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Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection (ACCORDION-1)

Primary Purpose

Hepatitis C Virus

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Simeprevir 150 mg

Daclatasvir 60 mg

Sofosbuvir 400 mg

About this trial

This is an interventional treatment trial for Hepatitis C Virus focused on measuring Hepatitis C virus, Hepatitis C virus genotype 1, Chronic Hepatitis C Virus Genotype 1 Infection, Liver fibrosis, Cirrhosis, Simeprevir, Daclatasvir, Sofosbuvir

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

HCV genotype 1 infection and HCV RNA plasma level greater than (>) 10,000 international units per milliliter (IU/mL), both determined at Screening
Participants of Arm A should have evidence of early stages of liver fibrosis, defined by a FibroSURE score less than or equal to (<=) 0.48 and aspartate aminotransferase to platelet ratio index (APRI) score <=1
Participants of Arm B should have evidence of cirrhosis, defined by a FibroSURE score >0.75 and APRI score >2, OR a previous (historical) biopsy documenting a METAVIR score F4. In addition, participants should have absence of esophageal varices or presence of small (grade 1) esophageal varices determined by upper gastrointestinal endoscopy, and absence of findings indicative of hepatocellular carcinoma in an ultrasonography
HCV treatment-naive, defined as not having received treatment with any approved or investigational drug for chronic HCV infection
Pegylated interferon (PegIFN) and ribavirin (RBV) eligible, defined as not having any contraindication to the use of PegIFN and RBV, in line with the prescribing information for each compound

Exclusion Criteria:

A. Main Study:

Co-infection with HCV of another genotype than genotype 1 and/or human immunodeficiency virus (HIV) type 1 or 2 (positive HIV-1 or HIV 2 antibody test at Screening)
Any evidence of liver disease of non-HCV etiology. This includes, but is not limited to, acute hepatitis A infection, hepatitis B infection (hepatitis B surface antigen positive), drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or any other non-HCV liver disease considered clinically significant by the Investigator
Evidence of clinical hepatic decompensation or presence of grade 2/3 esophageal varices
Any of the protocol defined laboratory abnormalities

B. Sub-study:

Presence of coagulopathy (hemophilia) or hemoglobinopathy (including sickle cell disease, thalassemia)
Use of any anti-coagulant (for example, warfarin, heparin) or anti-platelet medications within 1 week of the Screening visit
Any of the protocol defined laboratory abnormalities

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm A

Arm B

Arm Description

Chronic hepatitis C virus (HCV) genotype 1 infected participants with early stages of liver fibrosis, will receive Simeprevir (SMV) 150 milligram (mg), Daclatasvir (DCV) 60 mg and Sofosbuvir (SOF) 400 mg once daily for 6 weeks.

Chronic HCV genotype 1 infected participants with cirrhosis, will receive SMV 150 mg, DCV 60 mg and SOF 400 mg once daily for 8 weeks.

Outcomes

Primary Outcome Measures

Percentage of Participants With Sustained Virologic Response (SVR) at 12 Weeks After End of Study Drug Treatment (SVR12)

Participants were considered to have achieved SVR12 if the hepatitis C virus ribonucleic acid (HCV RNA) was less than (<) lower limit of quantification (LLOQ; 15 international unit per milliliter [IU/mL]) detectable or undetectable at 12 weeks after the end of study drug treatment.

Secondary Outcome Measures

Percentage of Participants With On-treatment Virologic Response

On-treatment virologic response was determined by hepatitis C virus (HCV) ribonucleic acid (RNA) results satisfying a specified threshold. The following thresholds were considered at any time point: <LLOQ undetectable, <LLOQ detectable, and <LLOQ undetectable or detectable. The LLOQ value was 15 IU/mL. Very rapid virologic response (vRVR) is undetectable HCV RNA at Week 2 while on treatment and Rapid virologic response (RVR) is undetectable HCV RNA at Week 4 while on treatment.

Percentage of Participants With Sustained Virologic Response at 4 Weeks (SVR4) and 24 Weeks (SVR24) After End of Study Drug Treatment

Participants were considered to have achieved SVR4 and SVR24 if the HCV RNA was <LLOQ detectable or undetectable at 4 weeks and 24 weeks respectively after the end of study drug treatment. The LLOQ value was 15 IU/mL.

Percentage of Participants With On-Treatment Failure

Participants who did not achieve SVR12 and with confirmed detectable HCV RNA at the actual end of treatment. Includes participants with: 1) viral breakthrough, defined as a confirmed increase of greater than (>)1 log10 in HCV RNA from nadir, or confirmed HCV RNA 2) confirmed detectable HCV RNA at the actual end of treatment (example, completed treatment, discontinued due to adverse events, withdrawal of consent) of >100 IU/mL in participants whose HCV RNA had previously been <LLOQ while on treatment.

Number of Participants With Viral Relapse

Viral Relapse: Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during followup.

