| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| 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 |
|
| 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 |
| To determine the effect of EYP001a on top of NA (SOC therapy) on HBsAg plasma levels |
|
| E.2.2 | Secondary objectives of the trial |
• To establish the effect of EYP001a on top of NA on HBsAg responder rate at the end of the 16-week EYP001a treatment and at 24-week of follow-up (Week 40).
• To establish the effect of EYP001a on top of NA on HBsAg loss rate at the end of the 16-week EYP001a treatment and at 24-week of follow-up (Week
40).
• To stablish the HBV virologic failure rate (breakthrough) during the 24-weeks follow-up period after stopping EYP001a with ongoing NA.
• To determine HBV viral response, HBV pgRNA, HBcrAg and HbeAg, anti-HBe and anti-HBs at the end of the 16-week EYP001a treatment and Week 40 of follow-up.
• To explore the safety profile of EYP001a treatment in combination with NA.
• To determine the plasma concentration of EYP001a and PD markers (plasma C4 (7α-hydroxy-4-cholesten-3-one)), FGF19 and BAs. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has given voluntary written informed consent before performance of any study related procedure.
2. Must be 18 to 65 years of age, inclusive
3. Are on stable NA therapy for at least 12 months from the screening date (ETV or TDF)
4. Has virally suppressed CHB:
a. HBV DNA < LLOQ and serum HBsAg >100 IU/mL
5. Has liver imaging to screen for hepatocellular carcinoma or concomitant pancreaticobiliary disease either in the prior 6 months or at screening.
6. Has liver tests during the Screening Period defined as follows:
a. The baseline values (i.e. two measurements at least 3 days apart: one can be from medical history if not older than 12 months and one during screening period) with both measurements of ALT or AST are ≤ 2 × ULN
b. Normal or clinically not relevant levels of ALP (≤ 1.5 ULN)
c. Has total bilirubin (TBL) ≤ 22.2 μmol/L, which corresponds to ≤ 1.3 mg/dL.
d. Has conjugated (direct) bilirubin of ≤ 0.3 mg/dL (i.e. 5.1 μmol/L)
e. Has normal or clinically not relevant levels of GGT (≤ 2.0 ULN)
f. International normalized ratio ≤ 1.2 x ULN, unless on anticoagulant therapy
g. Platelet count ≥ 100 G/L
h. Has albumin ≥3.5 g/dL.
7. Is not of childbearing potential or, if of childbearing potential, is not pregnant as confirmed by a negative serum human chorionic gonadotropin test at screening and is not planning a pregnancy during the course of the study.
8. Women of childbearing potential (WOCBP) and male patients with WOCBP partners must agree to use a dual method of contraception as defined in the study protocol or practice complete abstinence from sexual intercourse if this is the patient’s usual and preferred lifestyle throughout the duration of the study and for 90 days after stopping study drug. Patients who are using hormonal contraceptives should be instructed to use an additional contraceptive measure during the study. Note: A woman is considered of childbearing potential following menarche and until becoming postmenopausal unless permanently sterile. A postmenopausal state is defined as no menses for >12 consecutive months without an alternative medical cause.
A follicle stimulating hormone level in the postmenopausal range will be used to confirm a postmenopausal state in women <55 years of age. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. |
|
| E.4 | Principal exclusion criteria |
1. Is an employee of a CRO, vendor, or Sponsor involved with this study
2. Has known hepatocellular carcinoma or pancreaticobiliary disease
3. Neutropenia (defined by two confirmed values within screening period of <1500/μL)
4. Has Gilbert syndrome
5. Shows evidence of worsening liver function, defined as either a confirmed (two assessments at least 3 days apart) increase >2 ULN ALT or AST or an increase of >1.5 × first assessed value of TBL or associated with clinical signs or symptoms of liver impairment.
6. Has known or suspected non CHB liver disease, including, but not limited to, Hepatitis D virus co-infection, alcoholic liver disease, non alcoholic steatohepatitis diagnosed with liver biopsy, autoimmune disease, HIV, active hepatitis C virus (HCV ), Wilson disease, hemochromatosis, hepatocellular carcinoma (normal AFP at screening required) or suspected or known other liver cancer, primary biliary cholangitis, primary sclerosing cholangitis, drug induced liver injury (DILI), bile duct obstruction.
7. History of cirrhosis or liver decompensation, including ascites, hepatic encephalopathy, or presence of oesophageal varices
8. Probable or possible F3 stage with a vibration controlled transient elastography (VCTE). Patients with normal baseline ALT and VCTE >8.8 kPa are excluded. Patients with baseline ALT >ULN (but <2ULN per EC5) and who have VCTE >10.5 kPa at baseline are excluded
9. Has known history of alcohol abuse or daily heavy alcohol consumption (females: >14 units of alcohol per week; males: >21 units of alcohol per week [1 unit of alcohol is equivalent to a half pint of beer {285 mL}, 1 measure of spirits {25 mL}, or 1 glass of wine {125 mL}]). Has an AUDIT C score of >3 points for men and women AND a full AUDIT score of >8 points at screening.
