A Study to Evaluate Treatment of Hepatitis C Virus Infection in Pediatric Subjects (ZIRCON)

An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Ombitasvir (OBV), Paritaprevir (PTV), Ritonavir (RTV) With or Without Dasabuvir (DSV) and With or Without Ribavirin (RBV) in Pediatric Subjects With Genotype 1 or 4 Chronic Hepatitis C Virus (HCV) Infection (ZIRCON)

This was a Phase 2/3, open-label, multicenter study to evaluate the pharmacokinetics (PK), efficacy, and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/RTV) with or without dasabuvir (DSV) and with or without ribavirin (RBV) in Hepatitis C virus (HCV) genotype 1 or 4 (GT1 or GT4)-infected pediatric participants of ≥ 3 to 17 years of age.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C Infection
• Intervention / Treatment: Drug: Ombitasvir/paritaprevir/ritonavir; Drug: Dasabuvir; Drug: Ribavirin; Drug: Ombitasvir mini tablet; Drug: Paritaprevir mini tablet; Drug: Ritonavir mini tablet; Drug: Dasabuvir mini tablet; Drug: Ribavirin solution

Detailed Description

The study population for Part 1, the PK study, included GT1-infected participants who were noncirrhotic and treatment-naïve (TN). Part 2, the safety and efficacy study, included GT1 or GT4-infected participants who were TN or interferon ([IFN] or Pegylated-interferon alfa-2a or 2b [pegIFN] with or without RBV) treatment-experienced (TE) without cirrhosis or with compensated cirrhosis. In Part 1 and Part 2, the treatment regimen and duration were dependent on HCV GT, GT1 subtype, and cirrhosis status.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven /ID# 136911
  • Bruxelles-Capitale
    • Brussels, Bruxelles-Capitale, Belgium, 1200
      • Cliniques Universitaires Saint-Luc /ID# 136910
• Germany
  • Berlin, Germany, 10117
    • Charite Universitaetsmedizin Berlin /ID# 141620
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg /ID# 141618
  • Wuppertal, Germany, 42283
    • Helios Klinikum Wuppertal /ID# 142883
• Puerto Rico
  • San Juan, Puerto Rico, 00912-3310
    • San Jorge Children Hospital /ID# 136832
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron /ID# 137098
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz /ID# 137094
  • Valencia, Spain, 46026
    • Hospital Universitario y Politecnico La Fe /ID# 137097
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan de Deu /ID# 137096
• United States
  • California
    • San Francisco, California, United States, 94158
      • UCSF Benioff Childrens Hosp /ID# 136774
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado /ID# 137017
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Archer /ID# 136830
    • Orlando, Florida, United States, 32803
      • Advent Health /ID# 167663
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University /ID# 137015
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital /ID# 137174
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center /ID# 136831
  • New York
    • New York, New York, United States, 10032-3725
      • Columbia Univ Medical Center /ID# 136431
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia /ID# 137018
  • Texas
    • Houston, Texas, United States, 77030-3411
      • Baylor College of Medicine /ID# 136590
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital /ID# 137019

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Positive anti-hepatitis C virus antibody (HCV Ab) and HCV ribonucleic acid (RNA) ≥ 1000 IU/mL at the time of screening
2. HCV genotype 1 for enrollment into Part 1 of the study and genotype 1 or 4 for enrollment into Part 2
3. Parent or legal guardian with the willingness and ability to provide written informed consent and participant willing and able to give assent, as appropriate for age and country

Exclusion Criteria:

1. Female participant who is pregnant, breastfeeding or is considering becoming pregnant
2. Use of known strong inducers and inhibitors (e.g., gemfibrozil) of cytochrome P450 2C8 (CYP2C8) in participants receiving dasabuvir, or strong or moderate inducers of CYP3A, within 2 weeks or 10 half-lives, whichever is longer, of the respective medication/supplement prior to study drug administration.
3. Positive test result for Hepatitis B surface antigen (HbsAg) or anti-human immunodeficiency virus antibody (HIV Ab) test
4. Current enrollment in another interventional clinical study, previous enrollment in this study, prior or current use of any investigational or commercially available anti-HCV agents other than interferons or ribavirin or receipt of any investigational product within 6 weeks prior to study drug administration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adult tablet, 12-17 yr, Part 1; Participants with HCV GT1b without cirrhosis received the adult 3-DAA (OBV/PTV/RTV and DSV) regimen: two 12.5 mg ombitasvir /75 mg paritaprevir /50 mg ritonavir tablets taken orally every morning (QD) and one dasabuvir 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis received 12-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label.	Drug: Ombitasvir/paritaprevir/ritonavir; Film-coated tablet for oral use; Other Names: Ombitasvir also known as ABT-267; Paritaprevir also known as ABT-450; Ombitsvir/paritaprevir/ritonavir also known as Viekirax; Drug: Dasabuvir; Film-coated tablet for oral use; Other Names: ABT-333; Exviera; Drug: Ribavirin; Film-coated tablet for oral use
Experimental: Adult tablet, 12-17 yr, Part 2; Participants with HCV GT1b received the adult 3-DAA (OBV/PTV/RTV and DSV) regimen: two 12.5 mg ombitasvir /75mg paritaprevir /50 mg ritonavir tablets taken orally every morning (QD) and one dasabuvir 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis received 12-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label. Participants with HCV GT1a with compensated cirrhosis received 24-week treatment with the adult 3-DAA regimen and ribavirin 200 mg tablets were administered orally per local label. Participants with HCV GT4 received 12-week treatment with the OBV/PTV/RTV formulation and ribavirin 200 mg tablets were administered orally per local label.	Drug: Ombitasvir/paritaprevir/ritonavir; Film-coated tablet for oral use; Other Names: Ombitasvir also known as ABT-267; Paritaprevir also known as ABT-450; Ombitsvir/paritaprevir/ritonavir also known as Viekirax; Drug: Dasabuvir; Film-coated tablet for oral use; Other Names: ABT-333; Exviera; Drug: Ribavirin; Film-coated tablet for oral use
Experimental: Mini tablet, 9-11 yr, Part 1; Participants with HCV GT1b without cirrhosis were to receive the mini-tablet 3-DAA (OBV, PTV, RTV, and DSV) regimen for 12 weeks: ombitasvir 0.3 mg, paritaprevir 1.0 mg, and ritonavir 1.0 mg mini-tablets administered orally QD based on body weight and dasabuvir taken orally BID as 3.08 mg mini-tablets based on body weight. Participants with HCV GT1a without cirrhosis received 12-week treatment with the mini-tablet 3-DAA regimen and ribavirin was provided as a 40 mg/mL oral solution and administered per local label.	Drug: Ombitasvir mini tablet; Film-coated tablet for oral use; Other Names: ABT-267; Drug: Paritaprevir mini tablet; Film-coated tablet for oral use; Other Names: ABT-450; Drug: Ritonavir mini tablet; Film-coated tablet for oral use; Drug: Dasabuvir mini tablet; Film-coated tablet for oral use; Other Names: ABT-333; Exviera; Drug: Ribavirin solution; Oral solution
Experimental: Mini tablet, 3-8 yr, Part 1; Participants with HCV GT1b without cirrhosis were to receive the mini-tablet 3-DAA (OBV, PTV, RTV, and DSV) regimen for 12 weeks: ombitasvir 0.3 mg, paritaprevir 1.0 mg, and ritonavir 1.0 mg mini-tablets administered orally QD based on body weight and dasabuvir taken orally BID as 3.08 mg mini-tablets based on body weight. Participants with HCV GT1a without cirrhosis received 12-week treatment with the mini-tablet 3-DAA regimen and ribavirin was provided as a 40 mg/mL oral solution and administered per local label.	Drug: Ombitasvir mini tablet; Film-coated tablet for oral use; Other Names: ABT-267; Drug: Paritaprevir mini tablet; Film-coated tablet for oral use; Other Names: ABT-450; Drug: Ritonavir mini tablet; Film-coated tablet for oral use; Drug: Dasabuvir mini tablet; Film-coated tablet for oral use; Other Names: ABT-333; Exviera; Drug: Ribavirin solution; Oral solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Maximum Plasma Concentration (Cmax) of Ombitasvir (OBV)	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose.	At Week 2
Part 1: Concentration of Drug in Blood Plasma Over Time [Area Under the Curve (AUC)] of Ombitasvir (OBV)	AUC is a measure of how long and how much drug is present in the body after dosing. The amount of ombitasvir present was measured up to 24 hours after dosing.	At Week 2
Part 1: Lowest Plasma Concentration (Ctrough) of Ombitasvir (OBV)	Minimum plasma concentration (Ctrough; measured in ng/mL) was directly determined from the concentration-time data.	At Weeks 2 and 8
