on eye exam during physical examination.
  • Prior or current history of severe chronic obstructive pulmonary disease, interstitial lung disease or sarcoidosis
  • History of immunologically mediated disease (including but not limited to, rheumatoid arthritis, inflammatory bowel disease, moderate to severe psoriasis [mild psoriasis is allowed], and systemic lupus erythematosus)
  • History of or current severe psychiatric disease, especially untreated or unstable depression, psychotic disorder such as bipolar disease and history of hospitalization for suicidal ideation/attempt
  • Active seizure disorder as defined by either untreated seizure disorder or continued seizure activity within the past year prior to screening despite treatment with anti-seizure medication
  • Has, in the opinion of the investigator, any physical exam findings, laboratory abnormalities, or other medical, social, or psychosocial factors that may negatively impact compliance or subject's safety by participation in this study; this should include conditions which may affect hematologic parameters such as prior or current history of porphyria cutanea tarda and/or hemophilia
  • Fibroscan and Fibromax showing current evidence advanced cirrhosis at screening or known history of decompensated cirrhosis based on radiologic criteria or biopsy results and clinical criteria
  • Poor venous access making IV infusion too difficult
  • Inability to provide informed consent
  • Inability or unwillingness to provide weekly blood samples.
  • Patients not willing to come every week to receive therapy or to give blood.
  • Physical and Laboratory Test Findings
  • Evidence of significant heavy metal load in whole blood as determined at pre-screening visit.
  • Antinuclear antibody (ANA) titer ≥ 1:640, AMA or LKM-1antibody positive as determined at pre-screening visit
  • Hemoglobin < 12.0 g/dL (males), < 10.0 g/dL (female) at screening
  • Platelet count < 90,000/mm3as determined at screening visit
  • Creatinine clearance (CrCl) (as estimated by Cockcroft and Gault) ≤50 mL/min or confirmed creatinine persistently>1.5 mg/dl as determined at screening visit
  • Total serum bilirubin>25umol/L as determined at screening visit.
  • INR ≥ 2.0 as determined at screening visit
  • PTT ≥ 2.0 x ULN as determined at screening visit
  • Serum albumin ≤ 3.5 g/dL (35 g/L) as determined at screening visit
  • ALT >10x ULN as determined at screening visit
  • ANC ≤ 1,500 cells/mm3 as determined at screening visit
  • Diagnosed or suspected hepatocellular carcinoma as evidenced by screening alpha-fetoprotein (AFP) of ≥ 100 ng/mL. If AFP is ≥ 50 ng/mL and < 100 ng/mL, absence of mass/findings suspicious for HCC must be demonstrated by ultrasound/CT/MRI within the screening period.
  • Diabetes mellitus as evidenced by HbA1C ≥ 8.5% at screening
  • QTc interval > 500 msec.
  • Known hypersensitivity to drugs with a similar biochemical structure to REP 2139-Mg or REP 2165-Mg (e.g. other phosphorothioate oligonucleotides) or Pegasys® (e.g. other interferons), Zadaxin® or Viread® (e.g. other nucleoside analog polymerase inhibitors such as entecavir).
  • Any other criteria or known contraindication that would exclude the subject from receiving REP 2139-Mg, REP 2165-Mg, Pegasys® or Viread®.
  • Prisoners or subjects who are involuntarily incarcerated.
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
  • Employees, family members, or students of the investigator or clinical site
  • Individuals who participated in another clinical study of a medicinal product or medical device within 90 days of signing Informed Consent Form
  • Concomitant Treatments with any of the following medications:
  • Heparin
  • Coumadin
  • Blood products within 30 days prior to study enrollment
  • Hematologic growth factors within 90 days prior to study enrollment
  • Use of any investigational product within 1 year prior to study enrollment
  • Systemic antibiotics, antifungals, or antivirals for treatment of active infection within 14 days of enrollment.
  • Previous exposure to immunotherapy with 6 months prior to enrollment.

Trial locations and contacts

3 sites in 1 country.

Moldova3 sites

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

    Chisinau, 2004

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

    Chisinau, 2004

  • Repiblican Clinical Hospital (ARENSIA unit)

    Chisinau, 2025

Other trials in Moldova

About this study

Official title: An Open-label, Randomized, Active Controlled, Parallel Comparison Study of the Safety and Efficacy of REP 2139-Mg in Combination With Pegasys® and Viread® and REP 2165-Mg in Combination With Pegasys® and Viread® in Patients With HBeAg Negative Chronic Hepatitis B

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.

Read the detailed description

Nucleic acid polymers (NAPs) utilize the sequence independent properties of phosphorothioated oligonucleotides to target apolipoprotein interactions involved in the formation of HBV subviral particles (SVPs) which are comprised mainly of the hepatitis B surface antigen protein (HBsAg). The effect of NAPs is to block the formation of SVPs inside infected hepatocytes which prevents their secretion. As SVPs account for > 99.99% of HBsAg in the blood, NAPs are an effective approach for clearing HBsAg from the serum of HBV infected patient.

