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This is a randomized, parallel-group, placebo-controlled, multi-site, multinational, double-blind followed by open label period, Phase 3 trial of 100 mg of grazoprevir (MK-5172) in combination with 50 mg of elbasvir (MK-8742) (grazoprevir/elbasvir fixed-dose combination [FDC]) in treatment-naïve (TN) participants with chronic hepatitis C virus (HCV), genotype (GT) 1, 4 or 6 infection. The primary hypothesis is that the percentage of participants receiving grazoprevir/elbasvir FDC in the Immediate Treatment Group (ITG) achieving Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) will be superior to the historical reference rate of 73%.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Experimental | Participants receive a grazoprevir/elbasvir FDC tablet once daily (q.d.) by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and are followed-up for 24 weeks to Week 36. |
|
| Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Placebo Comparator | Participants receive a placebo tablet q.d. by mouth for 12 weeks (placebo treatment period). After a 4-week Follow-Up period, participants receive open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants are then followed-up for 24 weeks to Week 52. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Grazoprevir/Elbasvir | Drug | FDC tablet containing 100 mg of grazoprevir and 50 mg of elbasvir taken q.d. by mouth for 12 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\ | 12 weeks after end of all therapy (Study Week 24) |
| Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period and First 14 Follow-up Days | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. | DB Treatment period plus first 14 follow-up days (up to 14 weeks) |
| Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. A participant could discontinue from treatment but continue to participate in the study as long as consent was not withdrawn. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \ |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Study Therapy (SVR4) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR4 was defined as HCV RNA \ |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30311701 | Background | Wei L, Jia JD, Wang FS, Niu JQ, Zhao XM, Mu S, Liang LW, Wang Z, Hwang P, Robertson MN, Ingravallo P, Asante-Appiah E, Wei B, Evans B, Hanna GJ, Talwani R, Duan ZP, Zhdanov K, Cheng PN, Tanwandee T, Nguyen VK, Heo J, Isakov V, George J; C-CORAL Investigators. Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study. J Gastroenterol Hepatol. 2019 Jan;34(1):12-21. doi: 10.1111/jgh.14509. Epub 2018 Dec 9. | |
| 29761174 |
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A total of 489 participants were randomized to treatment, and 488 participants received ≥1 dose of study drug during the blinded period. One participant randomized to the ITG withdrew consent after randomization, but prior to receiving study drug.
For Subject Disposition, Period 1 covers Day 1 through Week 12 for both treatment groups. Period 2 covers Week 12 through Week 36 for the Immediate Treatment Group (ITG) and Week 12 through Week 28 for the Deferred Treatment Group (DTG). Period 3 covers Week 28 through Week 52 for the DTG; the ITG completed the study with Period 2.
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| ID | Title | Description |
|---|---|---|
| FG000 | Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Participants received a grazoprevir/elbasvir fixed-dose combination (FDC) tablet once daily (q.d.) by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and were followed-up for 24 weeks to Week 36. |
| FG001 | Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Participants received a placebo tablet q.d. by mouth for 12 weeks (placebo treatment period). After a 4-week Follow-Up period, participants received open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants were then followed-up for 24 weeks to Week 52. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 (Double-blind [DB]) |
|
| ||||||||||||||||||||||||
| Period 2 (ITG Follow-up/DTG Open Label) |
| |||||||||||||||||||||||||
| Period 3 (DTG Follow-up) |
|
All randomized participants who received at least one dose of study treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Participants received a grazoprevir/elbasvir FDC tablet q.d. by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and were followed-up for 24 weeks to Week 36. |
| BG001 | Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\ | All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in the primary efficacy analysis. | Posted | Number | 97.5% Confidence Interval | percentage of participants | 12 weeks after end of all therapy (Study Week 24) |
|
Immediate Treatment Group = Up to Week 36; Deferred Treatment: Placebo Group = Up to Week 16; Deferred Treatment: Grazoprevir/Elbasvir Group = Week 16 to Week 52
All randomized participants who received ≥1 dose of study treatment and had any safety follow-up data. AEs were reported by the treatment that participants were receiving at the time of the event; AEs for Deferred Group reported separately for placebo and active treatment periods.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Immediate Treatment Group (ITG): Grazoprevir/Elbasvir | Participants received a grazoprevir/elbasvir FDC tablet q.d. by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and were followed-up for 24 weeks to Week 36 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Evans syndrome | Blood and lymphatic system disorders | MedDRA 20.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D006526 | Hepatitis C |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D006525 | Hepatitis, Viral, Human |
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| ID | Term |
|---|---|
| C000611265 | elbasvir-grazoprevir drug combination |
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|
| Placebo | Drug | Placebo tablet matching grazoprevir/elbasvir FDC tablet taken q.d. by mouth for 12 weeks. |
|
| DB Treatment period (up to 12 weeks) |
| 24 weeks after end of all therapy (Study Week 36) |
| 4 weeks after end of all therapy (Study Week 16) |
