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    Summary
    EudraCT Number:2019-003419-68
    Sponsor's Protocol Code Number:HepBTer
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-03-24
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-003419-68
    A.3Full title of the trial
    From fungus to virus, a phase 2a clinical trial investigating the safety and efficacy of terbinafine in chronic hepatitis B patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to investigate the safety and efficacy of terbinafine for chronic infection of the liver with the hepatitis B virus.
    A.3.2Name or abbreviated title of the trial where available
    HepBTer Trial
    A.4.1Sponsor's protocol code numberHepBTer
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAcademic Medical Center (AMC)
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAcademic Medical Center (AMC)
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportZonMw
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Center (AMC)
    B.5.2Functional name of contact pointleverresearch
    B.5.3 Address:
    B.5.3.1Street Addressmeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205668468
    B.5.6E-mailleverresearch@amsterdamumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name terbinafine
    D.2.1.1.2Name of the Marketing Authorisation holderMedical Valley Invest AB
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic hepatitis B infection
    E.1.1.1Medical condition in easily understood language
    Chronic infection of the liver with the hepatitis B virus
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052552
    E.1.2Term Hepatitis B virus
    E.1.2System Organ Class 100000004848
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10047450
    E.1.2Term Viral hepatitis B
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10008910
    E.1.2Term Chronic hepatitis B
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10019743
    E.1.2Term Hepatitis B virus (HBV)
    E.1.2System Organ Class 100000004848
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10019737
    E.1.2Term Hepatitis B carrier
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective is to provide proof of concept for the inhibition of HBx mediated cccDNA transcription by terbinafine, both as monotherapy and add-on therapy next to tenofovir.
    E.2.2Secondary objectives of the trial
    Secondary outcomes will be the safety and tolerability of terbinafine in this specific group.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Age 18 – 60 years
    2) Proven chronic hepatitis B (CHB) for more than 6 months, based on serology (HBsAg positivity) and at screening a viral load of:
    i) Group A: HBV DNA ≥200 IU/mL and <20,000 IU/mL
    ii) Group B: HBV DNA < 20 IU/mL
    3) HBeAg-positive and –negative CHB patients
    4) No current use of any antiviral medication (group A) or currently treated with tenofovir only.
    5) Normal liver function, assessed by:
    i) Fibroscan of ≤ 7.0 kiloPascal (kPa)
    ii) Alanine aminotransferase (ALT) and/or aspirate aminotransferase (AST) at screening ≤ 1.25 x upper limit of normal (ULN)
    iii) Thrombocytes 150-400 10E9/L
    iv) Total bilirubin 0-17 µmol/L (elevated levels may be accepted if unconjugated portion is elevated in patients with Gilbert syndrome)
    v) Albumin within normal value (35 – 50 g/L)
    vi) Prothrombin Time (PT) within normal value (9,5 - 12.5 sec)
    vii) Alkaline phosphatase (ALP) and Gamma-glutamyltransferase (GGT) within normal values (40-120 U/L and 0-40 U/L respectively)
    6) Body mass index (BMI): 17.0-35.0 kg/m2
    7) Clinical chemistry, hematologic and coagulation tests at screening must be within normal limits or clinically non-significant, as by the investigators assessment.
    8) At screening, women of child bearing potential must be non-pregnant and non-lactating proven by negative urine or serum pregnancy test at screening.
    9) Female patients of child-bearing potential (with a fertile male sexual partner) and male patients (if not surgically sterilized) must be willing to use adequate contraception from screening until last study visit.
    10) At screening, has no recent (<3 months) history of any clinically significant conditions, which, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results.
    11) Voluntary written informed consent must be obtained before any study related interventions (including screening and enrollment) can be conducted.
    1) Leeftijd 18 - 60 jaar
    2) Bewezen chronische hepatitis B (CHB) gedurende meer dan 6 maanden, gebaseerd op serologie (HBsAg-positiviteit) en bij screening een virale load van:
    i) Groep A: HBV DNA ≥ 200 IU/ml en <20.000 IU/ml
    ii) Groep B: HBV DNA <20 IU/ml
    3) HBeAg positieve en negatieve CHB-patiënten
    4) Geen actueel gebruik van antivirale medicatie (groep A) of momenteel alleen behandeld met tenofovir.
    5) Normale leverfunctie, beoordeeld door:
    i) Fibroscan waarde van ≤7,0 kiloPascal (kPa)
    ii) Alanine-aminotransferase (ALT) en/of Aspartaat-aminotransferase (AST) bij screening ≤1,25 x bovengrens van normaal (ULN)
    iii) Trombocyten 150-400 10E9/L
    iv) Totaal bilirubine 0-17 µmol/L (verhoogde waarden kunnen worden geaccepteerd als alleen de niet-geconjugeerde portie verhoogd is bij patiënten met het Gilbert-syndroom)
    v) Albumine binnen normale waarde (35-50 g/L)
    vi) Prothrombinetijd (PT) binnen normale waarde (9,5-12,5 sec)
    vii) Alkalische fosfatase (ALP) en gamma glutamyl transpeptidase (GGT) binnen normale waarden (respectievelijk 40-120 U/L en 0-40 U/L)
    6) Body mass index (BMI): 17,0-35,0 kg/m2
    7) Klinische chemie, hematologische en coagulatietesten bij screening, moeten binnen normale limieten zijn of klinisch niet significant, op basis van de beoordeling van de onderzoek arts.
    8) Bij screening mogen vrouwen in de vruchtbare leeftijd niet zwanger zijn en geen borstvoeding geven en dus een negatieve uitslag hebben van urine- of serumzwangerschapstest bij screening.
