| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HBeAg negative chronic Hepatitis B virus (HBV) infection |
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| E.1.1.1 | Medical condition in easily understood language |
| HBeAg negative chronic Hepatitis B virus (HBV) infection |
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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 | 20.1 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < ULN (upper limit of normal) according to the local laboratory
8. Written informed consent
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| E.4 | Principal 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, TNFα-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
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| E.5 End points |
| E.5.1 | 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 after HBsAg became undetectable for the first time. If at week 96, HBsAg is for the first time not detectable, a further measurement will be performed at week 108 in order to confirm the HBsAg loss.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints are
• Sustained remission (i.e. HBV DNA < 2000 IU/mL and normal ALT levels, i.e. ALT < upper level normal) at week 96 in the non-treatment arm. Sustained remission is defined as HBV DNA < 2000 IU/mL and normal ALT levels in all subsequent assessments after the first occurrence of remission.
• HBsAg seroconversion status up to week 96 as a binary endpoint (anti-HBs detectable versus not detectable). HBsAg seroconversion is an event that follows HBsAg loss. Anti-HBs will be measured regularly in patients with HBsAg loss in a central laboratory until week 96.
• Time to HBsAg loss, defined as time from randomisation to the first confirmed occurrence of HBsAg loss or to the last available measurement, if no HBsAg loss has been documented.
• Time to HBsAg seroconversion, defined as time from randomisation to the first time when anti-HBs are detectable or to the last available measurement, if no HBsAg seroconversion has been documented
• Virologic response at week 96 as a binary endpoint (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)
• Time course of biochemical and viral parameters up to seven years after randomisation
• Number of ALT flares per patient, defined as ALT > 3x ULN, occurring after week 96 and up to seven years after randomisation
• After re-initiation of NUC-therapy: duration until normalisation of liver parameters, response to actual NUC-therapy, occurrence of resistance to NUC-therapy
In patients randomised to the control arm:
• Time to HBsAG loss up to seven years after randomisation
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
up to week 96 or
up to prolonged observation (4 to 7 years) for long-term endpoints |
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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 | Yes |
| E.6.13.1 | Other scope of the trial description |
- therapy optimization study
The STOP-NUC study is designed to evaluate a novel concept of finite nucleos(t)ide analogue treatment duration in non-cirrhotic, HBeAg-negative patients with chronic HBV infection.
We hypothesize that after treatment discontinuation, the rate of complete remissions will be significantly higher than under continued nucleos(t)ide analogue treatment.
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| novel concept: experimental arm - STOP-NUC therapy; control arm: standard NUC therapy |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
| 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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| In the exceptional case that at week 96, HBsAg is for the first time not detectable, a further measurement will be performed at week 108 in order to confirm the HBsAg loss. During this visit, a blood sample will be taken and sent to the central laboratory for analysis of HBV DNA, HBsAg and anti HBs. |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
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