Number of Participants With Late Viral Relapse

Late Viral Relapse: Participant who achieved SVR12 and the post treatment HCV RNA measurement fulfilled 1 the following conditions: a) at least 2 consecutive measurements not lesser than (<)15 IU/mL undetectable, of which at least the second measurement was >=15 IU/mL quantifiable or b) the last available measurement was >=15 IU/mL quantifiable.

Number of Participants With HCV Nonstructural Protein 3/4A (NS3/4A), NS5A and NS5B Sequence in Participants Not Achieving SVR

Sequencing of the HCV nonstructural protein 3/4A (NS3/4A), nonstructural protein 5A (NS5A) and nonstructural protein 5B (NS5B) genes was done to identify preexisting sequence polymorphisms and characterize emerging HCV viral variants in participants not achieving SVR.

Percentage of Participants With or Without an NS3 Q80K Polymorphism at Baseline Achieving SVR

The Q80K polymorphism, associated with low level SMV in vitro resistance. Percentage of participants who achieved SVR with or without an NS3 Q80K polymorphism at baseline were reported.

Full Information

NCT ID

NCT02349048

First Posted

January 22, 2015

Last Updated

January 11, 2017

Sponsor

Janssen Research & Development, LLC

1. Study Identification

Unique Protocol Identification Number

NCT02349048

Brief Title

Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection

Acronym

ACCORDION-1

Official Title

A Phase 2, Randomized, Open-label Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of 6 or 8 Weeks of Treatment With Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Subjects With Chronic Hepatitis C Virus Genotype 1 Infection

Study Type

Interventional

2. Study Status

Record Verification Date

January 2017

Overall Recruitment Status

Completed

Study Start Date

January 2015 (undefined)

Primary Completion Date

February 2016 (Actual)

Study Completion Date

May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of 6 or 8 weeks of treatment regimen containing simeprevir (SMV), daclatasvir (DCV) and sofosbuvir (SOF) in treatment-naive (not having received treatment with any approved or investigational drug) participants with chronic hepatitis (inflammation of the liver) C virus (HCV) genotype 1 infection with early stages of liver fibrosis or with cirrhosis.

Detailed Description

This is an open-label (participants and researchers are aware about the treatment participants are receiving), and multicenter (when more than 1 hospital or medical school team work on a medical research) study. The study will consist of a Screening Phase (6 weeks); an Open-label Treatment Phase (6 weeks for Arm A and 8 weeks for Arm B); and a Post-treatment Follow-up Phase (until 24 weeks after end of study treatment). Using a staggered approach, all eligible participants will be assigned to 1 of the 2 arms, according to their level of fibrosis. Arm A (consists of chronic HCV genotype 1 infected participants with early stages of liver fibrosis): participants will receive a combination therapy of SMV 150 milligram (mg), DCV 60 mg and SOF 400 mg once daily for 6 weeks. Arm B (consists of chronic HCV genotype 1 infected participants with cirrhosis): participants will receive a combination therapy of SMV 150 mg, DCV 60 mg and SOF 400 mg once daily for 8 weeks. A sub-study will be performed at a selected study site, where only participants who will be eligible to participate in both the main study and the sub-study will be enrolled. Intra-hepatic and plasma HCV ribonucleic acid (RNA) levels; intra-hepatic, peripheral innate and adaptive immune responses during the treatment, will be assessed in the sub-study. Participants' safety will be monitored throughout the study.

6. Conditions and Keywords

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

Hepatitis C Virus

Keywords

Hepatitis C virus, Hepatitis C virus genotype 1, Chronic Hepatitis C Virus Genotype 1 Infection, Liver fibrosis, Cirrhosis, Simeprevir, Daclatasvir, Sofosbuvir

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

68 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A

Arm Type

Experimental

Arm Description

Arm Title

Arm B

Arm Type

Experimental

Arm Description

Chronic HCV genotype 1 infected participants with cirrhosis, will receive SMV 150 mg, DCV 60 mg and SOF 400 mg once daily for 8 weeks.

Intervention Type

Drug

Intervention Name(s)

Simeprevir 150 mg

Intervention Description

Simeprevir 150 mg capsule orally once daily.

Intervention Type

Drug

Intervention Name(s)

Daclatasvir 60 mg

Intervention Description

Daclatasvir 60 mg tablet orally once daily.

Intervention Type

Drug

Intervention Name(s)

Sofosbuvir 400 mg

Intervention Description

Sofosbuvir 400 mg tablet orally once daily.

