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Safety and Efficacy of Grazoprevir (MK-5172) + Elbasvir (MK-8742) in Participants With Chronic Hepatitis C and Chronic Kidney Disease (MK-5172-052) (C-SURFER)

Primary Purpose

Hepatitis C Virus

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Grazoprevir
Elbasvir
Placebo to Grazoprevir
Placebo to Elbasvir
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C Virus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Documented chronic (at least 6 months) HCV GT 1 infection (with no evidence of mixed genotypes or genotype that cannot be assigned a type)
  • Evidence or no evidence of liver cirrhosis based on one of the following:
  • Liver biopsy performed within 24 months of Day 1 (if participant is cirrhotic then there is no time restriction on biopsy)
  • Fibroscan performed within 12 months of Day 1 of this study
  • Fibrosure™ (Fibrotest™) plus aspartate aminotransferase to platelet Ratio Index [APRI] obtained during the screening period)
  • Has HCV status that is one of the following:
  • Treatment naïve
  • Prior interferon or pegylated interferon with or without ribavarin failures (null responder, partial responder, or relapser)
  • Intolerant to prior interferon or pegylated intereferon with or without ribavarin regimen
  • Chronic kidney disease (defined as glomerular filtration rate [eGFR] <=29) non-dialysis dependent or on hemodialysis for at least 3 months, including individuals awaiting kidney transplant and those with failed kidney transplants but no longer on immunosuppressant therapy)
  • Female participant of reproductive potential must agree to remain abstinent or use (or have their partner use) 2 acceptable methods of contraception from at least 2 weeks prior to Day 1 through 14 days after the last dose of study drugs, or longer if dictated by local regulations

Exclusion Criteria:

  • Evidence of decompensated liver disease
  • On peritoneal dialysis for management of kidney disease
  • Co-infection with hepatitis B virus or human immunodeficiency virus (HIV)
  • History of malignancy <=5 years prior to signing informed consent
  • Clinical diagnosis of substance abuse
  • Pregnant, breast-feeding, expecting to conceive or donate eggs, or donate sperm from Day 1 through 14 days after the last study dose, or longer if dictated by local regulations
  • Organ transplant (including hematopoietic stem cell transplant) other than kidney, cornea, and hair
  • Conditions requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial
  • Uncontrolled or poorly controlled hypertension
  • Significant cardiovascular disorder (e.g. myocardial infarction or unstable angina) or cardiovascular procedure within 3 months prior to signing informed consent
  • New or worsening signs or symptoms of congestive heart failure within 3 months of signing informed consent
  • Severe active peripheral vascular disease
  • Recent (within 3 months prior to signing informed consent) episode or recurrence of stroke, transient ischemic attack (TIA) or neurological disorder, including but not limited to seizures
  • Evidence or history of chronic hepatitis not caused by HCV

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Experimental

    Arm Label

    Immediate Treatment

    Deferred Treatment

    Intensive PK

    Arm Description

    Participants receive grazoprevir 100 mg tablet, orally, once per day (QD) + elbasvir 50 mg tablet, orally, QD, for 12 weeks.

    Participants receive placebos to both grazoprevir and elbasvir for 12 weeks, and after a 4-week break, grazoprevir 100 mg tablet, orally, QD + elbasvir 50 mg tablet, orally, QD for 12 weeks.

    Participants receive grazoprevir 100 mg tablet, orally, QD + elbasvir 50 mg tablet, orally, QD for 12 weeks with intensive PK testing.

    Outcomes

    Primary Outcome Measures

    Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12)
    SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) lower than the limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
    Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods
    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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.
    Number of Participants Discontinuing Study Drug Due to AEs During the Initial 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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.

    Secondary Outcome Measures

    Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24)
    SVR24 was defined as HCV RNA <LLoQ 24 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
    Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4)
    SVR4 was defined as HCV RNA <LLoQ 4 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.

