Hepatitis C, Chronic
Conditions
Keywords
Hepatitis C, Chronic, Recurrent Chronic Hepatitis C, Pharmacokinetics, Simeprevir, Daclatasvir, Ribavirin, Orthotopic Liver Transplantation, TMC435, BMS-790052, RBV
Brief summary
The purpose of the study is to evaluate effect of steady-state (when the amount of drug administered (in a given time period is equal to the amount of drug eliminated in that same period) of simeprevir and daclatasvir on the steady-state pharmacokinetics (what a medication does to the body) of cyclosporine (applicable to Part 1 only) and tacrolimus when administered as a combinational regimen in post-orthotopic liver transplantation (OLT) participants with recurrent hepatitis C virus (HCV) genotype 1b infection and effectiveness of a 24-week treatment regimen containing simeprevir, daclatasvir, and ribavirin (RBV) with respect to the proportion of HCV genotype 1b infected post-OLT participants achieving sustained virologic response 12 weeks after end of treatment.
Detailed description
This is an open-label (all participants of this study know the identity of the intervention) and multicenter (study conducted at multiple sites) study. This study will be conducted in 2 parts. Both the parts of the study will consist of screening phase (4 weeks), treatment period (24 weeks), and a post-treatment follow-up (24 weeks). A total of 30 participants will be enrolled in Part 1 and Part 2 of the study. A minimum of 9 participants were planned to receive cyclosporine as stable immunosuppressant therapy and a minimum of 9 participants were planned to receive tacrolimus as stable immunosuppressant therapy during Part 1. All participants will be receiving tacrolimus as stable immunosuppressant therapy during Part 2. In Part 1 of the study, participants with Metavir score of F1-F2, will receive a combination of study drugs - simeprevir, daclatasvir, and ribavirin for 24 weeks. In Part 2 of the study, participants with Metavir score F1-F4 will receive a dosing regimen of study drugs based on the data from Part 1 of the study. Safety evaluations will include assessments of adverse events, clinical laboratory tests, urinalysis, electrocardiogram, vital signs, and physical examination. The total study duration for each participant will be approximately 52 weeks.
Interventions
DRUGSimeprevir
Participants will receive 150 milligram capsule of simeprevir orally (by mouth) once daily with food for 24 weeks. In Part 1, if simeprevir pre-dose plasma concentration is greater than 7,300 nanogram per milliliter (ng/mL), participants will receive simeprevir 150 milligram capsule orally every other day to complete 24 weeks of treatment.
DRUGDaclatasvir
Participants will receive 60 milligram tablet of daclatasvir orally once daily for 24 weeks.
DRUGRibavirin
Participants will receive 5 or 6 tablets of 200 milligram of ribavirin orally twice a day with food for 24 weeks.
DRUGCyclosporine
Participants will receive cyclosporine as one of the stable immunosuppressant therapy (no change in dose in the last month) for more than 3 months prior to the screening visit. Cyclosporine will be administered as per the manufacturer's prescribing information for 24 weeks.
DRUGTacrolimus
Participants will receive tacrolimus as one of the stable immunosuppressant therapy (no change in dose in the last month) for more than 3 months prior to the screening visit. Tacrolimus will be administered as per the manufacturer's prescribing information for 24 weeks.
