| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hepatitis B and Hepatitis D Viral Co-infection |
| Co-infezione da virus dell' Epatite B e D |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis B and Hepatitis D Viral Co-infection |
| Infezione doppia da virus dell' Epatite B e virus dell'epatite D |
|
| 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 | HLT |
| E.1.2 | Classification code | 10057212 |
| E.1.2 | Term | Hepatitis viral infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 on-treatment efficacy against HDV of JNJ-3989 + NA regimen compared to NA alone. |
| Valutare l'efficacia del trattamento contro l'HDV del regime JNJ-3989 + NA rispetto al solo NA. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate on-treatment efficacy of the JNJ-3989 + NA regimen in suppressing HDV replication as measured by HDV RNA.
- To evaluate efficacy of the JNJ-3989 + NA regimen on liver inflammation during study intervention phase.
- To evaluate the efficacy of the JNJ-3989 + NA regimen on liver fibrosis.
- To evaluate the efficacy of the JNJ-3989 + NA regimen in terms of HBsAg response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. male or female (according to their reproductive organs and functions assigned by chromosomal complement).
2. 18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 65 years of age, inclusive.
3. medically stable on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. Any abnormalities, must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator.
4. must have:
- chronic hepatitis B infection either HBeAg positive or HBeAg negative and either receiving NA treatment or no NA treatment. 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)
- chronic HDV infection documented by positive HDV antibodies or HDV RNA at screening. In addition, chronicity must be documented by positive HDV antibodies or HDV RNA at least 3 months prior to screening.
5. must have HDV RNA values at screening =1,000 IU/mL.
6. must have ALT levels <10x ULN at screening.
7. Participants must have a BMI (weight in kg divided by the square of height in meters) between 18.0 and 35.0 kg/m2, extremes included.
8. must have presence or absence of compensated cirrhosis based on:
a. No cirrhosis: LSM <12.5 kPa by VCTE (FibroScan) within 6 months prior to screening or at the time of screening or liver biopsy within 1 year prior to screening, OR
b. Cirrhosis: LSM =12.5 kPa by VCTE (FibroScan) within 6 months prior to screening or at the time of screening or liver biopsy within 1 year prior to screening; and a Child-Pugh score A.
Note: If FibroScan is not available, other radiologic liver staging modalities (eg, acoustic radiation force impulse) might be used at screening if standard practice at the site or if otherwise validated and agreed with the sponsor.
Note: Conventional imaging procedures (eg, conventional liver ultrasound, computed tomography [CT] or magnetic resonance imaging [MRI]) and serum marker panels are not allowed.
9. 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.
10. 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.
11. a woman of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin [beta-hCG]) at screening and a negative urine pregnancy test on Day 1 before the first dose of study intervention.
12. a woman must be (as defined in Section 10.8, Appendix 8, Contraceptive and Barrier Guidance)
a. Not of childbearing potential
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 - the end of relevant systemic exposure. Examples of highly effective methods of contraception are located in Section 10.8, Appendix 8, Contraceptive Guidance and Barrier Guidance.
13. a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 90 days after the last dose of study intervention.
14. a male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person while receiving study intervention and until 90 days after the last dose of study intervention.
15. a male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum 90 days after receiving the last dose of study intervention.
16. In the investigator’s opinion, the participant is able to understand and comply with protocol requirements, instructions, and lifestyle restrictions and be likely to complete the procedures as planned for this study. |
|
| E.4 | Principal exclusion criteria |
1. Participants with evidence of hepatitis A virus infection (hepatitis A antibody immunoglobulin M [IgM]), hepatitis C virus (HCV) infection (HCV antibody), or hepatitis E virus (HEV) infection (hepatitis E antibody IgM), or human immunodeficiency virus type 1 (HIV-1) or HIV type 2 (HIV-2) infection (confirmed by antibodies) at screening.
Note:
- Participants with a positive HCV antibody test can be enrolled if they have negative HCV RNA at screening and documented negative HCV RNA at least 6 months prior to screening.
- Participants with a positive IgM antibody test for HEV infection may be enrolled after discussion with the sponsor if an active HEV infection can be ruled out by documentation of negative anti-HEV IgG.
2. any of the following laboratory abnormalities within 12 months prior to screening or at time of screening:
a. Total bilirubin >1.7x ULN,
b. Direct bilirubin >1.4x ULN,
c. Prothrombin time >1.3x ULN,
d. 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.
Note: Participants with uncomplicated splenomegaly may be enrolled after consultation with the sponsor.
4. Child-Pugh score >6.
5. evidence of liver disease of non-HDV or 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 (mild cases are allowed, see exclusion criterion 2a), or any other non-HBV/HDV or non-viral liver disease considered clinically significant by the investigator.
6. 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 has been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT, or MRI).
7. 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 (ie, <60 mL/min/1.73 m2) at screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula,
b. Total amylase =grade 3,
c. Lipase elevation =grade 3,
d. Hemoglobin =10.9 g/dL (males), =10.4 g/dL (females),
e. Platelet count =100,000/dL,
f. Alpha-fetoprotein (AFP) >100 ng/mL,
g. Any other laboratory abnormality considered to be clinically significant by the investigator.
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, enhanced ultrasound, CT, or MRI) during screening.
8. hemoglobin A1c >8% at screening.
9. 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).
10. 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 interval =120 ms; PR interval >220 ms; abnormal conduction; or any other clinically significant abnormalities on a 12-lead ECG at screening.
11. 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.
Please refer to the protocol for a complete list of the exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is defined as the proportion of participants with HDV RNA =2 log10 IU/mL decline from baseline or HDV RNA TND in combination with normal ALT levels 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 HDV RNA =2 log10 IU/mL decline from baseline or HDV RNA TND at Week 48.
2. Proportion of participants with normal ALT levels at Week 48.
3. Proportion of participants with =2 kPa reduction from baseline in LSM assessed by VCTE (FibroScan) at Week 48.
4. Proportion of participants with HBsAg seroclearance at Week 48. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 | Information not present in EudraCT |
| 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 |
| Brazil |
| China |
| Japan |
| New Zealand |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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