HCV Infection
Conditions
Brief summary
The purpose of this study is to assess the pharmacokinetics (PK), safety, and efficacy of oral MK-5172 (a fixed dose combination \[FDC\] tablet containing elbasvir \[EBR\] 50 mg and grazoprevir \[GZR\] 100 mg) and EBR/GZR (varying doses) pediatric granules in pediatric hepatitis C virus (HCV)-infected participants who are 3 to \<18 years of age. Within each age cohort (Cohort 1: 12 to \<18 years of age; Cohort 2: 7 to \<12 years of age; and Cohort 3: 3 to \<7 years of age), a Mini Cohort of 7 participants will be enrolled first. For the oldest cohort (Cohort 1), the Mini Cohort will assess ability to swallow a placebo tablet prior to administering active FDC tablets; participants in Cohorts 2 and 3 will take pediatric granules instead of a tablet.
Interventions
DRUGEBR/GZR FDC Tablet
Participants who are 12 to \<18 years of age will receive oral FDC tablets with EBR 50 mg/GZR 100 mg once daily by mouth.
DRUGPlacebo
Placebo tablet matched to EBR/GZR FDC tablet.
DRUGGrazoprevir Oral Granules
Participants 3 to \<12 years of age take grazoprevir granules 0.5 mg by mouth in a soft food vehicle at a dose not to exceed 50 mg.
DRUGElbasvir Oral Granules
Participants 3 to \<12 years of age take elbasvir oral granules 1 mg by mouth in a soft food vehicle at a dose not to exceed 100 mg.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Has documented chronic HCV genotype (GT) 1 or GT4 infection * Has the following liver disease staging assessment: absence of cirrhosis or compensated cirrhosis * Has one of the following HCV treatment statuses: * GT1 and GT4: treatment-naïve (TN), defined as no prior exposure to any interferon (IFN)-containing regimen, ribavirin (RBV), or other HCV-specific direct acting antiviral (DAA) agent * GT1 only: treatment-experienced (TE) with no previous treatment with HCV specific DAA agents. * If female is not pregnant, not breastfeeding, and is either not of childbearing potential or follows the contraceptive guidance during the treatment period and for at least 14 days after the last dose of study treatment.
Exclusion criteria
* Has evidence of decompensated liver disease manifested by the presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy, or other signs or symptoms of advanced liver disease. * Is cirrhotic AND has a Child-Turcotte-Pugh score \>6, corresponding to a Child Class B or C. * Is co-infected with Human Immunodeficiency Virus (HIV). * Has evidence of past or present hepatitis B infection. * Has a history of malignancy ≤5 years prior to signing informed consent or is under evaluation for other active or suspected malignancy. * Female expects to conceive or donate eggs from Day 1 through at least 14 days after the last dose of study treatment or longer. * Has any of the following conditions: organ transplants other than cornea and hair; poor venous access; history of gastric surgery or malabsorption disorders; any clinically significant cardiac abnormalities/dysfunction that may interfere with participant treatment, assessment, or compliance; any major medical condition which might interfere with participant treatment, assessment, or compliance; history of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment; medical/surgical conditions that may result in a need for hospitalization during the study duration; any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, tumor necrosis factor antagonists, or immunosuppressant drugs; life-threatening serious adverse event (SAE) during the screening period; history of chronic hepatitis not caused by HCV. * If female has a positive urine pregnancy test within 24 hours before the first dose of study treatment. * Is taking or plans to take prohibited medications, or is taking herbal supplements. * Has had previous HCV direct acting antiviral (DAA) treatment. * Is currently participating or has participated in a study with an investigational compound within prior 30 days * Has significant emotional problems or a clinically significant psychiatric disorder that may interfere with participant treatment, assessment, or compliance with the protocol. * Has clinically relevant drug or alcohol abuse within prior 12 months that may interfere with participant treatment, assessment, or compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CL/F of GZR at Steady State | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The CL/F of GZR at steady state (Week 4) was determined in each cohort. |
| AUC0-24hr of GZR at Steady State | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The AUC0-24hr of GZR at steady state (Week 4) was determined in each cohort. |
| Cmax of GZR | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The Cmax of GZR at steady state (Week 4) was determined in each cohort. |
| Ctrough of GZR | Week 4: Predose | The Ctrough of GZR at steady state (Week 4) was determined at steady state prior to dosing in each cohort. |
| Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The AUC0-24hr of EBR at steady state (Week 4) was determined in each cohort. |
| Maximum Plasma Concentration (Cmax) of EBR | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The Cmax of EBR at steady state (Week 4) was determined in each cohort. |
| Steady State Predose Drug Concentration (Ctrough) of EBR | Week 4: Predose | The Ctrough of EBR at steady state (Week 4) was determined at steady state prior to dosing in each cohort. |
| Apparent Clearance (CL/F) of EBR at Steady State | Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose | The CL/F of EBR at steady state (Week 4) was determined in each cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Discontinuing Study Treatment Due to an AE | Up to 12 weeks | The percentage of participants discontinuing study therapy due to an AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12) | Week 24 | The percentage of participants achieving SVR12, defined as hepatitis C virus (HCV) ribonucleic acid (RNA) \< lower limit of quantification (LLOQ) 12 weeks after completing study therapy, was determined in each cohort. |
| Percentage of Participants With ≥1 Adverse Event (AE) | Up to 36 weeks | The percentage of participants with ≥1 AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. |
Countries
Germany, Poland, Sweden, United States
Participant flow
Recruitment details
Male and female participants 3 to \<18 years of age with chronic hepatitis C virus (HCV) genotype 1 (GT1) or GT4 were enrolled at 14 global study sites.
