Clinical trial NCT02498015: A Phase IV Trial of Paritaprevir/Ritonavir, Ombitasvir, Dasabuvir for Chronic Hepatitis C Genotype 1 Virus Infection
Official title: A Phase IV Open-label, Multicentre, International Trial of Paritaprevir/Ritonavir, Ombitasvir, Dasabuvir ±Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection and Recent Injection Drug Use or Receiving Opioid Substitution Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hepatitis C, Chronic
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
First posted: 2015-07-15
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A total of 100 people with chronic HCV and recent injection drug use or recipients of opioid substitution therapy will be enrolled in 5 countries and 21 study sites. Participants with genotype 1a infection or cirrhosis will receive 12 weeks of open-label paritaprevir/ritonavir/ombitasvir and dasabuvir ("3D"), and twice-daily ribavirin. Participants with genotype 1b infection without cirrhosis will receive 12 weeks of open-label "3D". The study consists of a screening phase (6 weeks), treatment phase (12 weeks) and follow-up phase (96 weeks) to evaluate treatment response and reinfection.

Detailed description: A total of 100 people with recent injection drug use or recipients of opioid substitution therapy will be enrolled from drug and alcohol clinics, tertiary liver and infectious diseases clinics and community health centres across Canada, Europe, New Zealand, France, and Australia. This will include at least 30 participants with F3/F4 liver disease. Participants will be considered recent injection drug users if they have used injection drugs in the 6 months prior to consent. Participants receiving stable opioid substitution therapy (stable dose for \>2 weeks) will also be included. Patients with frequent drug use that is judged by the treating physician to compromise treatment safety will be excluded. The study drugs consisting of two tablets of the co-formulated paritepravir/ritonavir/ombitasvir (75/50/12.5 mg) once daily, one dasabuvir tablet (250 mg) twice daily, ribavirin (1000 mg) daily in two divided doses (genotype 1a only and/or cirrhosis). Electronic blister packs will be used to improve and monitor treatment adherence. This innovative strategy with the "3D" interferon-free regimen could considerably enhance the capacity to scale-up HCV treatment among PWID, and is therefore being evaluated in this phase IV study within a well-defined PWID population.

Eligibility criteria: Inclusion criteria:

1. Detectable HCV RNA in plasma (\>1,000 IU/ml).
2. Evidence of positive HCV antibody \>6 months prior to screening.
3. HCV Genotype 1 infection.
4. Recent IDU (previous 6 months) or receiving stable OST (stable dose for \>2 weeks).
5. Never received treatment for HCV infection.
6. Compensated liver disease. Enrolment of patients with cirrhosis (FibroScan \>14.6 kPa or FIB-4 \> 3.25) will be capped to 60% of the total enrolment (maximum 3 per site).
7. Participants with FibroScan \> 12KPa or AFP \>50 ng/mL must have abdominal ultrasound or CT scan without evidence of hepatocellular carcinoma within 2 months before screening.
8. Negative pregnancy test (for women of childbearing potential) within the 24-hour period before the first dose of study drug.
9. All fertile participants must be using effective contraception during treatment and 24 weeks post treatment (patients treated with ribavirin) or 2 weeks post treatment (patients not treated with ribavirin).

Exclusion criteria:

1. Any systemic anti-viral, anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) ≤6 months before the first dose of study drug.
2. Any investigational drug ≤6 weeks before the first dose of study drug.
3. HIV infection.
4. History or other evidence of decompensated liver disease.
5. Neutrophil \<1000 cells/mm3 or platelet \<50,000 cells/mm3 at screening.
6. Serum creatinine \>1.5 x upper limit of normal at screening.
7. Ongoing severe psychiatric disease as judged by the treating physician.
8. Frequent IDU that is judged by the treating physician to compromise treatment safety.
9. Hemoglobin \<12 g/dL (\<7.4 mmol/L) in women or \<13 g/dL (\<8.1 mmol/L) in men at screening.
10. Any exclusion specific to paritaprevir/ritonavir/ombitasvir, dasabuvir or ribavirin.
11. Pregnancy/lactation or male subjects whose female partners are pregnant.
12. Subject has current or past clinical evidence of decompensated liver disease, such as ascites, hepatic encephalopathy, oesophageal varices, and/or any of the following screening laboratory results;

