| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| A serious liver infection caused by the hepatitis B virus |
|
| 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 |
|
| 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 evaluate efficacy of 24 weeks of study treatment, in terms of changes in hepatitis B surface antigen (HBsAg) levels. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of 24 weeks of study treatment.
• To evaluate efficacy in terms of changes in HBsAg levels.
• To evaluate efficacy in terms of changes in HBV DNA levels.
• To evaluate efficacy in terms of changes in HBeAg levels (in HBeAg-positive subjects only).
• To evaluate efficacy in terms of HBsAg (in all subjects) or HBeAg (in HBeAg-positive subjects only) seroclearance and/or seroconversion.
• To evaluate the frequency of subjects with biochemical response.
• To evaluate the frequency of HBV virological breakthrough.
• To evaluate the potential effect of JNJ-56136379 on the pharmacokinetics of
nucleos(t)ide analog (NA) when coadministered.
• To evaluate the pharmacokinetics of JNJ-56136379 when administered as monotherapy.
• To evaluate the potential effect of NA on the pharmacokinetics of JNJ-56136379 when coadministered.
• To assess changes in the HBV genome sequence. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subjects must be 18 (or older legal age of consent as per local requirements) to 70 years of age, inclusive.
• Subjects must have CHB infection documented by:
- Serum HBsAg-positive at screening and at least 6 months prior to screening.
- Serum IgM anti-HBc antibody negative at screening.
• In subjects currently not being treated (Treatment Arms 1-2-3 and 6-7-8):
- Subjects must not be receiving any CHB treatment at screening, ie,
○ Have never received treatment with HBV antiviral medicines, including NAs or IFN products, OR
○ Have not been on treatment with HBV antiviral medicines, including NAs or IFN products within 6 months prior to baseline (first intake of study drugs), AND
- Subjects must be HBeAg-positive and have HBV DNA ≥20,000 IU/mL, OR be HBeAg-negative and have HBV DNA ≥2,000 IU/mL at screening, AND
- Subjects must have HBsAg >250 IU/mL at screening, AND
- Subjects must have ALT > ULN and ≤5 x ULN at screening, determined in the central laboratory.
Note: If subjects were treated with investigational anti-HBV agents more than 6 months before screening, the sponsor should be contacted to discuss the case. Subjects who have received treatment with a CAM for more than 4 weeks any time prior to screening are excluded.
• In virologically suppressed subjects (Treatment Arms 4-5 and 9-10):
- Subjects must be virologically suppressed by current NA treatment (ETV or TDF) as defined by HBV DNA <60 IU/mL at screening and at least 6 months prior to screening, AND
- Subjects must be on the same NA treatment (ETV or TDF) and the same dose for ≥12 months prior to screening, AND
- Subjects must have HBsAg >250 IU/mL at screening, AND
- Subjects must have ALT ≤2x ULN at screening
Note: If subjects were treated with investigational anti-HBV agents more than 6 months before screening, the sponsor should be contacted to discuss the case. Subjects who have received treatment with a CAM for more than 4 weeks any time prior to screening are excluded.
• Subjects must have:
- A liver biopsy result classified as Metavir F0-F2 within 1 year prior to screening or at the time of screening, OR
- FibroScan™ liver stiffness measurement <8.0 kPa within 6 months prior to screening or at the time of screening.
• Female subjects of childbearing potential must have a negative highly sensitive serum pregnancy test (beta-human chorionic gonadotropin) at screening.
• Female subjects must be:
- Not of childbearing potential
- Of childbearing potential and
o Practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study treatment and until 90 days after last dose of JNJ-56136379.
• A female subject must agree not to donate eggs (ova, oocytes) during the study until at least 90 days after the last dose of JNJ-56136379.
• A male subject must agree to wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study until at least 90 days after the last dose of JNJ-56136379.
• A male subject must agree not to donate sperm during the study and for at least 90 days after receiving the last dose of JNJ-56136379.
• Subject must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• Subject must sign a separate ICF if he or she agrees to provide an optional DNA sample for research. Refusal to give consent for the optional DNA research sample does not exclude a subject from participation in the study.