Participants by arm
| Arm | Count |
|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded Pediatric participants 12 to \<18 years of age received EBR/GZR 50 mg/100 mg FDC tablets once daily for 12 weeks. | 22 |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded Participants who are 7 to \<12 years of age received EBR/GZR 30 mg/60 mg pediatric granules once daily for 12 weeks. | 17 |
| Age Cohort 3: 3 to <7 Years: Mini Participants who are 3 to \<7 years of age received a pediatric formulation of EBR/GZR (weight-based dosing) once daily for 12 weeks. The Mini cohort consists of the first 7 participants enrolled into Age Cohort 3. Participants \<20 kg received EBR/GZR 15 mg/30 mg, and participants ≥20 kg received EBR/GZR 15 mg/50 mg. | 7 |
| Age Cohort 3: 3 to <7 Years: Expanded Participants who are 3 to \<7 years of age received a pediatric formulation of EBR/GZR 25 mg/50 mg once daily for 12 weeks. The Expanded cohort consists of 11 participants enrolled after the Mini Cohort of 7 participants. | 11 |
| Total | 57 |
Baseline characteristics
| Characteristic | Age Cohort 1: 12 to <18 Years: Mini and Expanded | Age Cohort 2: 7 to <12 Years: Mini and Expanded | Age Cohort 3: 3 to <7 Years: Mini | Age Cohort 3: 3 to <7 Years: Expanded | Total |
|---|---|---|---|---|---|
| Age, Continuous | 14.1 Years STANDARD_DEVIATION 1.9 | 8.7 Years STANDARD_DEVIATION 1.2 | 3.7 Years STANDARD_DEVIATION 0.8 | 4.8 Years STANDARD_DEVIATION 1.3 | 9.4 Years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 14 Participants | 6 Participants | 11 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 17 Participants | 7 Participants | 11 Participants | 56 Participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 3 Participants | 8 Participants | 29 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 4 Participants | 3 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 17 | 0 / 7 | 0 / 11 |
| other Total, other adverse events | 17 / 22 | 13 / 17 | 6 / 7 | 9 / 11 |
| serious Total, serious adverse events | 1 / 22 | 0 / 17 | 0 / 7 | 1 / 11 |
Outcome results
Primary
Apparent Clearance (CL/F) of EBR at Steady State
The CL/F of EBR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Apparent Clearance (CL/F) of EBR at Steady State | 23.53 L/hr |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Apparent Clearance (CL/F) of EBR at Steady State | 12.21 L/hr |
| Age Cohort 3: 3 to <7 Years: Mini | Apparent Clearance (CL/F) of EBR at Steady State | 9.94 L/hr |
| Age Cohort 3: 3 to <7 Years: Expanded | Apparent Clearance (CL/F) of EBR at Steady State | 8.98 L/hr |
Primary
Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State
The AUC0-24hr of EBR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their pharmacokinetic (PK) data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State | 2.41 µM*hr |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State | 2.79 µM*hr |
| Age Cohort 3: 3 to <7 Years: Mini | Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State | 1.71 µM*hr |
| Age Cohort 3: 3 to <7 Years: Expanded | Area Under the Plasma Concentration-Time Curve From Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State | 3.15 µM*hr |
Primary
AUC0-24hr of GZR at Steady State
The AUC0-24hr of GZR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | AUC0-24hr of GZR at Steady State | 1.45 µM*hr |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | AUC0-24hr of GZR at Steady State | 1.42 µM*hr |
| Age Cohort 3: 3 to <7 Years: Mini | AUC0-24hr of GZR at Steady State | 0.77 µM*hr |
| Age Cohort 3: 3 to <7 Years: Expanded | AUC0-24hr of GZR at Steady State | 1.66 µM*hr |
Primary
CL/F of GZR at Steady State
The CL/F of GZR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: No participants are included in the analysis as the CL/F of GZR was not calculable due to nonlinear PK.