Previous clinical trials have demonstrated that treatment with the NAP REP 2139 (REP 2139-Ca) results in the rapid and effective clearance ofHBsAg from the blood. This HBsAg removal has the immediate effect of unmasking the underlying, pre-existing anti-HBsAg (anti-HBs) response, allowing clearance of HBV virus from the blood.

Although REP 2139-Ca has been shown to be safe in human patients, it shares the same class effect as other phosphorothioate oligonucleotides in that it accumulates in the liver with repeated dosing. REP 2165 is a version of REP 2139 which is designed to have an increased rate of degradation to slow down liver accumulation while keeping its antiviral activity intact. The antiviral efficacy of REP 2165 has been shown to be comparable to REP 2139 in a pre-clinical model of HBV infection with significantly less accumulation in the liver. As such, REP 2165 is expected to have comparable antiviral efficacy in human patients with reduced liver accumulation during treatment.

HBsAg has important immunosuppressive effects in HBV infection which have been shown to block both adaptive and innate immune processes. Removal of HBsAg from the blood of patients removes this immunosuppressive effect.

Thus, an important additional effect of removal of HBsAg from the blood is to greatly enhance the effect of pegylated interferon alpha 2a. It is expected that elimination of serum HBsAg with REP 2139-Mg or REP 2165-Mg will lead to creation of a favourable immunological activation in the absence of HBsAg, appearance of free anti-HBs, clearance of HBV virions in the blood and synergistic immunostimulation with conventional dosing of pegylated interferon alpha-2a and improved control of HBV infection in the presence of tenofovir disoproxil fumarate (TDF). All patients will receive 24 weeks of monotherapy with TDF prior to entry into experimental or active comparator arms.

Being tested
REP 2139-Mg, Pegasys, Viread, REP 2165-Mg
Medical subject headings
Hepatitis B, Chronic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • REP 2139-MgDrug

    Also called not availalble

    REP 2139-Mg = magnesium chelate complex of REP 2139

  • PegasysDrug

    Also called pegylated interferon alpha-2a

    immunotherapy

  • VireadDrug

    Also called tenofovir disoproxil fumarate

    HBV RT polymerase inhibitor

  • REP 2165-MgDrug

    Also called unaivalable

    REP 2165-Mg = magnesium chelate complex of REP 2165

Study groups in NCT02565719
Study groupRoleWhat they receive
REP 2139-Mg with Viread and PegasysExperimentalREP 2139-Mg in combination with tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys).
Receives: Drug: REP 2139-Mg; Drug: Pegasys; Drug: Viread
REP 2165-Mg with Viread and PegasysExperimentalREP 2165-Mg in combination with tenofovir disoproxil fumarate (Viread) and pegylated interferon alpha-2a (Pegasys).
Receives: Drug: Pegasys; Drug: Viread; Drug: REP 2165-Mg
Viread and Pegasys with crossover to REP 2139-Mg and PegasysActive comparatorTenofovir 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.
Receives: Drug: REP 2139-Mg; Drug: Pegasys; Drug: Viread
Viread and Pegasys with crossover to REP 2165-Mg and PegasysActive comparatorTenofovir 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.
Receives: Drug: Pegasys; Drug: Viread; Drug: REP 2165-Mg

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of patients with adverse events

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

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

Secondary outcomes (2)

  1. Number of patients with reduction of serum HBsAg

    The primary action of NAPs is to lower serum HBsAg. This effect is monitored throughout treatment and for 48 weeks following treatment.

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

  2. Number of patients with controlled HBV infection following treatment

    The synergistic antiviral effect of HBsAg removal and immunotherapy has restored immunological control of HBV mono-infection in human patients which has persisted after treatment was stopped. The persistence of immunological control of HBV infection observed in this study will be followed for 48 weeks after treatment has stopped.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2015 (estimated)
  2. Study startMar 2016
  3. Primary completionMay 2019
  4. Study completionMay 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
40 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02565719
Sponsor's protocol ID
REP 401
Status last verified
Sep 2019
First submitted
29 Sep 2015
Last updated
10 Sep 2019
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 23939902

  • 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.

    PubMed 23939904

  • 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.

    PubMed 34558823

  • 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.

    PubMed 32147484

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing REP 2139-Mg, Pegasys and Viread in people with Chronic Hepatitis B, run by Replicor Inc. at 3 sites in Moldova.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 60 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Moldova. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients with adverse events (time frame: 48 or 72 weeks (treatment duration) + 48 weeks (follow-up)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02565719, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2019.

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