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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-003836-38 | EudraCT Number |
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This is a study comparing grazoprevir (MK-5172) plus elbasvir (MK-8742) treatment with sofosbuvir (SOF) plus Pegylated Interferon plus Ribavirin (RBV) [PR] treatment in treatment-naïve and prior PR treatment failure participants with chronic Hepatitis C Virus (HCV) genotype (GT)1, GT4, or GT6 infection. The primary objectives are to compare efficacy (assessed by the percentage of participants achieving sustained virologic response 12 weeks after ending study treatment [SVR12]) and safety between the grazoprevir plus elbasvir treatment arm and the SOF plus PR treatment arm. The primary hypothesis is that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir treatment arm is non-inferior to that in the SOF plus PR treatment arm.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Grazoprevir + Elbasvir | Experimental | Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up. |
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| SOF + PR | Active Comparator | Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sofosbuvir | Drug | 400 mg tablets, taken orally (PO) every day (QD) for 12 weeks. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12) | Hepatitis C Virus ribonucleic acid (HCV-RNA) levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR12 was defined as HCV RNA below the lower limit of quantification (\ | 12 weeks after end of all therapy (Study Week 24) |
| Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who experienced at least one AE was reported for each treatment arm. | Treatment + First 14 days of follow-up (Up to Week 14) |
| Percentage of Participants Discontinuing Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who discontinued study treatment due to an AE was reported for each treatment arm. Participants that discontinued study drug treatment due to an AE may have still continued on trial. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 safety events were pre-specified by the protocol to evaluate safety and test the safety superiority hypothesis. Tier 1 safety events were chosen to assess broad tolerability, hematological side effects and liver-related laboratory abnormalities. For this study, Tier 1 safety events included: any serious drug-related AE, any drug-related AE leading to permanent discontinuation (DC) of all study drugs, neutrophil count <0.75 x 10^9/L, hemoglobin <10 g/dL, severe depression, hepatic events of clinical interest (defined by abnormal increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST], or alkaline phosphatase [ALP]), or events meeting stopping rule criteria for DC from trial (due to abnormal increases of ALT, AST, or ALP with/without pre-specified related AEs). The percentage of participants who experienced each individual event that was defined as a Tier 1 safety event during the study treatment period was reported for each treatment arm. |
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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 |
|---|---|---|---|
| 27542322 | Result | Sperl J, Horvath G, Halota W, Ruiz-Tapiador JA, Streinu-Cercel A, Jancoriene L, Werling K, Kileng H, Koklu S, Gerstoft J, Urbanek P, Flisiak R, Leiva R, Kazenaite E, Prinzing R, Patel S, Qiu J, Asante-Appiah E, Wahl J, Nguyen BY, Barr E, Platt HL. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial. J Hepatol. 2016 Dec;65(6):1112-1119. doi: 10.1016/j.jhep.2016.07.050. Epub 2016 Aug 16. | |
| 30587935 |
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A total of 257 participants were randomized to treatment: 129 to Grazoprevir + Elbasvir arm and 128 to Sofosbuvir plus Pegylated Interferon/Ribavirin (SOF + PR) arm. Two participants in the SOF + PR arm withdrew from study prior to treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Grazoprevir + Elbasvir | Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up. |
| FG001 | SOF + PR |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| PegIntron |
| Biological |
PegIntron administered subcutaneously every week (QW) at 1.5 mcg/kg for 12 weeks. |
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| Ribavirin | Drug | Capsule and/or tablet administered PO twice daily (BID) based on weight (1000 - 1200 mg) for 12 weeks. |
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| Grazoprevir/Elbasvir (100 mg/50 mg) FDC | Drug | Grazoprevir/Elbasvir (100 mg/50 mg) FDC, taken PO QD for 12 weeks. |
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| Up to Week 12 |
| Treatment + First 14 days of follow-up (Up to Week 14) |
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR24 was defined as HCV RNA \ | 24 weeks after end of all therapy (Study Week 36) |
| Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR4 was defined as HCV RNA \ | 4 weeks after end of all therapy (Study Week 16) |
| Derived |
| Ng X, Nwankwo C, Arduino JM, Corman S, Lasch KE, Lustrino JM, Patel S, Platt HL, Qiu J, Sperl J. Patient-reported outcomes in individuals with hepatitis C virus infection treated with elbasvir/grazoprevir. Patient Prefer Adherence. 2018 Dec 11;12:2631-2638. doi: 10.2147/PPA.S172732. eCollection 2018. |
| 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. |
| 29404492 | Derived | Reau N, Robertson MN, Feng HP, Caro L, Yeh WW, Nguyen BT, Wahl J, Barr E, Hwang P, Klopfer SO. Concomitant proton pump inhibitor use does not reduce the efficacy of elbasvir/grazoprevir: A pooled analysis of 1,322 patients with hepatitis C infection. Hepatol Commun. 2017 Aug 22;1(8):757-764. doi: 10.1002/hep4.1081. eCollection 2017 Oct. |
| 29344726 | Derived | Zeuzem S, Serfaty L, Vierling J, Cheng W, George J, Sperl J, Strasser S, Kumada H, Hwang P, Robertson M, Wahl J, Barr E, Talwani R, Platt H. The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection. J Gastroenterol. 2018 May;53(5):679-688. doi: 10.1007/s00535-018-1429-3. Epub 2018 Jan 17. |
Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up.