    Full Information

    First Posted
    March 17, 2014
    Last Updated
    August 23, 2018
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02092350
    Brief Title
    Safety and Efficacy of Grazoprevir (MK-5172) + Elbasvir (MK-8742) in Participants With Chronic Hepatitis C and Chronic Kidney Disease (MK-5172-052)
    Acronym
    C-SURFER
    Official Title
    A Phase II/III Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-8742 in Subjects With Chronic Hepatitis C Virus Infection and Chronic Kidney Disease
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    March 17, 2014 (Actual)
    Primary Completion Date
    March 11, 2015 (Actual)
    Study Completion Date
    September 2, 2015 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This study will evaluate the safety and efficacy of combination treatment with grazoprevir (MK-5172) + elbasvir (MK-8742) for cirrhotic and non-cirrhotic participants with chronic Genotype 1 (GT1) hepatitis C virus (HCV) infection and chronic kidney disease (CKD). The primary study hypothesis is that the proportion of HCV GT1-infected CKD participants within the Immediate Treatment and Intensive Pharmacokinetics (PK) groups achieving a sustained viral response 12 weeks after the end of all study treatment (SVR12) will be >45%.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hepatitis C Virus

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2, Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    237 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Immediate Treatment
    Arm Type
    Experimental
    Arm Description
    Participants receive grazoprevir 100 mg tablet, orally, once per day (QD) + elbasvir 50 mg tablet, orally, QD, for 12 weeks.
    Arm Title
    Deferred Treatment
    Arm Type
    Experimental
    Arm Description
    Participants receive placebos to both grazoprevir and elbasvir for 12 weeks, and after a 4-week break, grazoprevir 100 mg tablet, orally, QD + elbasvir 50 mg tablet, orally, QD for 12 weeks.
    Arm Title
    Intensive PK
    Arm Type
    Experimental
    Arm Description
    Participants receive grazoprevir 100 mg tablet, orally, QD + elbasvir 50 mg tablet, orally, QD for 12 weeks with intensive PK testing.
    Intervention Type
    Drug
    Intervention Name(s)
    Grazoprevir
    Other Intervention Name(s)
    MK-5172
    Intervention Description
    Grazoprevir 100 mg tablet
    Intervention Type
    Drug
    Intervention Name(s)
    Elbasvir
    Other Intervention Name(s)
    MK-8742
    Intervention Description
    Elbasvir 50 mg tablet
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo to Grazoprevir
    Intervention Description
    Placebo tablet matched to grazoprevir
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo to Elbasvir
    Intervention Description
    Placebo tablet matched to elbasvir
    Primary Outcome Measure Information:
    Title
    Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12)
    Description
    SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) lower than the limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
    Time Frame
    Week 24 (Immediate Treatment + Intensive PK) or Week 40 (Deferred Treatment)
    Title
    Number of Participants Experiencing an Adverse Event (AE) During the Initial Treatment and 14-day Follow-up Periods
    Description
    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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.
    Time Frame
    Up to Week 14
    Title
    Number of Participants Discontinuing Study Drug Due to AEs During the Initial Treatment Period
    Description
    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. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group.
    Time Frame
    Up to Week 12
    Secondary Outcome Measure Information:
    Title
    Percentage of Participants With Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24)
    Description
    SVR24 was defined as HCV RNA <LLoQ 24 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
    Time Frame
    Week 36 (Immediate Treatment + Intensive PK) or Week 52 (Deferred Treatment)
    Title
    Percentage of Participants With Sustained Virologic Response 4 Weeks After Completing Study Therapy (SVR4)
    Description
    SVR4 was defined as HCV RNA <LLoQ 4 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL.
    Time Frame
