Hepatitis C
Conditions
Keywords
Direct Acting Antiviral, Liver, Hepatitis C, HCV
Brief summary
Background: \- GS-7977 is a new drug that is being developed to treat hepatitis C infection. It works by blocking the hepatitis C virus from dividing in the body. This medication has been used along with other medications commonly used to treat hepatitis C, such as interferon and ribavirin. When used with interferon and ribavirin, GS-7977 seems to be very effective in eliminating the hepatitis C virus from the body. However, interferon can have serious side effects, so researchers want to see if GS-7977 can work by itself or with only ribavirin. Objectives: \- To test the safety and effectiveness of GS-7977 alone or given with ribavirin for hepatitis C infection. Eligibility: \- Individuals at least 18 years of age who have hepatitis C with liver disease, and have never received drugs for it. Design: * This study will require multiple clinic visits over 18 months. A liver biopsy will be required before the start of the study if participants have not had one within the past 3 years. * Participants will be screened with a medical history and physical exam. * Participants will have either GS-7977 alone or GS-7977 with ribavirin. GS-7977 is taken by mouth once a day. Ribavirin is taken by mouth in the morning and evening. * Participants will have study visits on Days 1, 3, 5, 7, 10, and 14. These visits will involve regular blood tests and symptom monitoring. * After the second week, participants will have study visits during Weeks 3, 4, 6, 8, 12, 16, and 20. Blood and urine tests will be given to study virus levels in the body, and symptoms will be discussed. * Participants will stop receiving the study drugs at Week 24. * Followup clinic visits with blood tests will take place in Weeks 28, 36, 48, 52, 60, and 72. Another liver biopsy will be performed at 48 weeks. * Some participants may also be part of a smaller study. This study involves frequent blood draws to study drug and virus levels in the blood. The study will require a 36-hour hospital inpatient visit.
Detailed description
Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated 180 million people infected worldwide. In the United States an estimated 4.1 million people are infected and HCV is the principal cause of death from liver disease and leading indication for liver transplantation. A combination of ribavirin (RBV) and pegylated interferon (PegIFN) is the currently recommended therapy for chronic HCV infection and this may achieve viral clearance in 19% to 52% of patients infected with HCV genotype 1 (GT-1) and in 76% -80% of patients infected with HCV genotypes 2 and 3. The standard of care is changing and will soon become an HCV protease inhibitor \[Boceprevir/ Telaprevir in combination with PegIFN and RBV\]. The registration studies for the new protease inhibitors demonstrated increased sustained virologic response (SVR) rates of 60 70%. However, this is still associated with a high incidence of adverse events (AEs) and lower cure rates in several populations. Novel therapies that do not rely on an Interferon backbone will be required to enhance cure rates in various populations. This is a randomized controlled open-label study to assess safety, tolerability and efficacy of GS-7977 (a potent and selective HCV NS5B inhibitor) given at a dose of 400 mg daily in combination with RBV to a total of 60 treatment-na(SqrRoot) ve HCV genotype 1 mono-infected individuals with less than or equal to stage 2 fibrosis. The findings from this study will aid in the understanding of antiviral and host responses to an interferon (IFN) free regimen as well as determine the role of RBV in IFN-free therapies.
Interventions
DRUGGS7977
drug intervention
DRUGRBV
drug intervention
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: 1. Over 18 years of age at screening A female is allowed to enter and participate in the study if she is either of: 1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who: * Has had a hysterectomy or * Has had a bilateral oophorectomy (ovariectomy) or * Is post-menopausal (a demonstration of a total cessation of menses for greater than or equal to 1 year) * Has had a bilateral tubal ligation or fallopian tube inserts 2. Childbearing potential, has a negative serum pregnancy test at Screening, and agrees to acceptable birth control such as any of the following: * Complete abstinence from sexual intercourse from 2 weeks prior to administration of the study drug until completion of the follow-up procedures and at least 6 months after the last dose of RBV * Vasectomized partner * Use of an intrauterine device from 2 weeks prior to administration of study drug until completion of the Follow-up procedures and at least 6 months after the last dose of RBV\< TAB\> * Double contraceptive method (condom or occlusive cap \[diaphragm or cervical/vault caps\]; spermicidal foam/gel/film/cream/suppository; oral, implantable, transdermal, or injectable contraceptives) This is advised on the basis of using RBV, which may have a potential teratogenic effect on the fetus in pregnant women. Furthermore reproductive and developmental toxicity studies have not been conducted with GS-7977. A male is allowed to enter and participate in the study if he either: 1. Is sterile or 2. Agrees to use from 2 weeks prior to administration of the study drug until completion of the follow up procedures and at least 6 months after the last dose of RBV at least 1 of the following approved methods of contraception: * a male condom with spermicide * a sterile sexual partner * use by female sexual partner of an IUD * use by female sexual partner of a female condom with spermicide; an intravaginal system (e.g., NuvaRing ) * use by female sexual partner of a diaphragm with spermicide * use by female sexual partner of a cervical cap with spermicide; or oral, implantable, transdermal, or injectable contraceptives 2. Chronic Genotype 1 infection as documented by at least one measurement of serum HCV RNA greater than or equal to 2,000 IU/mL during screening and at least one of the following: 1. A positive anti-HCV antibody, HCV RNA, or an HCV genotype test at least 12 months prior to baseline (Day 0) visit together with positive HCV RNA test and anti-HCV antibody. or 2. A positive HCV RNA test and anti-HCV antibody test together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of CHC disease, such as the presence of fibrosis). 