Trial of Simplified Treatment Monitoring for 8 Weeks Glecaprevir/Pibrentasvir in Chronic Hepatitis C Patients

Phase 3

Completed

• Conditions: Hepatitis C, Chronic
• Interventions: Drug: glecaprevir (300mg)/pibrentasvir (120mg)

• Registration Number: NCT03117569
• Lead Sponsor: Kirby Institute

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.

Study Timeline

• Study First Submitted: 2017-04-07
• Study First Submitted QC: 2017-04-12
• Study First Posted: 2017-04-18
• Study Start: 2017-08-21
• Primary Completion: 2018-12-19
• Study Completion: 2018-12-19
• Results First Submitted: 2019-07-17
• Status Verified: 2019-12
• Results First Submitted QC: 2019-12-09
• Last Update Submitted: 2019-12-09
• Results First Posted: 2019-12-11
• Last Update Posted: 2019-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 380

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard monitoring schedule	glecaprevir (300mg)/pibrentasvir (120mg)	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).
Simplified monitoring schedule	glecaprevir (300mg)/pibrentasvir (120mg)	Participants will have no on-treatment clinic visits at weeks 4 and 8. Participants have phone contact-based visits at weeks 4 and 8.

Primary Outcome Measures

Name	Time	Method
Undetectable HCV RNA (ITT Population)	12 weeks post end of treatment (SVR12)	Number of participants with undetectable HCV RNA based on ITT population.

Secondary Outcome Measures

Name	Time	Method
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.
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.
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
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).

Trial Locations

Locations (33)

St Vincent's Hospital Sydney; 🇦🇺 Sydney, New South Wales, Australia

William Osler Health System; 🇨🇦 Brampton, Ontario, Canada

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

New York University Langone Medical Center; 🇺🇸 New York, New York, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

SSM Health Dean Medical Group; 🇺🇸 Madison, Wisconsin, United States

East Sydney Doctors; 🇦🇺 Sydney, New South Wales, Australia

Holdsworth House Medical Practice; 🇦🇺 Sydney, New South Wales, Australia

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

The Alfred Hospital; 🇦🇺 Melbourne, Victoria, Australia

(G.I.R.I.) GI Research Institute; 🇨🇦 Vancouver, British Columbia, Canada

St Joseph's Healthcare Hamilton; 🇨🇦 Hamilton, Ontario, Canada

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

Hopital Henri Mondor; 🇫🇷 Créteil, France

Hopital Saint Antoine; 🇫🇷 Paris, France

zibp - Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH; 🇩🇪 Berlin, Germany

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

Calder Center; 🇳🇿 Auckland, New Zealand

Christchurch Hospital; 🇳🇿 Christchurch, New Zealand

Imperial College Healthcare NHS Trust (St Mary's Hospital); 🇬🇧 London, United Kingdom

King's College Hospital; 🇬🇧 London, United Kingdom

Hopital Saint Joseph; 🇫🇷 Marseille, France

Barts Health; 🇬🇧 London, United Kingdom

St Vincent's Hospital Melbourne; 🇦🇺 Melbourne, Victoria, Australia

McGill University Health Centre (MUHC); 🇨🇦 Montréal, Quebec, Canada

CHU de Québec-Université Laval; 🇨🇦 Québec, Quebec, Canada

Inselspital - Universitaetsspital Bern; 🇨🇭 Bern, Switzerland

University Hospital Zurich; 🇨🇭 Zürich, Switzerland

Center for HIV and Hepatogastroenterology; 🇩🇪 Düsseldorf, Germany

Hannover Medical School; 🇩🇪 Hanover, Germany

CIM-Centrum fuer Interdisziplinaere Medizin GmbH; 🇩🇪 Münster, Germany

Dunedin Hospital; 🇳🇿 Dunedin, New Zealand

Lair Centre; 🇨🇦 Vancouver, British Columbia, Canada