Hepatitis C, Chronic
Conditions
Keywords
Hepatitis C, Individualised therapy, Response-guided therapy, Telaprevir, PEG-IFN, Ribavirin, Hepatitis
Brief summary
To examine the safety and efficacy of response guided triple therapy (PEG-IFN, Ribavirin, Telaprevir) for the treatment of early chronic Hepatitis C Virus (HCV) infection.
Detailed description
DARE-C is a prospective open label multi-centre pilot study examining the safety and efficacy of response guided triple therapy (PEG-IFN, Ribavirin and Telaprevir) for the treatment of early chronic HCV genotype 1 infection in individuals with and without HIV infection.
Interventions
DRUGTPV/PEG-IFN/RBV
Drug Telaprevir (TPV): dosed 1125mg twice daily (given as three 375 mg film-coated tablets) orally, except in the situation where a patient is on efavirenz in which case the dose of telaprevir will be 1125mg three times daily. Drug Ribavirin (RBV): 1000mg or 1200mg p.o daily in split doses (1000mg for patients weighing \<75kg and 1200mg for patients weighing ≥ 75kg). Drug PEG-IFN (other name: Pegasys): 180mcg in 0.5ml (pre-filled syringes) administered subcutaneously once weekly.
Sponsors
Janssen-Cilag Ltd.
Kirby Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of written, informed consent. 2. HCV genotype 1 infection 3. Quantifiable HCV RNA at screening and baseline (\>10,000 IU/ml) 4. Recent hepatitis C infection with an estimated duration of Infection \>6 months and ≤ 18 months defined as A) i) First anti-HCV antibody or HCV RNA positive within the previous 6 months and ii) Documented anti-HCV antibody negative or HCV RNA negative within the 24 months prior to anti-HCV antibody positive result OR B) i) First anti-HCV antibody or HCV RNA positive within the previous 6 months and ii) acute clinical hepatitis (jaundice or ALT\> 10 X ULN) within the 12 months prior to first positive HCV antibody or HCV RNA with no other cause of acute hepatitis identifiable 5. Compensated liver disease (Child-Pugh A) 6. Negative pregnancy test at screening and 24 hours prior to the first dose of study drugs. 7. If heterosexually active, a female subject of childbearing potential and a nonvasectomized male subject who has a female partner of childbearing potential must agree to use 2 effective contraceptives from screening onwards until 6 months (female subject) or 7 months (male subject) after RBV therapy has ended. Note: Hormonal contraceptives may be continued but may not be reliable during telaprevir dosing and for 2 months following cessation of telaprevir. Therefore, subjects should agree to use 2 effective non-hormonal methods of contraception during telaprevir combination therapy and for 2 months after the last intake of telaprevir. As of two months after completion of telaprevir hormonal contraceptives can again be used as one of the two required effective methods of birth control. 8. Subject is judged to be medically stable on the basis of physical examination, medical history and vital signs. 9. Adequate English to provide written, informed consent and to provide reliable responses to the study interview Additional inclusion criteria for HIV positive individuals * Confirmed HIV infection \> 6 months duration * CD4 \> 200 cells/mm3 and HIV \< 50 c/ml on stable antiretroviral therapy (ART) at least 3 months prior to treatment * Or * CD4 \>= 500 cells/mm3 and HIV viral load (VL) \< 100,000 not on ART * If on ART must be taking a regimen containing an accepted\* combination of the following drugs: tenofovir ( TDF), lamivudine ( 3TC), emtricitabine (FTC), efavirenz (EFV), abacavir (ABC), raltegravir (RAL), etravirine (ETV), rilpivirine (RIL), ritonavir boosted atazanavir (r/ATZ) \* Combination must be supported by current HIV treatment guidelines
Exclusion criteria
