| 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 evaluate the efficacy in terms of HBsAg levels of the study intervention (ie,JNJ-3989 + JNJ-6379 + NA and PegIFN-α2a). |
|
| 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 at the end of the 24-week treatment period.
3. To evaluate the efficacy of the study intervention as measured by blood markers (such as HBsAg, HBeAg, HBV DNA, and ALT) during the study intervention and follow-up (FU) period.
4. To evaluate the frequency of virologic breakthrough during the 24-week treatment period, as well as during the FU period for participants who continue treatment with NA.
5. To evaluate the efficacy of the study intervention during the FU period.
6. To evaluate the PK of JNJ-3989 and optionally of JNJ-6379, NA and PegIFN-α2a. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A01. Male or female participants ≥18 years of age (or older if the legal age of consent in the jurisdiction in which the study is taking place is >18) to ≤65 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.
A03. Participants must have chronic HBV infection. HBV infection must be 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. If none of the above are available, the following ways of documenting chronicity are acceptable at the time of screening: liver biopsy with changes consistent with chronic HBV, or absence of marker for acute HBV infection such as positive immunoglobulin M (IgM) anti-hepatitis B surface (HBs) and anti HBc antibodies.
Participants should:
• be on stable HBV treatment, defined as currently receiving NA treatment for at least 6 months prior to screening and having been on the same NA treatment regimen (at the same dose) as used in this study for at least 3 months at the time of screening, AND
• have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 6 months apart (one of which is at screening), AND
• 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 (BMI; weight in kg divided by the square of height in meters) between 18.0 and 35.0 kg/m2, extremes included.
A05. Participants 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 additional 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.
A07. 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 (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 Section 10.5 Appendix 5 of Protocol.
M08. Female participants of childbearing potential must have a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin) 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).
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 serum HBsAg >100 IU/mL at screening, as assessed by qualitative HBsAg assay.
A14. 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.
A15. Participants must separately consent if he or she agrees to participate in the PK substudy. Refusal to give consent does not exclude participation in the main study.
Please refer to the protocol for a full list of the inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
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.
A02. Participants with evidence of hepatic decompensation at any time point prior to or at the time of screening:
a. Total bilirubin >1.5x ULN, OR
b. Direct bilirubin >1.2x ULN, OR
c. Prothrombin time >1.3x ULN (unless caused by anticoagulation therapy or vitamin K deficiency), OR
d. Serum albumin <3.2 g/dL.
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) or any other non-HBV liver disease considered clinically significant by the investigator.
A05. Participants with signs of hepatocellular carcinoma (HCC) or clinically relevant renal abnormalities on an abdominal ultrasound performed within 3 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 has been ruled out by a more specific imaging procedure (contrast-enhanced ultrasound, CT or MRI).
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 (see Section 10.9, Appendix 9: DAIDS Table):
a. Estimated glomerular filtration rate (eGFR) <80 mL/min/1.73 m2 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 (AFP) >100 ng/mL;
Note: Participants with AFP >ULN but ≤100 ng/mL may be eligible if HCC can be ruled out based on a sensitive imaging study (eg, contrast-enhanced ultrasound, CT or MRI) during screening.
g. Any other laboratory abnormality considered to be clinically significant by the investigator (also see exclusion criterion 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.
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 a reduction of at least 2 log10 IU/mL in HBsAg levels from baseline to Week 24 (end of study intervention [EOSI]). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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, renal biomarkers), 12-lead ECGs, vital signs, and ophthalmic and physical examinations throughout the study.
2. Proportion of participants meeting the protocol defined NA treatment completion criteria at EOSI.
3a. Proportion of participants with HBeAg, HBsAg, HBV DNA, and ALT levels below/above different cut-offs.
3b. Proportion of participants with HBsAg and/or HBeAg seroconversion.
3c. Change from baseline over time in HBsAg, HBeAg, and/or HBV DNA.
3d. Time to achieve HBsAg and/or HBeAg seroclearance/seroconversion, and/or HBV DNA <LLOQ.
4. Proportion of participants with virologic breakthrough.
5a. Proportion of participants with HBsAg seroclearance at Week 48 (ie, 24 weeks after completion of all study interventions at Week 24) without re-starting NA treatment.
5b. Proportion of participants with HBV DNA <LLOQ at Week 48 (ie, 24 weeks after completion of all study interventions at Week 24) without re-starting NA treatment.
5c. Frequency of virologic and/or biochemical flares.
5d. Proportion of participants requiring NA re treatment.
6a. PK parameters of JNJ-3989.
6b. Optionally, PK parameters of JNJ-6379, NA and/or PegIFN-α2a compared to historical data.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the duration of the study. |
|
| 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 | 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 | No |
| 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 | No |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Japan |
| New Zealand |
| Taiwan |
| Poland |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 12 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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