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Reversal of Hepatic Impairment in Patients With Hepatitis C Virus (HCV) and Early Decompensation of Cirrhosis

Primary Purpose

Hepatitis C

Status

Terminated

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Simeprivir (SMV)

Sofosbuvir (SOF)

Ribavirin (RBV)

About this trial

This is an interventional other trial for Hepatitis C focused on measuring HCV, Hepatitis C

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

HCV genotype 1 infection (all subtypes and Q80K a type of mutation are allowed), and have been approved by a third party payer for the FDA-approved combination of sofosbuvir (SOF) plus ribavirin. The study drug, simeprevir (SMV)
Biopsy proven cirrhosis, or clinical cirrhosis with APRI (AST to Platelet Ratio Index to determine clinical cirrhosis)> 2, Fibrotest > 0.75, or Fibroscan > 12.5 Results Stiffness (kPa).
MELD 10 or less
Expected survival without liver transplantation of >1 year
Patients with Hepatocellular carcinoma (HCC) are included as long as disease MELD is 10 or less, and anticipated time to transplant is >1 year. An example, might be a patient with a subcentimeter HCC who is undergoing serial imaging to document tumor growth to tumor diameter >2 cm prior to listing for transplantation (in order to secure MELD exception). In this case, there could be a time lapse of 3 months or more while monitoring tumor growth, and a further time lapse of 9 months or more until the time of transplantation.
Patients with TIPS or Portal Vein Thrombosis may be included. -

Exclusion Criteria:

Inability to provide informed consent
Known hypersensitivity or serious adverse reaction to any of the study drugs
Age <18 or >80 years
Pregnancy as determined by subject reporting and urine dipstick testing at screening.
Other underlying chronic liver disease - examples that would exclude a patient from participating include but are not limited to nonalcoholic liver disease, alcoholic liver disease, hepatitis B, hemochromatosis, and autoimmune liver disease.
Serious other underlying medical condition - examples include but are not limited to unstable cardiovascular, coronary, or pulmonary disease including right and left sided heart failure, active malignancy other than HCC, or serious infection.
Estimated creatinine clearance < 30 mL min-1 1.73 m2 surface area (BSA)
Hemoglobin <10 g/dL
Neutrophils <500 /μL
Platelets <50,000 /μL
Bilirubin >4 mg/dL
Albumin < 2.8 g/dL
Blood Clotting: International Normalised Ratio (INR) > 2
MELD >10
Child-Turcotte-Pugh class B or C; or, CTP score >7
Conditions that would affect the absorption of orally administered cholate used in the HepQuant® test - such as, extensive intestinal resection, diabetic gastroparesis, and ileal disease or resection.
Concomitant use of both beta-blocker and ACE inhibitor
Subjects taking any other medications with significant drug drug interactions related to the study medications (sofosbuvir, simeprevir, or ribavirin) who cannot discontinue or substitute that medication, will be excluded.

Sites / Locations

University of Colorado Denver (Leprino Building)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HCV positive group

Arm Description

A single arm study of 'Simeprivir (SMV), Sofosbuvir (SOF) and Ribavirin (RBV) in an HCV positive population.

Outcomes

Primary Outcome Measures

The Sustained Virologic Response (SVR) in Patients Infected With HCV Genotype 1, Cirrhosis, and Early Clinical Decompensation

Number of participants who cleared Hepatitis C (HCV) after 12 weeks was collected (HCV RNA level was "Not Detected".

Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: Baseline

Liver function as assessed via MELD score. The Model For End-Stage Liver Disease (MELD) score assesses the severity of patient liver disease. Possible scores range from 6 to 40, with higher scores indicating more severe liver disease and a worse outcome.

Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: 12 Weeks

Secondary Outcome Measures

Full Information

NCT ID

NCT02455167

First Posted

April 21, 2015

Last Updated

August 16, 2021

Sponsor

University of Colorado, Denver

Collaborators

Janssen Scientific Affairs, LLC

1. Study Identification

Unique Protocol Identification Number

NCT02455167

Brief Title

Reversal of Hepatic Impairment in Patients With Hepatitis C Virus (HCV) and Early Decompensation of Cirrhosis

Official Title

Reversal of Hepatic Impairment by Achieving Sustained Virologic Response (SVR) With 12 Weeks of Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) in Patients With Hepatitis C Virus (HCV) Genotype 1 Infection and Early Decompensation of Cirrhosis (MELD 10 or Less)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Terminated

