| 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 |
| Chronic Hepatitis B Virus Infection |
|
| 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 assess changes in intrahepatic HBsAg between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess changes in intrahepatic immune response between baseline and on-treatment liver biopsy.
2. To assess changes in intrahepatic viral nucleic acids and proteins between baseline and on-treatment liver biopsy.
3. To evaluate the efficacy of the study intervention as measured in blood.
4. To evaluate the frequency of virologic breakthrough during study intervention.
5. To assess HBV-specific T-cell responses.
6. To evaluate the safety and tolerability of the study intervention.
7. To evaluate the plasma PK of JNJ-3989, and optionally of JNJ-6379, NA and PegIFN-α2a, as applicable. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult participants ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) to ≤65 years of age.
2. Participants must be medically stable on the basis of physical examination, medical history, vital signs, and triplicate 12-lead ECG performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator.
3. Participants must have HBV infection documented by serum HBsAg positivity at screening. In addition, chronicity must be documented by any of the following at least 6 months prior to screening: serum HBsAg positivity, HBeAg positivity or HBV DNA positivity, ALT elevation above ULN without another cause than HBV infection, documented transmission event, liver biopsy with changes consistent with chronic HBV. If none of the above are available, the following ways of documenting chronicity are acceptable at the time of screening: absence of marker for acute infection such as immunoglobulin M (IgM) anti-HBs and anti-HBc antibodies, which can be tested at screening.
4. Participants who are not currently treated (defined as not having been on HBV treatment, including NAs and IFN products within 6 months prior to screening), including treatment-naïve participants (defined as never having received HBV treatment, including NAs and IFN products) should:
a. be HBeAg positive, AND
b. have serum HBV DNA at screening ≥20,000 IU /mL, AND
c. have ALT levels at screening <10x ULN, AND
d. have indication for NA treatment according to local standard practice.
5. Virologically suppressed participants should:
a. be HBeAg negative, AND
b. be on stable HBV treatment, defined as currently receiving NA treatment (ETV, tenofovir disoproxil, or TAF) for at least 6 months prior to screening and have been on the same NA treatment regimen (at the same dose) for at least 3 months at the time of screening, AND
c. have serum HBV DNA <60 IU/mL on 2 measurements at least 3 months apart (one of which is at screening), AND
d. have documented ALT values <2.0x ULN on 2 measurements at least 3 months apart (one of which is at screening).
6. Participants must have HBsAg >100 IU/mL at screening.
7. Participants must have a body mass index (weight in kg divided by the square of height in meters) between 18.0 and 35.0 kg/m2, extremes included.
8. Participants must have fibroscan liver stiffness measurement ≤9.0 kPa within 6 months prior to screening or at the time of screening.
9.Female participants of childbearing potential must have a negative highly sensitive serum pregnancy test (B-human chorionic gonadotropin [B-hCG]) at screening and a negative urine pregnancy test on Day 1 before the first dose of study intervention.
10. A woman must be (as defined in Section 10.8, Appendix 8, Contraceptive and Barrier Guidance and Collection of Pregnancy Information):
a. not of childbearing potential
b. of childbearing potential and practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and correctly) for at least 30 days prior to screening and agrees to remain on a highly effective method while receiving study intervention and until 90 days after last dose of study intervention.
Examples of highly effective methods of contraception are located in Section 10.8, Appendix 8, Contraceptive and Barrier Guidance and Collection of Pregnancy Information.
11. Male participants must agree to wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study intervention period and until 90 days after last dose of study intervention.
12. Female participants must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study intervention period and until 90 days after last dose of study intervention.
13. Male participants must agree not to donate sperm for the purpose of reproduction during the study intervention phase and until 90 days after last dose of study intervention.
14. Participants 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.
15. Participants must separately consent if he or she agrees to undergo optional study procedures (ie, leukapheresis, intensive PK, and/or optional biopsy). Refusal to give consent to one or all of these optional study procedures does not exclude from participation in the study.
16. In the investigator’s opinion, the participant is able to understand and comply with protocol requirements, instructions, and study restrictions and is likely to complete the procedures as planned for this this study.
Please refer to the protocol for a full list of the inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
1. Participants with evidence of hepatitis A virus infection (hepatitis A antibody IgM), HCV infection (HCV antibody), hepatitis D virus (HDV) infection (HDV antibody), or hepatitis E virus (HEV) infection (HEV antibody IgM), or HIV-1 or HIV-2 infection (laboratory confirmed) at screening.
