Hepatitis D, Chronic
Conditions
Brief summary
The purpose of the study is to evaluate on-treatment efficacy against hepatitis D virus (HDV) of JNJ-73763989 + nucleos(t)ide analog (NA) regimen compared to NA alone.
Interventions
DRUGJNJ-73763989
JNJ-73763989 will be administered as a SC injection.
DRUGPlacebo
Matching placebo to JNJ-73763989 will be administered as a SC injection.
ETV monohydrate film coated tablet will be administered orally.
DRUGTenofovir disoproxil
Tenofovir disoproxil film-coated tablet will be administered orally.
TAF film coated tablet will be administered orally.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Medically stable based on physical examination, medical history, vital signs, electrocardiogram (ECG) at screening * Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection with documentation at least 6 months prior to screening * For Part 1: hepatitis D RNA (HDV RNA) greater than or equal to (\>=) 1000 international units per milliliter (IU/mL) at screening. For Part 2: must have HDV RNA values \>= 500 IU/mL, and must have hepatitis B surface antigen (HBsAg) values less than or equal to (\<=) 10000 IU/mL at screening or HDV RNA values at screening are \<= 100000 IU/mL * Alanine aminotransferase (ALT) greater than upper limit normal (ULN) but less than 10 times (ULN) * Body mass index (BMI) between 18.0 and 35.0 kilogram per meter square (kg/m\^2), extremes included * Highly effective contraceptive measures in place for female participants of childbearing potential or male participants with female partners of childbearing potential * Non-cirrhotic participants and participants with compensated cirrhosis (Child Pugh class A) at screening (Part 1) and participants must have absence of cirrhosis and platelet count of \>= 140000 per deciliter (dL) for enrollment into Part-2
Exclusion criteria
* Evidence of infection with hepatitis A, C, or E virus infection or evidence of human immunodeficiency, virus type 1 (HIV-1) or HIV-2 infection at screening * History or evidence of clinical signs/symptoms of hepatic decompensation including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices or any laboratory abnormalities indicating a reduced liver function as defined in the protocol * Evidence of liver disease of non-HBV/HDV etiology * Signs of hepatocellular carcinoma (HCC) * Significant laboratory abnormalities as defined in the protocol at screening * Participants with a history of malignancy within 5 years before screening * Abnormal sinus rhythm or ECG parameters at screening as defined in the protocol * History of or current cardiac arrhythmia or history or clinical evidence of significant or unstable cardiac disease * 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 * History of or current clinically significant skin disease or drug rash * Participants with known allergies, hypersensitivity, or intolerance to JNJ-3989 or its excipients or excipients of the placebo content * Contraindications to the use of entecavir (ETV), tenofovir disoproxil, or tenofovir alafenamide (TAF) per local prescribing information * Participants who have taken any therapies disallowed per protocol * Female participants who are pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study intervention * Male participants who plan to father a child while enrolled * Participants who had or planned major surgery, (example, requiring general anesthesia) or who have received an organ transplant * Vulnerable participants (example, incarcerated individuals, individuals under a legal protection measure)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind: Part 1: Percentage of Participants With HDV Ribonucleic Acid (RNA) >=2 log10 IU/mL Decline From Baseline or HDV RNA Target Not Detected (TND) in Combination With Normal Alanine Aminotransferase (ALT) at Week 48 (Multiple Imputation Approach) | At Week 48 | Percentage of participants with HDV RNA greater than or equal to (\>=) 2 log10 International Units Per Milliliter (IU/mL) decline from baseline or HDV RNA TND in combination with normal ALT at Week 48 using multiple imputation approach was reported. Target not detected (TND) was defined as no traces of HBV RNA were detected/found. Normal ALT was defined as ALT less than (\<) upper limit of normal (ULN) with ULN = 34 units per liter (U/L) for female and 43 U/L for male. The baseline assessment was defined as the last observed non-missing measurement before the date and time of the first administration of any of study intervention on Day 1. The multiple imputation approach was derived using a longitudinal multiple regression model to impute missing data. |
| Double-blind: Part 2: Percentage of Participants With HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination With ALT at Week 48 (Multiple Imputation Approach) | At Week 48 | Percentage of participants with HDV RNA \>=2 log10 IU/mL decline from baseline or HDV RNA TND in combination with normal ALT at Week 48 using multiple imputation approach was reported. TND was defined as no traces of HBV RNA were detected/found. Normal ALT was defined as ALT \<ULN with ULN = 34 U/L for female and 43 U/L for male. The baseline assessment was defined as the last observed non-missing measurement before the date and time of the first administration of any of study intervention on Day 1. The multiple imputation approach was derived using a longitudinal multiple regression model to impute missing data. |
Countries
Australia, Brazil, China, France, Germany, Italy, Japan, New Zealand, Russia, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Adult participants co-infected with hepatitis B virus (HBV) and hepatitis D virus (HDV) were considered eligible for participation. Participants with compensated cirrhosis were allowed to be enrolled in Part 1 but excluded from Part 2 of the study.