Why Stopped

Study stopped due to low accrual and availability of other treatment options

Study Start Date

May 2015 (undefined)

Primary Completion Date

July 18, 2016 (Actual)

Study Completion Date

July 18, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Colorado, Denver

Collaborators

Janssen Scientific Affairs, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Achieve sustained virologic response (SVR) in patients infected with HCV genotype 1, cirrhosis, and early clinical decompensation using 12 weeks of Olysio/Sovaldi/Ribavirin (or known as: Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin (RBV). Hepatic improvement during and after Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) treatment using a new test of liver function, HepQuant-SHUNT.

Detailed Description

The proposed study will quantify hepatic improvement and antiviral efficacy of the open-label interferon-free combination of 12 weeks of simeprevir (SMV, Simeprevir), sofosbuvir (SOF, Sofosbuvir), and ribavirin (RBV) in patients with HCV genotype 1 infection and early decompensation of cirrhosis. Early decompensation is defined by clinical complications or laboratory deterioration but with a model for end-stage liver disease (MELD) score of 10 or less. The primary objective of this trial is determination of hepatic functional improvement as measured by the HepQuant (HQ) test during and after Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV). Standard laboratory tests, clinical models (MELD, CTP), liver biopsy, hepatic venous pressure gradient (HVPG), and other imaging tests are insensitive, invasive, or nonspecific. They may not adequately assess the liver's improvement after viral eradication. In contrast, HepQuant (HQ) tests (Systemic Hepatic Filtration Rate (HFR), Portal HFR, SHUNT,single point cholate concentration (STAT), and DSI) are noninvasive, sensitive, specific, and target an endogenous function, the hepatic uptake of cholate. HQ tests uses serum sampling over a time period of up to 90 minutes to quantify the systemic circulation, portal circulation, and portal-systemic shunt and to derive a disease severity index (DSI) in intact human subjects. The primary endpoint in this treatment trial will be improvement in hepatic function measured by HepQuant (HQ) tests that occurs during and after successful Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV).

6. Conditions and Keywords

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

Hepatitis C

Keywords

HCV, Hepatitis C

7. Study Design

Primary Purpose

Other

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

HCV positive group

Arm Type

Experimental

Arm Description

A single arm study of 'Simeprivir (SMV), Sofosbuvir (SOF) and Ribavirin (RBV) in an HCV positive population.

Intervention Type

Drug

Intervention Name(s)

Simeprivir (SMV)

Other Intervention Name(s)

Olysio (Simeprivir);

Intervention Description

Experimental Single arm study. All participants will get the same treatment.

Intervention Type

Drug

Intervention Name(s)

Sofosbuvir (SOF)

Other Intervention Name(s)

Solvaldi (Sofosbuvir);

Intervention Description

Experimental Single arm study. All participants will get the same treatment.

Intervention Type

Drug

Intervention Name(s)

Ribavirin (RBV)

Other Intervention Name(s)

Virazole (Ribavirin);

Intervention Description

Experimental Single arm study. All participants will get the same treatment.

Primary Outcome Measure Information:

Title

The Sustained Virologic Response (SVR) in Patients Infected With HCV Genotype 1, Cirrhosis, and Early Clinical Decompensation

Description

Number of participants who cleared Hepatitis C (HCV) after 12 weeks was collected (HCV RNA level was "Not Detected".