    Week 16 (Immediate Treatment + Intensive PK) or Week 32 (Deferred Treatment)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Documented chronic (at least 6 months) HCV GT 1 infection (with no evidence of mixed genotypes or genotype that cannot be assigned a type) Evidence or no evidence of liver cirrhosis based on one of the following: Liver biopsy performed within 24 months of Day 1 (if participant is cirrhotic then there is no time restriction on biopsy) Fibroscan performed within 12 months of Day 1 of this study Fibrosure™ (Fibrotest™) plus aspartate aminotransferase to platelet Ratio Index [APRI] obtained during the screening period) Has HCV status that is one of the following: Treatment naïve Prior interferon or pegylated interferon with or without ribavarin failures (null responder, partial responder, or relapser) Intolerant to prior interferon or pegylated intereferon with or without ribavarin regimen Chronic kidney disease (defined as glomerular filtration rate [eGFR] <=29) non-dialysis dependent or on hemodialysis for at least 3 months, including individuals awaiting kidney transplant and those with failed kidney transplants but no longer on immunosuppressant therapy) Female participant of reproductive potential must agree to remain abstinent or use (or have their partner use) 2 acceptable methods of contraception from at least 2 weeks prior to Day 1 through 14 days after the last dose of study drugs, or longer if dictated by local regulations Exclusion Criteria: Evidence of decompensated liver disease On peritoneal dialysis for management of kidney disease Co-infection with hepatitis B virus or human immunodeficiency virus (HIV) History of malignancy <=5 years prior to signing informed consent Clinical diagnosis of substance abuse Pregnant, breast-feeding, expecting to conceive or donate eggs, or donate sperm from Day 1 through 14 days after the last study dose, or longer if dictated by local regulations Organ transplant (including hematopoietic stem cell transplant) other than kidney, cornea, and hair Conditions requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial Uncontrolled or poorly controlled hypertension Significant cardiovascular disorder (e.g. myocardial infarction or unstable angina) or cardiovascular procedure within 3 months prior to signing informed consent New or worsening signs or symptoms of congestive heart failure within 3 months of signing informed consent Severe active peripheral vascular disease Recent (within 3 months prior to signing informed consent) episode or recurrence of stroke, transient ischemic attack (TIA) or neurological disorder, including but not limited to seizures Evidence or history of chronic hepatitis not caused by HCV
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    26456905
    Citation
    Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, Martin P, Pol S, Londono MC, Hassanein T, Zamor PJ, Zuckerman E, Wan S, Jackson B, Nguyen BY, Robertson M, Barr E, Wahl J, Greaves W. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015 Oct 17;386(10003):1537-45. doi: 10.1016/S0140-6736(15)00349-9. Epub 2015 Oct 5. Erratum In: Lancet. 2015 Nov 7;386(10006):1824.
    Results Reference
    result
    PubMed Identifier
    28576451
    Citation
    Bruchfeld A, Roth D, Martin P, Nelson DR, Pol S, Londono MC, Monsour H Jr, Silva M, Hwang P, Arduino JM, Robertson M, Nguyen BY, Wahl J, Barr E, Greaves W. Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):585-594. doi: 10.1016/S2468-1253(17)30116-4. Epub 2017 May 30.
    Results Reference
    result
    PubMed Identifier
    30680407
    Citation
    Caro L, Wenning L, Feng HP, Guo Z, Du L, Bhagunde P, Fandozzi C, Panebianco D, Marshall WL, Butterton JR, Iwamoto M, Yeh WW. Pharmacokinetics of elbasvir and grazoprevir in subjects with end-stage renal disease or severe renal impairment. Eur J Clin Pharmacol. 2019 May;75(5):665-675. doi: 10.1007/s00228-018-2585-3. Epub 2019 Jan 25.
    Results Reference
    derived
    PubMed Identifier
    29404492
    Citation
    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.
    Results Reference
    derived
    PubMed Identifier
    28193518
    Citation
    Jacobson IM, Lawitz E, Kwo PY, Hezode C, Peng CY, Howe AYM, Hwang P, Wahl J, Robertson M, Barr E, Haber BA. Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. Gastroenterology. 2017 May;152(6):1372-1382.e2. doi: 10.1053/j.gastro.2017.01.050. Epub 2017 Feb 11.
    Results Reference
    derived

    Learn more about this trial

    Safety and Efficacy of Grazoprevir (MK-5172) + Elbasvir (MK-8742) in Participants With Chronic Hepatitis C and Chronic Kidney Disease (MK-5172-052)

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