| Result |
| George J, Burnevich E, Sheen IS, Heo J, Kinh NV, Tanwandee T, Cheng PN, Kim DY, Tak WY, Kizhlo S, Zhdanov K, Isakov V, Liang L, Lindore P, Ginanni J, Nguyen BY, Wahl J, Barr E, Robertson M, Ingravallo P, Talwani R; C-CORAL Study Investigators. Elbasvir/grazoprevir in Asia-Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection. Hepatol Commun. 2018 Apr 4;2(5):595-606. doi: 10.1002/hep4.1177. eCollection 2018 May. |
| 35920743 | Derived | Dalgard O, Litwin AH, Shibolet O, Grebely J, Nahass R, Altice FL, Conway B, Gane EJ, Luetkemeyer AF, Peng CY, Iser D, Gendrano IN, Kelly MM, Haber BA, Platt H, Puenpatom A; CO-STAR Investigators. Health-related quality of life in people receiving opioid agonist treatment and treatment for hepatitis C virus infection. J Addict Dis. 2023 Jul-Sep;41(3):213-224. doi: 10.1080/10550887.2022.2088978. Epub 2022 Aug 3. |
| 33319038 | Derived | Wei L, Jia JD, Duan ZP, Wang FS, Niu JQ, Xie W, Huang WX, Zhang MX, Huang Y, Wang MR, Wu SM, Zhao YR, Jia ZS, Zhao XM, Mu SM, Liang LW, Wang Z, Puenpatom A, Hwang P, Robertson MN, Ingravallo P, Asante-Appiah E, Wei B, Evans B, Hanna GJ, Talwani R. Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial. JGH Open. 2020 Jul 15;4(6):1065-1073. doi: 10.1002/jgh3.12387. eCollection 2020 Dec. |
| 29461687 | Derived | Asselah T, Reesink H, Gerstoft J, de Ledinghen V, Pockros PJ, Robertson M, Hwang P, Asante-Appiah E, Wahl J, Nguyen BY, Barr E, Talwani R, Serfaty L. Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis. Liver Int. 2018 Sep;38(9):1583-1591. doi: 10.1111/liv.13727. Epub 2018 Mar 31. |
| Withdrawal by Subject |
|
| Not Treated |
|
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
Participants received a placebo tablet q.d. by mouth for 12 weeks (placebo treatment period). After a 4-week Follow-Up period, participants received open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants were then followed-up for 24 weeks to Week 52. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Participants received a grazoprevir/elbasvir FDC tablet q.d. by mouth during a 12-week Active Treatment period (Week 1 to Week 12) and were followed-up for 24 weeks to Week 36. |
| OG001 | Deferred Treatment Group (DTG): Placebo > Grazoprevir/Elbasvir | Participants received a placebo tablet q.d. by mouth for 12 weeks (placebo treatment period). After a 4-week Follow-Up period, participants received open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants were then followed-up for 24 weeks to Week 52. |
|
|
|
| Primary | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the DB Treatment Period and First 14 Follow-up Days | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. | All randomized participants who received at least one dose of study treatment during the double-blind treatment period. | Posted | Number | percentage of participants | DB Treatment period plus first 14 follow-up days (up to 14 weeks) |
|
|
|
|
| Primary | Percentage of Participants That Discontinued From Study Therapy Due to AEs During the DB Treatment Period | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that is temporally associated with the use of the Sponsor's product, is also an AE. A participant could discontinue from treatment but continue to participate in the study as long as consent was not withdrawn. The primary safety analysis compared the safety data of the Immediate Treatment Group during the active treatment period to those of the Deferred Treatment Group during the placebo treatment period. | All randomized participants who received at least one dose of study treatment during the double-blind treatment period. | Posted | Number | percentage of participants | DB Treatment period (up to 12 weeks) |
|
|
|
|
| Secondary | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \ | All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in the secondary efficacy analysis. | Posted | Number | 95% Confidence Interval | percentage of participants | 24 weeks after end of all therapy (Study Week 36) |
|
|
|
| Other Pre-specified | Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Study Therapy (SVR4) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a LLOQ of 15 IU/mL. SVR4 was defined as HCV RNA \ | All randomized participants in the Immediate Treatment Group who received at least one dose of study treatment. The Deferred Treatment Group was not included in this efficacy analysis. | Posted | Number | 95% Confidence Interval | percentage of participants | 4 weeks after end of all therapy (Study Week 16) |
|
|
|
| 9 |
| 365 |
| 85 |
| 365 |
| EG001 | Deferred Treatment Group (DTG): Placebo | Participants received a placebo tablet q.d. by mouth for 12 weeks during the double-blind treatment period (Weeks 1 to 12). Participants were then followed-up for 4 weeks to Week 16. | 3 | 123 | 30 | 123 |
| EG002 | Deferred Treatment Group (DTG): Grazoprevir/Elbasvir | Participants received open-label grazoprevir/elbasvir FDC during a 12-week Active Treatment period (Week 16 to Week 28). Participants were then followed-up for 24 weeks to Week 52. | 6 | 121 | 21 | 121 |
| Enteritis | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Irritable bowel syndrome | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Concussion | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Foot fracture | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 20.0 | Systematic Assessment |
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| Completed suicide | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Uterine polyp | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
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| Atrial fibrillation | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Cholecystitis acute | Hepatobiliary disorders | MedDRA 20.0 | Systematic Assessment |
|
| Ankle fracture | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Uterine haemorrhage | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
| D014777 |
| Virus Diseases |
| D018178 | Flaviviridae Infections |
| D012327 | RNA Virus Infections |
| D006505 | Hepatitis |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |