E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis B (CHB) |
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E.1.1.1 | Medical condition in easily understood language |
CHB is a serious liver infection caused by the hepatitis B virus (HBV) the virus is transmitted through contact with the blood or other body fluids of an infected person |
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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 |
•To estimate the effect of new molecular entity (NME) combination therapies on inducing a functional cure over the control arm |
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E.2.2 | Secondary objectives of the trial |
•To characterize the efficacy profile of NME combination therapies •To characterize the Pharmacodynamic (PD) profile of NME combination therapies •To characterize the plasma Pharmacokinetic (PK) profiles of NMEs •To assess the safety and tolerability of NME combination therapies •To identify presence of PK/PD relationship •To explore potential effects of anti drug antibodies (ADA) on NMEs and/or IMP, as applicable.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participant must be 18 to 65 years of age - Body mass index between 18 and 32 kg/m2 inclusive - Participants with CHB infection (HBsAg [Hepatitis B surface antigen] positive for >= 6 months) who are on established Nucleos[t]ide (NUC) monotherapy for >=12 months, having received the same NUC therapy for >=3 months prior to screening - Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) below the limit of quantification (LLOQ) or < 20 IU/mL for > 6 months prior to screening and confirmed at screening - Alanine transaminase (ALT) <=1.5 x upper limit of normal (ULN) for > 6 months prior to screening, and confirmed at screening - Screening laboratory values within normal range, or judged not clinically significant by the Investigator and Medical Monitor - Female Participants: Women of non-childbearing potential or women of childbearing potential who agree to remain abstinent or use highly effective contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the final dose of study treatment and willing to undergo a urine pregnancy test every 3 months until the end of the study - Male Participants: remain abstinent, refrain from donating sperm or use contraceptive measures such as condom with a pregnant female partner or such as condom plus an additional contraceptive method that together result in failure rate of <1% per year with a female partner of childbearing potential during the treatment period and for at least 6 months after the final dose of study treatment
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E.4 | Principal exclusion criteria |
- Pregnant or lactating women - Co-infection with pathogens such as hepatitis A (HAV), hepatitis C (HCV), hepatitis D (HDV), hepatitis E (HEV), or human immunodeficiency virus (HIV) - History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis, or decompensated liver disease (e.g., ascites, hepatic encephalopathy). Liver biopsy or transient/ Acoustic radiation force impulse/ magnetic resonance elastography result must be obtained within 6 months prior to randomisation - History of or suspicion of Hepatocellular carcinoma - Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests at screening, as judged by the Investigator and Medical Monitor - Clinically significant disease other than CHB that, in the opinion of the Investigator, makes the participant unsuitable for the study - Pre-existing cardiac disease that in the opinion of the Investigator would increase the risk for the participant to take part in the study - History of alcohol abuse and/or drug abuse within one year of randomization. - History of having received (in the last 6 months) or currently receiving any systemic antineoplastic or immunosuppressive or immune modulating treatment for malignant or non-malignant disorders. - Currently taking, or have received within 3 months of Day 1, systemic corticosteroids at a high-dose (e.g., 40 mg prednisolone per day for) > 7 days, or a low-dose (e.g., 20 mg prednisolone per day) for > 14 days. - Electrocardiogram with clinically significant abnormalities - Laboratory parameters at screening •Hemoglobin < 12 g/dL (females) or < 13 g/dL (males); platelets < lower limit of normal (LLN); international normalized ratio (INR) > 1.1 •Albumin < 3 g/dL; total bilirubin > ULN (exception: Gilbert’s disease). •Positive results for anti-mitochondrial antibodies (AMA > 1:80), antinuclear antibody (ANA > 1:80), anti–smooth muscle antibody (ASMA > 1:40), or anti-thyroperoxidase antibodies (a-TPO > 10) •White blood cell count < 2500 cells/mm3; neutrophil count < 1500 cells/mm3 •Glomerular filtration rate < 60 mL/min •Positive test for drugs of abuse and/or positive alcohol test at screening. For positive cannabinoids test, the eligibility is at the Investigator’s discretion. - Previous treatment with an investigational agent for HBV within 6 months prior to screening - Unable to comply with any drugs or nutrients listed in prohibited medications and prohibited food sections in the respective treatment arm appendix.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Percentage of participants with HBsAg loss at 24 weeks post-end of treatment (EOT) |
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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) |
1.Percentage of participants with HBsAg loss over time 2.Percentage of participants with HBsAg seroconversion over time 3.Percentage of participants with HBeAg (Hepatitis Be antigen) loss (baseline HBeAg-positive participants) over time 4.Percentage of participants with HBeAg seroconversion (baseline HBeAg-positive participants) over time 5.Percentage of participants with HBV DNA < LLOQ, ≤ 200 IU/mL and ≤ 2,000 IU/mL over time 6.Including but not limited to: change from baseline in quantitative HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, Hepatitis B core-related antigen (HBcrAg), HBV Ribonucleic acid (RNA), and HBV DNA levels over time 7.Estimated PK parameters from sparse sampling and population PK models NMEs and NUCs 8.Incidence, nature, and severity of AEs and laboratory abnormalities over time 9.Analyses of PK/PD data 10.Relationship between ADA status, PK, safety, PD, and efficacy
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to Week 96 4. Baseline (Day 1) up to Week 96 5. Up to Week 96 6. Baseline (Day 1) up to Week 96 7. NME PK: Day 1 up to Week 49 and at virological breakthrough/relapse. NUC PK: Day 1 up to Week 49 and at virological breakthrough/relapse 8 - 10. Up to Week 96
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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 | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
adaptive, platform design |
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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 |
nucleos(t)ide analogues (NUCs) controlled arm |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
Brazil |
Canada |
China |
Hong Kong |
Korea, Republic of |
New Zealand |
Taiwan |
Thailand |
United States |
Belgium |
Bulgaria |
France |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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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A participant is considered to have completed the study if he/she has completed all phases of the study including the last study visit. The end-of-study is defined as the date when the last participant completes the last visit (LPLV). |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 6 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 6 |