2. Participants with any of the following laboratory abnormalities within 12 months prior to screening or at the time of screening:
a. Total bilirubin >1.5x ULN, OR
b. Direct bilirubin >1.2x ULN, OR
c. Serum albumin <3.2 g/dL,
3. History or evidence of clinical signs/symptoms of hepatic decompensation including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices.
4. Participants with evidence of liver disease of non-HBV etiology. This includes but is not limited to hepatitis virus infections mentioned in exclusion criterion 1, drug- or alcohol related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, α 1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, Gilbert’s syndrome (mild cases are allowed, see exclusion criterion 2a), or any other non HBV liver disease considered clinically significant by the investigator.
5. Participants with history or signs of cirrhosis or portal hypertension (nodules, no smooth liver contour, no normal portal vein, spleen size ≥12 cm), signs of HCC or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening.
6. Participants with one or more of the following laboratory abnormalities at screening as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity Grading Scale:
a. Estimated glomerular filtration rate (eGFRcr) ≥grade 3 (<60 mL/min/1.73m²), calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula;
b. Pancreatic lipase elevation ≥grade 3;
c. Pancreatic amylase elevation ≥grade 3
d. Hemoglobin ≤10.9 g/dL (males), ≤10.4 g/dL (females);
e. Platelet count ≤lower limit of normal (LLN);
f. Alpha-fetoprotein (AFP) >100 ng/mL;
g. Any other laboratory abnormality considered to be clinically significant by the investigator.
7. Participants with presence of coagulopathy or bleeding disorder as indicated by:
a. International normalized ratio (INR) ≥1.1 x ULN;
b. Partial thromboplastin time > 1.1 x ULN;
c. Any signs of prolonged bleeding (>10 minutes).
8. Participants with presence of hemoglobinopathy (including sickle cell disease, thalassemia).
9. Participants who had a liver biopsy performed prior to screening that led to complications and that in the opinion of the investigator would prohibit another liver biopsy.
10. Participants with history of amyloidosis.
11. Participant refusal to accept blood transfusions.
12. Participants with hemoglobin A1c >8% at screening.
13. Participants with a history of malignancy within 5 years prior to screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which are considered cured with minimal risk of recurrence).
14. Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute [bpm]); QT interval corrected for heart rate according to Fridericia’s formula (QTcF) >450 ms for males and >470 ms for females; QRS interval ≥120 ms; PR interval >220 ms ; abnormal conduction; or any other clinically significant abnormalities on a 12-lead ECG at screening.
15. Participants with a history of or current cardiac arrhythmias (eg, extrasystole, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome) or history or other clinical evidence of significant or unstable cardiac disease (eg, angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia and/or coronary heart disease), moderate to severe valvular disease, or uncontrolled hypertension at screening.
Please refer to the protocol for a full list of the exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Changes in the proportion of HBsAg positive hepatocytes between baseline and on-treatment Week 40. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Changes between baseline and on-treatment liver biopsy in intrahepatic immune response (eg, CD45+ T-cells, CD4+ T-cells, CD8+ T-cells,
Natural Killer cells, and dendritic cells) in terms of proportion of cells, cell types, and spatial redistribution.
2a. Changes from baseline in intrahepatic viral parameters (such as cccDNA, pgRNA, intrahepatic RNA, or HBsAg in terms of copy number, or number of positive cells).
2b. Changes from baseline in intrahepatic cccDNA levels and transcriptional activity (pgRNA/cccDNA ratio).
3a. The proportion of participants during the study intervention and follow-up phases with:
-HBsAg seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment.
-(Sustained) Reduction, suppression, and/or seroclearance considering single and multiple markers (such as HBsAg, HBeAg, HBV DNA and ALT)
-HBsAg and HBeAg seroconversion
-Flares (virologic, biochemical, and clinical)
3b. Time to first HBsAg seroclearance
4. Proportion of participants with virologic breakthrough.
5. Changes from baseline in HBV-specific peripheral blood T-cell responses during the study intervention and follow-up phases.
6. Proportion of participants with (S)AEs and abnormalities in clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal biomarkers), 12-lead ECGs, vital signs, and physical examinations throughout the study.
7. Plasma PK parameters of JNJ-3976, JNJ-3924, and optionally of JNJ-6379, NA and PegIFN-α2a, as applicable. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study duration. |
|
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| France |
| Germany |
| Italy |
| New Zealand |
| Poland |
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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