Ledipasvir/Sofosbuvir for Hepatitis B Virus Infection (APOSTLE)

A Phase II Open-Label Study of Ledipasvir/Sofosbuvir for 12 Weeks in Subjects With Hepatitis B Virus Infection

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis B
• Intervention / Treatment: Drug: Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet [Harvoni]; Drug: Sofosbuvir 400 MG [Sovaldi]; Drug: Ledipasvir 90 MG

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Institute of Human Virology (IHV), University of Maryland Baltimore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group A (LDV/SOF for low replicative HBV); 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B in low replicative state.	Drug: Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet [Harvoni]; 1 pill once daily for 12 weeks for Group A; Other Names: Harvoni
EXPERIMENTAL: Group B (LDV/SOF for viral suppressed HBV); 12 week treatment with ledipasvir/sofosbuvir (Harvoni) for chronic hepatitis B, virally suppressed.	Drug: Ledipasvir 90 MG / Sofosbuvir 400 MG Oral Tablet [Harvoni]; 1 pill once daily for 12 weeks for Group A; Other Names: Harvoni
EXPERIMENTAL: 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.	Drug: Sofosbuvir 400 MG [Sovaldi]; 1 pill once daily for 12 weeks for Group C; Other Names: GS-7977
EXPERIMENTAL: 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.	Drug: Ledipasvir 90 MG; 1 pill once daily for 12 weeks for Group D; Other Names: GS-5885

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks
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	12 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: Gilead Sciences
• Investigators: Principal Investigator: Joel V Chua, MD, University of Maryland, College Park

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2018
• Primary Completion (ACTUAL): August 10, 2020
• Study Completion (ACTUAL): June 30, 2021

Study Registration Dates

• First Submitted: September 29, 2017
• First Submitted That Met QC Criteria: October 11, 2017
• First Posted (ACTUAL): October 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 20, 2021
• Last Update Submitted That Met QC Criteria: August 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Hepatitis B; HBsAg; Ledipasvir/Sofosbuvir; Hepatitis B treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Virus Diseases; Herpesviridae Infections; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir
• Other Study ID Numbers: HP-00074723

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No