* Individuals considered by the study investigators to be unlikely to participate in intensive follow-up and/or unwilling to provide extra blood samples * Current injecting drug use (any injecting within previous 4 weeks) * Standard exclusions to Pegylated-interferon (PEG-IFN), Ribavirin (RBV) and Telaprevir (TPV) therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR12 (Sustain Virological Response, HCV RNA Undetectable 12 Weeks Post-treatment) | 12 weeks post-treatment | Proportion of subjects achieving SVR 12 (negative qualitative HCV RNA 12 weeks after therapy completion) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Undetectable HCV RNA (ETR) | Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | To evaluate the proportion of patients with undetectable HCV RNA at end of treatment (ETR) |
| Undetectable HCV RNA (Week 1) | Week 1 of therapy | To evaluate the proportion of patients with undetectable HCV RNA at week 1 of therapy. |
| Undectectable HCV RNA (Week 2) | Week 2 of therapy | To evaluate the proportion of patients with undetectable HCV RNA at week 1 of therapy. |
| Undetectable HCV RNA (Week 3) | Week 3 of therapy | To evaluate the proportion of patients with undetectable HCV RNA at week 3 of therapy. |
| Undetectable HCV RNA (Week 4) | Week 4 of therapy | To evaluate the proportion of patients with undetectable HCV RNA at week 4 of therapy. |
| Decrease in Absolute Neutrophil Count (ANC) ≤0.75 | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | — |
| SVR24 | 24 weeks post-treatment | To evaluate the proportion of patients with undetectable HCV RNA 24 weeks after therapy completion (SVR24) |
| Change in Hemoglobin at End of Treatment | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | To evaluate indicators of toxicity during telaprevir based therapy |
| Resistance-associated Variants | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | To examine the emergence of resistance-associated variants during telaprevir based therapy for early chronic infection |
| Baseline Resistance-associated Variants | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | To correlate the presence and frequency of baseline resistance-associated variants (RAVs) with the response of Telaprevir based therapy for early chronic HCV infection. |
| Plasma Ribavirin Levels | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | To correlate plasma ribavirin levels with treatment outcome and changes in haemoglobin during therapy |
| CD4 and HIV RNA | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | In HIV positive participants to evaluate changes in CD4 counts and HIV RNA during telaprevir based therapy |
| Gene IL28B Polymorphism | Baseline | To examine treatment outcome by IL28B polymorphism |
| Decrease in Platelets <50 | Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C) | — |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A - 8 Weeks Total Therapy 8 weeks total therapy of TPV/PEG-IFN/RBV if undetectable HCV RNA after 2 weeks of therapy
TPV/PEG-IFN/RBV: Drug Telaprevir (TPV): dosed 1125mg twice daily (given as three 375 mg film-coated tablets) orally, except in the situation where a patient is on efavirenz in which case the dose of telaprevir will be 1125mg three times daily.
Drug Ribavirin (RBV): 1000mg or 1200mg p.o daily in split doses (1000mg for patients weighing \<75kg and 1200mg for patients weighing ≥ 75kg).
Drug PEG-IFN (other name: Pegasys): 180mcg in 0.5ml (pre-filled syringes) administered subcutaneously once weekly. | 7 |
| Group B - 12 Weeks Total Therapy 12 weeks total therapy of TPV/PEG-IFN/RBV if undetectable HCV RNA after 4 weeks of therapy
TPV/PEG-IFN/RBV: Drug Telaprevir (TPV): dosed 1125mg twice daily (given as three 375 mg film-coated tablets) orally, except in the situation where a patient is on efavirenz in which case the dose of telaprevir will be 1125mg three times daily.
Drug Ribavirin (RBV): 1000mg or 1200mg p.o daily in split doses (1000mg for patients weighing \<75kg and 1200mg for patients weighing ≥ 75kg).
