Efficacy and Safety of Grazoprevir (MK-5172) and Uprifosbuvir (MK-3682) With Elbasvir (MK-8742) or Ruzasvir (MK-8408) for Chronic Hepatitis C Genotype (GT)1 and GT2 Infection (MK-3682-011)

NCT02332707 | Completed Phase 2 Results

• 3 other identifiers: 3682-0112014-003304-73MK-3682-011
• Study Type: interventional
• Target: 443
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a randomized, three-part, open-label trial of grazoprevir (GZR; MK-5172) (100 mg) and uprifosbuvir (UPR; MK-3682) (300 mg or 450 mg), with either elbasvir (EBR; MK-8742) (50 mg) or ruzasvir (RZR; MK-8408) (60 mg), and with or without ribavirin (RBV), in treatment-naïve (TN) cirrhotic (C) or non-cirrhotic (NC) hepatitis C virus (HCV) participants with chronic HCV genotype (GT) 1 or GT2 infection. Part A will consist of 8 arms to evaluate the safety of dose combinations. In Part B, participants will take 2 UPR+GZR+RZR fixed dose combination (FDC) tablets once daily (q.d.) by mouth, with or without twice-daily (b.i.d.) RBV (200 mg capsules; weight-based dosing). Participants who relapse following completion of therapy in Part A will be offered the option of retreatment with 16 weeks of UPR+GZR+RZR with RBV in Part C (data obtained from Part C will not be used in the analysis of outcome measures).

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12)

  The percentage of participants with Hepatitis C virus (HCV) ribonucleic acid (RNA) \< Lower Limit of Quantification (LLoQ) 12 weeks after completing treatment (i.e., SVR12) in each arm was determined. Plasma levels of HCV RNA levels were measured using the Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 assay, which has a LLoQ of 15 IU/mL.

  Up to 28 weeks

• Percentage of Participants Experiencing an Adverse Event (AE)

  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.

  Up to 18 weeks

• Percentage of Participants Discontinuing From Study Treatment Due to an AE

  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.

  Up to 16 weeks

Secondary Outcomes (1)

• Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24)

  Up to 40 weeks

Study Arms (18)

A1: GT1 NC GZR+UPR+EBR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT1-infected NC participants will take GZR 100 mg + UPR 300 mg + EBR 50 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Elbasvir

A2: GT1 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT1-infected NC participants will take GZR 100 mg + UPR 300 mg + RZR 60 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir

A3: GT2 NC GZR+UPR+EBR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT2-infected NC participants will take GZR 100 mg + UPR 300 mg + EBR 50 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Elbasvir

A4: GT2 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT2-infected NC participants will take GZR 100 mg + UPR 300 mg + RZR 60 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir

A5: GT1 NC GZR+UPR+EBR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT1-infected NC participants will take GZR 100 mg + UPR 450 mg + EBR 50 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Elbasvir

A6: GT1 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT1-infected NC participants will take GZR 100 mg + UPR 450 mg + RZR 60 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir

B7: GT2 NC GZR+UPR+EBR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT2-infected NC participants will take GZR 100 mg + UPR 450 mg + EBR 50 mg q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Elbasvir

A8: GT2 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part A, HCV GT2-infected NC participants will take GZR 100 mg + UPR 450 mg + RZR 60 mg q.d. by mouth for 8 weeks. In Part B, HCV GT2-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir

B9: GT1 NC GZR+UPR+RZR (12 weeks)

EXPERIMENTAL

In Part B, HCV GT1-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 12 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV

EXPERIMENTAL

In Part B, HCV GT2-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 8 weeks. Participants will also take RBV b.i.d. at a total daily dose of 800-1600 mg based on body weight.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir; Drug: Ribavirin

B11: GT2 NC GZR+UPR+RZR (12 weeks)

EXPERIMENTAL

In Part B, HCV GT2-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 12 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B12: GT1 C GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part B, HCV GT1-infected C participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 8 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B13: GT1 C GZR+UPR+RZR (12 weeks)

EXPERIMENTAL

In Part B, HCV GT1-infected C participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 12 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B14: GT2 C GZR+UPR+RZR (12 weeks)

EXPERIMENTAL

In Part B, HCV GT2-infected C participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 12 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV

EXPERIMENTAL

In Part B, HCV GT2-infected C participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 12 weeks. Participants will also take RBV b.i.d. at a total daily dose of 800-1600 mg based on body weight.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir; Drug: Ribavirin

B16: GT2 C GZR+UPR+RZR (16 weeks)

EXPERIMENTAL

In Part B, HCV GT2-infected C participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 16 weeks.

Drug: Grazoprevir; Drug: Uprifosbuvir; Drug: Ruzasvir; Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B6: GT1 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part B, HCV GT1-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 8 weeks.

Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

B8: GT2 NC GZR+UPR+RZR (8 weeks)

EXPERIMENTAL

In Part B, HCV GT2-infected NC participants will take 2 FDC tablets containing UPR 225 mg + GZR 50 mg + RZR 30 mg per tablet q.d. by mouth for 8 weeks.