    9) Vrouwelijke patiënten in de vruchtbare leeftijd (met een vruchtbare mannelijke seksuele partner) en mannelijke patiënten (indien niet chirurgisch gesteriliseerd) moeten bereid zijn om adequate anticonceptie te gebruiken vanaf screening tot het laatste studiebezoek.
    10) Heeft bij screening geen recente (<3 maanden) geschiedenis van klinisch significante aandoeningen die, naar de mening van de onderzoek arts, de veiligheid van de patiënt in gevaar zouden kunnen brengen of de geldigheid van de onderzoeksresultaten zou kunnen aantasten.
    11) Vrijwillige schriftelijke geïnformeerde toestemming moet worden verkregen voordat eventuele studie gerelateerde interventies (inclusief screening) kunnen worden uitgevoerd.
    E.4Principal exclusion criteria
    1) Currently active, or a history of liver cirrhosis determined by one or more of the following:
    i) Liver biopsy;
    ii) Elastography (e.g. Fibroscan);
    iii) Combination of usual radiological and biochemical criteria
    2) Currently active, liver disease other than CHB
    3) Co-infection with HCV, HDV, HEV and/or HIV
    4) Acute HAV at screening
    5) Renal impairment (estimated glomerular filtration rate (eGRF) < 60ml/min)
    6) Currently active, or a history of: psoriasis or lupus erythematodes
    7) Use of oral medication that interacts with the liver metabolism enzyme CYP2D6, or which is known to be hepatotoxic or otherwise known to interact with terbinafine (such as rifampicine).
    8) Usage or plans to receive systemic immunosuppressive or immunomodulating medications (e.g. IFN) during the study or ≤ 4 months prior to the first investigational product administration.
    9) Clinical diagnosis of substance abuse ≤ 12 months prior to screening with narcotics or cocaine or with alcohol (regular consumption > 14 units/week [men] and > 7 units/week [women])
    10) Inability to understand the patient information and make an informed decision to participate
    1) Momenteel actief, of een voorgeschiedenis van levercirrose bepaald door een of meer van de volgende:
    i) leverbiopsie;
    ii) Elastografie (bijvoorbeeld Fibroscan);
    iii) Combinatie van gebruikelijke radiologische en biochemische criteria
    2) Momenteel actief, andere leverziekte dan CHB
    3) Co-infectie met HCV, HDV, HEV en / of HIV
    4) Acute HAV infectie bij screening
    5) Nierinsufficiëntie (geschatte glomerulaire filtratiesnelheid (eGRF) <60 ml / min)
    6) Momenteel actief, of een geschiedenis van: psoriasis of lupus erythematosus
    7) Gebruik van orale medicatie die een interactie aangaat met het levermetabolisme enzym CYP2D6, of waarvan bekend is dat het hepatotoxisch is of anderszins bekend is dat het een interactie aangaat met terbinafine (zoals rifampicine).
    8) Gebruik of voornemens om systemische immunosuppressieve of immunomodulerende medicijnen (bijvoorbeeld IFN) te ontvangen tijdens de studie of ≤ 4 maanden voorafgaand aan de eerste toediening van de studiemedicatie.
    9) Klinische diagnose van middelenmisbruik ≤ 12 maanden voorafgaand aan screening met verdovende middelen of cocaïne of alcohol (normale consumptie> 14 eenheden / week [mannen] en> 7 eenheden / week [vrouwen])
    10) Onvermogen om de informatie over de studie te begrijpen en een geïnformeerde beslissing te nemen over deelname.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Objective: provide proof of concept for the inhibition of HBx mediated cccDNA transcription by terbinafine by means of:
    - Decline in level of serum HBsAg >0.32 log10 IU/mL at the end of study treatment (week 10 vs baseline).
    - Decline in serum HBV DNA >0.86 log10 in group A (monotherapy) at the end of study treatment (week 10 vs baseline).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The HBsAg levels and HBV DNA will be measured at: screening, baseline, week 2, week 4, week 6, week 8, week 10 and 1 month after end of treatment.
    E.5.2Secondary end point(s)
    Secondary Objective(s): safety and tolerability of terbinafine and changes in alternative virology markers:
    - Level of serum HBsAg and HBV DNA at 3 months follow-up, all HBV RNA, large HBsAg (LHBs) HBcrAg levels, and HBeAg status (at baseline and end of study).
    - Safety and tolerability of terbinafine as mono- or combination therapy, based on serum markers including among others: ALT, AST, total bilirubin (if >17 µmol/L, add conjugated bilirubin), ALP, GGT, albumin, thrombocytes, prothrombin time (PT); Fibroscan measurements, clinical significant changes in physical examination and/or reported physical complaints as assessed by the investigator.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - The HBV RNA, large HBsAg (LHBs) and HBcrAg levels levels will be measured at: screening, baseline, week 2, week 4, week 6, week 8, week 10 and 1 month after end of treatment.
    - HBV DNA will be measured at: 3 months after end of treatment
    - HBeAg and antiHBeAg levels will be measured at: baseline, week 10 and 1 month after en of study
    - General lab including liver and kidney function test: screening, baseline, week 1,2,3,4,6,7,8,9,10 and 1 and 3 months after end of treatment.
    - Fibroscan (Transient Elastography): screen and 3 months after end of study
    - (Short) physical examination is performed at baseline, week 1, week 4, week 6, week 7, week 10, 1 month after end of treatment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 26
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After patients have completed the study, they will return to the standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-03-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
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