Hepatitis B
Conditions
Keywords
Hepatitis B, HBsAg, Ledipasvir/Sofosbuvir, Hepatitis B treatment
Brief summary
The goals of therapy against chronic hepatitis B are to decrease the morbidity and mortality related to chronic HBV infection. Currently available antiviral therapy can suppress viral replication but only a small proportion attain functional cure, which is defined as HBV surface antigen-to-antibody seroconversion. Hepatitis B surface antigen (HBsAg) is a marker of persistent hepatitis B infection. It has been observed that patients who had both hepatitis B and hepatitis C, and who were treated for their hepatitis C with 12 weeks of ledipasvir/sofosbuvir for had a decline in HBsAg levels. This study hypothesizes that a similar decrease would be seen in mono-infected hepatitis B subjects over the course of 12 weeks treatment with ledipasvir/sofosbuvir.
Interventions
DRUGLedipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet [Harvoni]
1 pill once daily for 12 weeks for Group A
DRUGSofosbuvir 400 MG [Sovaldi]
1 pill once daily for 12 weeks for Group C
DRUGLedipasvir 90 MG
1 pill once daily for 12 weeks for Group D
Sponsors
Gilead Sciences
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Ten potential subjects for Groups C and D will be randomized in a 1:1 fashion.
Intervention model description
Open-label Study, multi-arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants in Groups A, C & D (Chronic HBV, low replicative state not requiring treatment): 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18 or older at screening 4. Diagnosed with chronic hepatitis B infection defined as one of the following: 1. HBsAg or HBV DNA positivity for at least 6 months 2. Medical records indicating a chronic HBV infection 5. HBeAg negative at screening 6. HBV DNA \> lower level of quantitation (LLOQ) 7. Quantitative HBsAg at least 10 IU/mL at screening 8. Ability to take oral medication and be willing to adhere to the twelve week study drug regimen 9. For females of reproductive potential: usual practice of complete abstinence from sexual intercourse with a member of the opposite sex OR use of at least one form of highly effective contraception for at least 1 month prior to enrollment and agreement to use such a method during study participation and for an additional 30 days after the end of study drug administration 10. For males of reproductive potential: usual practice of complete abstinence from sexual intercourse with a member of the opposite sex OR use of at least one form of highly effective contraception for at least 1 month prior to enrollment and agreement to use such a method during study participation and for an additional 14 days after the end of study drug administration 11. Ability to communicate effectively with the study investigator and key staff 12. Medical management provided by a primary care provider 13. Ability to store medications at a room temperature of less than 86 degrees Fahrenheit 14. Not on antiviral therapy or requiring treatment for HBV during screening Participants in Group B (Chronic HBV, virally suppressed): 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18 or older at screening 4. Diagnosed with chronic hepatitis B infection defined as one of the following: 1. HBsAg or HBV DNA positivity for at least 6 months 2. Medical records indicating a chronic HBV infection 5. Receiving oral anti-HBV medications (either tenofovir alafenamide, tenofovir disoproxil fumarate, entecavir, or a combination of no more than 2 of these agents) for at least three months prior to enrollment 6. HBV DNA ˂ lower level of quantitation (LLOQ) at screening and for at least three months prior 7. Quantitative HBsAg at least 10 IU/mL at screening 8. Ability to take oral medication and be willing to adhere to the twelve week study drug regimen 9. For females of reproductive potential: usual practice of complete abstinence from sexual intercourse with a member of the opposite sex OR use of at least one form of highly effective contraception for at least 1 month prior to enrollment and agreement to use such a method during study participation and for an additional 30 days after the end of study drug administration 10. For males of reproductive potential: usual practice of complete abstinence from sexual intercourse with a member of the opposite sex OR use of at least one form of highly effective contraception for at least 1 month prior to enrollment and agreement to use such a method during study participation and for an additional 14 days after the end of study drug administration 11. Ability to communicate effectively with the study investigator and key staff 12. Medical management provided by a primary care provider 13. Ability to store medications at a room temperature of less than 86 degrees Fahrenheit
