Clinical trial NCT02455167: 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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hepatitis C
Keywords: HCV
Hepatitis C
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Janssen Scientific Affairs, LLC
First posted: 2015-05-27
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 1. 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).
2. 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).

Eligibility criteria: Inclusion Criteria:

1. 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)
2. 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).
3. MELD 10 or less
4. Expected survival without liver transplantation of \>1 year
5. 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.
6. Patients with TIPS or Portal Vein Thrombosis may be included. -

Exclusion Criteria:

1. Inability to provide informed consent
2. Known hypersensitivity or serious adverse reaction to any of the study drugs
3. Age \<18 or \>80 years
4. Pregnancy as determined by subject reporting and urine dipstick testing at screening.
5. 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.
6. 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.
7. Estimated creatinine clearance \< 30 mL min-1 1.73 m2 surface area (BSA)
8. Hemoglobin \<10 g/dL
9. Neutrophils \<500 /μL
10. Platelets \<50,000 /μL
11. Bilirubin \>4 mg/dL
12. Albumin \< 2.8 g/dL
13. Blood Clotting: International Normalised Ratio (INR) \> 2
14. MELD \>10
15. Child-Turcotte-Pugh class B or C; or, CTP score \>7
16. 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.
17. Concomitant use of both beta-blocker and ACE inhibitor
18. 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.

Primary outcomes:
measure: The Sustained Virologic Response (SVR) in Patients Infected With HCV Genotype 1, Cirrhosis, and Early Clinical Decompensation
timeFrame: 12 weeks
measure: Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: Baseline
timeFrame: Baseline
measure: Hepatic Improvement During and After Simeprevir(SMV)/Sofosbuvir(SOF)/Ribavirin(RBV) Treatment Using a New Test of Liver Function, HepQuant-SHUNT: 12 Weeks
timeFrame: 12 Weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado Denver (Leprino Building)
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Amanda Wieland, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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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.
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.