Drug PEG-IFN (other name: Pegasys): 180mcg in 0.5ml (pre-filled syringes) administered subcutaneously once weekly. | 3 |
| Group C - 24 Weeks Total Therapy 24 weeks total therapy - TPV/PEG-IFN/RBV for 12 weeks + PEG-IFN/RBV for 12 weeks if undetectable HCV RNA after 8 weeks of therapy
TPV/PEG-IFN/RBV: Drug Telaprevir (TPV): dosed 1125mg twice daily (given as three 375 mg film-coated tablets) orally, except in the situation where a patient is on efavirenz in which case the dose of telaprevir will be 1125mg three times daily.
Drug Ribavirin (RBV): 1000mg or 1200mg p.o daily in split doses (1000mg for patients weighing \<75kg and 1200mg for patients weighing ≥ 75kg).
Drug PEG-IFN (other name: Pegasys): 180mcg in 0.5ml (pre-filled syringes) administered subcutaneously once weekly. | 2 |
| No Group Allocated Early treatment discontinuation or non-responder | 2 |
| Total | 14 |
Baseline characteristics
| Characteristic | Group A - 8 Weeks Total Therapy | Group B - 12 Weeks Total Therapy | Group C - 24 Weeks Total Therapy | No Group Allocated | Total |
|---|---|---|---|---|---|
| Age, Continuous | 49 years | 45 years | 44 years | 57 years | 48 years |
| Estimated Duration of infection at baseline | 39 weeks | 46 weeks | 50 weeks | 33 weeks | 40.9 weeks |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 3 Participants | 2 Participants | 2 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| HIV infection | 5 participants | 2 participants | 2 participants | 2 participants | 11 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 2 Participants | 2 Participants | 14 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 | 7 / 7 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 2 / 7 | 1 / 3 | 0 / 2 |
Outcome results
Primary
SVR12 (Sustain Virological Response, HCV RNA Undetectable 12 Weeks Post-treatment)
Proportion of subjects achieving SVR 12 (negative qualitative HCV RNA 12 weeks after therapy completion)
Time frame: 12 weeks post-treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | SVR12 (Sustain Virological Response, HCV RNA Undetectable 12 Weeks Post-treatment) | 71 percentage of participants |
| Group B - 12 Weeks Total Therapy | SVR12 (Sustain Virological Response, HCV RNA Undetectable 12 Weeks Post-treatment) | 100 percentage of participants |
| Group C - 24 Weeks Total Therapy | SVR12 (Sustain Virological Response, HCV RNA Undetectable 12 Weeks Post-treatment) | 100 percentage of participants |
Secondary
Baseline Resistance-associated Variants
To correlate the presence and frequency of baseline resistance-associated variants (RAVs) with the response of Telaprevir based therapy for early chronic HCV infection.
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
Population: Baseline resistance-associated variants analysis have not yet been performed. These are planned to be performed at a later date.
Secondary
CD4 and HIV RNA
In HIV positive participants to evaluate changes in CD4 counts and HIV RNA during telaprevir based therapy
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
Population: This data will not be analysed.
Secondary
Change in Hemoglobin at End of Treatment
To evaluate indicators of toxicity during telaprevir based therapy
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Change in Hemoglobin at End of Treatment | -31 g/L |
| Group B - 12 Weeks Total Therapy | Change in Hemoglobin at End of Treatment | -53 g/L |
| Group C - 24 Weeks Total Therapy | Change in Hemoglobin at End of Treatment | -17.5 g/L |
Secondary
Decrease in Absolute Neutrophil Count (ANC) ≤0.75
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Decrease in Absolute Neutrophil Count (ANC) ≤0.75 | 1 participants |
| Group B - 12 Weeks Total Therapy | Decrease in Absolute Neutrophil Count (ANC) ≤0.75 | 1 participants |
| Group C - 24 Weeks Total Therapy | Decrease in Absolute Neutrophil Count (ANC) ≤0.75 | 0 participants |
Secondary
Decrease in Platelets <50
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Decrease in Platelets <50 | 0 participants |
| Group B - 12 Weeks Total Therapy | Decrease in Platelets <50 | 0 participants |
| Group C - 24 Weeks Total Therapy | Decrease in Platelets <50 | 0 participants |
Secondary
Gene IL28B Polymorphism
To examine treatment outcome by IL28B polymorphism
Time frame: Baseline
Population: IL28B polymorphisms have not yet been performed. These are planned to be performed at a later date.
