STRIVE-4: Strategic Treatment Reduction in Very Early Liver Disease With 4 Weeks Sofosbuvir Plus Glecepravir-pibrentasvir
Study Details
Study Description
Brief Summary
This study aims to evaluate the efficacy, safety and feasibility of four weeks of sofosbuvir plus glecaprevir-pibrentasvir, followed by immediate retreatment of virological relapse with glecepravir-pibrentasvir for 12 weeks, in treatment-naïve participants with chronic HCV infection and early liver disease (F0-F2).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
The capacity to eliminate HCV through rapid direct acting antiviral (DAA) therapy scale-up would be enhanced by shortened duration therapy in key populations. The "next generation" DAA regimen of glecaprevir/pibrentasvir (300mg/120mg), an NS3/4a protease inhibitor and NS5A inhibitor, provides key features for potential simplified shortened duration therapy in people with early liver disease (F0-2), including pangenotypic activity, high efficacy, and favourable on-treatment HCV RNA kinetics. The addition of sofosbuvir (400 mg) may provide further feasibility for shortened duration therapy with a potent triple class DAA regimen.
Shortened duration therapy (4-6 weeks) has been evaluated in chronic HCV populations with several DAA regimens, with generally unfavourable outcomes (SVR<50%) for 4 week durations.8-11 In a study among a predominantly African American population of 4 week duration therapy of 3 or 4 DAAs, with sofosbuvir/ledipasvir/GS-9451 (protease inhibitor) and sofosbuvir/ledipasvir/GS-9451/GS-9669 (non-nucleoside polymerase inhibitor), SVR was only 40% (10/25) and 20% (5/25) in the 3 and 4 DAA regimen groups, respectively.10 In separate phase II studies that included evaluation of 6 weeks sofosbuvir (400mg)/velpatasvir (100mg)/voxilaprevir (100 mg) in treatment naïve patients without cirrhosis, SVR was 88% (29/33) among patients with genotype 2, 3, 4, or 6,12 93% (14/15) in patients with genotype 13,13 and and 71% (24/34) in patients with genotype 1.14 Non-published data (provided by Gilead Sciences) from the latter study demonstrates a higher SVR (88%, 14/16) in the sub-population of patients with F0-2. Thus, in patients with relatively early liver disease virological failure is uncommon with 6-week duration sofosbuvir/velpatasvir/voxilaprevir therapy.
These studies would suggest that a 6-week duration therapy, particularly with a potent 3 DAA triple class regimen, may be feasible for many patients with chronic HCV infection, but a 4-week duration would probably compromise treatment outcomes. However, in a small study (n=16) among younger people who inject drugs (PWID) with early liver disease (<50 years, F0-2) in Denmark, a 4-week regimen of sofosbuvir/ledipasvir plus ribavirin provided a per protocol (PP)(n=13) SVR of 92% (one relapse) with intention to treat (ITT) SVR of 75%. In the same study 16 PWID were treated with the same regimen plus pegylated interferon with PP and ITT SVR of 100% and 94%, respectively. Further evidence for the potential of ultra-short duration DAA therapy comes from a response-guided study in Hong Kong. Patients with HCV genotype 1b were treated with three different triple class DAA regimens, including sofosbuvir/ledipasvir + asunaprevir, sofosbuvir + daclatasvir + simeprevir, or sofosbuvir + daclatasvir + asunaprevir, and those with an ultra-rapid virological response (HCV RNA <500 IU/mL at day 2; 18/26) had treatment duration shortened to three weeks. The SVR rate was 100% (18/18) in the three-week treated population.
While efficacy has been suboptimal in most studies of short duration DAA therapy to date, the emergence of clinically significant resistance-associated substitutions (RAS) has not been seen, and retreatment with the same regimen for 12 weeks has been successful.8,9 The FOURward study examined the safety and efficacy of short-duration therapy (4 or 6 weeks) with sofosbuvir + daclatasvir/asunaprevir/beclabuvir in patients with HCV genotype 1 and without cirrhosis.9 Although efficacy was suboptimal (SVR12 43%), among those with virological relapse (n=16), 44% (n=7) had no emergent RAS detected at failure. Furthermore, in the nine patients with treatment-emergent NS5A RAS, the clinical significance was uncertain, as all emergent NS5A RAS conferred low-nanomolar resistance in vitro. Regardless of RAS emergence, retreatment of patients who experienced virological relapse with 12 weeks sofosbuvir + daclatasvir/asunaprevir/beclabuvir + ribavirin resulted in SVR of 100%. C-SWIFT evaluated the efficacy and safety of sofosbuvir + elbasvir/grazoprevir in patients with HCV genotype 1 and without cirrhosis for four and six weeks, with SVR12 rates of 32% (10/31) and 87% (26/30), respectively.8 All patients with virological relapse who received retreatment with 12 weeks of sofosbuvir + elbasvir/grazoprevir + ribavirin achieved SVR12, despite the majority having NS5A and/or NS3 RAS.
