Hepatitis C, Chronic
Conditions
Brief summary
The aim of this study is to determine if treatment monitoring schedule for chronic HCV patients treated with glecaprevir (300mg)/pibrentasvir (120mg) can be simplified. Data has shown that direct acting antiviral (DAA) regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease inhibitor and NS5A inhibitor respectively , provides key features for HCV treatment simplification. Eligible participants (naïve pre-cirrhosis chronic HCV patients) will be randomized (1:2) to the standard or simplified monitoring arm and will receive treatment for 8 weeks. One post treatment visit will be conducted 12 weeks after the final dose of study medication to evaluate the proportion of patients with undetectable HCV RNA at this timepoint (SVR12).
Detailed description
The capacity to scale-up interferon-free DAA therapy would be enhanced by simplified treatment monitoring strategies. The next generation DAA regimen of glecaprevir (300mg)/pibrentasvir (120mg), a protease inhibitor and NS5A inhibitor, provides key features for HCV treatment simplification, including on-treatment monitoring: 1) pangenotypic activity with extremely high efficacy (SVR\>95%); 2) no relationship between time to undetectable HCV RNA and SVR; 3) minimal drug-related toxicity; 4) ease of dosing (three pills once daily); and short duration (8 weeks in non-cirrhosis and 12 weeks in cirrhosis for treatment naïve patients). In phase II and III clinical trials in participants without cirrhosis, 8 weeks of glecaprevir (300mg)/pibrentasvir (120mg) has provided intention-to-treat SVR rates of 99.1%, 98%, 97%, and 93.1% in genotype 1, 2, 3, and 4-6 populations, respectively. Current standard on-treatment monitoring in clinical trials involves clinic-based visits every 4 weeks. In the DAA era where treatments are highly tolerable, effective and short duration, this intensive monitoring strategy may no longer be required. A simplified on-treatment monitoring strategy is hypothesised to be non-inferior to the standard clinical trial on treatment monitoring strategy. If successful, a simplified on-treatment monitoring strategy is likely to be highly attractive to patients, clinicians and health care payers. It has the potential to improve the rapid scale up of treatment providing population level benefits in the reduction of global hepatitis C disease burden. This study will be conducted as a Phase IIIb, randomised, controlled, multicentre, international trial. There will be a maximum screening period of 6 weeks prior to Baseline. Eligible patients will be randomised into one of two on-treatment monitoring strategies; standard clinical trial monitoring (4-weekly on-treatment visits) vs simplified monitoring (no on-treatment visits). Randomisation will be 1:2 (standard vs simplified) and all participants will receive treatment with glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks. All participants will attend the clinic for screening and baseline visit. Randomisation will occur at the baseline visit. The two on-treatment monitoring strategies will differ as follows: * Standard monitoring arm participants will have on-treatment clinic visits at weeks 4 and 8 (EoT). * Simplified monitoring arm participants will have no on-treatment clinic visits. Study nurse phone contact will also be made to participants in BOTH arms 1-2 days prior Week 4 and EoT (Week 8) visits to provide standardized reporting of adverse events, concomitant medication and adherence. One post treatment clinic visit will be conducted at SVR12 (week 20) for all participants.
Interventions
DRUGglecaprevir (300mg)/pibrentasvir (120mg)
glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks
Sponsors
Kirby Institute
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
1. Have voluntarily signed the informed consent form. 2. 18 years of age or older. 3. Chronic HCV infection as defined by anti-HCV antibody or HCV RNA detection for greater than 6 months. 4. HCV RNA plasma ≥ 10,000 IU/ml at screening. 5. HCV genotype 1-6. 6. HCV treatment naïve (no prior treatment with an approved or investigation anti-HCV medication). 7. Stage F0-3, based on: hepatic elastography \<12.5 kPa on Fibroscan® or APRI \<1.0. 8. If co-infection with HIV is documented, the subject must meet the following criteria: * ART naïve with CD4 T cell count \>500 cells/mm3; OR * On a stable ART regimen (containing only permissible ART - see protocol section 3.2) for \>8 weeks prior to screening visit, with CD4 T cell count \>200 cells/mm3 and a plasma HIV RNA level below the limit of detection. 9. Negative pregnancy test at screening and baseline (females of childbearing potential only). 10. All fertile females must be using effective contraception during treatment and during the 30 days after treatment end.