Exclusion criteria
1. Coinfection with hepatitis C, hepatitis D or human immunodeficiency virus (HIV) 2. Pregnancy or lactation 3. Known allergic reactions to sofosbuvir or ledipasvir 4. Treatment with another investigational drug or other intervention within three months 5. Evidence of cirrhosis or hepatic decompensation such as: * Platelets less than 100,000 /mm3 * Albumin less than 3.5 g/dL * INR greater than 1.7 or Prothrombin time of 1.5 times the upper limit of normal (ULN) * Total bilirubin of 1.5 times the upper limit of normal * FibroTest (or FibroSure®) of 0.75 or greater 6. Abnormal hematological and biochemical parameters at screening including: * White blood cell count less than 2500 cells/uL * Absolute neutrophil count (ANC) less than 1,000 cells/mm3 (less than 750 mm3 for African or African-American subjects) * Hemoglobin less than 12 g/dL for males, less than 11 g/dL for females * AST or ALT of two times the upper limit of normal * Estimated GFR less than 50 mL/min * Glycosylated hemoglobin (HbA1c) greater than 8.5% 7. Current or prior history of any of the following: * Immunodeficiency disorders or autoimmune disease (e.g. Systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel diseases, sarcoidosis, psoriasis of greater than mild severity) * Severe pulmonary disorders, significant cardiac diseases * Gastrointestinal disorder with post-operative condition that could interfere with the absorption of the study drugs * Significant psychiatric illness that in the judgment of the Investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent * Any malignancy diagnosed within 5 years (not including recent localized treatment of squamous or non-invasive basal cell skin cancer; cervical carcinoma in situ appropriately treated prior to screening) * Solid organ transplantation * Poor venous access 8. Screening ECG with clinically significant findings 9. Evidence of HCC (e.g., α fetoprotein \> 50ng/mL or radiologic evidence) 10. Clinically significant illicit drug or alcohol abuse within 12 months of screening. Subjects on methadone maintenance treatment or prescribed opioid may be included. 11. Use of amiodarone within 90 days of enrollment; or carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, rifapentine, St. John's wort, rosuvastatin, or interferon within 30 days of enrollment or expected use of these prohibited drugs during study participation. Use of or expected need of proton-pump inhibitors more than 20 mg omeprazole equivalent or H2 receptor antagonist more than 40 mg famotidine BID equivalent within 7 days of enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment. | 12 weeks | Subjects with chronic hepatitis B will be give 12 weeks of ledipasvir and/or sofosbuvir and their HBsAg will be measured at baseline, on each visits during therapy, and at end of therapy (week 12). The change (decline) in HBsAg from baseline to end of the 12 week treatment will be compared. |
| Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection. | 12 Weeks | Number of subjects who discontinued study drug due to adverse event |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection. | 12 weeks | Subjects with chronic hepatitis B will be give 12 weeks of ledipasvir and/or sofosbuvir and their serum hepatitis B DNA levels (HBV DNA) will be measured at baseline, on each visits during therapy, and at end of therapy (week 12). The change in HBV DNA levels from baseline to end of the 12 week treatment will be compared. Note: Group B (virally suppressed HBV subjects) - all had HBV DNA below the limit of detection; Hence, mean change was 0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A (LDV/SOF for Low Replicative HBV) 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B in low replicative state.
Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet \[Harvoni\]: 1 pill once daily for 12 weeks for Group A | 8 |
| Group B (LDV/SOF for Viral Suppressed HBV) 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B, virally suppressed.
Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet \[Harvoni\]: 1 pill once daily for 12 weeks for Group A | 5 |
| Group C (SOF for Low Replicative HBV) 12 weeks treatment with sofosbuvir (Sovaldi) for chronic hepatitis B in low replicative state.
Randomized 1:1 with Group D.
Sofosbuvir 400 MG \[Sovaldi\]: 1 pill once daily for 12 weeks for Group C | 4 |
| Group D (LDV for Low Replicative HBV) 12 weeks treatment with ledipasvir for chronic hepatitis B in low replicative state.
Randomized 1:1 with Group C.