Sponsors
Janssen R&D Ireland
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Liver transplant between 6 months and 10 years prior to the screening visit * Hepatitis C virus (HCV) genotype 1 subtype b infection confirmed at screening * Screening HCV ribonucleic acid level greater than 10,000 IU/mL * HCV treatment-naïve participants must not have received post orthotopic liver transplant treatment with any approved or investigational drug for the treatment of HCV * Receiving stable immunosuppressant therapy (ie, no change in dose in the last month) with cyclosporine (only allowed in Part 1) or tacrolimus for more than 3 months prior to the screening visit
Exclusion criteria
* Evidence of acute or chronic hepatic decompensation after the liver transplantation (including ascites, bleeding varices or hepatic encephalopathy) * Any liver disease of non-HCV etiology, including current evidence of graft rejection except the presence of liver steatosis * Any other clinically significant disease that in the opinion of the investigator would be exacerbated by the known effects of ribavirin * Coinfection with HCV of another genotype than genotype 1b, HIV type 1 or 2 (positive HIV-1 or HIV-2 antibodies test at screening), and hepatitis B virus (hepatitis B surface antigen positive) * Multi-organ transplant that included heart, lung, pancreas, or kidney
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12) | Week 36 | Participants were considered to have achieved SVR12 if hepatitis C virus ribonucleic acid (HCV RNA) levels were less than (\<) 25 international unit per milliliter (IU/mL) detectable or undetectable at 12 weeks after the end of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24) | Week 48 | Participants were considered to have achieved SVR 24 if hepatitis C virus ribonucleic acid (HCV RNA) levels were (\<) 25 IU/mL detectable or undetectable at 24 weeks after the end of treatment. |
| Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Weeks 2, 4, 12, and 24 | Percentage of participants with detectable and undetectable HCV RNA (\<) 25 IU/mL during treatment at Weeks 2,4, 12, and 24 were reported. |
| Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4 | Week 4 | Percentage of participants with HCV RNA (\<) 100 IU/mL at week 4 were reported. |
| Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4) | Week 28 | Participants were considered to have achieved SVR4 if HCV RNA levels were (\<) 25 IU/mL detectable or undetectable at 4 weeks after the end of treatment. |
| Number of Participants With Viral Breakthrough | Up to week 24 | Viral breakthrough is defined as a confirmed increase of \>1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of \>100 IU/mL in participants whose HCV RNA levels had previously been below the limit of quantification (\<25 IU/mL detectable) or undetectable (\<25 IU/mL undetectable) while on study treatment. |
| Number of Participants With Viral Relapse | Up to Week 24 after actual EOT (week 24) | Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (\>=) LLOQ during follow-up. |
| Number of Participants With On-Treatment Failure | Up to Week 24 after actual EOT (week 24) | On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (\>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of \>100 IU/mL in participants whose HCV RNA had previously been \<lower limit of quantification (LLOQ) while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to adverse events (AEs), withdrawal of consent). |
Countries
Germany, Poland, Spain
Participant flow
Pre-assignment details
The study was conducted in 2 parts (part 1 and part 2) to sequentially enroll the participants. All analyses were conducted on the overall study population (part 1 and part 2 combined).
Participants by arm
| Arm | Count |
|---|---|
| Cyclosporine Participants received simeprevir (SMV) 150 milligram (mg) once daily (qd) or once every other day (qod) as applicable with food and daclatasvir (DCV) 60 mg qd with food and ribavirin (RBV) 1000 or 1200 milligram per day (mg/day) twice daily (bid) with food for 24 Weeks along with cyclosporine as immunosuppressant therapy for more than 3 months prior to the screening visit. | 10 |
| Tacrolimus Participants received SMV 150 mg qd or qod as applicable with food and DCV 60 mg qd with food and RBV 1000 or 1200 mg/day bid with food for 24 Weeks along with tacrolimus as immunosuppressant therapy for more than 3 months prior to the screening visit. | 25 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cyclosporine | Tacrolimus | Total |
|---|---|---|---|
| Age, Continuous | 64.5 years | 61 years | 62 years |
| Region of Enrollment Germany | 1 Participants | 6 Participants | 7 Participants |
| Region of Enrollment Italy | 6 Participants | 3 Participants | 9 Participants |
| Region of Enrollment Poland | 0 Participants | 7 Participants | 7 Participants |
| Region of Enrollment Spain | 3 Participants | 9 Participants | 12 Participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 16 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 23 / 25 |
| serious Total, serious adverse events | 4 / 10 | 4 / 25 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12)
Participants were considered to have achieved SVR12 if hepatitis C virus ribonucleic acid (HCV RNA) levels were less than (\<) 25 international unit per milliliter (IU/mL) detectable or undetectable at 12 weeks after the end of treatment.
