HBeAg negative chronic Hepatitis B virus (HBV) infection MedDRA version: 20.1 Level: PT Classification code 10008910 Term: Chronic hepatitis B System Organ Class: 10021881 - Infections and infestations
Conditions
Interventions
Pharmaceutical Form: Tablet
INN or Proposed INN: LAMIVUDINE
CAS Number: 134678-17-4
Pharmaceutical Form: Tablet
INN or Proposed INN: ADEFOVIR DIPIVOXIL
CAS Number: 142340-99-6
Pharmaceutical Form: T
Sponsors
Universität Leipzig
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet ALL of the following criteria: 1. HBeAg negative chronic hepatitis B since the begin of antiviral treatment and HBV-DNA >2000 IU/ml at the begin of treatment 2. HBsAg positive at screening 3. Age = 18 years, male or female 4. Continuous nucleoside or nucleotide analogue therapy with either mono or combination therapy with adefovir dipivoxil (ADV), lamivudine (LMV), telbivudine (LdT), entecavir (ETV) or tenofovir disoproxil fumarate (TDF) for at least 4 years prior to screening. Of note, as in previous observation the rates of HBsAg loss in HBeAg negative patients were comparable during treatment with all the mentioned drugs (Figure 3) we anticipate that the different drug regimes do not represent a factor influencing the response rates after treatment cessation in this trial. However, randomisation will be stratified with respect to the kind of previous therapy (see 8.1.1) 5. Documented undetectable HBV DNA level during treatment for at least 4 years prior to screening (quantification of HBV DNA must have been performed about every 4 to 8 months). Please note: In terms of this trial, we define “undetectable” as below 1000 copies/mL (172 IU/mL). This comparatively high upper limit of HBV DNA levels was chosen for the definition of response to take into account that assays for HBV DNA quantification with different sensitivity are used in the participating centres. 6. Undetectable HBV DNA level at screening (analysed by central laboratory, Limbach and partners, Heidelberg) 7. Normal serum ALT levels =65 years) yes F.1.3.1 Number of subjects for this age range 160
Exclusion criteria
Exclusion criteria: Patients will be excluded for ANY ONE of the following reasons: 1. Compensated or decompensated liver cirrhosis 2. History of decompensated liver disease 3. Advanced fibrosis - defined either histologically by Scheuer score = stage 3 (within last year before screening) and/or liver stiffness = 10 kPa by elastography (Fibroscan®) or = 1.5 m/s by Acoustic Radiation Force Impulse (ARFI) (each within 6 months before screening) 4. Evidence of hepatocellular carcinoma (HCC) 5. HIV, HDV or HCV co-infection 6. Iatrogenic or disease-related immunosuppression (e.g. treatment with systemic glucocorticoids, TNFa-antibodies and other immunosuppressive drugs as well as chemotherapy or malignant disorders) 7. HBV associated extra hepatic manifestations (e.g. glomerulonephritis, panarteriitis nodosa, HBV-associated dermatosis) 8. Patients with Gilbert-Meulengracht syndrome can be included in the study if other potentially underlying liver diseases causing bilirubin elevation or hemolysis can be ruled out. 9. Significant alcohol consumption (> 30 g/day for women and > 50 g/day for men) 10. Patients who work in the medical field and have patient contact. 11. Pregnant or nursing women 12. Participation in any other interventional trial 13. Suspected lack of compliance 14. Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects from the antiviral medication on contraception). 15. Patient is incapable to give informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the STOP-NUC trial is to assess the potential of treatment cessation of nucleos(t)ide analogue treatment to induce complete and definitive remission in patients showing complete treatment response for at least 4 years. According to the EASL Clinical Practice Guidelines, sustained HBsAg loss will be used as marker for complete remission. We hypothesize that after treatment discontinuation, the rate of complete remissions will be significantly higher than under continued nucleos(t)ide analogue treatment. ;Secondary Objective: Secondary objectives in terms of efficacy are •to assess and compare virologic and biochemical response •to evaluate if sustained HBsAG loss is followed by HBsAG seroconversion •to describe the time course of HBsAG loss and HBsAG seroconversion •to assess the effect of treatment cessation on liver stiffness (applicable only for trial sites where liver stiffness measurement is feasible). In the experimental arm the number of patients fulfilling criteria for re-therapy as well as the respective time to re-therapy is of particular interest and will be evaluated. For safety reasons, but also to better understand the underlying immune mechanisms, the number of ALT flares per patient will be described Additional objectives of the prolonged observation period: see trial protocol;Primary end point(s): Primary outcome measure is sustained HBsAg loss up to week 96. As stated in the EASL Clinical Practice Guidelines, “In HBeAg-positive and HBeAg-negative patients, the ideal end-point of therapy is sustained HBsAg loss with or without seroconversion to anti-HBs. This is associated with a complete and definitive remission of the activity of chronic hepatitis B and an improved long-term outcome (A1: high quality evidence, strong recommendation)”.[4] HBsAg will be quantified in a central laboratory at every scheduled visit until week 96. HBsAg loss is defined as not detectable HBsAg in all subsequent assessments aft | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints are • Sustained remission (i.e. HBV DNA 12 IU/mL versus = 12 IU/mL), measured at week 96 in the central laboratory. • Biochemical response at week 96 as a binary endpoint (Alanine transaminase (ALT) > upper level normal (ULN) according to local laboratory versus = ULN). ALT will be measured regularly in the local laboratory. Biochemical response refers to the upper level normal of the local laboratory. • Optional: Liver stiffness in kPa by liver elastography (Fibroscan®) at week 96 • Time to fulfilling criteria for re-therapy in the experimental (non-treatment) arm (details see 5.3.2), defined as time from randomisation to the first time point when criteria for re-therapy are met or to the last visit, if the criteria have not been met. • Number of ALT flares per patient, defined as ALT > 3x ULN after treatment discontinuation in the experimental (non-treatment) arm Assessment of safety The liver function (ALT, Bilirubin, PT or Quick or INR) as well as the virologic parameters, especially HBV DNA levels will be regularly monitored. Patients fulfilling the criteria for severe hepatitis B reactivation or chronic hepatitis B reactivation in need for retreatment have to be immediately reported. In addition, adverse events will be documented. Further long-term endpoints: During the interval between the visit at week 96 and the first visit of the prolonged observation time patients were off-study, and their treatment and observation was performed according to standard of care. Therefore, the endpoints concerning long-term observation are purely descriptive. In patients randomised to the experimental arm: • Time to HBsAG loss up to seven years after randomisation • Time to HBsAG seroconversion up to seven years after randomisation • Cumulative incidence of indication for re-therapy (counting re-initiation of NUC-therapy without prior fulfilment of a criterion for re-therapy as a concurring event) • Tim | — |
Countries
Germany
Contacts
Public ContactFlorian van Bömmel
authorized representative of the sponsor
Outcome results
None listed