The combination of sofosbuvir (400 mg) + glecaprevir/pibrentasvir (300mg/120mg) has not been evaluated as a shortened duration triple class DAA regimen. It has been evaluated as a 12 and 16-week regimen in combination with ribavirin for treatment of prior glecaprevir-pibrentasvir virological failure (8 or 12-week duration prior therapy), with very high efficacy of 96% (22/23) and good tolerability (Wyles D. et al. ILC 2018). A non-ribavirin containing regimen would be expected to have further enhanced tolerability.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sof plus G/P Four weeks of sofosbuvir (400mg) plus glecaprevir-pibrentasvir (300mg/120mg) will be administered, followed by immediate retreatment of virological relapse with glecepravir/pibrentasvir (300mg/120mg) for 12 weeks, in treatment-naïve participants with chronic HCV infection and early liver disease (F0-F2). |
Drug: Sofosbuvir 400mg [Sovaldi]
Four weeks.
Other Names:
Drug: Glecaprevir/pibrentasvir (300mg/120mg)
Four weeks.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- SVR12 [16 weeks]
To evaluate the proportion achieving a sustained virological response at 12 weeks post treatment (SVR12) with sofosbuvir (400 mg) plus glecaprevir/pibrentasvir (300mg/120mg) for four weeks.
Secondary Outcome Measures
- Virological relapse [16 weeks]
To evaluate virological relapse following 4 weeks sofosbuvir (400 mg) plus glecaprevir/pibrentasvir (300mg/120mg) in HCV treatment-naïve chronic HCV patients with early liver disease (F0-2).
- Relapse characteristics [32 weeks]
In patients with virological relapse, to evaluate the time course of relapse and emergence of treatment-associated resistance substitutions.
- Re-treatment SVR [32 weeks]
To evaluate SVR following re-treatment of virological relapse with 12 weeks glecaprevir/pibrentasvir (300mg/120mg).
- Adherence [32 weeks]
To evaluate the proportion adherent to treatment and study visits.
- Cost-effectiveness [32 weeks]
To evaluate cost-effectiveness of a shortened duration with re-treatment of relapse strategy, against a standard duration (8-week, historical data).
Eligibility Criteria
Criteria
Inclusion Criteria:
- Participants must meet all inclusion criteria to be eligible to participate in this study:
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Have voluntarily signed the informed consent form.
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18 years of age or older.
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Chronic HCV infection as defined by anti-HCV antibody or HCV RNA detection for greater than 6 months.
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Quantifiable HCV RNA at screening.
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HCV treatment naïve (no prior treatment with an approved or investigation anti-HCV medication).
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Liver fibrosis stage F0-F2, defined by at least one of the following:
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Liver stiffness measurement <9.5 kPa by transient elastography (FibroScan®)
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AST to platelet ratio index (APRI) <0.5
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Liver biopsy
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If co-infection with HIV is documented, the subject must meet the following criteria:
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ART naïve with CD4 T cell count >500 cells/mm3; OR
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On a stable ART regimen (containing only permissible ART - see protocol section 6.3) 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.
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Negative pregnancy test at screening and baseline (females of childbearing potential only).
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All fertile females must be using effective contraception during treatment and during the 30 days after treatment end.
Exclusion Criteria:
- Participants who meet any of the exclusion criteria are not to be enrolled in this study.
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History of any of the following:
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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.
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Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage).
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Solid organ transplant.
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History of severe, life-threatening or other significant sensitivity to any excipients of the study drugs.
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Any of the following lab parameters at screening:
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ALT > 10 x ULN
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AST > 10 x ULN
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Direct bilirubin > ULN
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Platelets < 150,000/μL (cells/mm3)
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Creatinine clearance (CLcr) < 50 mL/min
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Albumin < LLN
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INR > 1.5 ULN
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Pregnant or breastfeeding female.
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HBV infection (HBsAg positive).
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Use of prohibited concomitant medications as described in protocol section 6.3.
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Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day for >2 weeks).
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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.
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Any investigational drug ≤6 weeks prior to the first dose of study drug.
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Ongoing severe psychiatric disease as judged by the treating physician.
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Inability or unwillingness to provide informed consent or abide by the requirements of the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | St Vincent's Hospital | Darlinghurst | New South Wales | Australia | 2010 |
| 2 | Blacktown Mt Druitt Hospital | Sydney | New South Wales | Australia | 2148 |
| 3 | Royal Adelaide Hospital | Adelaide | South Australia | Australia | 5000 |
Sponsors and Collaborators
- Kirby Institute
Investigators
- Principal Investigator: Marianne Martinello, MD, PhD, Kirby Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VHCRP1901