Drug: Uprifosbuvir (+) Grazoprevir (+) Ruzasvir

Interventions

Grazoprevir DRUG

One GZR 100 mg tablet (Part A), or 2 FDC tablets containing GZR 50 mg per tablet (Part B), taken q.d.by mouth.

Also known as: MK-5172

A1: GT1 NC GZR+UPR+EBR (8 weeks); A2: GT1 NC GZR+UPR+RZR (8 weeks); A3: GT2 NC GZR+UPR+EBR (8 weeks); A4: GT2 NC GZR+UPR+RZR (8 weeks); A5: GT1 NC GZR+UPR+EBR (8 weeks); A6: GT1 NC GZR+UPR+RZR (8 weeks); A8: GT2 NC GZR+UPR+RZR (8 weeks); B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV; B11: GT2 NC GZR+UPR+RZR (12 weeks); B12: GT1 C GZR+UPR+RZR (8 weeks); B13: GT1 C GZR+UPR+RZR (12 weeks); B14: GT2 C GZR+UPR+RZR (12 weeks); B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV; B16: GT2 C GZR+UPR+RZR (16 weeks); B7: GT2 NC GZR+UPR+EBR (8 weeks); B9: GT1 NC GZR+UPR+RZR (12 weeks)

Uprifosbuvir DRUG

Two or 3 UPR 150 mg (300 mg and 450 mg total daily dose) tablets (Part A), or 2 FDC tablets containing UPR 225 mg (Part B), taken q.d. by mouth.

Also known as: MK-3682

A1: GT1 NC GZR+UPR+EBR (8 weeks); A2: GT1 NC GZR+UPR+RZR (8 weeks); A3: GT2 NC GZR+UPR+EBR (8 weeks); A4: GT2 NC GZR+UPR+RZR (8 weeks); A5: GT1 NC GZR+UPR+EBR (8 weeks); A6: GT1 NC GZR+UPR+RZR (8 weeks); A8: GT2 NC GZR+UPR+RZR (8 weeks); B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV; B11: GT2 NC GZR+UPR+RZR (12 weeks); B12: GT1 C GZR+UPR+RZR (8 weeks); B13: GT1 C GZR+UPR+RZR (12 weeks); B14: GT2 C GZR+UPR+RZR (12 weeks); B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV; B16: GT2 C GZR+UPR+RZR (16 weeks); B7: GT2 NC GZR+UPR+EBR (8 weeks); B9: GT1 NC GZR+UPR+RZR (12 weeks)

Elbasvir DRUG

One EBR 50 mg tablet (Part A), taken q.d. by mouth.

Also known as: MK-8742

A1: GT1 NC GZR+UPR+EBR (8 weeks); A3: GT2 NC GZR+UPR+EBR (8 weeks); A5: GT1 NC GZR+UPR+EBR (8 weeks); B7: GT2 NC GZR+UPR+EBR (8 weeks)

Ruzasvir DRUG

Six RZR 10 mg (60 mg total daily dose) capsules (Part A), or 2 FDC tablets containing RZR 30 mg per tablet (Part B), taken q.d. by mouth.

Also known as: MK-8408

A2: GT1 NC GZR+UPR+RZR (8 weeks); A4: GT2 NC GZR+UPR+RZR (8 weeks); A6: GT1 NC GZR+UPR+RZR (8 weeks); A8: GT2 NC GZR+UPR+RZR (8 weeks); B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV; B11: GT2 NC GZR+UPR+RZR (12 weeks); B12: GT1 C GZR+UPR+RZR (8 weeks); B13: GT1 C GZR+UPR+RZR (12 weeks); B14: GT2 C GZR+UPR+RZR (12 weeks); B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV; B16: GT2 C GZR+UPR+RZR (16 weeks); B9: GT1 NC GZR+UPR+RZR (12 weeks)

Uprifosbuvir (+) Grazoprevir (+) Ruzasvir DRUG

Two FDC tablets, each containing GZR 50 mg + UPR 225 mg + RZR 30 mg (Part B), taken q.d. by mouth.

Also known as: MK-3682B

B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV; B11: GT2 NC GZR+UPR+RZR (12 weeks); B12: GT1 C GZR+UPR+RZR (8 weeks); B13: GT1 C GZR+UPR+RZR (12 weeks); B14: GT2 C GZR+UPR+RZR (12 weeks); B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV; B16: GT2 C GZR+UPR+RZR (16 weeks); B6: GT1 NC GZR+UPR+RZR (8 weeks); B8: GT2 NC GZR+UPR+RZR (8 weeks); B9: GT1 NC GZR+UPR+RZR (12 weeks)

Ribavirin DRUG

RBV 200 mg capsules taken b.i.d. at a total daily dose of 800-1400 mg based on participant body weight.

Also known as: Rebetol®

B10: GT2 NC GZR+UPR+RZR (8 weeks) + RBV; B15: GT2 C GZR+UPR+RZR (12 weeks) + RBV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Parts A and B:
• Previously untreated chronic HCV GT1 or GT2 with no evidence of non-typeable or mixed genotype infection
• Has HCV ribonucleic acid (RNA) \>= 10,000 IU/mL in peripheral blood at the time of screening
• Is NC (Part A and B)
• Is HCV treatment naïve (defined as no prior exposure to any interferon, ribavirin, or other approved or experimental HCV-specific direct-acting antiviral agent
• Is of non-childbearing potential or agrees to avoid becoming pregnant or impregnating a partner beginning at least 2 weeks prior to administration of the initial dose of study drug and either for 14 days after the last dose of study drug if not taking RBV or for 6 months after the last dose of study drug if taking RBV (or longer if dictated by local regulations). If not abstinent from heterosexual activity, participants in Part A must use 2 acceptable forms of barrier contraception whereas participants in Part B must use 2 acceptable forms of contraception which may include oral contraceptives
• Part B only:
• Has cirrhosis of the liver
• If coinfected with human immunodeficiency virus (HIV) is not currently on antiretroviral therapy (ART) and has no plans to initiate ART treatment while participating in this study OR has well controlled HIV on ART (the ART regimen must contain only the following antiretroviral medications: tenofovir, abacavir, lamivudine, emtricitabine, raltegravir, dolutegravir, and rilpivirine with no dose modifications or changes in drugs in the 4 weeks prior to study entry \[Day 1\])
• Has at least one viable ART regimen alternative beyond their current regimen in the event of HIV virologic failure and the development of antiretroviral drug resistance

You may not qualify if:

• Parts A, B, and C (unless noted otherwise):
• 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
• For cirrhotics (Part B only), participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score \>5
• Is coinfected with hepatitis B virus
• Is coinfected with HIV (Part A only)
• If coinfected with HIV (Part B only), has a history of opportunistic infection in the preceding 6 months prior to screening
• Has a history of malignancy \<=5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy
• Has cirrhosis and has had liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC
• Has clinically-relevant drug or alcohol abuse within 12 months of screening
• Pregnant or breast-feeding, or expecting to conceive or donate eggs from at least 2 weeks prior to Day 1 and 90 days after the last dose of study medication, or longer if dictated by local regulations
• Has any of the following conditions:
• organ transplants (including hematopoietic stem cell transplants) other than cornea and hair
• poor venous access that precludes routine peripheral blood sampling required for this trial
• has a history of gastric surgery (e.g., stapling, bypass) or history of malabsorption disorders (e.g., celiac sprue disease)
• current or history of any clinically significant cardiac abnormalities/dysfunction, including but not limited to: angina, congestive heart failure, myocardial infarction, pulmonary hypertension, complex congenital heart disease, cardiomyopathy, significant arrhythmia, uncontrolled hypertension, a history of use of antianginal or anti-arrhythmic agents for cardiac conditions, prolonged electrocardiogram (ECG) QTc interval (\>470 ms for males or \>480 ms for females by the Fridericia formula) at the screening visit, personal or family history of Torsade de pointes

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• Lawitz E, Buti M, Vierling JM, Almasio PL, Bruno S, Ruane PJ, Hassanein TI, Muellhaupt B, Pearlman B, Jancoriene L, Gao W, Huang HC, Shepherd A, Tannenbaum B, Fernsler D, Li JJ, Grandhi A, Liu H, Su FH, Wan S, Dutko FJ, Nguyen BT, Wahl J, Robertson MN, Barr E, Yeh WW, Plank RM, Butterton JR, Yoshida EM. Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials. Lancet Gastroenterol Hepatol. 2017 Nov;2(11):814-823. doi: 10.1016/S2468-1253(17)30163-2. Epub 2017 Aug 10.

  PMID: 28802814 RESULT

• Gane EJ, Pianko S, Roberts SK, Thompson AJ, Zeuzem S, Zuckerman E, Ben-Ari Z, Foster GR, Agarwal K, Laursen AL, Gerstoft J, Gao W, Huang HC, Fitzgerald B, Fernsler D, Li JJ, Grandhi A, Liu H, Su FH, Wan S, Zeng Z, Chen HL, Dutko FJ, Nguyen BT, Wahl J, Robertson MN, Barr E, Yeh WW, Plank RM, Butterton JR, Esteban R. Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. Lancet Gastroenterol Hepatol. 2017 Nov;2(11):805-813. doi: 10.1016/S2468-1253(17)30159-0. Epub 2017 Aug 10.

  PMID: 28802816 DERIVED

MeSH Terms

Conditions

Hepatitis C

Interventions

grazoprevir; uprifosbuvir; elbasvir; ruzasvir; Ribavirin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Senior VIce President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2015
• First Posted: January 7, 2015
• Study Start: January 22, 2015
• Primary Completion: September 16, 2016
• Study Completion: December 6, 2016
• Last Updated: July 23, 2019
• Results First Posted: December 21, 2017

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share