Impact of HCV Treatment on Neurocognitive Functions and Brain Metabolism (HEPCOG-II)

Impact of HCV Eradication on Neurocognitive Functions and CNS Metabolism: a Trial of Daclatasvir, Asunaprevir and Beclabuvir for Patients With HCV Genotype 1 Infection

The purpose of this study is to examine whether neurocognitive impairments experienced by patients with chronic hepatitis C virus (HCV) infection can be reversed by treating HCV, with a new combination of direct acting antiviral drugs (daclatasvir (DCV), asunaprevir (ASV) and beclabuvir (BCV)). The study will assess the effect of HCV on the central nervous system (CNS) by assessing neurocognitive function and brain injury prior to treatment, and comparing it to the end of treatment, and 4, 12 and 24 weeks after treatment.

Study Overview

• Status: Withdrawn
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: DCV/ASV/BCV

Detailed Description

This study will evaluate the effect of DCV/ASV/BCV on neurocognitive functioning and brain metabolite concentrations in the frontal white matter and the basal ganglia in people with chronic HCV genotype 1 infection, through a comparison of baseline and post-treatment parameters.

This is an open label single arm multi-centre study. All participants will each receive daclatasvir (30mg), asunaprevir (200mg) and beclabuvir (75mg) in a fixed-dose combination oral tablet for twice daily administration with food.

Duration of treatment will be 12 weeks for all subjects followed by 24 weeks of observational follow-up.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St Vincent's Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 18 to 65 years
• Chronic HCV infection as documented by positive HCV RNA at screening and positive HCV RNA or anti-HCV antibody at least 6 months prior to screening
• HCV genotype 1 - mixed subtype, indeterminate subtype or other variants of genotype 1 are permissible
• Non-advanced cirrhotic defined as FibroScan ≤9.6 kPA at screening
• HCV treatment naïve
• Seronegative for HIV and HBsAg
• HCV RNA level of ≥104 IU/mL (10,000 IU/mL)
• Body Mass Index (BMI) between 18 and 35 kg/m2

• Women of childbearing potential (WOCBP) must:

  i. Have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/mL or equivalent units of HCG) within 24 hours prior to the start of study drug ii. Not be breastfeeding iii. Agree to follow instructions for methods of contraception for the duration of the treatment and for five weeks post-treatment completion

• Men who are sexually active with WOCBP must agree to follow instructions for methods of contraception for the duration of the treatment and for 14 weeks post-treatment completion
• Sufficient proficiency in English to complete the neurocognitive assessment, as judged by the investigator

Exclusion Criteria:

Target disease

• Infected with HCV other than genotype 1

Medical history and concurrent diseases

• Current hazardous consumption of alcohol, defined by an AUDIT-C score ≥4 for men and ≥3 for women
• Illicit substance use, identified by urinary drug test at screening
• Past history of non HCV-related CNS disorder, including seizures and traumatic brain injury
• Currently on an SSRI or other neuropsychiatric therapy
• Liver or any other organ transplant other than cornea and hair
• Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrolment
• Evidence of a medical condition contributing to chronic liver disease other than HCV (such, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcohol liver disease)
• Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug (subjects who have cholecystectomy are permitted to enter the study)
• Known history of coagulopathy including, but not limited to, hemophilia
• Uncontrolled diabetes defined as HbA1c >7% at screening
• Confirmed, uncontrolled hypertension (any screening systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg should be excluded unless discussed with the study medical monitor)
• Inability to tolerate oral medication
• Poor venous access
• Any other medical, psychiatric and/or social reason which, in the opinion of the investigator would make the subject inappropriate for the study

Physical and Laboratory Test Findings

• ALT ≥ 5 x ULN
• Total Bilirubin ≥ 34 µmol/L (≥ 2 mg/dl), unless subject has documented history of Gilbert's disease
• INR ≥ 1.3
• Albumin < 3.5 g/dL (35g/L)
• Platelets < 100 x 109 cells/L
• ANC < 0.75 x 109 cells/L
• Hemoglobin < 10 g/dL (100g/L)
• Creatinine clearance (CrCL) ≤ 50 mL/min
• Alpha fetoprotein (AFP) > 50ng/mL
• QTcF or QTcB > 580mSec
• Positive HBsAg, HIV-1 or HIV-2 Ab

Allergies and Adverse Drug Reaction

• History of hypersensitivity to drugs with a similar biochemical structure to DCV, ASV or BCV
• Any other criteria or know contraindication that would exclude the subject from receiving DCV, ASV or BCV Prohibited treatments and/or Therapies
• Exposure to any investigational drug or placebo within 4 weeks of study drug administration
• Refer to 5.5 for prohibited and/or restricted treatments during and post-treatment Sex and reproductive status
• Males and females who do not or are unable to meet the requirements outlined in Inclusion Criterias 9 and 10

Other Exclusion Criteria

• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infection disease) illness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hepatitis C treatment; 12 weeks of DCV/ASV/BCV therapy.	Drug: DCV/ASV/BCV; Each participant will each receive daclatasvir (30mg), asunaprevir (200mg) and beclabuvir (75mg) in a fixed-dose combination oral tablet for twice daily administration with food.; Other Names: Daclatasvir; Asunaprevir; Beclabuvir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurocognitive functioning	Mean change in neurocognitive functioning (global z-score representing overall neurocognitive performance across CogState, pegboard and colours trails)	36 weeks
Brain metabolite concentrations	Mean change in five absolute metabolite concentrations (NAA,Cho, Cr, mlo, glx)	36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurocognitive functioning	Mean change in neurocognitive functioning (global z-score representing overall neurocognitive performance across CogState, pegboard and colours trails)	12 and 24 weeks
NAA metabolite concentration in the brain		12 and 24 weeks
Cho metabolite concentration in the brain		12 and 24 weeks
Cr metabolite concentration in the brain		12 and 24 weeks
MLO metabolite concentration in the brain		12 and 24 weeks
Glx metabolite concentration in the brain		12 and 24 weeks
Change in neurocognitive functioning compared between subjects with and without sustained virological response (SVR)	Mean change in neurocognitive functioning (global z-score representing overall neurocognitive performance across CogState, pegboard and colours trails)	24 weeks
Change in brain metabolite concentrations compared between subjects with and without sustained virological response (SVR)	Mean change in absolute metabolite concentrations (NAA,Cho, Cr, mlo, glx)	24 weeks

Collaborators and Investigators

• Sponsor: Kirby Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Gregory Dore, BSc, MBBS, FRACP, MPH, PhD, The Kirby Institute, University of New South Wales

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Anticipated): June 1, 2016
• Study Completion (Anticipated): June 1, 2016

Study Registration Dates

• First Submitted: September 25, 2014
• First Submitted That Met QC Criteria: November 13, 2014
• First Posted (Estimate): November 18, 2014

Study Record Updates

• Last Update Posted (Estimate): June 3, 2016
• Last Update Submitted That Met QC Criteria: June 2, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Hepatitis C; Hepatitis; Daclatasvir; Neurocognitive function; Asunaprevir; Beclabuvir; Brain metabolites; Direct acting antiviral therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Asunaprevir
• Other Study ID Numbers: VHCRP1304