10. Is pregnant or breastfeeding
11. Has clinically relevant immunosuppression, including, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
12. Has a known pre existing medical or psychiatric condition that could interfere with the patient’s ability to provide informed consent or participate in study conduct, or that may confound study findings.
13. Has known dyslipidaemia with higher cardio-vascular risk from worsening lipid parameters (history of clinically significant cardiovascular or cerebrovascular disease during 12 months prior to study entry).
14. Has, in the opinion of the Investigator, clinically significant cardiovascular or cerebrovascular disease within 12 months prior to the first study drug administration, including, but not limited to, myocardial infarction, acute coronary syndrome, revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or ischemic stroke, or implanted defibrillator or pacemaker
15. Has participated in any study with administration of an investigational drug in the past 30 days, or 5 half lives, whichever is longer, prior to the first study drug administration in the current study
16. Has had major visceral or orthopaedic surgery within 30 days prior to the first study drug administration in the current study
17. Has a hypersensitivity to the study drug or to any of the excipients or placebo
18. Has a history of relevant drug and/or food allergies
19. Has used anti-HBV medications other than NAs within 90 days prior to screening
20. Is using any of the following disallowed medications within 30 days or 5 half lives prior to screening whichever is longer, or planned use later during study participation: vitamin K antagonists such as warfarin, anticancer drug(s), immunomodulator(s), or immunosuppressant(s) or any drug with known liver toxicity for >2 weeks in the year prior to screening, ursodeoxycholic acid, or obeticholic acid within 90 days prior to screening. Agents (including OTC weight loss preparations) or medications known to significantly impact body weight within 30 days prior to screening.
21. Is using lipid lowering drugs such as statins (other than rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin or lovastatin).
22. Has planned major visceral, orthopaedic or neuro surgery during the study period.
23. Has uncontrolled type 1 diabetes mellitus or type 2 diabetes mellitus (T2DM) (haemoglobin A1c >9.5%).
24. Has any of the following exclusionary laboratory results at screening:
a. Estimated glomerular filtration rate <60 mL/min/1.73 m2 (the Modification of Diet in Renal Disease formula).
b. TSH >1.5× ULN or abnormal free triiodothyronine or free thyroxine.
25. Has a history of clinically significant gastrointestinal disease, especially peptic ulcerations, gastrointestinal bleeding, inflammatory bowel disease, bariatric surgery, renal, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, or cardiovascular disease or any other condition, which, in the opinion of the Investigator, would jeopardize the safety of the patient or impact the validity of the study results |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy assessed as HBsAg decline (Δ log10) from Day 1 to Week 16 of treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Day 1 to Week 16 of treatment |
|
| E.5.2 | Secondary end point(s) |
• Efficacy assessed as:
o HBsAg responder rate (decrease from baseline ≥ 1.0 on the log10 scale) at Week 16 of treatment and Weeks 20, 28 and 40 of follow up.
o HBsAg responder rate (decrease from baseline ≥ 0.5 on the log10 scale) at Weeks 12 and 16 of treatment and Weeks 20, 28 and 40 of
follow up.
o HBsAg loss rate (% patients with HBsAg < LLOQ) at Week 16 of treatment and Weeks 20, 28 and 40 of follow-up.
o HBsAg loss rate (Proportion of results that are Target Not Detected versus Target Detected) at Week 16 of treatment and Weeks 20, 28 and
40 of follow up
o Relapse rate HBsAg (% patients who became negative [HBsAg <LLOQ], then increased with HBsAg > LLOQ) at Week 16 of treatment
period and Weeks 20, 28 and 40 during follow-up period
o Virologic failure rate (breakthrough) of HBV-DNA (% patients with a confirmed quantifiable HBV DNA increase of ≥ 1log10 HBV DNA
copies/mL above LLOQ) assessed at Week 16 of treatment period and Weeks 20, 28 and 40 during follow-up period
o HBV-pgRNA decline (Δ log10) from Day 1 to Weeks 4, 8, 12, 16 of treatment period and Week 40 of maintenance period
o HBcrAg decline (Δ log10) from Day 1 to Weeks 4, 8, 12, 16 of treatment period and Week 40 of maintenance period
o HBeAg quantification for HBeAg pos patients and changes at Week 16 of treatment and Week 40 of follow-up
o Fibroscan VCTE change from screening value to Weeks 16 and 40 or ET value
• Safety and Tolerability assessed as:
o Treatment-emergent adverse events (TEAEs) (including SAEs)
o All-cause mortality
o Clinical laboratory tests
o Pruritus assessment
o Vital signs (blood pressure, heart rate, respiratory rate, and temperature)
o Concomitant medications
o Physical examinations
o 12-lead ECG
• PK assessed as:
o Plasma concentration of EYP001a or any relevant active metabolites (as identified in an ongoing phase 1 study)
• PD biomarkers:
o Plasma C4 (7α-hydroxy-4-cholesten-3-one)
o FGF19
o Plasma primary and secondary BAs
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | 6 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Korea, Republic of |
| Poland |
|
| 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
|
The end of this study is defined as the date when the last Visit of the last participant occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last participant, whichever occurs later.
Follow-up Visit 3 planned in Week 40 on Day 280 ±3 days is considered as EoS visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
Print