Ledipasvir 90 MG: 1 pill once daily for 12 weeks for Group D | 4 |
| Total | 21 |
Baseline characteristics
| Characteristic | Group A (LDV/SOF for Low Replicative HBV) | Group B (LDV/SOF for Viral Suppressed HBV) | Group C (SOF for Low Replicative HBV) | Group D (LDV for Low Replicative HBV) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.3 years | 57.6 years | 43.5 years | 52.3 years | 50.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 5 Participants | 4 Participants | 4 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Negative eAg | 8 Participants | 5 Participants | 4 Participants | 4 Participants | 21 Participants |
| Normal ALT | 8 Participants | 5 Participants | 3 Participants | 4 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 12 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 8 participants | 5 participants | 4 participants | 4 participants | 21 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 2 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 5 | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 7 / 8 | 2 / 5 | 4 / 4 | 1 / 4 |
| serious Total, serious adverse events | 0 / 8 | 0 / 5 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment.
Subjects with chronic hepatitis B will be give 12 weeks of ledipasvir and/or sofosbuvir and their HBsAg will be measured at baseline, on each visits during therapy, and at end of therapy (week 12). The change (decline) in HBsAg from baseline to end of the 12 week treatment will be compared.
Time frame: 12 weeks
Population: Intention to treat population - all subjects who have received at least one study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (LDV/SOF for Low Replicative HBV) | Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment. | 0.39 Log10 IU/mL | Standard Deviation 0.2 |
| Group B (LDV/SOF for Viral Suppressed HBV) | Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment. | 0.40 Log10 IU/mL | Standard Deviation 0.3 |
| Group C (SOF for Low Replicative HBV) | Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment. | 0.19 Log10 IU/mL | Standard Deviation 0.3 |
| Group D (LDV for Low Replicative HBV) | Change of Serum Hepatitis B Surface Antigen (HBsAg as Measured in log10 IU/mL) Level as an Indicator of Antiviral Activity of Ledipasvir and/or Sofosbuvir in Subjects With Chronic Hepatitis B From Baseline to End of 12 Weeks Treatment. | -0.05 Log10 IU/mL | Standard Deviation 0.1 |
Primary
Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection.
Number of subjects who discontinued study drug due to adverse event
Time frame: 12 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (LDV/SOF for Low Replicative HBV) | Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection. | 0 Participants |
| Group B (LDV/SOF for Viral Suppressed HBV) | Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection. | 0 Participants |
| Group C (SOF for Low Replicative HBV) | Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection. | 0 Participants |
| Group D (LDV for Low Replicative HBV) | Incidence of Adverse Events Leading to Permanent Discontinuation of Ledipasvir and/or Sofosbuvir Treatment in Subjects With Chronic Hepatitis B Infection. | 0 Participants |
Secondary
Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection.
Subjects with chronic hepatitis B will be give 12 weeks of ledipasvir and/or sofosbuvir and their serum hepatitis B DNA levels (HBV DNA) will be measured at baseline, on each visits during therapy, and at end of therapy (week 12). The change in HBV DNA levels from baseline to end of the 12 week treatment will be compared. Note: Group B (virally suppressed HBV subjects) - all had HBV DNA below the limit of detection; Hence, mean change was 0.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (LDV/SOF for Low Replicative HBV) | Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection. | 0.51 Log10 IU/mL | Standard Deviation 0.6 |
| Group B (LDV/SOF for Viral Suppressed HBV) | Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection. | 0 Log10 IU/mL | Standard Deviation 0 |
| Group C (SOF for Low Replicative HBV) | Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection. | 0.68 Log10 IU/mL | Standard Deviation 0.4 |
| Group D (LDV for Low Replicative HBV) | Changes in Serum Hepatitis B Virus DNA Levels (HBV DNA as Measured in IU/mL) With Treatment of Ledipasvir and/or Sofosbuvir From Baseline to End of 12 Weeks of Treatment in Subjects With Chronic Hepatitis B Infection. | 0.21 Log10 IU/mL | Standard Deviation 0.8 |