Pre-assignment details
The study consisted of 2 parts: 1 and 2. Part 2 was initiated when the protocol specified antiviral activity criteria was met in Part 1 and when all participants of Part 1 had completed at least Week 16 or discontinued earlier. Unique participants were randomized (4:1) to JNJ-73763989 + NA and Placebo + NA in Part 1 and 2. Two ongoing participants in double-blind phase Part 2 completed Week 48 visit. Hence, included in the primary analysis at Week 48.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: JNJ-73763989 + Nucleos(t)Ide Analog (NA) In the double-blind phase, participants received JNJ-73763989 100 milligrams (mg) subcutaneous (SC) injection every 4 weeks (Q4W) along with NA (entecavir \[ETV\] monohydrate 0.5 mg, tenofovir disoproxil 245 mg, or tenofovir alafenamide \[TAF\] 25 mg) tablet orally once daily for 52 weeks. After completion of double-blind phase, participants entered open-label phase and continued to receive JNJ-73763989 100 mg SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 92 weeks (up to Week 144). After completion of open-label phase, participants entered 48-week follow-up phase during which JNJ-73633989 treatment was stopped and NA treatment alone was continued. | 17 |
| Part 1: Placebo + NA In the double-blind phase, participants received placebo matching to JNJ-73763989 SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 52 weeks. After completion of double-blind phase, participants entered open-label phase and received JNJ-73763989 100 mg SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 96 weeks (up to Week 148). After completion of open-label phase, participants entered 48-week follow-up phase during which JNJ-73633989 treatment was stopped and NA treatment alone was continued. | 5 |
| Part 2: JNJ-73763989 + NA In the double-blind phase, participants received JNJ-73763989 100 mg SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 52 weeks. After completion of double-blind phase, participants entered open-label phase and continued to receive JNJ-73763989 100 mg SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 92 weeks (up to Week 144). After completion of open-label phase, participants entered 48-week follow-up phase and stopped JNJ-73633989 treatment and continued NA treatment alone. | 24 |
| Part 2: Placebo + NA In the double-blind phase, participants received placebo matching to JNJ-73763989 SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 52 weeks. After completion of double-blind phase, participants entered open-label phase and received JNJ-73763989 100 mg SC injection Q4W along with NA (ETV 0.5 mg, tenofovir disoproxil 245 mg, or TAF 25 mg) tablet orally once daily for 96 weeks (up to Week 148). After completion of open-label phase, participants entered 48-week follow-up phase and stopped JNJ-73633989 treatment and continued NA treatment alone. | 6 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind (Day 1 up to Week 52) | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Double-blind (Day 1 up to Week 52) | Ongoing after Week 48 | 0 | 0 | 1 | 1 |
| Double-blind (Day 1 up to Week 52) | Withdrawal by Subject | 1 | 0 | 2 | 0 |
| Follow-up (Week 148 up to Week 161) | Ongoing | 4 | 0 | 0 | 0 |
| Follow-up (Week 148 up to Week 161) | Other | 0 | 0 | 1 | 0 |
| Follow-up (Week 148 up to Week 161) | Withdrawal by Subject | 5 | 0 | 4 | 0 |
| Open-label (Week 52 up to Week 148) | Ongoing | 0 | 1 | 14 | 4 |
| Open-label (Week 52 up to Week 148) | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1: Placebo + NA | Part 2: JNJ-73763989 + NA | Part 1: JNJ-73763989 + Nucleos(t)Ide Analog (NA) | Part 2: Placebo + NA | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 24 Participants | 17 Participants | 6 Participants | 52 Participants |
| Age, Continuous | 44.2 years STANDARD_DEVIATION 11.88 | 43.8 years STANDARD_DEVIATION 9.49 | 40.9 years STANDARD_DEVIATION 10.44 | 44.8 years STANDARD_DEVIATION 11.96 | 43 years STANDARD_DEVIATION 10.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 24 Participants | 15 Participants | 6 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 20 Participants | 13 Participants | 4 Participants | 41 Participants |
| Region of Enrollment FRANCE | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment GERMANY | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment ITALY | 0 Participants | 8 Participants | 0 Participants | 2 Participants | 10 Participants |
| Region of Enrollment NEW ZEALAND | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 6 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment SPAIN | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Region of Enrollment SWEDEN | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment TAIWAN | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment TURKEY | 4 Participants | 8 Participants | 2 Participants | 1 Participants | 15 Participants |
