A Clinical Study to Assess Immunologic and Virologic Changes in the Liver in Response to Combination Regimens Containing JNJ-73763989 and Nucleos(t)ide Analog With or Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection.
- Conditions
- Chronic Hepatitis B Virus InfectionTherapeutic area: Diseases [C] - Virus Diseases [C02]
- Registration Number
- EUCTR2019-004475-39-IT
- Lead Sponsor
- Janssen Sciences Ireland Unlimited Company
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 24
1. Adult participants =18 years of age 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.
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.
4. Participants who are not currently treated, including treatment-naïve participants 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 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 .
6. Participants must have HBsAg >100 IU/mL at screening.
7. Participants must have a body mass index 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):
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 stud
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 (confirmed by antibodies) 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, a 1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, Gilbert’s syndrome , or any other non HBV liver disease considered clinically significant by the investigator.
5. Participants with history or signs of cirrhosis or portal hypertension, 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 (eGFR) =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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Timepoint(s) of evaluation of this end point: Week 40;Main Objective: To assess changes in intrahepatic HBsAg between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment;Primary end point(s): Changes in the proportion of HBsAg positive hepatocytes between baseline and on-treatment Week 40.;Secondary Objective: 1. To assess changes in intrahepatic immune response between baseline and on-treatment liver biopsy.<br>2. To assess changes in intrahepatic viral nucleic acids and proteins between baseline and on-treatment liver biopsy.<br>3. To evaluate the efficacy of the study intervention as measured in the periphery. <br>4. To evaluate the frequency of virologic breakthrough during study intervention.<br>5. To assess HBV-specific T-cell responses.<br>6. To evaluate the safety and tolerability of the study intervention.<br>7. To evaluate the plasma PK of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379, and optionally of NA, as applicable.
- Secondary Outcome Measures
Name Time Method