Exclusion criteria
1. History of any of the following: 1. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with the participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded. 2. Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage). 3. Solid organ transplant. 4. History of severe, life-threatening or other significant sensitivity to any excipients of the study drugs. 2. Any of the following lab parameters at screening: 1. ALT \> 10 x ULN 2. AST \> 10 x ULN 3. Direct bilirubin \> ULN 4. Platelets \< 90,000/μL (cells/mm3) if Fibroscan® \<12.5 kPa OR \< 150,000/μL (cells/mm3) if Fibroscan® is unavailable and patient is included with APRI \<1 5. Creatinine clearance (CLcr) \< 50 mL/min 6. Haemoglobin \< 12g/dL for males; \<11g/dL for females 7. Albumin \< LLN 8. INR \> 1.5 ULN unless subject has known haemophilia or is stable on an anticoagulant regimen affecting INR 3. Pregnant or breastfeeding female. 4. HBV infection (HBsAg positive). 5. Use of prohibited concomitant medications as described in protocol section 5.2. 6. Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent \> 10 mg/day for \>2 weeks). 7. Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) ≤6 months prior to the first dose of study drug. 8. Any investigational drug ≤6 weeks prior to the first dose of study drug. 9. Ongoing severe psychiatric disease as judged by the treating physician. 10. Positive result of a urine drug screen at the Screening Visit for opiates, barbiturates, amphetamines, cocaine, benzodiazepines, phencyclidine, propoxyphene, or alcohol, with the exception of a positive result (including methadone) associated with documented short-term use or chronic stable use of a prescribed medication in that class. 11. Injecting drug use within the previous six months. 12. Inability or unwillingness to provide informed consent or abide by the requirements of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Undetectable HCV RNA (ITT Population) | 12 weeks post end of treatment (SVR12) | Number of participants with undetectable HCV RNA based on ITT population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment and Study Visits Adherence | 12 weeks post end of treatment (SVR12) | Number adherent to treatment and study visits (on-treatment adherence and early treatment discontinuation). |
| Health-related Quality of Life | Screening and 12 weeks post end of treatment (SVR12) | Change in health-related quality of life score pre and post-treatment (measured by EQ-5D-3L). The EQ visual analogue scale records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'Best imaginable health state' (value of 100) and 'Worst imaginable health state' (value of 0). The VAS can be used as a quantitative measure of health outcome that reflects the patient's own judgement. Higher scores indicate better outcomes. |
| Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | Baseline and 12 weeks post-treatment | Distribution of baseline resistance associated substitutions (RAS) in participants with virological failures. Baseline polymorphisms were detected by Sanger sequencing at the following amino acid positions: NS3: 36, 56, 80, 155, 156, 166, 168 NS5A: 24, 28, 30, 31, 58, 93 |
| Patient Treatment Satisfaction | 12 weeks post end of treatment (SVR12) | Patient was satisfied with their treatment follow-up plan. |
| Undetectable HCV RNA (mITT Population) | 12 weeks post end of treatment (SVR12) | Number of participants with undetectable HCV RNA based on mITT population. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | 12 weeks post end of treatment (SVR12) | Provider acceptability of simplified monitoring strategy measured by study specific questionnaire completed by each site Principal Investigator and the primary Research Nurse. |
| Severe/Life Threatening Adverse Events (Safety Outcome) | 12 weeks post end of treatment (SVR12) | Proportion of patients with at least one severe or potentially life threatening (grade 3 or 4) adverse event. |
| Common Adverse Events (Safety Outcome) | 12 weeks post end of treatment (SVR12) | Proportion of patients with common adverse events (reported in greater than 5%). |
Countries
Australia, Canada, France, Germany, New Zealand, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
From 21 August 2017 to 16 July 2018, participants were screened and enrolled at 33 sites in Australia (n=6), Canada (n=7), France (n=3), Germany (n=4), New Zealand (n=4), Switzerland (n=2), United Kingdom (n=3), and United States (n=4). Study recruitment was in tertiary specialist viral hepatitis clinics (n=30) and primary care clinics (n=3).
Participants by arm
| Arm | Count |
|---|---|
| Standard Monitoring Schedule Participants will have on-treatment clinic visits at weeks 4 and 8. Participants have also phone contact-based visits at weeks 4 and 8 (1-2 days prior to scheduled clinic visits).
Participants receive glecaprevir (300mg)/pibrentasvir (120mg): glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks | 127 |
| Simplified Monitoring Schedule Participants will have no on-treatment clinic visits at weeks 4 and 8. Participants have phone contact-based visits at weeks 4 and 8.