Time frame: Week 36
Population: Intent to treat (ITT) analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12) | 100 percentage of participants |
| Tacrolimus | Percentage of Participants With Sustained Virologic Response 12 Weeks After the End of Treatment (SVR 12) | 88 percentage of participants |
Secondary
Number of Participants With On-Treatment Failure
On-treatment failure is defined as participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. This was to include participants with: 1) Viral breakthrough, defined as a confirmed increase of greater than (\>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA of \>100 IU/mL in participants whose HCV RNA had previously been \<lower limit of quantification (LLOQ) while on treatment; 2) Other with confirmed detectable HCV RNA at the actual end of treatment (example, completed, discontinued due to adverse events (AEs), withdrawal of consent).
Time frame: Up to Week 24 after actual EOT (week 24)
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Number of Participants With On-Treatment Failure | 0 participants |
| Tacrolimus | Number of Participants With On-Treatment Failure | 3 participants |
Secondary
Number of Participants With Viral Breakthrough
Viral breakthrough is defined as a confirmed increase of \>1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of \>100 IU/mL in participants whose HCV RNA levels had previously been below the limit of quantification (\<25 IU/mL detectable) or undetectable (\<25 IU/mL undetectable) while on study treatment.
Time frame: Up to week 24
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Number of Participants With Viral Breakthrough | 0 participants |
| Tacrolimus | Number of Participants With Viral Breakthrough | 3 participants |
Secondary
Number of Participants With Viral Relapse
Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (\>=) LLOQ during follow-up.
Time frame: Up to Week 24 after actual EOT (week 24)
Population: Intent to treat (ITT) analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Number of Participants With Viral Relapse | 0 participants |
| Tacrolimus | Number of Participants With Viral Relapse | 0 participants |
Secondary
Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4
Percentage of participants with HCV RNA (\<) 100 IU/mL at week 4 were reported.
Time frame: Week 4
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4 | 100 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (<) 100 IU/mL at Week 4 | 100 percentage of participants |
Secondary
Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable
Percentage of participants with detectable and undetectable HCV RNA (\<) 25 IU/mL during treatment at Weeks 2,4, 12, and 24 were reported.
Time frame: Weeks 2, 4, 12, and 24
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 12: <25 IU/mL detectable | 0 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 4: <25 IU/mL detectable | 30 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 12: <25 IU/mL undetectable | 100 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 2: <25 IU/mL detectable | 30 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 24: <25 IU/mL detectable | 0 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 4: <25 IU/mL undetectable | 70 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 24: <25 IU/mL undetectable | 100 percentage of participants |
| Cyclosporine | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 2: <25 IU/mL undetectable | 10 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 24: <25 IU/mL undetectable | 100 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 2: <25 IU/mL detectable | 36 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 4: <25 IU/mL detectable | 24 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 4: <25 IU/mL undetectable | 68 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 12: <25 IU/mL detectable | 0 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 12: <25 IU/mL undetectable | 96 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 24: <25 IU/mL detectable | 0 percentage of participants |
| Tacrolimus | Percentage of Participants With HCV RNA (< 25 IU/mL Undetectable) and HCV RNA < 25 IU/mL Detectable | Week 2: <25 IU/mL undetectable | 12 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24)
Participants were considered to have achieved SVR 24 if hepatitis C virus ribonucleic acid (HCV RNA) levels were (\<) 25 IU/mL detectable or undetectable at 24 weeks after the end of treatment.
Time frame: Week 48
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24) | 100 percentage of participants |
| Tacrolimus | Percentage of Participants With Sustained Virologic Response 24 Weeks After the End of Treatment (SVR 24) | 88 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4)
Participants were considered to have achieved SVR4 if HCV RNA levels were (\<) 25 IU/mL detectable or undetectable at 4 weeks after the end of treatment.
Time frame: Week 28
Population: ITT analysis set included all enrolled participants who took at least 1 dose of investigational medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine | Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4) | 100 percentage of participants |
| Tacrolimus | Percentage of Participants With Sustained Virologic Response 4 Weeks After the End of Treatment (SVR 4) | 88 percentage of participants |