| 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 establish the dose-response relationship for antiviral activity of 3 doses of JNJ-3989+NA and to evaluate the efficacy of combination regimens of JNJ-3989+NA (with and without JNJ-6379) and of JNJ-6379+NA. |
|
| 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 during follow-up phase.
3. To evaluate efficacy as measured by blood markers (such as HBsAg, HBeAg, HBV DNA, and ALT) during study intervention and follow-up.
4. To evaluate the frequency of virologic breakthrough.
5. To evaluate the efficacy of NA re-treatment in participants who meet the criteria for NA re-treatment.
6. To evaluate the PK of JNJ-3989, JNJ-6379, and NA, as applicable. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult male or female participants ≥18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 65 years of age, inclusive.
2. Participants must be medically stable, with the exception of HBV disease, on the basis of 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.
3. Participants must have chronic HBV infection documented by serum HBsAg positivity at screening. In addition, chronicity must be documented by serum HBsAg positivity at least 6 months prior to screening or alternative markers of chronicity (HBeAg positivity or HBV DNA positivity at least 6 months prior to screening, ALT elevation above ULN at least 6 months prior to screening without another cause than HBV infection, liver biopsy, or documented transmission event at least 6 months prior to screening).
Note: if documentation of chronicity (as mentioned above) at least 6 months prior to screening is not available, participants may be included if HBsAg positive and negative for immunoglobulin M (IgM) antibodies to HBV core antigen at screening.
4. Participants who are not currently treated (defined as not having been on treatment with HBV antiviral medicines, including NAs and IFN products within 6 months prior to screening), including treatment-naïve participants (defined as never having received treatment with HBV antiviral medicines, including NAs and IFN products) should have:
a. Serum HBV DNA at screening ≥2,000 IU /mL for HBeAg-negative
participants and ≥20,000 IU/mL for HBeAg-positive participants, AND
b. ALT levels at screening <10x ULN AND >ULN on two measurements at least 3 months apart (one of which is at screening).
5. Virologically suppressed participants should:
a. be on stable HBV treatment, defined as currently receiving NA treatment (ETV, TDF, or TAF) 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 (see Protocol Section 6.1) for at least 3 months at the time of screening, AND b. have serum HBV DNA <60 IU/mL on two measurements at least 6 months apart (one of which is at screening), AND
c. have ALT values ≤2x ULN on two measurements at least 6 months apart (one of which is at screening).
6. Participants must have HBsAg >100 IU/mL at screening.
7. Participants must have a BMI (weight in kg divided by the square of height in meters) between 18.0 and 35 kg/m2, extremes included.
8. 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.
Note: Other radiologic liver staging modalities (eg, acoustic radiation force impulse) might be used if standard practice at the site or if otherwise validated and agreed with the sponsor. Results should be equivalent to Metavir F0-F2.
Note: Conventional imaging procedures (eg, conventional liver ultrasound, computed tomography [CT] or magnetic resonance imaging [MRI]) and serum marker panels are not allowed to rule out severe fibrosis or cirrhosis.
9. Participants must sign an ICF indicating that they understand the purpose of, and procedures required for, the study and is willing to participate in the study.
10. Participants must sign a separate ICF if they agree 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.
11. Female participants of childbearing potential must have a negative highly sensitive serum pregnancy test (b-human chorionic gonadotropin) at screening and a negative urine pregnancy test on Day 1 before the first dose of study intervention.
Please refer to the protocol for a complete 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 [participants with undetectable HCV RNA and documentation of sustained virological response at least 24 weeks after completion of HCV treatment might be enrolled after discussion with the sponsor]), HDV infection (HDV antibody), or hepatitis E virus infection (hepatitis E 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,
b. Direct bilirubin >1.2x ULN,
c. Prothrombin time >1.5x ULN,
d. Serum albumin <3.0 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 signs of HCC or clinically relevant 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 abnormalities has been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
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 (see Protocol Section 10.8, Appendix 8, DAIDS Table):
a. Estimated glomerular filtration rate (eGFR) ≥grade 3 (i.e. <60
ml/min/1.73 m2) at screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula,
b. Pancreatic amylase ≥grade 3,
c. Lipase 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 hemoglobin A1c >8% at screening.
8. 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 is considered cured with minimal risk of recurrence).
9. Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute [bpm]); QT interval corrected for heart rate according to Fridericia (QTcF) >450 ms for male participants and >470 ms for female participants; QRS ≥120 ms; PR interval >220 ms; abnormal conduction; or any other clinically significant abnormalities on a 12-lead ECG at screening.
10. Participants with a history of or current cardiac arrhythmias (eg, 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, coronary heart disease), moderate to severe valvular disease, or uncontrolled hypertension at screening. Any evidence of atrioventricular block or bundle branch block is also exclusionary.
11. 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.
12. Participants with any history of or current clinically significant skin disease requiring regular or periodic treatment.
Please refer to the protocol for a full list of the exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of participants meeting the NA treatment completion criteria at Week 48. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of participants with (S)AEs and abnormalities in clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, and urinalysis, urine chemistry, and renal biomarkers), 12-lead ECGs, and vital signs.
2a. Proportion of participants with HBsAg seroclearance 24 weeks after
completion of all study intervention at Week 48.
2b. Proportion of participants with HBsAg seroclearance 48 weeks after completion of all study intervention at Week 48.
2c. Proportion of participants with HBsAg seroclearance 24 weeks and 48 weeks after completion of all study intervention at any time during follow-up.
2d. Proportion of participants with HBV DNA <LLOQ 24 and 48 weeks after completion of all study intervention.
2e. Proportion of participants meeting the NA treatment completion criteria during follow-up.
2f. Frequency of relapse.
2g. Proportion of participants not requiring NA re-treatment during follow-up.
3a. Proportion of participants with (sustained) reduction, suppression, and/or seroclearance considering single and multiple markers (such as HBsAg, HBeAg,* HBV DNA and ALT).
3b. Proportion of participants with HBsAg and HBeAg* seroconversion.
3c. Change from baseline over time in HBsAg, HBeAg,* and HBV DNA.
3d. Time to achieve HBsAg and HBeAg* seroclearance.
3e. 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).
3f. Proportion of HBeAg-positive participants with HBeAg* levels and/or changes from baseline below/above different cut-offs.
3g. Proportion of participants with HBV DNA levels and/or changes from baseline below/above different cut-offs (eg, <LLOQ of the assay).
3h. Proportion of participants with ALT decrease and normalization.
3i. Proportion of participants meeting the NA treatment completion criteria during follow-up.
4. Proportion of participants with virologic breakthrough.
5. Proportion of participants who reach HBV DNA undetectability after re-start of NA treatment during follow-up.
6. PK parameters of JNJ-3989, JNJ-6379, and NA, as applicable. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 6 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Brazil |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Poland |
| Russian Federation |
| Spain |
| Thailand |
| Turkey |
| 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
|
| The EOS is considered as the last visit ([Extended] Follow-up Week 48 or early discontinuation) for the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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