Participants receive glecaprevir (300mg)/pibrentasvir (120mg): glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks | 253 |
| Total | 380 |
Baseline characteristics
| Characteristic | Simplified Monitoring Schedule | Standard Monitoring Schedule | Total |
|---|---|---|---|
| Age, Continuous | 52 Years | 50 Years | 51 Years |
| Fibrosis Stage Mild fibrosis (F2) | 49 Participants | 29 Participants | 78 Participants |
| Fibrosis Stage No or mild fibrosis (F0/F1) | 190 Participants | 93 Participants | 283 Participants |
| Fibrosis Stage Severe fibrosis (F3) | 14 Participants | 5 Participants | 19 Participants |
| Genotype Genotype 1 | 118 Participants | 61 Participants | 179 Participants |
| Genotype Genotype 2 | 35 Participants | 17 Participants | 52 Participants |
| Genotype Genotype 3 | 80 Participants | 41 Participants | 121 Participants |
| Genotype Genotype 4 | 14 Participants | 4 Participants | 18 Participants |
| Genotype Genotype 5 | 0 Participants | 1 Participants | 1 Participants |
| Genotype Genotype 6 | 5 Participants | 3 Participants | 8 Participants |
| Genotype Indeterminate | 1 Participants | 0 Participants | 1 Participants |
| HCV RNA | 6.27 Log10 IU/mL | 6.29 Log10 IU/mL | 6.28 Log10 IU/mL |
| HIV Infection | 14 Participants | 13 Participants | 27 Participants |
| Opioid Substitution Therapy (OST) | 21 Participants | 17 Participants | 38 Participants |
| Race/Ethnicity, Customized Ethnicity Asian | 22 Participants | 12 Participants | 34 Participants |
| Race/Ethnicity, Customized Ethnicity Black | 13 Participants | 7 Participants | 20 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 24 Participants | 11 Participants | 35 Participants |
| Race/Ethnicity, Customized Ethnicity White | 194 Participants | 97 Participants | 291 Participants |
| Region of Enrollment Australia | 30 participants | 15 participants | 45 participants |
| Region of Enrollment Canada | 58 participants | 28 participants | 86 participants |
| Region of Enrollment France | 28 participants | 14 participants | 42 participants |
| Region of Enrollment Germany | 28 participants | 13 participants | 41 participants |
| Region of Enrollment New Zealand | 57 participants | 29 participants | 86 participants |
| Region of Enrollment Switzerland | 15 participants | 8 participants | 23 participants |
| Region of Enrollment United Kingdom | 15 participants | 9 participants | 24 participants |
| Region of Enrollment United States | 22 participants | 11 participants | 33 participants |
| Sex/Gender, Customized Gender Female | 96 Participants | 53 Participants | 149 Participants |
| Sex/Gender, Customized Gender Male | 157 Participants | 72 Participants | 229 Participants |
| Sex/Gender, Customized Gender Transgender | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 127 | 1 / 253 |
| other Total, other adverse events | 81 / 127 | 112 / 253 |
| serious Total, serious adverse events | 0 / 127 | 3 / 253 |
Outcome results
Primary
Undetectable HCV RNA (ITT Population)
Number of participants with undetectable HCV RNA based on ITT population.
Time frame: 12 weeks post end of treatment (SVR12)
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Monitoring Schedule | Undetectable HCV RNA (ITT Population) | 121 Participants |
| Simplified Monitoring Schedule | Undetectable HCV RNA (ITT Population) | 233 Participants |
p-value: <0.0595% CI: [-8.2, 1.8]t-test, 2 sided
Secondary
Health-related Quality of Life
Change in health-related quality of life score pre and post-treatment (measured by EQ-5D-3L). The EQ visual analogue scale records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'Best imaginable health state' (value of 100) and 'Worst imaginable health state' (value of 0). The VAS can be used as a quantitative measure of health outcome that reflects the patient's own judgement. Higher scores indicate better outcomes.
Time frame: Screening and 12 weeks post end of treatment (SVR12)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard Monitoring Schedule | Health-related Quality of Life | Post-treatment week 12 | 85 score on a scale |
| Standard Monitoring Schedule | Health-related Quality of Life | Screening | 80 score on a scale |
| Simplified Monitoring Schedule | Health-related Quality of Life | Post-treatment week 12 | 89 score on a scale |
| Simplified Monitoring Schedule | Health-related Quality of Life | Screening | 80 score on a scale |
Secondary
Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12
Distribution of baseline resistance associated substitutions (RAS) in participants with virological failures. Baseline polymorphisms were detected by Sanger sequencing at the following amino acid positions: NS3: 36, 56, 80, 155, 156, 166, 168 NS5A: 24, 28, 30, 31, 58, 93
Time frame: Baseline and 12 weeks post-treatment
Population: Number of participants in the ITT population with virological failure (detectable HCV RNA)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS3 Variants at Baseline | 0 Participants |
| Standard Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS3 Variants at Failure | 1 Participants |
| Standard Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS5A Variants at Baseline | 0 Participants |
| Standard Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS5A Variants at Failure | 0 Participants |
| Simplified Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS5A Variants at Failure | 5 Participants |
| Simplified Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS3 Variants at Baseline | 1 Participants |
| Simplified Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS5A Variants at Baseline | 3 Participants |
| Simplified Monitoring Schedule | Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12 | NS3 Variants at Failure | 3 Participants |
Secondary
Patient Treatment Satisfaction
Patient was satisfied with their treatment follow-up plan.