Secondary
Plasma Ribavirin Levels
To correlate plasma ribavirin levels with treatment outcome and changes in haemoglobin during therapy
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
Population: Ribavirin concentration have not yet been performed. These are planned to be performed at a later date.
Secondary
Resistance-associated Variants
To examine the emergence of resistance-associated variants during telaprevir based therapy for early chronic infection
Time frame: Baseline, Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
Population: Resistance-associated variants analysis have not yet been performed. These are planned to be performed at a later date.
Secondary
SVR24
To evaluate the proportion of patients with undetectable HCV RNA 24 weeks after therapy completion (SVR24)
Time frame: 24 weeks post-treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | SVR24 | 43 percentage of participants |
| Group B - 12 Weeks Total Therapy | SVR24 | 100 percentage of participants |
| Group C - 24 Weeks Total Therapy | SVR24 | 100 percentage of participants |
Secondary
Undectectable HCV RNA (Week 2)
To evaluate the proportion of patients with undetectable HCV RNA at week 1 of therapy.
Time frame: Week 2 of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Undectectable HCV RNA (Week 2) | 100 percentage of participants |
| Group B - 12 Weeks Total Therapy | Undectectable HCV RNA (Week 2) | 0 percentage of participants |
| Group C - 24 Weeks Total Therapy | Undectectable HCV RNA (Week 2) | 0 percentage of participants |
Secondary
Undetectable HCV RNA (ETR)
To evaluate the proportion of patients with undetectable HCV RNA at end of treatment (ETR)
Time frame: Wk 8 (Group A), Wk 12 (Group B), Wk 24 (Group C)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Undetectable HCV RNA (ETR) | 100 percentage of participants |
| Group B - 12 Weeks Total Therapy | Undetectable HCV RNA (ETR) | 100 percentage of participants |
| Group C - 24 Weeks Total Therapy | Undetectable HCV RNA (ETR) | 100 percentage of participants |
Secondary
Undetectable HCV RNA (Week 1)
To evaluate the proportion of patients with undetectable HCV RNA at week 1 of therapy.
Time frame: Week 1 of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Undetectable HCV RNA (Week 1) | 71.43 percentage of participants |
| Group B - 12 Weeks Total Therapy | Undetectable HCV RNA (Week 1) | 0 percentage of participants |
| Group C - 24 Weeks Total Therapy | Undetectable HCV RNA (Week 1) | 0 percentage of participants |
Secondary
Undetectable HCV RNA (Week 3)
To evaluate the proportion of patients with undetectable HCV RNA at week 3 of therapy.
Time frame: Week 3 of therapy
Population: Missing data carried forward if previously \<LLoQ (lower limit of quantification)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Undetectable HCV RNA (Week 3) | 100 percentage of participants |
| Group B - 12 Weeks Total Therapy | Undetectable HCV RNA (Week 3) | 33.33 percentage of participants |
| Group C - 24 Weeks Total Therapy | Undetectable HCV RNA (Week 3) | 0 percentage of participants |
Secondary
Undetectable HCV RNA (Week 4)
To evaluate the proportion of patients with undetectable HCV RNA at week 4 of therapy.
Time frame: Week 4 of therapy
Population: Missing data carried forward if previously \<LLoQ
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - 8 Weeks Total Therapy | Undetectable HCV RNA (Week 4) | 100 percentage of participants |
| Group B - 12 Weeks Total Therapy | Undetectable HCV RNA (Week 4) | 66.67 percentage of participants |
| Group C - 24 Weeks Total Therapy | Undetectable HCV RNA (Week 4) | 0 percentage of participants |