A Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Pediatric Subjects With Genotypes 1-6 Chronic Hepatitis C Virus (HCV) Infection (DORA)

An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Pediatric Subjects With Genotypes 1-6 Chronic Hepatitis C Virus (HCV) Infection

The objectives of this study are to assess the pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir adult formulation in adolescents ages 12 to 17 years and a pediatric formulation of glecaprevir and pibrentasvir in children ages 3 to < 12 years.

Study Overview

• Status: Completed
• Conditions: Hepatitis C Virus (HCV)
• Intervention / Treatment: Drug: Glecaprevir/Pibrentasvir Adult Formulation; Drug: Glecaprevir + Pibrentasvir Pediatric Formulation

Detailed Description

This was a multicenter study to evaluate the pharmacokinetics (PK), efficacy, and safety of glecaprevir (GLE) and pibrentasvir (PIB) treatment for 8, 12, or 16 weeks in hepatitis C virus (HCV) genotype 1 - 6 (GT1 - GT6)-infected pediatric participants 3 to < 18 years of age, with or without compensated cirrhosis, with or without human immunodeficiency virus (HIV) coinfection, who are either treatment-naïve (TN), treatment-experienced (TE) with pegylated interferon (pegIFN) with or without ribavirin (RBV), or TE with sofosbuvir (SOF) + RBV with or without pegIFN.

The study was divided into 2 parts, according to the formulation of GLE/PIB administered. Part 1 of the study enrolled HCV GT1 - GT6 infected adolescent participants into the 12 to < 18 years old age group who were willing to swallow the adult formulation of GLE/PIB (Cohort 1). Part 2 of the study enrolled HCV GT1 - GT6 infected pediatric participants divided into the 9 to < 12 (Cohort 2), 6 to < 9 (Cohort 3), and 3 to < 6 (Cohort 4) years old age groups, to receive the pediatric formulation of GLE + PIB. Part 1 enrolled first and once the pediatric formulation was available enrollment into Part 2 commenced, with each cohort enrolled in parallel.

In each cohort, the first group of participants were enrolled into an intense pharmacokinetics (IPK) portion to characterize the PK and safety in each age group, followed by enrollment into a non-IPK safety/efficacy portion. Study participants enrolled in the IPK portion must have been HIV-negative, treatment-naive, and have an identified HCV genotype. In the IPK portion the first approximately six participants received an initial proposed dose of GLE and PIB based on the child's weight and age at screening. PK samples from these participants were evaluated to determine if therapeutic efficacious exposures were attained, comparable to those of adults, and if any dose adjustments were needed. After the intensive PK analysis results for the first six participants were available, enrollment of the remaining IPK portion resumed with subsequent participants receiving an adjusted final dose as applicable. Additional participants may have been required for further intensive PK analysis per age cohort if therapeutic exposure targets were not achieved.

Enrollment into the non-IPK safety and efficacy portions began when the dosing recommendations per age group based on the PK and clinical data from the IPK analysis were ascertained.

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2; Phase 3

Expanded Access

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Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven /ID# 162174
  • Bruxelles-Capitale
    • Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium, 1200
      • Cliniques Universitaires Saint Luc /ID# 162173
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A9
      • Alberta Children's Hospital /ID# 163449
    • Edmonton, Alberta, Canada, T6G 2X8
      • Stollery Children's Hospital /ID# 163450
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children /ID# 163448
• Germany
  • Berlin, Germany, 10117
    • Charite Universitaetsmedizin Berlin /ID# 165186
  • Wuppertal, Germany, 42283
    • Helios Klinikum Wuppertal /ID# 165185
  • Baden-Wuerttemberg
    • Freiburg im Breisgau, Baden-Wuerttemberg, Germany, 79106
      • Universitatsklinikum Freiburg /ID# 165187
• Japan
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan, 830-0011
      • Kurume University Hospital /ID# 165718
  • Osaka
    • Osaka-shi, Osaka, Japan, 558-8558
      • Osaka General Medical Center /ID# 212745
    • Suita-shi, Osaka, Japan, 565-0871
      • Osaka University Hospital /ID# 165709
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Juntendo University Hospital /ID# 212912
• Puerto Rico
  • San Juan, Puerto Rico, 00912-3310
    • San Jorge Children Hospital /ID# 160850
• Russian Federation
  • Saint-petersburg, Russian Federation, 197022
    • Scientific and Research Institute of pediatric infections /ID# 163343
  • Moskva
    • Moscow, Moskva, Russian Federation, 109240
      • Federal State Budgetary Institution - Institute of Nutrition /ID# 163345
    • Moscow, Moskva, Russian Federation, 119296
      • National Medical Scientific Centre of children health /ID# 163344
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron /ID# 163323
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz /ID# 163283
  • Valencia, Spain, 46026
    • Hospital Universitario y Politecnico La Fe /ID# 163325
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan de Deu /ID# 163282
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Childrens Hospital /ID# 162718
  • Glasgow, United Kingdom, G514TF
    • Queen Elizabeth University Hos /ID# 162719
  • London, United Kingdom, SE5 9RS
    • King's College Hospital NHS /ID# 162717
• United States
  • California
    • San Francisco, California, United States, 94158
      • Univ of California San Francis /ID# 158002
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado /ID# 157996
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • CT Childrens Medical Ctr, US /ID# 158639
  • Florida
    • Gainesville, Florida, United States, 32610-0272
      • UF Hepatology Research at CTRB /ID# 158008
    • Orlando, Florida, United States, 32803
      • Advent Health /ID# 166022
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University /ID# 158001
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital /ID# 157988
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center /ID# 157997
  • New York
    • New York, New York, United States, 10032-3725
      • Columbia Univ Medical Center /ID# 158000
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Health Care /ID# 157991
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Childrens Hosp Med /ID# 158007
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia /ID# 158003
    • Pittsburgh, Pennsylvania, United States, 15213-2583
      • Child Hosp of Pittsburgh,PA /ID# 158004
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe-Carell Jr. Children's H /ID# 169037
  • Texas
    • Houston, Texas, United States, 77030-3411
      • Baylor College of Medicine /ID# 157989

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Hepatitis C virus (HCV) infection demonstrated by positive anti-HCV antibody (Ab) and HCV ribonucleic acid (RNA) greater than or equal to 1000 International Unit (IU)/mL
• Subjects participating in the intense pharmacokinetic (IPK) part must have been HCV treatment-naive, with or without compensated cirrhosis (Child-Pugh A), human immunodeficiency virus type 1 (HIV-1) negative and must have had a Screening laboratory result indicating HCV genotype (GT) 1, 2, 3, 4, 5, or 6-infection.

Exclusion Criteria:

• Females who were pregnant or breastfeeding
• Positive test result for hepatitis B surface antigen (HbsAg) or positive test result for hepatitis B virus deoxyribonucleic acid (DNA)
• Participants with other known liver diseases
• Decompensated cirrhosis defined as: presence of ascites, history of variceal bleeding, lab values consistent with Child-Pugh class B or C cirrhosis

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: Cohort 1: Adult Formulation; 12 to < 18 years; Adolescents aged 12 to < 18 years old received the adult formulation of glecaprevir (GLE)/pibrentasvir (PIB) 100 mg/ 40 mg co-formulated film-coated tablets for a once daily (QD) total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.	Drug: Glecaprevir/Pibrentasvir Adult Formulation; Co-formulated film-coated tablet (100 mg/40 mg); Other Names: ABT-493/ABT-530; MAVYRET®
Experimental: Cohort 2: Pediatric Formulation; 9 to < 12 years; Children aged 9 to < 12 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The initial proposed dose for children 9 to < 12 years old (30 to < 45 kg) was GLE 200 mg + PIB 75 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 250 mg + PIB 100 mg.	Drug: Glecaprevir + Pibrentasvir Pediatric Formulation; Film-coated pellets/granules (15.67%/8.25%) administered by mixing with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.; Other Names: ABT-493/ABT-530
Experimental: Cohort 3: Pediatric Formulation; 6 to < 9 years; Children aged 6 to < 9 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The initial proposed dose for children 6 to < 9 years old (20 to < 30 kg) was GLE 160 mg + PIB 60 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 200 mg + PIB 80 mg.	Drug: Glecaprevir + Pibrentasvir Pediatric Formulation; Film-coated pellets/granules (15.67%/8.25%) administered by mixing with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.; Other Names: ABT-493/ABT-530
Experimental: Cohort 4: Pediatric Formulation; 3 to < 6 years; Children aged 3 to < 6 years old received a pediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The initial proposed dose for children 3 to < 6 years old (12 to < 20 kg) was GLE 120 mg + PIB 45 mg. After PK analysis from the first 5 enrolled participants the dose was adjusted to GLE 150 mg + PIB 60 mg.	Drug: Glecaprevir + Pibrentasvir Pediatric Formulation; Film-coated pellets/granules (15.67%/8.25%) administered by mixing with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.; Other Names: ABT-493/ABT-530

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Steady-state Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Glecaprevir	The area under the plasma concentration-time curve (AUC) is a method of measurement of the total exposure of a drug in blood plasma. The steady-state exposure of GLE was measured up to 24 hours after dosing at Week 2 and estimated using non-compartmental analysis.	Week 2 from predose to 24 hours post-dose
Steady-state AUC0-24 of Pibrentasvir	The area under the plasma concentration-time curve (AUC) is a method of measurement of the total exposure of a drug in blood plasma. The steady-state exposure of PIB was measured up to 24 hours after dosing at Week 2 and estimated using non-compartmental analysis.	Week 2 from predose to 24 hours post-dose
Percentage of Participants With Sustained Virologic Response 12 Weeks Post Treatment (SVR12)	SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ; 15 IU/mL) 12 weeks after the last actual dose of study drug. Plasma HCV RNA levels were collected using the COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test v2.0. SVR12 was considered a primary efficacy endpoint by the United States (US) regulatory agency and was considered secondary outside of the US.	12 weeks after last dose of study drug (Week 20, 24, or 28 depending on treatment duration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) of Glecaprevir	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administered and before administration of a second dose.	Week 2 from predose to 24 hours post-dose
Apparent Clearance (CL/F) of Glecaprevir From Plasma	CL/F is a quantitative measure of the rate at which a drug substance is removed from the body. It was estimated by non-compartmental pharmacokinetic analysis.	Week 2 from predose to 24 hours post-dose
Maximum Plasma Concentration of Pibrentasvir	Cmax is the peak concentration that a drug or drug metabolite achieves in a specified compartment after the drug has been administered and before administration of a second dose.	Week 2 from predose to 24 hours post-dose
Apparent Clearance of Pibrentasvir From Plasma	CL/F is a quantitative measure of the rate at which a drug substance is removed from the body. It was estimated by non-compartmental pharmacokinetic analysis.	Week 2 from predose to 24 hours post-dose
Percentage of Participants Who Experienced On-treatment Virologic Failure	On-treatment virologic failure is defined as meeting one of the following: A confirmed (defined as two consecutive HCV RNA measurements) increase of > 1 log₁₀ IU/mL above nadir during treatment;; Confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < 15 IU/mL during treatment;; HCV RNA ≥ 15 IU/mL at the end of treatment with at least 6 weeks of treatment.	Up to Week 8, 12, or 16 (depending on treatment duration)
Percentage of Participants With Post-treatment Relapse up to 12 Weeks Post Treatment	Post-treatment relapse is defined as confirmed HCV RNA ≥ 15 IU/mL between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment; excluding participants who had been shown to be re-infected.	Up to 12 weeks after the last dose of study drug (Week 20, 24, or 28 depending on treatment duration)
Percentage of Participants With New Hepatitis C Virus Infection (Reinfection)	Reinfection is defined as confirmed HCV RNA ≥ 15 IU/mL in the post-treatment period in a participant who had HCV RNA < 15 IU/mL at the Final Treatment Visit, along with post-treatment detection of a different HCV genotype, subtype, or clade compared with Baseline, as determined by phylogenetic analysis of the nonstructural viral protein 3 (NS3) or NS5A, and/or NS5B gene sequences.	From the end of treatment up to post-treatment Week 144
Palatability Questionnaire Question 1: How Convenient or Inconvenient Was it to Prepare the Dose?	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE + PIB formulation. Question 1 "How Convenient or Inconvenient Was it to Prepare the Dose?" was answered as "very convenient", "convenient", "borderline", "inconvenient", or "very inconvenient".	Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)
Palatability Questionnaire Question 2: How Long Did it Typically Take for the Child to Take the Dose?	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE + PIB formulation. Question 2 "How Long Did it Typically Take for the Child to Take the Dose?" was answered as "5 minutes or less", "5 to 15 minutes", "15 to 30 minutes", or "more than 30 minutes".	Final treatment visit (up to Week 8, 12, or 16, depending on duration of treatment)
Palatability Questionnaire Question 3: Were You Able to Successfully Administer the Whole Dose to the Child With 1 to 2 Teaspoons (5 to 10 mL) of Soft Food?	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE + PIB formulation. Question 3 "Were You Able to Successfully Administer the Whole Dose to the Child With 1 to 2 Teaspoons (5 to 10 mL) of Soft Food?" was answered as "Yes" or "No".	Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)
Palatability Questionnaire Question 4: Did You Experience Any Resistance When Feeding the Child the Medicine?	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE + PIB formulation. Question 4 "Did You Experience Any Resistance When Feeding the Child the Medicine?" was answered as "Yes" or "No".	Final treatment visit (up to Week 8, 12, or 16 depending on treatment duration)
Palatability Questionnaire Question 4a: Type of Feeding Resistance	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE + PIB formulation. Question 4a "Type of feeding resistance?" tracks feeding resistance experienced at any time during treatment, and was answered as "Did not like taste of medicine", "Did not like texture of medicine", "Did not like the soft food used", "Did not like to swallow the amount of medicine", or "Unrelated to the medicine".	Up to final treatment visit (up to Week 8, 12, or 16 depending on treatment duration)
Palatability Questionnaire Question 5: How Easy or Difficult Was it for the Child to Swallow the Medicine?	For each participant who received the pediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the pediatric GLE/PIB formulation. Question 5 "How Easy or Difficult Was it for the Child to Swallow the Medicine?" was answered as "very easy", "easy", "borderline", "difficult", or "very difficult."	Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Jonas MM, Rhee S, Kelly DA, Del Valle-Segarra A, Feiterna-Sperling C, Gilmour S, Gonzalez-Peralta RP, Hierro L, Leung DH, Ling SC, Lobzin Y, Lobritto S, Mizuochi T, Narkewicz MR, Sabharwal V, Wen J, Kei Lon H, Marcinak J, Topp A, Tripathi R, Sokal E. Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study. Hepatology. 2021 Jul;74(1):19-27. doi: 10.1002/hep.31841.
• Jonas MM, Squires RH, Rhee SM, Lin CW, Bessho K, Feiterna-Sperling C, Hierro L, Kelly D, Ling SC, Strokova T, Del Valle-Segarra A, Lovell S, Liu W, Ng TI, Porcalla A, Gonzalez YS, Burroughs M, Sokal E. Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study. Hepatology. 2020 Feb;71(2):456-462. doi: 10.1002/hep.30840. Epub 2019 Aug 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Actual): May 21, 2020
• Study Completion (Actual): September 12, 2022

Study Registration Dates

• First Submitted: February 24, 2017
• First Submitted That Met QC Criteria: February 24, 2017
• First Posted (Actual): March 1, 2017

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: April 12, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Treatment experienced; Pharmacokinetic; Sofosbuvir; Treatment naïve; Ribavirin (RBV); Glecaprevir; Pibrentasvir; Chronic Hepatitis C Virus; Interferon (IFN); Pegylated interferon (pegIFN); Non-cirrhotic cirrhosis; Compensated (Child-Pugh A) cirrhosis
• 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; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic
• Other Study ID Numbers: M16-123; 2016-004102-34 (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: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• 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 and execution of a data sharing statement. Data requests can be submitted at any time after approval in the US and/or EU and a primary manuscript is accepted for publication. For more information on the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; 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