Time Frame

12 weeks

Title

Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: Baseline

Description

Time Frame

Baseline

Title

Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: 12 Weeks

Description

Time Frame

12 Weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: HCV genotype 1 infection (all subtypes and Q80K a type of mutation are allowed), and have been approved by a third party payer for the FDA-approved combination of sofosbuvir (SOF) plus ribavirin. The study drug, simeprevir (SMV) Biopsy proven cirrhosis, or clinical cirrhosis with APRI (AST to Platelet Ratio Index to determine clinical cirrhosis)> 2, Fibrotest > 0.75, or Fibroscan > 12.5 Results Stiffness (kPa). MELD 10 or less Expected survival without liver transplantation of >1 year Patients with Hepatocellular carcinoma (HCC) are included as long as disease MELD is 10 or less, and anticipated time to transplant is >1 year. An example, might be a patient with a subcentimeter HCC who is undergoing serial imaging to document tumor growth to tumor diameter >2 cm prior to listing for transplantation (in order to secure MELD exception). In this case, there could be a time lapse of 3 months or more while monitoring tumor growth, and a further time lapse of 9 months or more until the time of transplantation. Patients with TIPS or Portal Vein Thrombosis may be included. - Exclusion Criteria: Inability to provide informed consent Known hypersensitivity or serious adverse reaction to any of the study drugs Age <18 or >80 years Pregnancy as determined by subject reporting and urine dipstick testing at screening. Other underlying chronic liver disease - examples that would exclude a patient from participating include but are not limited to nonalcoholic liver disease, alcoholic liver disease, hepatitis B, hemochromatosis, and autoimmune liver disease. Serious other underlying medical condition - examples include but are not limited to unstable cardiovascular, coronary, or pulmonary disease including right and left sided heart failure, active malignancy other than HCC, or serious infection. Estimated creatinine clearance < 30 mL min-1 1.73 m2 surface area (BSA) Hemoglobin <10 g/dL Neutrophils <500 /μL Platelets <50,000 /μL Bilirubin >4 mg/dL Albumin < 2.8 g/dL Blood Clotting: International Normalised Ratio (INR) > 2 MELD >10 Child-Turcotte-Pugh class B or C; or, CTP score >7 Conditions that would affect the absorption of orally administered cholate used in the HepQuant® test - such as, extensive intestinal resection, diabetic gastroparesis, and ileal disease or resection. Concomitant use of both beta-blocker and ACE inhibitor Subjects taking any other medications with significant drug drug interactions related to the study medications (sofosbuvir, simeprevir, or ribavirin) who cannot discontinue or substitute that medication, will be excluded.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amanda Wieland, MD

Organizational Affiliation

University of Colorado, Denver

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Colorado Denver (Leprino Building)

City

Denver

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

17635375

Citation

Everson GT, Martucci MA, Shiffman ML, Sterling RK, Morgan TR, Hoefs JC; HALT-C trial group. Portal-systemic shunting in patients with fibrosis or cirrhosis due to chronic hepatitis C: the minimal model for measuring cholate clearances and shunt. Aliment Pharmacol Ther. 2007 Aug 1;26(3):401-10. doi: 10.1111/j.1365-2036.2007.03389.x.

Results Reference

result

PubMed Identifier

18266997

Citation

Everson GT, Shiffman ML, Morgan TR, Hoefs JC, Sterling RK, Wagner DA, Kulig CC, Curto TM, Wright EC; Halt-C Trial Group. The spectrum of hepatic functional impairment in compensated chronic hepatitis C: results from the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis Trial. Aliment Pharmacol Ther. 2008 May;27(9):798-809. doi: 10.1111/j.1365-2036.2008.03639.x. Epub 2008 Feb 7.

Results Reference

result

PubMed Identifier

19053983

Citation

Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, Desanto JL, Curto TM, Wright EC; HALT-C Trial Group. Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial. Aliment Pharmacol Ther. 2009 Mar 1;29(5):589-601. doi: 10.1111/j.1365-2036.2008.03908.x. Epub 2008 Dec 1.

Results Reference

result

PubMed Identifier

8213790

Citation

Everson GT. Hepatic cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 1993 Oct;22(4):520-5. doi: 10.1016/s0272-6386(12)80923-1. No abstract available.

Results Reference

result

PubMed Identifier

9346731

Citation

Shrestha R, McKinley C, Showalter R, Wilner K, Marsano L, Vivian B, Everson GT. Quantitative liver function tests define the functional severity of liver disease in early-stage cirrhosis. Liver Transpl Surg. 1997 Mar;3(2):166-73. doi: 10.1002/lt.500030210.

Results Reference

result

PubMed Identifier

17850410

Citation

Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol. 2007 Nov;102(11):2589-600. doi: 10.1111/j.1572-0241.2007.01466.x. Epub 2007 Sep 10.

Results Reference

result

PubMed Identifier

17593061

Citation

Tripodi A, Caldwell SH, Hoffman M, Trotter JF, Sanyal AJ. Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease. Aliment Pharmacol Ther. 2007 Jul 15;26(2):141-8. doi: 10.1111/j.1365-2036.2007.03369.x.

Results Reference

result

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Reversal of Hepatic Impairment in Patients With Hepatitis C Virus (HCV) and Early Decompensation of Cirrhosis

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