    a. International normalised ration (INR) \>1.5; i. Patients with a known inherited blood disorder and INR \> 1.5 may be enrolled after discussion with the Principal Investigator b. Serum albumin \<3.3 g/dL; c. Serum total bilirubin \>1.8 x ULN, unless isolated in subjects with Gilbert's syndrome.
13. Subject shows evidence of significant liver disease in addition to HCV, which may include but is not limited to drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson's disease, non-alcoholic steatohepatitis (NASH), or primary biliary cirrhosis.
14. Subject has active malignant disease or history of malignant disease within the past 5 years (except treated basal cell carcinoma).
15. History of chronic pulmonary disease associated with functional limitation, severe cardiac disease, major organ transplantation or other evidence of severe illness, malignancy, or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
16. Poorly controlled diabetes mellitus as evidenced by haemoglobin A1c (HbA1c) ≥8.5%.
17. Positive test at screening for anti-HAV IgM Ab, anti-HBc IgM Ab or HBsAg.
18. Confirmed presence of hepatocellular carcinoma indicated on imaging techniques such as computed tomography (CT) scan or magnetic resonance imaging (MRI) within 3 months prior to screening or on an ultrasound performed at screening (a positive ultrasound result will be confirmed with CT scan or MRI).
19. Subject has history of organ transplant that requires chronic immunosuppression.
20. Corneal, skin, and hair grafts are allowed.
21. History of severe psychiatric disease that in the opinion of the investigator is unstable enough to compromise treatment adherence.
22. Prohibited medications and herbal remedies as detailed in the study protocol.

Primary outcomes:
measure: The proportion of participants with undetectable HCV RNA at 12 weeks post end of treatment (SVR12)
timeFrame: 12 weeks post treatment
Secondary outcomes:
measure: The proportion of participants with undetectable HCV RNA at 2 weeks following the initiation of treatment - week 2
timeFrame: 2 weeks following the initiation of treatment
measure: The proportion of participants with undetectable HCV RNA at 4 weeks following the initiation of treatment - week 4
timeFrame: 4 weeks following the initiation of treatment
measure: The proportion of participants with undetectable HCV RNA at the end of treatment - week 12
timeFrame: End of treatment week 12
measure: The proportion of participants with undetectable HCV RNA at 24 weeks post end of treatment (SVR24)
timeFrame: 24 weeks post treatment
measure: Treatment adherence
timeFrame: Baseline to week 12
measure: Association between adherence and response to treatment
timeFrame: Early (0-3 weeks), mid (4-7 weeks), late (8-11 weeks) during treatment
measure: Safety and tolerability (number and type of adverse events and serious adverse events)
timeFrame: Baseline to week 24 (SVR24)
measure: Change in injecting drug use and injecting risk behaviour
timeFrame: Baseline to week 12
measure: Change in mental health
timeFrame: Baseline to week 12
measure: Change in health-related quality of life Questionnaire
timeFrame: Baseline to week 12
measure: Impact of mixed HCV infection on treatment response
timeFrame: Baseline to SVR12
measure: Change in opioid substitution therapy
timeFrame: Baseline to week 12
measure: HCV reinfection rate
timeFrame: Week 108
measure: Emergence of viral resistance-associated variants (RAVs)
timeFrame: Baseline to week 12
measure: Utility of HCV core antigen testing as a simple method for HCV monitoring
timeFrame: Week 108
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: The Kirby Institute, University of New South Wales Australia
state: New South Wales
Study officials:
affiliation: Kirby Institute
name: Gregory Dore, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cunningham EB, Hajarizadeh B, Amin J, Hellard M, Bruneau J, Feld JJ, Cooper C, Powis J, Litwin AH, Marks P, Dalgard O, Conway B, Moriggia A, Stedman C, Read P, Bruggmann P, Lacombe K, Dunlop A, Applegate TL, Matthews GV, Fraser C, Dore GJ, Grebely J. Reinfection Following Successful Direct-acting Antiviral Therapy for Hepatitis C Virus Infection Among People Who Inject Drugs. Clin Infect Dis. 2021 Apr 26;72(8):1392-1400. doi: 10.1093/cid/ciaa253.
citation: Artenie AA, Cunningham EB, Dore GJ, Conway B, Dalgard O, Powis J, Bruggmann P, Hellard M, Cooper C, Read P, Feld JJ, Hajarizadeh B, Amin J, Lacombe K, Stedman C, Litwin AH, Marks P, Matthews GV, Quiene S, Erratt A, Bruneau J, Grebely J. Patterns of Drug and Alcohol Use and Injection Equipment Sharing Among People With Recent Injecting Drug Use or Receiving Opioid Agonist Treatment During and Following Hepatitis C Virus Treatment With Direct-acting Antiviral Therapies: An International Study. Clin Infect Dis. 2020 May 23;70(11):2369-2376. doi: 10.1093/cid/ciz633.