| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic genotype 1 or genotype 4 Hepatitis C Virus infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic genotype 1 or genotype 4 Hepatitis C Virus infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10047457 |
| E.1.2 | Term | Viral hepatitis C |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the steadystate EBR and GZR PK in children and adolescents grouped by age. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of 12 weeks of treatment with EBR/GZR in children and adolescents grouped by age.
2. To evaluate the efficacy of 12 weeks of treatment with EBR/GZR in children and adolescents grouped by age, as assessed by the proportion of participants achieving SVR12.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial if the subject consents to participate in this research. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of
collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1. The participant has HCV RNA (≥1,000 IU/mL in peripheral blood) at the time of screening.
2. The participant has documented chronic HCV GT1 or GT4 infection as follows:
a) positive for anti-HCV antibody, HCV RNA, or HCV GT1 or GT4 at least 6 months before Day 1; or
b) positive for anti-HCV antibody or HCV RNA with a liver biopsy consistent with chronic HCV infection (such as the presence of fibrosis) before Day 1.
3. For participants with GT4, HCV RNA <800,000 IU/mL at the time of screening.
4. For participants with GT1a, no evidence of NS5A RASs detected at screening at positions 28, 30, 31, and/or 93.
5. The participant has liver disease staging assessment as follows:
a) Absence of cirrhosis (F0 to F3) defined as any one of the following:
i. Liver biopsy performed within 24 months of Day 1 showing absence of cirrhosis, or
ii. FibroScan® performed within 12 months of Day 1 with a result ≤12.5 kPa (only for participants aged 12 years up to 18 years), or
iii. In the absence of criterion i. or ii. above, absence of cirrhosis can be determined by the investigator according to local clinical standards that includes physical examination during screening in combination
with laboratory evaluation during screening and/or imaging test within 6 months of screening.
b) Compensated Cirrhosis (F4) defined as any one of the following:
i. Liver biopsy performed prior to Day 1 showing cirrhosis, or
ii. FibroScan® performed within 12 months of Day 1 with a result >12.5 kPa (only for participants aged 12 years up to 18 years), or
iii. In the absence of criterion i. or ii. above, cirrhosis can be determined by the investigator according to local clinical standards that includes physical examination during screening in combination with historical
or current laboratory evaluation and/or imaging with findings consistent with cirrhosis (such as firm or enlarged liver, splenomegaly).
6. The participant has an HCV treatment status that is one of the following:
a) GT1 and GT4: HCV TN (defined as no prior exposure to any interferon [IFN]-containing regimen, RBV, or other HCV-specific DAA agent).
b) GT1 only: HCV TE (defined as prior virologic failure during or after treatment with an IFN or pegylated-IFN with or without RBV; or intolerance to IFN or pegylated-IFN with or without RBV). Participants cannot have previously received treatment with HCV specific DAA agents.
7. The participant is male or female between 3 years to less than 18 years of age on day of signing informed consent/assent.
8. For participants in the Mini Age Cohorts only (these restrictions do not apply for the Expanded Age Cohorts):
a) Weight:
i. Age Cohort 1: ≥32 kg
ii. Age Cohort 2: ≥19 kg
iii. Age Cohort 3: ≥12 kg
b) Race: Participants of non-Asian Race.
9. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in the protocol OR
b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 14 days after the last dose of study treatment.
10. The participant’s legally acceptable representative(s) provides written informed consent for the study and, when applicable, the participant provides written informed assent.
11. The participant must be able to swallow the placebo to EBR/GZR (FDC) prior to allocation. This is applicable only to participants in Mini Age Cohort 1 and, if it is determined by PK analysis that Expanded Age Cohort 1 will also receive the adult FDC dose, to participants in Expanded Age Cohort 1. |
|
| E.4 | Principal exclusion criteria |
1. The participant 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.
2. The participant is cirrhotic AND has a Child-Turcotte-Pugh score >6, corresponding to a Child Class B or C.
3. The participant is co-infected with HIV.
4. Has evidence of past or present hepatitis B infection (either hepatitis B core antibody [anti-HBc] positive and/or hepatitis B surface antigen [HBsAg] positive) at screening.
5. The participant has a history of malignancy ≤5 years prior to signing informed consent or is under evaluation for other active or suspected malignancy including HCC.
6. A WOCBP is expecting to conceive or donate eggs from Day 1 through at least 14 days after the last dose of study treatment or longer if dictated by local regulations.
7. The participant has any of the following conditions:
a) organ transplants (including hematopoietic stem cell transplants) other than cornea and hair.
b) poor venous access that precludes routine peripheral blood sampling required for this study.
c) history of gastric surgery (eg, stapling, bypass) or malabsorption disorders (eg, uncontrolled celiac sprue disease).
d) any clinically significant cardiac abnormalities/dysfunction that may interfere with participant treatment, assessment, or compliance with the protocol, including but not limited to: unstable angina, unstable congestive heart failure, unstable arrhythmia; participants currently under evaluation for a potentially clinically significant cardiac abnormality/dysfunction are also excluded.
e) any major medical condition, clinically significant illness (other than HCV), pre study laboratory or electrocardiogram (ECG) abnormality, or history of any illness, including failure to thrive, which, in the opinion of the investigator, might interfere with participant treatment, assessment, compliance with the
protocol, or confound the results of the study or pose additional risk in administering the study drug to the participant.
f) history of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment, other than for minor elective procedures.
g) medical/surgical conditions that may result in a need for hospitalization during the study duration.
h) any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, tumor necrosis factor antagonists, or other immunosuppressant drugs through FW24.
i) life-threatening serious adverse event (SAE) during the screening period.
j) Evidence of history of chronic hepatitis not caused by HCV, including but not limited to, drug-induced hepatitis, hemochromatosis, Wilson’s disease, α1 antitrypsin deficiency, alcoholic liver disease, and autoimmune hepatitis.
8. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
9. The participant is taking or plans to take any of the prohibited medications listed in the protocol or is taking herbal supplements, including but not limited to St. John’s Wort (Hypericum perforatum), from 2 weeksprior to Day 1 through 2 weeks after the study treatment period.
10. The participant has had previous HCV DAA treatment.
11. The participant is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent/assent and is not willing to refrain from participating in another such study through 24 weeks after the study treatment period (FW24).
12. The participant has exclusionary laboratory values at the screening visit as listed in the protocol.
13. The participant has significant emotional problems or a clinically significant psychiatric disorder that may interfere with participant treatment, assessment, or compliance with the protocol.
14. The participant has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with participant treatment, assessment, or compliance with the protocol.
15. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Week 4 AUC0-24, maximum observed drug concentration (Cmax), drug concentration immediately pre-dose (Ctrough), and apparent clearance (CL/F). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Number of participants experiencing AEs.
2. Number of participants discontinuing study drug due to AEs.
3. SVR12: defined as HCV RNA <lower limit of quantification (LLOQ) (either target detected, but unquantifiable [TD(u)] or target not detected [TND]) 12 weeks after the end of all study therapy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after treatment completion |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The overall study ends when the last participant completes the last study-related phone-call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be contacted by the investigator) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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