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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
129
Co-formulated film-coated tablet (100 mg/40 mg)
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.
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.
Time frame: 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.
Time frame: 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.
Time frame: 12 weeks after last dose of study drug (Week 20, 24, or 28 depending on treatment duration)
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.
Time frame: 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.
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Univ of California San Francis /ID# 158002
San Francisco, California, United States
Childrens Hospital Colorado /ID# 157996
Aurora, Colorado, United States
CT Childrens Medical Ctr, US /ID# 158639
Hartford, Connecticut, United States
UF Hepatology Research at CTRB /ID# 158008
Gainesville, Florida, United States
Advent Health /ID# 166022
Orlando, Florida, United States
Indiana University /ID# 158001
Indianapolis, Indiana, United States
Boston Childrens Hospital /ID# 157988
Boston, Massachusetts, United States
Boston Medical Center /ID# 157997
Boston, Massachusetts, United States
Columbia Univ Medical Center /ID# 158000
New York, New York, United States
UNC Health Care /ID# 157991
Chapel Hill, North Carolina, United States
...and 28 more locations
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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."
Time frame: Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)