• In the investigator’s opinion, the subject must be able to understand and comply with protocol requirements, instructions, and lifestyle restrictions (Section 4.3) and be likely to complete the study as planned.
|
|
| E.4 | Principal exclusion criteria |
• Subjects who test positive for anti-HBs antibodies.
• Subjects with current hepatitis A virus infection (confirmed by hepatitis A antibody IgM), HCV infection (confirmed by HCV antibody), HDV infection (confirmed by HDV antibody), hepatitis E virus infection (confirmed by hepatitis E antibody IgM), or HIV-1 or HIV-2 infection (confirmed by antibodies) at screening. Evidence of other active infection (bacterial, viral, fungal, including acute tuberculosis) deemed clinically relevant by the investigator that would interfere with study conduct or its interpretation will also lead to exclusion.
• Subjects with any evidence of hepatic decompensation at any time point prior to or at the time of screening:
- Direct bilirubin >1.2x ULN, or
- International normalized ratio >1.5x ULN, or
- Serum albumin < lower limit of normal (LLN), or
- Documented history or current evidence of variceal bleeding, ascites, or hepatic encephalopathy.
• Subjects with any evidence of liver disease of non-HBV etiology. This includes but is not limited to hepatitis virus infections mentioned above, drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, Gilbert’s syndrome, α-1 antitrypsin deficiency, primary biliary cirrhosis, primary sclerosing cholangitis, or any other non-HBV liver disease considered clinically significant by the investigator.
• Subjects who have signs of hepatocellular carcinoma (HCC) on an abdominal ultrasound performed within 2 months prior to screening or at the time of screening. In case of suspicious findings on conventional ultrasound, subject may still be eligible if HCC has been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in HBsAg levels at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Safety and tolerability data including but not limited to (S)AEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, and urinalysis) throughout the study.
• Change from baseline in HBsAg levels during study treatment and follow-up.
• Proportion of subjects with HBsAg levels by response subcategory, such as HBsAg <1,000 or <100 IU/mL, or with >0.5 or >1 log10 IU/mL reduction in HBsAg from baseline as detailed in the Statistical Analysis Plan (SAP) during study treatment and follow-up.
• Change from baseline in HBV DNA levels during study treatment and follow-up.
• Proportion of subjects with HBV DNA levels by response subcategory as detailed in the SAP during study treatment and follow-up.
• Change from baseline in HBeAg levels during study treatment and follow-up.
• Proportion of subjects with HBeAg levels by response subcategory as detailed in the SAP during study treatment and follow-up.
• Proportion of subjects with HBsAg or HBeAg seroclearance (defined as HBsAg or HBeAg negativity, respectively, based on the assay used) during study treatment and follow-up.
• Proportion of subjects with HBsAg or HBeAg seroconversion (defined as HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively) during study treatment and follow-up.
• Proportion of subjects with ALT improvement and normalization during study treatment and follow-up.
• Proportion of subjects with virological breakthrough during study treatment defined as confirmed on-treatment HBV DNA increase by >1 log10 from nadir level or confirmed on-treatment HBV DNA level >200 IU/mL in subjects who had HBV DNA level below the lower limit of quantification (LLOQ) of the HBV DNA assay.
• Pharmacokinetics of NA when administered as monotherapy or when coadministered with JNJ-56136379.
• Pharmacokinetics of JNJ-56136379 when administered as monotherapy or when coadministered with an NA.
• Emergence of treatment-associated mutations during study treatment and follow-up. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: throughout the study
HBsAg, HBeAg, HBV DNA: Screening, Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24
Anti-HBs and anti-HBe: Screening, Treatment phase: Day 1 and Week 24, and Follow-up phase: Weeks 2, 4, 12, 24
PK samples: Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 20, 24, and Follow-up phase: Weeks 2 and 4
Blood chemistry (ALT): Screening, Treatment phase: Day 1, Weeks 1, 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24
Viral genome sequencing: Screening, Treatment phase: Day 1, Weeks 2, 4, 8, 12 (D84), 16, 20, 24, and Follow-up phase: Weeks 2, 4, 12, 24 |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarker and Patient-Reported Outcome Analyses |
|
| 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 | 10 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Belgium |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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