Clinical trial NCT03117569: Trial of Simplified Treatment Monitoring for 8 Weeks Glecaprevir/Pibrentasvir in Chronic Hepatitis C Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis C, Chronic
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
First posted: 2017-04-18
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Undetectable HCV RNA (ITT Population)
timeFrame: 12 weeks post end of treatment (SVR12)
Secondary outcomes:
measure: Undetectable HCV RNA (mITT Population)
timeFrame: 12 weeks post end of treatment (SVR12)
measure: Treatment and Study Visits Adherence
timeFrame: 12 weeks post end of treatment (SVR12)
measure: Health-related Quality of Life
timeFrame: Screening and 12 weeks post end of treatment (SVR12)
measure: Number of Virological Failure Participants With NS3 and NS5A Polymorphisms at Baseline and Post-treatment Week 12
timeFrame: Baseline and 12 weeks post-treatment
measure: Patient Treatment Satisfaction
timeFrame: 12 weeks post end of treatment (SVR12)
Other outcomes:
measure: Common Adverse Events (Safety Outcome)
timeFrame: 12 weeks post end of treatment (SVR12)
measure: Severe/Life Threatening Adverse Events (Safety Outcome)
timeFrame: 12 weeks post end of treatment (SVR12)
measure: Provider Acceptability of Simplified Monitoring Strategy (Exploratory Outcome)
timeFrame: 12 weeks post end of treatment (SVR12)
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Madison
country: United States
facility: SSM Health Dean Medical Group
state: Wisconsin
city: Sydney
country: Australia
facility: East Sydney Doctors
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Sydney
country: Australia
facility: Holdsworth House Medical Practice
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Vancouver
country: Canada
facility: Lair Centre
state: British Columbia
city: Vancouver
country: Canada
facility: (G.I.R.I.) GI Research Institute
state: British Columbia
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Hamilton
country: Canada
facility: St Joseph's Healthcare Hamilton
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre (MUHC)
state: Quebec
city: Québec
country: Canada
facility: CHU de Québec-Université Laval
state: Quebec
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Marseille
country: France
facility: Hopital Saint Joseph
city: Paris
country: France
facility: Hopital Saint Antoine
city: Berlin
country: Germany
facility: zibp - Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH
city: Düsseldorf
country: Germany
facility: Center for HIV and Hepatogastroenterology
city: Hanover
country: Germany
facility: Hannover Medical School
city: Münster
country: Germany
facility: CIM-Centrum fuer Interdisziplinaere Medizin GmbH
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Calder Center
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Bern
country: Switzerland
facility: Inselspital - Universitaetsspital Bern
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: London
country: United Kingdom
facility: Barts Health
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust (St Mary's Hospital)
Study officials:
affiliation: Kirby Institute, University of New South Wales Sydney, Australia
name: Gregory Dore
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.