| Region of Enrollment UNITED KINGDOM | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Region of Enrollment UNITED STATES | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 8 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 15 Participants | 9 Participants | 3 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 5 | 0 / 24 | 0 / 6 | 0 / 5 | 0 / 4 | 0 / 14 | 0 / 5 | 0 / 16 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 17 / 17 | 3 / 5 | 20 / 24 | 5 / 6 | 4 / 5 | 4 / 4 | 2 / 14 | 2 / 5 | 11 / 16 | 3 / 3 | 4 / 6 |
| serious Total, serious adverse events | 2 / 17 | 0 / 5 | 3 / 24 | 0 / 6 | 0 / 5 | 1 / 4 | 0 / 14 | 0 / 5 | 1 / 16 | 0 / 3 | 0 / 6 |
Outcome results
Primary
Double-blind: Part 1: Percentage of Participants With HDV Ribonucleic Acid (RNA) >=2 log10 IU/mL Decline From Baseline or HDV RNA Target Not Detected (TND) in Combination With Normal Alanine Aminotransferase (ALT) at Week 48 (Multiple Imputation Approach)
Percentage of participants with HDV RNA greater than or equal to (\>=) 2 log10 International Units Per Milliliter (IU/mL) decline from baseline or HDV RNA TND in combination with normal ALT at Week 48 using multiple imputation approach was reported. Target not detected (TND) was defined as no traces of HBV RNA were detected/found. Normal ALT was defined as ALT less than (\<) upper limit of normal (ULN) with ULN = 34 units per liter (U/L) for female and 43 U/L for male. The baseline assessment was defined as the last observed non-missing measurement before the date and time of the first administration of any of study intervention on Day 1. The multiple imputation approach was derived using a longitudinal multiple regression model to impute missing data.
Time frame: At Week 48
Population: Intent-to-Treat analysis set (ITT) included all participants who were randomly assigned to an intervention arm and who received at least 1 dose of study intervention. Participants were analyzed according to the study intervention they were randomly assigned to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: JNJ-73763989 + Nucleos(t)Ide Analog (NA) | Double-blind: Part 1: Percentage of Participants With HDV Ribonucleic Acid (RNA) >=2 log10 IU/mL Decline From Baseline or HDV RNA Target Not Detected (TND) in Combination With Normal Alanine Aminotransferase (ALT) at Week 48 (Multiple Imputation Approach) | 23.5 Percentage of Participants |
| Part 1: Placebo + NA | Double-blind: Part 1: Percentage of Participants With HDV Ribonucleic Acid (RNA) >=2 log10 IU/mL Decline From Baseline or HDV RNA Target Not Detected (TND) in Combination With Normal Alanine Aminotransferase (ALT) at Week 48 (Multiple Imputation Approach) | 0.0 Percentage of Participants |
Comparison: Stratum-adjusted Mantel-Haenszel (MH) test was used to assess the difference of percentage based on stratification factor: HBeAg status at screening (positive vs negative).p-value: 0.01195% CI: [3.52, 43.96]Mantel-Haenszel
Primary
Double-blind: Part 2: Percentage of Participants With HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination With ALT at Week 48 (Multiple Imputation Approach)
Percentage of participants with HDV RNA \>=2 log10 IU/mL decline from baseline or HDV RNA TND in combination with normal ALT at Week 48 using multiple imputation approach was reported. TND was defined as no traces of HBV RNA were detected/found. Normal ALT was defined as ALT \<ULN with ULN = 34 U/L for female and 43 U/L for male. The baseline assessment was defined as the last observed non-missing measurement before the date and time of the first administration of any of study intervention on Day 1. The multiple imputation approach was derived using a longitudinal multiple regression model to impute missing data.
Time frame: At Week 48
Population: ITT analysis set included all participants who were randomly assigned to an intervention arm and who received at least 1 dose of study intervention. Participants were analyzed according to the study intervention they were randomly assigned to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: JNJ-73763989 + Nucleos(t)Ide Analog (NA) | Double-blind: Part 2: Percentage of Participants With HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination With ALT at Week 48 (Multiple Imputation Approach) | 27.1 Percentage of Participants |
| Part 1: Placebo + NA | Double-blind: Part 2: Percentage of Participants With HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination With ALT at Week 48 (Multiple Imputation Approach) | 0.0 Percentage of Participants |
Comparison: Stratum-adjusted MH test was used to assess the difference of percentage based on stratification factor: HBeAg status at screening (positive vs negative).p-value: 0.00395% CI: [7.38, 46.21]Mantel-Haenszel