Primary Outcome Measure Information:

Title

Percentage of Participants With Sustained Virologic Response (SVR) at 12 Weeks After End of Study Drug Treatment (SVR12)

Description

Time Frame

12 weeks after end of study drug treatment (week 18 for Arm A and week 20 for Arm B)

Secondary Outcome Measure Information:

Title

Percentage of Participants With On-treatment Virologic Response

Description

Time Frame

Day 2, Day 3, Week 1, 2, 3, 4, 6 (for Arm A) and 8 (for Arm B only)

Title

Percentage of Participants With Sustained Virologic Response at 4 Weeks (SVR4) and 24 Weeks (SVR24) After End of Study Drug Treatment

Description

Time Frame

4 weeks after end of study drug treatment (week 10 for Arm A and 12 for Arm B); 24 weeks after end of study drug treatment (week 30 for Arm A and 32 for Arm B)

Title

Percentage of Participants With On-Treatment Failure

Description

Time Frame

Baseline up to End of Treatment (Week 6 for Arm A and Week 8 for Arm B)

Title

Number of Participants With Viral Relapse

Description

Viral Relapse: Participants who did not achieve SVR12, with undetectable HCV RNA at the actual end of study drug treatment and confirmed HCV RNA greater than or equal to (>=) LLOQ during followup.

Time Frame

From Week 6 to Week 18 (for Arm A) and From Week 8 to Week 20 (for Arm B)

Title

Number of Participants With Late Viral Relapse

Description

Time Frame

From Week 18 to Week 30 (for Arm A), From Week 20 to Week 32 (for Arm B)

Title

Number of Participants With HCV Nonstructural Protein 3/4A (NS3/4A), NS5A and NS5B Sequence in Participants Not Achieving SVR

Description

Time Frame

Up to Week 30 for Arm A and up to Week 32 for Arm B

Title

Percentage of Participants With or Without an NS3 Q80K Polymorphism at Baseline Achieving SVR

Description

The Q80K polymorphism, associated with low level SMV in vitro resistance. Percentage of participants who achieved SVR with or without an NS3 Q80K polymorphism at baseline were reported.

Time Frame

up to Week 30 for Arm A and Week 32 for Arm B

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: HCV genotype 1 infection and HCV RNA plasma level greater than (>) 10,000 international units per milliliter (IU/mL), both determined at Screening Participants of Arm A should have evidence of early stages of liver fibrosis, defined by a FibroSURE score less than or equal to (<=) 0.48 and aspartate aminotransferase to platelet ratio index (APRI) score <=1 Participants of Arm B should have evidence of cirrhosis, defined by a FibroSURE score >0.75 and APRI score >2, OR a previous (historical) biopsy documenting a METAVIR score F4. In addition, participants should have absence of esophageal varices or presence of small (grade 1) esophageal varices determined by upper gastrointestinal endoscopy, and absence of findings indicative of hepatocellular carcinoma in an ultrasonography HCV treatment-naive, defined as not having received treatment with any approved or investigational drug for chronic HCV infection Pegylated interferon (PegIFN) and ribavirin (RBV) eligible, defined as not having any contraindication to the use of PegIFN and RBV, in line with the prescribing information for each compound Exclusion Criteria: A. Main Study: Co-infection with HCV of another genotype than genotype 1 and/or human immunodeficiency virus (HIV) type 1 or 2 (positive HIV-1 or HIV 2 antibody test at Screening) Any evidence of liver disease of non-HCV etiology. This includes, but is not limited to, acute hepatitis A infection, hepatitis B infection (hepatitis B surface antigen positive), drug- or alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, non-alcoholic steatohepatitis, primary biliary cirrhosis, or any other non-HCV liver disease considered clinically significant by the Investigator Evidence of clinical hepatic decompensation or presence of grade 2/3 esophageal varices Any of the protocol defined laboratory abnormalities B. Sub-study: Presence of coagulopathy (hemophilia) or hemoglobinopathy (including sickle cell disease, thalassemia) Use of any anti-coagulant (for example, warfarin, heparin) or anti-platelet medications within 1 week of the Screening visit Any of the protocol defined laboratory abnormalities

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Research & Development, LLC Clinical Trial

Organizational Affiliation

Janssen Research & Development, LLC

Official's Role

Study Director

Facility Information:

City

Bakersfield

State/Province

California

Country

United States

City

Jacksonville

State/Province

Florida

Country

United States

City

Lutherville

State/Province

Maryland

Country

United States

City

Winston Salem

State/Province

North Carolina

Country

United States

City

Knoxville

State/Province

Tennessee

Country

United States

City

Arlington

State/Province

Texas

Country

United States

City

San Antonio

State/Province

Texas

Country

United States

City

Toronto

State/Province

Ontario

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

29274193

Citation

Sulkowski MS, Feld JJ, Lawitz E, Felizarta F, Corregidor AM, Khalid O, Ghalib R, Smith WB, Van Eygen V, Luo D, Vijgen L, Gamil M, Kakuda TN, Ouwerkerk-Mahadevan S, Van Remoortere P, Beumont M. Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection. J Viral Hepat. 2018 Jun;25(6):631-639. doi: 10.1111/jvh.12853. Epub 2018 Feb 6.

Results Reference

derived

Learn more about this trial

Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of Simeprevir, Daclatasvir and Sofosbuvir in Treatment-naive Participants With Chronic Hepatitis C Virus Genotype 1 Infection

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