| 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 a treatment regimen of JNJ-3989 + JNJ-6379 + NA with or without PegIFN α2a. |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of the study intervention.
2. To evaluate the efficacy of the study intervention during the treatment period.
3. To evaluate the efficacy of the study intervention during the follow-up (FU) phase.
4. To evaluate efficacy of the study intervention as measured by blood markers (such as HBsAg, HBeAg, HBV DNA, and alanine aminotransferase [ALT]) during study intervention and follow-up.
5. To evaluate the frequency of virologic breakthrough.
6. To evaluate the efficacy of NA re-treatment in participants who meet the criteria for NA re treatment.
7. To evaluate the pharmacokinetics (PK) of JNJ 3989 (ie, JNJ-3976 and JNJ-3924) and JNJ-6379, and optionally of NA and PegIFN α2a.
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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 ≤45 years of age.
M02 Participants 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.
M03d/A03 Participants must have chronic HBeAg positive 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, documented transmission event. If none of the above are available, the following ways of documenting chronicity are acceptable at time of screening: liver biopsy with changes consistent with chronic HBV, or absence of marker for acute infection such as positive immunoglobulin M (IgM) antihepatitis B surface (HBs) and anti-HBc antibodies.
In addition, participants must:
a. be treatment-naïve participants (defined as never having received treatment with HBV antiviral medicines, including NAs and IFN products), AND
b. be HBeAg positive, AND
c. have serum HBV DNA at screening ≥20,000 IU/mL, AND
d. have normal ALT at screening and at least once >6 months prior to screening.
M04 Participants must have a body mass index (BMI; weight in kg divided by the square of height in meters) between 18.0 and 35.0 kg/m2, extremes included.
M05/A05 Participants (or their legally acceptable representative) must sign a Master ICF (specific for the Master Protocol PLATFORMPAHPB2001) and must sign an ICF specific for this intervention cohort, indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
M06 Participants 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/A07 Female participants must be (as defined in Attachment 5 of the Master Protocol PLATFORMPAHPB2001):
a. Not of childbearing potential, OR
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 provided in Attachment 5 of the Master Protocol PLATFORMPAHPB2001.
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 and is likely to complete the study as planned per ISA (including the procedures outlined in the Master protocol PLATFORMPAHPB2001).
M10/A10 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.
A11 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.
A12 Male participants must agree not to donate sperm for the purpose of reproduction during the study intervention period and until 90 days after last dose of study intervention.
A13 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 1 year prior to screening or at the time of screening.
A14 Participants must separately consent if he or she agrees to participate in the PK substudy. Refusal to give consent does not exclude from participation in the study.
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), HCV infection (HCV antibody), hepatitis D virus (HDV) infection (HDV antibody), hepatitis E virus (HEV) infection (hepatitis E antibody IgM), or HIV-1 or HIV 2 infection (confirmed by antibodies) at screening.
M02.1 Participants with evidence of hepatic decompensation at any time point prior to or at the time of screening:
a. Total bilirubin >1.5xULN, OR
b. Direct bilirubin >1.2xULN, OR
c. Prothrombin time >1.3xULN (unless caused by anticoagulation therapy or vitamin K deficiency), OR
d. Serum albumin <3.2 g/dL, OR
e. 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 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 M02.1) or any other non-HBV liver disease considered clinically significant by the investigator.
M05 Participants with 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. 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/A06 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) <80 mL/min/1.73 m^2 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.
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).
M09.1 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.
M11. Participants with any current or previous illness for which, in the opinion of the investigator and/or sponsor, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol specified assessments. This may include but is not limited to significant vascular, pulmonary (eg, chronic obstructive pulmonary disease), gastrointestinal (eg, significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence drug absorption or bioavailability), endocrine (eg, thyroid disease), neurologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic disturbances. Any condition possibly affecting drug absorption (eg, gastrectomy or other significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel resection, or active enterostomy) will also lead to exclusion.
M12 Participants who have received an organ transplant (except for skin, hair, or cornea transplants).
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 24 weeks after stopping all study interventions of the consolidation phase and without restarting NA treatment |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after stopping all study interventions of the consolidation phase and without restarting NA treatment |
|
| E.5.2 | Secondary end point(s) |
1. Safety and tolerability including but not limited to the proportion of participants with (serious) adverse events (S)AEs and abnormalities in clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal biomarkers), 12 lead electrocardiograms (ECGs), vital signs, and physical examinations throughout the study.
2a. Proportion of participants meeting RGT criterion (HBsAg <10 IU/mL) at or before Week 60 of the induction phase.
2b. Time to meet RGT criterion (HBsAg <10 IU/mL).
2c. Proportion of participants meeting the NA treatment completion criteria at the end of the consolidation phase.
3a. Proportion of participants with HBsAg seroclearance 48 weeks after stopping all study interventions of the consolidation phase and without restarting NA treatment.
3b. Proportion of participants with HBV DNA <LLOQ 48 weeks after stopping all study interventions of the consolidation phase and without restarting NA treatment.
3c. Frequency of viral and/or biochemical flares and/or clinical flares.
3d. Proportion of participants requiring NA re-treatment.
4a. Proportion of participants with (sustained) reduction, suppression, and/or seroclearance considering single and multiple markers (such as HBsAg, HBeAg, HBV DNA, and ALT).
4b. Proportion of participants with HBsAg and HBeAg seroconversion.
4c. Change from baseline over time in HBsAg, HBeAg, and HBV DNA.
4d. Time to achieve HBsAg seroclearance, HBeAg seroclearance, and/or HBV DNA <LLOQ.
4e. Proportion of participants with HBeAg, HBsAg, and HBV DNA levels and/or changes from baseline below/above different cut-offs.
5. Proportion of participants with virologic breakthrough.
6. Proportion of participants who reach HBV DNA undetectability after re-start of NA treatment during follow-up.
7a. PK parameters of JNJ-3976, JNJ-3924, and JNJ-6379.
7b. Optionally, PK parameters of NA and/or PegIFN α2a compared to historical data. |
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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 | Yes |
| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Czechia |
| France |
| Germany |
| Japan |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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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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| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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