| Treated |
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| COMPLETED |
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| NOT COMPLETED |
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Full Analysis Set (FAS); all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | Grazoprevir + Elbasvir | Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up. |
| BG001 | SOF + PR | Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| 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 | Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12) | Hepatitis C Virus ribonucleic acid (HCV-RNA) levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR12 was defined as HCV RNA below the lower limit of quantification (\ | FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | percentage of participants | 12 weeks after end of all therapy (Study Week 24) |
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| Primary | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who experienced at least one AE was reported for each treatment arm. | All Subjects as Treated (ASaT) population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | percentage of participants | Treatment + First 14 days of follow-up (Up to Week 14) |
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| Primary | Percentage of Participants Discontinuing Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), 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 preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who discontinued study treatment due to an AE was reported for each treatment arm. Participants that discontinued study drug treatment due to an AE may have still continued on trial. | ASaT population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | percentage of participants | Up to Week 12 |
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| Secondary | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 safety events were pre-specified by the protocol to evaluate safety and test the safety superiority hypothesis. Tier 1 safety events were chosen to assess broad tolerability, hematological side effects and liver-related laboratory abnormalities. For this study, Tier 1 safety events included: any serious drug-related AE, any drug-related AE leading to permanent discontinuation (DC) of all study drugs, neutrophil count <0.75 x 10^9/L, hemoglobin <10 g/dL, severe depression, hepatic events of clinical interest (defined by abnormal increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST], or alkaline phosphatase [ALP]), or events meeting stopping rule criteria for DC from trial (due to abnormal increases of ALT, AST, or ALP with/without pre-specified related AEs). The percentage of participants who experienced each individual event that was defined as a Tier 1 safety event during the study treatment period was reported for each treatment arm. | ASaT population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | percentage of participants | Treatment + First 14 days of follow-up (Up to Week 14) |
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| Secondary | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR24 was defined as HCV RNA \ | FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | percentage of participants | 24 weeks after end of all therapy (Study Week 36) |
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| Secondary | Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR4 was defined as HCV RNA \ | FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis. | Posted | Number | 95% Confidence Interval | percentage of participants | 4 weeks after end of all therapy (Study Week 16) |
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Up to Follow-up Week 24
ASaT population; all randomized participants who received at least one dose of study treatment. Two randomized participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
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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 | Grazoprevir + Elbasvir | Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up. | 1 | 129 | 44 | 129 | ||
| EG001 | SOF + PR | Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up. | 6 | 126 | 114 | 126 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Angina pectoris | Cardiac disorders | MedDRA 18.1 | Systematic Assessment |
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| Proctitis | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Infection | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Influenza | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Proctitis infectious | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Tooth abscess | Infections and infestations | MedDRA 18.1 | Systematic Assessment |
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| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Cerebrovascular accident | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
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| Drug dependence | Psychiatric disorders | MedDRA 18.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | MedDRA 18.1 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Asthenia | General disorders | MedDRA 18.1 | Systematic Assessment |
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| Chills | General disorders | MedDRA 18.1 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 18.1 | Systematic Assessment |
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| Influenza like illness | General disorders | MedDRA 18.1 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 18.1 | Systematic Assessment |
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| Accidental overdose | Injury, poisoning and procedural complications | MedDRA 18.1 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 18.1 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 18.1 | Systematic Assessment |
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| Irritability | Psychiatric disorders | MedDRA 18.1 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Systematic Assessment |
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| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Systematic Assessment |
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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.
| 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 |
| D014777 | Virus Diseases |
| D018178 | Flaviviridae Infections |
| D012327 | RNA Virus Infections |
| D006505 | Hepatitis |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D000069474 | Sofosbuvir |
| C417083 | peginterferon alfa-2b |
| D012254 | Ribavirin |
| C578009 | grazoprevir |
| C000589335 | elbasvir |
| ID | Term |
|---|---|
| D014542 | Uridine Monophosphate |
| D014500 | Uracil Nucleotides |
| D011742 | Pyrimidine Nucleotides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009711 | Nucleotides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012265 | Ribonucleotides |
| D012263 | Ribonucleosides |
| D009705 | Nucleosides |
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| Male |
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The lower bound of 95% CIs was compared to pre-specified non-inferiority margin, -10% to evaluate non-inferiority. The Missing=Failure (M=F) approach was used to handle missing values.
| Secondary Analysis Approach: Superiority Analyses of the percentage of participants achieving SVR12 was conducted using the M&N method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir +elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% CIs and p-values were provided. | Miettinen & Nurminen Method | The lower bound of 95% CIs was compared to zero to evaluate superiority. The M=F approach was used to handle missing values. | 0.001 | Adjusted Difference in Percentage | 8.8 | 2-Sided | 95 | 3.6 | 15.3 | Superiority or Other |
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| OG001 |
| SOF + PR |
Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up. |
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