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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 129
- 试验地点
- 38
- 主要终点
- Steady-state AUC0-24 of Pibrentasvir
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Glecaprevir/Pibrentasvir Adult Formulation (Drug)
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.
干预措施: Glecaprevir + Pibrentasvir Pediatric Formulation (Drug)
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.
干预措施: Glecaprevir + Pibrentasvir Pediatric Formulation (Drug)
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.
干预措施: Glecaprevir + Pibrentasvir Pediatric Formulation (Drug)
结局指标
主要结局
Steady-state AUC0-24 of Pibrentasvir
时间窗: Week 2 from predose to 24 hours post-dose
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.
Steady-state Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Glecaprevir
时间窗: Week 2 from predose to 24 hours post-dose
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.
Percentage of Participants With Sustained Virologic Response 12 Weeks Post Treatment (SVR12)
时间窗: 12 weeks after last dose of study drug (Week 20, 24, or 28 depending on treatment duration)
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.
次要结局
- Maximum Plasma Concentration (Cmax) of Glecaprevir(Week 2 from predose to 24 hours post-dose)
- Percentage of Participants With Post-treatment Relapse up to 12 Weeks Post Treatment(Up to 12 weeks after the last dose of study drug (Week 20, 24, or 28 depending on treatment duration))
- Apparent Clearance (CL/F) of Glecaprevir From Plasma(Week 2 from predose to 24 hours post-dose)
- Percentage of Participants Who Experienced On-treatment Virologic Failure(Up to Week 8, 12, or 16 (depending on treatment duration))
- Percentage of Participants With New Hepatitis C Virus Infection (Reinfection)(From the end of treatment up to post-treatment Week 144)
- Maximum Plasma Concentration of Pibrentasvir(Week 2 from predose to 24 hours post-dose)
- Apparent Clearance of Pibrentasvir From Plasma(Week 2 from predose to 24 hours post-dose)
- Palatability Questionnaire Question 2: How Long Did it Typically Take for the Child to Take the Dose?(Final treatment visit (up to Week 8, 12, or 16, depending on duration of treatment))
- Palatability Questionnaire Question 5: How Easy or Difficult Was it for the Child to Swallow the Medicine?(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?(Final treatment visit (up to Week 8, 12, or 16 depending on treatment duration))
- Palatability Questionnaire Question 1: How Convenient or Inconvenient Was it to Prepare the Dose?(Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration))
- 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?(Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration))
- Palatability Questionnaire Question 4a: Type of Feeding Resistance(Up to final treatment visit (up to Week 8, 12, or 16 depending on treatment duration))