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

A Phase IIIb, Open-label, Multicentre, International Randomised Controlled Trial of Simplified Treatment Monitoring for 8 Weeks Glecaprevir (300mg)/Pibrentasvir (120mg) in Chronic HCV Treatment naïve Patients Without Cirrhosis

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).

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: glecaprevir (300mg)/pibrentasvir (120mg)

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 Type: Interventional
• Enrollment (Actual): 380
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St Vincent's Hospital Sydney
    • Sydney, New South Wales, Australia, 2010
      • East Sydney Doctors
    • Sydney, New South Wales, Australia
      • Holdsworth House Medical Practice
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
    • Melbourne, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2K5
      • (G.I.R.I.) GI Research Institute
    • Vancouver, British Columbia, Canada, V5Z 1H2
      • Lair Centre
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Health System
    • Hamilton, Ontario, Canada, L8N 4A6
      • St Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, ON M57 2S8
      • Toronto General Hospital
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre (MUHC)
    • Québec, Quebec, Canada, G1V 4G2
      • CHU de Quebec-Université Laval
• France
  • Créteil, France, 94000
    • Hôpital Henri Mondor
  • Marseille, France, 13008
    • Hopital Saint Joseph
  • Paris, France, 75012
    • Hopital Saint Antoine
• Germany
  • Berlin, Germany, 10439
    • zibp - Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH
  • Düsseldorf, Germany, 40237
    • Center for HIV and Hepatogastroenterology
  • Hanover, Germany, 30625
    • Hannover Medical School
  • Münster, Germany, 48143
    • CIM-Centrum fuer Interdisziplinaere Medizin GmbH
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital
  • Auckland, New Zealand
    • Calder Center
  • Christchurch, New Zealand
    • Christchurch Hospital
  • Dunedin, New Zealand
    • Dunedin Hospital
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital - Universitaetsspital Bern
  • Zürich, Switzerland, 8091
    • University Hospital Zurich
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, E1 1BB
    • Barts Health
  • London, United Kingdom, W2 1NY
    • Imperial College Healthcare NHS Trust (St Mary's Hospital)
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • New York
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • SSM Health Dean Medical Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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).	Drug: glecaprevir (300mg)/pibrentasvir (120mg); glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks; Other Names: Mavyret
Experimental: 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.	Drug: glecaprevir (300mg)/pibrentasvir (120mg); glecaprevir (300mg)/pibrentasvir (120mg) for 8 weeks; Other Names: Mavyret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Undetectable HCV RNA (ITT Population)	Number of participants with undetectable HCV RNA based on ITT population.	12 weeks post end of treatment (SVR12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Undetectable HCV RNA (mITT Population)	Number of participants with undetectable HCV RNA based on mITT population.	12 weeks post end of treatment (SVR12)
Treatment and Study Visits Adherence	Number adherent to treatment and study visits (on-treatment adherence and early treatment discontinuation).	12 weeks post end of treatment (SVR12)
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.	Screening and 12 weeks post end of treatment (SVR12)
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	Baseline and 12 weeks post-treatment
Patient Treatment Satisfaction	Patient was satisfied with their treatment follow-up plan.	12 weeks post end of treatment (SVR12)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Common Adverse Events (Safety Outcome)	Proportion of patients with common adverse events (reported in greater than 5%).	12 weeks post end of treatment (SVR12)
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.	12 weeks post end of treatment (SVR12)
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.	12 weeks post end of treatment (SVR12)

Collaborators and Investigators

• Sponsor: Kirby Institute
• Investigators: Principal Investigator: Gregory Dore, Kirby Institute, University of New South Wales Sydney, Australia

Publications and helpful links

General Publications

• Dore GJ, Feld JJ, Thompson A, Martinello M, Muir AJ, Agarwal K, Mullhaupt B, Wedemeyer H, Lacombe K, Matthews GV, Schultz M, Klein M, Hezode C, Mercade GE, Kho D, Petoumenos K, Marks P, Tatsch F, Dos Santos AGP, Gane E; SMART-C Study Group. Simplified monitoring for hepatitis C virus treatment with glecaprevir plus pibrentasvir, a randomised non-inferiority trial. J Hepatol. 2020 Mar;72(3):431-440. doi: 10.1016/j.jhep.2019.10.010. Epub 2019 Oct 23.

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2017
• Primary Completion (Actual): December 19, 2018
• Study Completion (Actual): December 19, 2018

Study Registration Dates

• First Submitted: April 7, 2017
• First Submitted That Met QC Criteria: April 12, 2017
• First Posted (Actual): April 18, 2017

Study Record Updates

• Last Update Posted (Actual): December 11, 2019
• Last Update Submitted That Met QC Criteria: December 9, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic
• Other Study ID Numbers: VHCRP1701

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: No individual participant data will be shared. The results of the project will be presented at scientific meetings, and published in peer reviewed scientific literature. Sharing of data generated by this project is an essential part of our proposed activities and will be carried out in several different ways. We plan to make our results available to the community of scientists interested in recently acquired hepatitis C, community organisations representing the affected communities and participants. We also welcome collaboration with others who could make use of data and samples.
• IPD Sharing Time Frame: Submitted as part of J Hepatology accepted publication
• IPD Sharing Access Criteria: Access via the J Hepatology accepted publication
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No