Primary
Cmax of GZR
The Cmax of GZR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Cmax of GZR | 0.25 µM |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Cmax of GZR | 0.19 µM |
| Age Cohort 3: 3 to <7 Years: Mini | Cmax of GZR | 0.09 µM |
| Age Cohort 3: 3 to <7 Years: Expanded | Cmax of GZR | 0.29 µM |
Primary
Ctrough of GZR
The Ctrough of GZR at steady state (Week 4) was determined at steady state prior to dosing in each cohort.
Time frame: Week 4: Predose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included. One participant in Age Cohort 2: 7 to \<12 Years: Mini and Expanded had missing Ctrough data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Ctrough of GZR | 16.20 nM |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Ctrough of GZR | 16.27 nM |
| Age Cohort 3: 3 to <7 Years: Mini | Ctrough of GZR | 13.79 nM |
| Age Cohort 3: 3 to <7 Years: Expanded | Ctrough of GZR | 16.17 nM |
Primary
Maximum Plasma Concentration (Cmax) of EBR
The Cmax of EBR at steady state (Week 4) was determined in each cohort.
Time frame: Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Maximum Plasma Concentration (Cmax) of EBR | 0.19 µM |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Maximum Plasma Concentration (Cmax) of EBR | 0.21 µM |
| Age Cohort 3: 3 to <7 Years: Mini | Maximum Plasma Concentration (Cmax) of EBR | 0.14 µM |
| Age Cohort 3: 3 to <7 Years: Expanded | Maximum Plasma Concentration (Cmax) of EBR | 0.28 µM |
Primary
Steady State Predose Drug Concentration (Ctrough) of EBR
The Ctrough of EBR at steady state (Week 4) was determined at steady state prior to dosing in each cohort.
Time frame: Week 4: Predose
Population: All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included. One participant in Age Cohort 2: 7 to \<12 Years: Mini and Expanded had missing Ctrough data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Steady State Predose Drug Concentration (Ctrough) of EBR | 59.76 nM |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Steady State Predose Drug Concentration (Ctrough) of EBR | 59.43 nM |
| Age Cohort 3: 3 to <7 Years: Mini | Steady State Predose Drug Concentration (Ctrough) of EBR | 34.61 nM |
| Age Cohort 3: 3 to <7 Years: Expanded | Steady State Predose Drug Concentration (Ctrough) of EBR | 68.92 nM |
Secondary
Percentage of Participants Discontinuing Study Treatment Due to an AE
The percentage of participants discontinuing study therapy due to an AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Up to 12 weeks
Population: All randomized participants who received ≥1 dose of study drug are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.0 Percentage of Participants |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.0 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Mini | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.0 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Expanded | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.0 Percentage of Participants |
Secondary
Percentage of Participants With ≥1 Adverse Event (AE)
The percentage of participants with ≥1 AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Time frame: Up to 36 weeks
Population: All randomized participants who received ≥1 dose of study drug are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Percentage of Participants With ≥1 Adverse Event (AE) | 81.8 Percentage of Participants |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Percentage of Participants With ≥1 Adverse Event (AE) | 76.5 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Mini | Percentage of Participants With ≥1 Adverse Event (AE) | 85.7 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Expanded | Percentage of Participants With ≥1 Adverse Event (AE) | 81.8 Percentage of Participants |
Secondary
Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12)
The percentage of participants achieving SVR12, defined as hepatitis C virus (HCV) ribonucleic acid (RNA) \< lower limit of quantification (LLOQ) 12 weeks after completing study therapy, was determined in each cohort.
Time frame: Week 24
Population: All randomized participants who received ≥1 dose of study treatment are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort 1: 12 to <18 Years: Mini and Expanded | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12) | 100.0 Percentage of Participants |
| Age Cohort 2: 7 to <12 Years: Mini and Expanded | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12) | 100.0 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Mini | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12) | 100.0 Percentage of Participants |
| Age Cohort 3: 3 to <7 Years: Expanded | Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12) | 100.0 Percentage of Participants |