E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic hepatitis B infection |
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E.1.1.1 | Medical condition in easily understood language |
Chronic infection of the liver with the hepatitis B virus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052552 |
E.1.2 | Term | Hepatitis B virus |
E.1.2 | System Organ Class | 100000004848 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10047450 |
E.1.2 | Term | Viral hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019743 |
E.1.2 | Term | Hepatitis B virus (HBV) |
E.1.2 | System Organ Class | 100000004848 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019737 |
E.1.2 | Term | Hepatitis B carrier |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary objectives of the trial |
Secondary outcomes will be the safety and tolerability of terbinafine in this specific group. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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).
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E.5.1.1 | Timepoint(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.
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |