E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis B Virus Infection |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Hepatitis B Virus Infection |
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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 evaluate the efficacy of 48-week study intervention with JNJ-3989+JNJ-6379+NA regimen compared to NA alone. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of the study intervention throughout the study.
2. To evaluate the efficacy of the study intervention at the end of treatment.
3. To evaluate the efficacy as measured by blood markers (such as HBsAg, HBV DNA, and ALT) during study intervention and follow-up.
4. To evaluate the frequency of virologic breakthrough during study intervention.
5. To evaluate the proportion of participants requiring NA re-treatment during follow-up.
6. To identify baseline and on-treatment markers associated with sustained off-treatment response.
7. To evaluate the PK of JNJ 3989 (JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
M01/A01. Male or female 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.
M02. Participant must be medically stable based on physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. This determination must be recorded in the participant’s source documents and initialed by the investigator.
M03/A02. 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 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, or should be documented by absence of marker for acute infection such as positive immunoglobulin M (IgM) anti-hepatitis B surface (HBs) and anti-HBc antibodies, which can be tested at screening.
The participants should be virologically suppressed. They should:
o Be HBeAg-negative,
o Be on stable HBV treatment, defined as currently receiving NA treatment (ETV, TDF, or TAF) for at least 24 months prior to screening and having been on the same NA treatment regimen (at the same dose) as used in this study (see Section 6.1) for at least 3 months at the time of screening, AND
o Have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 6 months apart (one of which is at screening), AND
o Have documented ALT values <2.0x ULN on 2 sequential measurements at least 6 months apart (one of which is at screening).
M04. 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.
M05/A03. Participant must sign a Master ICF (specific for the Master Protocol PLATFORMPAHPB2001) and an ICF specific for this ISA indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
M06. Participant must sign a separate ICF if he or she agrees to provide an optional DNA sample for research (where local regulations permit). Refusal to give consent for the optional DNA research sample does not exclude a participant from participation in the study.
M07/A04. Female participants must be:
a. Not of childbearing potential, OR
b. Of childbearing potential and practicing a highly effective, preferably user independent method of contraception at least 30 days prior to
screening (failure rate of <1% per year when used consistently and correctly) and must agree 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 provided in Section 10.8 Appendix 8 of Study Protocol.
M08. Female participants of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test on Day 1 before the first dose of study intervention.
M09. In the investigator’s opinion, the participant is able to understand and comply with protocol requirements, instructions, and study restrictions (Section 5.3, Lifestyle Considerations) and is likely to complete the study as planned in this ISA (including the procedures outlined in the Master Protocol PLATFORMPAHPB2001).
A05. Participants must have HBsAg >100 IU/mL at screening.
A06. Participants must have:
a. Fibroscan liver stiffness measurement ≤9.0 kPa within 6 months prior to screening or at the time of screening, OR
b. If a fibroscan result is not available: a liver biopsy result classified as Metavir F0-F2 within 2 years prior to screening or at the time of screening.
A07. 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 phase and until 90 days after last dose of study intervention.
A08. Female participants must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study intervention phase and until 90 days after last dose of study intervention.
A09. Male participants must agree not to donate sperm for the purpose of reproduction during the study intervention phase and until 90 days after the last dose of study intervention.
Please refer to the protocol for a complete list of the inclusion criteria
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E.4 | Principal exclusion criteria |
M01/A01. Participants with evidence of hepatitis A virus infection (hepatitis A antibody IgM), hepatitis C virus (HCV) infection (HCV antibody and detectable HCV RNA), hepatitis D virus (HDV) infection (HDV antibody), hepatitis E virus infection (hepatitis E antibody IgM), or HIV 1 or HIV-2 infection (confirmed by antibodies) at screening.
M02. Participants with evidence of hepatic decompensation at any time point prior to or at the time of screening:
a. Total bilirubin >1.5xULN
b. Direct bilirubin >1.2xULN, OR Prothrombin time >1.3xULN (unless caused by anticoagulation therapy or vitamin K deficiency), OR
c. Serum albumin <3.2 g/dL, OR
d. History of clinical symptoms of hepatic decompensation (eg, ascites, jaundice, hepatic encephalopathy or coagulopathy, especially if resulting in a Child Pugh classification B or C at the time clinical symptoms present or at screening).
M03. History or evidence of clinical signs or symptoms of hepatic decompensation, including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices.
M04. Participants with evidence of liver disease of non-HBV etiology. This includes but is not limited to hepatitis infections mentioned in exclusion criterion M01/A01, 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 M02a) or any other non-HBV liver disease considered clinically significant by the investigator.
M05/A02. Participants with history or signs of cirrhosis or portal hypertension (nodules, no smooth liver contour, no normal portal vein, spleen size ≥12 cm) or signs of HCC on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening or clinically relevant renal abnormalities. In case of suspicious findings on conventional ultrasound the participant may still be eligible if HCC or clinically relevant renal abnormalities have been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
M06/A03. 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 (see Section 10.9, Appendix 9, DAIDS Table):
a. Estimated creatinine clearance ≥grade 3 (<60 mL/min) at screening, 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 >100 ng/mL;
g. Any other laboratory abnormality considered to be clinically significant by the investigator (also see inclusion criterion M03/A02).
M07. Participants with hemoglobin A1c >8% at screening.
M08. Participants with a history of malignancy within 5 years before 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).
M09. 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.
M10. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants with HBsAg seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment. |
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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. Safety and tolerability including but not limited to the 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.
2a. Proportion of participants with HBsAg seroclearance at Week 48.
2b. Proportion of participants with HBV DNA <LLOQ at Week 48.
3a. Proportion of participants with HBsAg seroclearance at Week 96 (ie, 48 weeks after completion of all study interventions at Week 48) without restarting NA treatment.
3b. Proportion of participants with HBsAg seroclearance 24 weeks after stopping all study interventions without restarting NA treatment.
3c. Proportion of participants with HBsAg seroclearance 48 weeks after stopping all study interventions without restarting NA treatment.
3d. Proportion of participants with (sustained) reduction, suppression, and/or seroclearance considering single and multiple markers (such as HBsAg, HBV DNA and ALT).
3e. Proportion of participants with HBsAg seroconversion.
3f. Change from baseline over time in HBsAg and HBV DNA.
3g. Time to achieve first HBsAg seroclearance.
3h. Proportion of participants with HBsAg levels and/or changes from baseline below/above different cut-offs (eg, HBsAg <100 IU/mL or >1 log10 IU/mL reduction in HBsAg from baseline).
3i. Proportion of participants with HBV DNA levels and/or changes from baseline below/above different cut-offs (eg, <LLOQ of the assay).
3j. Proportion of participants with flares (virologic, biochemical, and clinical).
4. Proportion of participants with virologic breakthrough.
5. Proportion of participants who meet the NA re-treatment criteria.
6. Correlation of baseline characteristics and baseline/on-treatment viral blood markers (such as baseline NA treatment duration, age, and baseline/on-treatment HBsAg levels) with selected off-treatment efficacy variables.
7. Population PK parameters of JNJ-3989 (JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 12 |
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 | 11 |