3. Na(SqrRoot) ve to all HCV antiviral treatment(s), including but not limited to immunomodulatory and nucleoside/tide treatments for chronic HCV infection. 4. Body mass index (BMI) of greater than or equal to 18 kg/m(2). 5. Otherwise healthy as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at Screening. 6. Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 0 visit, with a fibrosis classification of less than or equal to stage 2 fibrosis. If no recent (\< 36 months) liver biopsy is available, a study qualifying biopsy must be performed prior to the baseline (Day 0) visit. 7. Able to effectively communicate with the Investigator and other center personnel. Willing to give written informed consent and comply with the study restrictions and requirements. 8. If opioid-dependent, participants must be participating in a supervised treatment program. 9. Have a primary doctor outside of OP8 and the NIH for medical management. 10. Willingness to allow stored blood or tissue samples to be used in the future for studying liver disease and immune function. 11. Willingness to permit HLA typing to be performed. 12. Subjects with compensated cirrhosis may be included (up to \< 20 percent of subjects randomized). Cirrhosis is defined as any one of the following: 1. Any biopsy (or transient elastography, where locally approved) showing cirrhosis. 2. Where approved by the local regulatory agency, transient elastography during the screening period with a result of \> 12.5 kPa 3. A FibroSURE(r) score of \> 0.75 AND an AST:platelet ratio (APRI) of \> 2 performed during screening. Absence of cirrhosis is defined as one of the following: 1. A liver biopsy performed within 24 calendar months of screening showing absence of cirrhosis 2. Where approved by the local regulatory agency, transient elastography performed within 12 calendar months preceding Day 1 with a result of \< 12.5 kPa 3. A FibroSURE(r) score of \< 0.48 AND APRI of \< 1 performed during screening In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. The FibroSURE can be performed at an outside institution and results obtained and used to determine inclusion and
Exclusion criteria
. No more than 20 percent of the subjects randomized into the study will be cirrhotic.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Adverse Events | 24 weeks | Number of participants with Grade 3-4 Adverse Events During the Study Treatment Period as a measure of safety and tolerability. |
| Sustained Virologic Response | 24 weeks post treatment completion | Sustained virology response at 24 weeks post treatment completion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 (N =10): Participants will be enrolled and will receive GS-7977 QD in combination with RBV for a total of 24 weeks. The study team will perform an interim evaluation of data and safety at the end of 12 weeks of treatment. | 10 |
| Phase 2 Arm A (N =25): 24 weeks of GS-7977 QD in combination with weight based RBV (1000 mg for participants weighing \<75 kg and 1200 mg for participants weighing ≥75kg) | 25 |
| Phase 2 Arm B (N = 25): 24 weeks of GS-7977 QD with low dose RBV (600mg). | 25 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Discontinued | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Phase 1 | Phase 2 Arm A | Phase 2 Arm B | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 25 Participants | 25 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 23 Participants | 25 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 18 Participants | 23 Participants | 50 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 6 Participants | 2 Participants | 9 Participants |
| Region of Enrollment United States | 10 participants | 25 participants | 25 participants | 60 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Male | 4 Participants | 19 Participants | 14 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 10 | 24 / 25 | 21 / 25 |
| serious Total, serious adverse events | 0 / 10 | 0 / 25 | 2 / 25 |
Outcome results
Primary
Participants With Adverse Events
Number of participants with Grade 3-4 Adverse Events During the Study Treatment Period as a measure of safety and tolerability.
Time frame: 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 | Participants With Adverse Events | Discontinuation owing to an adverse event | 0 partipants |
| Phase 1 | Participants With Adverse Events | Any grade 3-4 event | 1 partipants |
| Phase 1 | Participants With Adverse Events | Death | 0 partipants |
| Phase 1 | Participants With Adverse Events | Any Serious Adverse Event | 0 partipants |
| Phase 2 Arm A (Sofosbuvir + Weight Based RBV) | Participants With Adverse Events | Death | 0 partipants |
| Phase 2 Arm A (Sofosbuvir + Weight Based RBV) | Participants With Adverse Events | Discontinuation owing to an adverse event | 0 partipants |
| Phase 2 Arm A (Sofosbuvir + Weight Based RBV) | Participants With Adverse Events | Any Serious Adverse Event | 0 partipants |
| Phase 2 Arm A (Sofosbuvir + Weight Based RBV) | Participants With Adverse Events | Any grade 3-4 event | 1 partipants |
| Phase 2 Arm B (Sofosbuvir + Low-dose RBV) | Participants With Adverse Events | Discontinuation owing to an adverse event | 0 partipants |
| Phase 2 Arm B (Sofosbuvir + Low-dose RBV) | Participants With Adverse Events | Any Serious Adverse Event | 1 partipants |
| Phase 2 Arm B (Sofosbuvir + Low-dose RBV) | Participants With Adverse Events | Death | 0 partipants |
| Phase 2 Arm B (Sofosbuvir + Low-dose RBV) | Participants With Adverse Events | Any grade 3-4 event | 5 partipants |
Primary
Sustained Virologic Response
Sustained virology response at 24 weeks post treatment completion
Time frame: 24 weeks post treatment completion
Population: on protocol analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 | Sustained Virologic Response | 100 percentage of total participants |
| Phase 2 Arm A (Sofosbuvir + Weight Based RBV) | Sustained Virologic Response | 71 percentage of total participants |
| Phase 2 Arm B (Sofosbuvir + Low-dose RBV) | Sustained Virologic Response | 55 percentage of total participants |