Time frame: 12 weeks post end of treatment (SVR12)
Population: ITT population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Monitoring Schedule | Patient Treatment Satisfaction | Strongly Disagree | 1 Participants |
| Standard Monitoring Schedule | Patient Treatment Satisfaction | Disagree | 0 Participants |
| Standard Monitoring Schedule | Patient Treatment Satisfaction | No Opinion | 3 Participants |
| Standard Monitoring Schedule | Patient Treatment Satisfaction | Agree | 29 Participants |
| Standard Monitoring Schedule | Patient Treatment Satisfaction | Strongly Agree | 83 Participants |
| Standard Monitoring Schedule | Patient Treatment Satisfaction | Missing | 11 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | No Opinion | 9 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | Strongly Disagree | 4 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | Missing | 28 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | Strongly Agree | 149 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | Disagree | 2 Participants |
| Simplified Monitoring Schedule | Patient Treatment Satisfaction | Agree | 61 Participants |
Secondary
Treatment and Study Visits Adherence
Number adherent to treatment and study visits (on-treatment adherence and early treatment discontinuation).
Time frame: 12 weeks post end of treatment (SVR12)
Population: ITT
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Monitoring Schedule | Treatment and Study Visits Adherence | >=95% Adherence | 125 Participants |
| Standard Monitoring Schedule | Treatment and Study Visits Adherence | <95% Adherence | 2 Participants |
| Simplified Monitoring Schedule | Treatment and Study Visits Adherence | >=95% Adherence | 241 Participants |
| Simplified Monitoring Schedule | Treatment and Study Visits Adherence | <95% Adherence | 12 Participants |
Secondary
Undetectable HCV RNA (mITT Population)
Number of participants with undetectable HCV RNA based on mITT population.
Time frame: 12 weeks post end of treatment (SVR12)
Population: The mITT population wexcludes patients who have completed treatment (\>95% adherence) (according to phone contact at week 8), but have not returned for their SVR12 assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Monitoring Schedule | Undetectable HCV RNA (mITT Population) | 121 Participants |
| Simplified Monitoring Schedule | Undetectable HCV RNA (mITT Population) | 233 Participants |
Other Pre-specified
Common Adverse Events (Safety Outcome)
Proportion of patients with common adverse events (reported in greater than 5%).
Time frame: 12 weeks post end of treatment (SVR12)
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Monitoring Schedule | Common Adverse Events (Safety Outcome) | Fatigue | 30 participants |
| Standard Monitoring Schedule | Common Adverse Events (Safety Outcome) | Headache | 26 participants |
| Standard Monitoring Schedule | Common Adverse Events (Safety Outcome) | Nausea | 25 participants |
| Simplified Monitoring Schedule | Common Adverse Events (Safety Outcome) | Fatigue | 52 participants |
| Simplified Monitoring Schedule | Common Adverse Events (Safety Outcome) | Headache | 43 participants |
| Simplified Monitoring Schedule | Common Adverse Events (Safety Outcome) | Nausea | 17 participants |
Other Pre-specified
Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome)
Provider acceptability of simplified monitoring strategy measured by study specific questionnaire completed by each site Principal Investigator and the primary Research Nurse.
Time frame: 12 weeks post end of treatment (SVR12)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Prefers Standard Monitoring | 14 Participants |
| Standard Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Prefers Simplified Monitoring | 52 Participants |
| Standard Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Other | 0 Participants |
| Simplified Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Prefers Standard Monitoring | 7 Participants |
| Simplified Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Prefers Simplified Monitoring | 54 Participants |
| Simplified Monitoring Schedule | Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome) | Other | 1 Participants |
Other Pre-specified
Severe/Life Threatening Adverse Events (Safety Outcome)
Proportion of patients with at least one severe or potentially life threatening (grade 3 or 4) adverse event.
Time frame: 12 weeks post end of treatment (SVR12)
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Monitoring Schedule | Severe/Life Threatening Adverse Events (Safety Outcome) | 1 participants |
| Simplified Monitoring Schedule | Severe/Life Threatening Adverse Events (Safety Outcome) | 2 participants |