Part 1: Maximum Plasma Concentration (Cmax) of Paritaprevir (PTV)	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose.	At Week 2
Part 1: Concentration of Drug in Blood Plasma Over Time [Area Under the Curve (AUC)] of Paritaprevir (PTV)	AUC is a measure of how long and how much drug is present in the body after dosing. The amount of paritaprevir present was measured up to 24 hours after dosing.	At Week 2
Part 1: Lowest Plasma Concentration (Ctrough) of Paritaprevir (PTV)	Minimum plasma concentration (Ctrough; measured in ng/mL) was directly determined from the concentration-time data.	At Weeks 2 and 8
Part 1: Maximum Plasma Concentration (Cmax) of Dasabuvir (DSV)	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose.	At Week 2
Part 1: Concentration of Drug in Blood Plasma Against Time [Area Under the Curve (AUC)] of Dasabuvir (DSV)	AUC is a measure of how long and how much drug is present in the body after dosing. The amount of dasabuvir present was measured up to 12 hours after dosing. For two subjects in the 15-29 kg group, the 24 h concentration was used as the 12 h concentration due to the significant sampling time deviation. For one subject in the 30-44 kg group, the 24 h concentration was used as the 12 h concentration due to the significant sampling time deviation.	At Week 2
Part 1: Lowest Plasma Concentration (Ctrough) of Dasabuvir (DSV)	Minimum plasma concentration (Ctrough; measured in ng/mL) was directly determined from the concentration-time data.	At Weeks 2 and 8
Part 1: Maximum Plasma Concentration (Cmax) of Ritonavir (RTV)	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administrated and before administration of a second dose.	At Week 2
Part 1: Concentration of Drug in Blood Plasma Over Time [Area Under the Curve (AUC)] of Ritonavir (RTV)	AUC is a measure of how long and how much drug is present in the body after dosing. The amount of ritonavir present was measured up to 24 hours after dosing.	At Week 2
Part 1: Lowest Plasma Concentration (Ctrough) of Ritonavir (RTV)	Minimum plasma concentration (Ctrough; measured in ng/mL) was directly determined from the concentration-time data.	At Weeks 2 and 8
Parts 1 and 2: Percentage of Participants With Sustained Virologic Response 12 Weeks After the Last Actual Dose of Study Drug (SVR12)	SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) < lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.	12 weeks after last dose of study drug (Week 24 or 36 depending on treatment duration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts 1 and 2: Percentage of Participants With Sustained Virologic Response 12 Weeks After the Last Actual Dose of Study Drug (SVR12) Summarized by Formulation, Age and Weight Group, and Across All Subjects on the Adult Formulations	SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) < lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.	12 weeks after last dose of study drug (Week 24 or 36 depending on treatment duration)
Parts 1 & 2: Percentage of Participants With Sustained Virologic Response 24 Weeks After the Last Actual Dose of Study Drug (SVR24), Summarized by Formulation, Age and Weight Group, Across All Subjects, and Across All Subjects on the Adult Formulations	SVR24 is defined as hepatitis C virus ribonucleic acid (HCV RNA) < lower limit of quantification (LLOQ) 24 weeks after the last actual dose of study drug.	24 weeks after last dose of study drug (Week 36 or 48 depending on treatment duration)
Parts 1 and 2: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization During Treatment by Formulation, Age and Weight Group, Across All Subjects, and Across All Subjects on the Adult Formulations	Alanine aminotransferase (ALT) normalization during treatment is defined as ALT ≤ the upper limit of normal (ULN) at the final treatment visit for participants with ALT > ULN at baseline.	12 or 24 weeks after starting study drug, depending on treatment duration

Collaborators and Investigators

• Sponsor: AbbVie

Publications and helpful links

General Publications

• Rosenthal P, Narkewicz MR, Yao BB, Jolley CD, Lobritto SJ, Wen J, Molleston JP, Hsu EK, Jonas MM, Zha J, Liu L, Leung DH. Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir Mini-Tabs Plus Ribavirin for Children Aged 3-11 Years with Hepatitis C Genotype 1a. Adv Ther. 2020 Jul;37(7):3299-3310. doi: 10.1007/s12325-020-01389-9. Epub 2020 May 25.

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2015
• Primary Completion (Actual): November 19, 2020
• Study Completion (Actual): November 19, 2020

Study Registration Dates

• First Submitted: June 17, 2015
• First Submitted That Met QC Criteria: June 29, 2015
• First Posted (Estimate): July 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: September 7, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric; Hepatitis C Genotype 1; Hepatitis C Virus; Hepatitis C Genotype 4
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Infections; Communicable Diseases; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ribavirin; Ritonavir
• Other Study ID Numbers: M14-748; 2015-000111-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• IPD Sharing Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No