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Strategic Treatment Reduction in Very Early Liver Disease With 4 Weeks Sofosbuvir Plus Glecepravir-pibrentasvir (STRIVE-4)

Primary Purpose

Hepatitis C

Status
Recruiting
Phase
Phase 4
Locations
Australia
Study Type
Interventional
Intervention
Sofosbuvir 400mg [Sovaldi]
Glecaprevir/pibrentasvir (300mg/120mg)
Sponsored by
Kirby Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

- Participants must meet all inclusion criteria to be eligible to participate in this study:

  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. Quantifiable HCV RNA at screening.
  5. HCV treatment naïve (no prior treatment with an approved or investigation anti-HCV medication).
  6. Liver fibrosis stage F0-F2, defined by at least one of the following:

    1. Liver stiffness measurement <9.5 kPa by transient elastography (FibroScan®)
    2. AST to platelet ratio index (APRI) <0.5
    3. Liver biopsy
  7. 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 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.
  8. Negative pregnancy test at screening and baseline (females of childbearing potential only).
  9. 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.

    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 < 150,000/μL (cells/mm3)
      5. Creatinine clearance (CLcr) < 50 mL/min
      6. Albumin < LLN
      7. INR > 1.5 ULN
    3. Pregnant or breastfeeding female.
    4. HBV infection (HBsAg positive).
    5. Use of prohibited concomitant medications as described in protocol section 6.3.
    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. Inability or unwillingness to provide informed consent or abide by the requirements of the study.

Sites / Locations

  • St Vincent's HospitalRecruiting
  • Blacktown Mt Druitt HospitalRecruiting
  • Royal Adelaide HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sof plus G/P

Arm Description

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).

Outcomes

Primary Outcome Measures

SVR12
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
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
In patients with virological relapse, to evaluate the time course of relapse and emergence of treatment-associated resistance substitutions.
Re-treatment SVR
To evaluate SVR following re-treatment of virological relapse with 12 weeks glecaprevir/pibrentasvir (300mg/120mg).
Adherence
To evaluate the proportion adherent to treatment and study visits.
Cost-effectiveness
To evaluate cost-effectiveness of a shortened duration with re-treatment of relapse strategy, against a standard duration (8-week, historical data).

Full Information

First Posted
February 25, 2019
Last Updated
March 28, 2022
Sponsor
Kirby Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03855917
Brief Title
Strategic Treatment Reduction in Very Early Liver Disease With 4 Weeks Sofosbuvir Plus Glecepravir-pibrentasvir
Acronym
STRIVE-4
Official Title
A Phase IV Open-label Multicentre International Pilot Study of 4-week Treatment With Sofosbuvir (400 mg) Plus Glecaprevir/Pibrentasvir (300mg/120mg) in Chronic HCV Treatment naïve Patients With Early Liver Disease
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 11, 2020 (Actual)
Primary Completion Date
February 2023 (Anticipated)
Study Completion Date
February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kirby Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sof plus G/P
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Sofosbuvir 400mg [Sovaldi]
Other Intervention Name(s)
Sovaldi
Intervention Description
Four weeks.
Intervention Type
Drug
Intervention Name(s)
Glecaprevir/pibrentasvir (300mg/120mg)
Other Intervention Name(s)
Maviret
Intervention Description
Four weeks.
Primary Outcome Measure Information:
Title
SVR12
Description
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.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Virological relapse
Description
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).
Time Frame
16 weeks
Title
Relapse characteristics
Description
In patients with virological relapse, to evaluate the time course of relapse and emergence of treatment-associated resistance substitutions.
Time Frame
32 weeks
Title
Re-treatment SVR
Description
To evaluate SVR following re-treatment of virological relapse with 12 weeks glecaprevir/pibrentasvir (300mg/120mg).
Time Frame
32 weeks
Title
Adherence
Description
To evaluate the proportion adherent to treatment and study visits.
Time Frame
32 weeks
Title
Cost-effectiveness
Description
To evaluate cost-effectiveness of a shortened duration with re-treatment of relapse strategy, against a standard duration (8-week, historical data).
Time Frame
32 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: - Participants must meet all inclusion criteria to be eligible to participate in this study: Have voluntarily signed the informed consent form. 18 years of age or older. Chronic HCV infection as defined by anti-HCV antibody or HCV RNA detection for greater than 6 months. Quantifiable HCV RNA at screening. HCV treatment naïve (no prior treatment with an approved or investigation anti-HCV medication). Liver fibrosis stage F0-F2, defined by at least one of the following: Liver stiffness measurement <9.5 kPa by transient elastography (FibroScan®) AST to platelet ratio index (APRI) <0.5 Liver biopsy 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 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. Negative pregnancy test at screening and baseline (females of childbearing potential only). 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. History of any of the following: 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. Clinical hepatic decompensation (i.e. ascites, encephalopathy or variceal haemorrhage). Solid organ transplant. History of severe, life-threatening or other significant sensitivity to any excipients of the study drugs. Any of the following lab parameters at screening: ALT > 10 x ULN AST > 10 x ULN Direct bilirubin > ULN Platelets < 150,000/μL (cells/mm3) Creatinine clearance (CLcr) < 50 mL/min Albumin < LLN INR > 1.5 ULN Pregnant or breastfeeding female. HBV infection (HBsAg positive). Use of prohibited concomitant medications as described in protocol section 6.3. Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day for >2 weeks). 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. Any investigational drug ≤6 weeks prior to the first dose of study drug. Ongoing severe psychiatric disease as judged by the treating physician. Inability or unwillingness to provide informed consent or abide by the requirements of the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marianne Martinello, MD, PhD
Phone
+61293850900
Email
mmartinello@kirby.unsw.edu.au
First Name & Middle Initial & Last Name or Official Title & Degree
Pip Marks, MPH Hons
Phone
+61293850900
Email
pmarks@kirby.unsw.edu.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne Martinello, MD, PhD
Organizational Affiliation
Kirby Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Vincent's Hospital
City
Darlinghurst
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Greg Dore
Email
gdore@kirby.unsw.edu.au
First Name & Middle Initial & Last Name & Degree
Greg Dore, MBBS, PhD
Facility Name
Blacktown Mt Druitt Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2148
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Golo Ahlenstiel, MD
Email
golo.ahlenstiel@health.nsw.gov.au
First Name & Middle Initial & Last Name & Degree
Golo Ahlenstiel
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emily Rowe
Email
emily.rowe@sa.gov.au
First Name & Middle Initial & Last Name & Degree
Emily Rowe

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Protocol and SAP will be submitted along with the primary manuscript for publication.

Learn more about this trial

Strategic Treatment Reduction in Very Early Liver Disease With 4 Weeks Sofosbuvir Plus Glecepravir-pibrentasvir

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