Cognitive Impairments in Chronic Hepatitis C Patients and Potential Reversibility With New Agents (CICHepC)

Study Overview
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Brief Summary
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The overall aim of this study is to evaluate the prevalence of cognitive impairments and brain anomalies in Chronic Hepatitis C infected individuals and to investigate likely changes in cognition and brain structure and function after treatment with Direct-acting Antivirals (DAAs).

Detailed Description
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Design: Prospective interventional study. Chronic HCV infected patients who are going to initiate a DAA-based antiviral regimen according to clinical practice will be recruited to participate in the study. Patients will be treated according to the current national and international guidelines for the treatment of HCV chronic hepatitis. The participation in the study will not influence neither the indication for de treatment nor the type of treatment prescribed. The only intervention in this study refers to the performance of extraordinary neuro-psychological evaluations and MRI studies at different times along the study. Patients and methods: This study will be performed in a cohort of 80 patients with CHC (≤ F3). The number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, α =0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region (Liem et al., 2015). Sample size calculations performed for functional magnetic resonance using values of medium Cohen's d effect size of 0.6 and 0.7 yield sample sizes of 88, 66 respectively to achieve 80% power at a significance level of 0.05 (Guo et al., 2012). Therefore, the sample size estimated in this project would yield enough power to detect small and medium effects size. The following studies will be conducted: - Cognitive assessment: The assessment with widely-used neuropsychological test batteries may yield summary scores for the domains: attention and reaction time (Continuous Performance Test (CPT), working memory (digits forward and backward WAIS-III subtest), information processing speed (digit symbol WAIS-III subtest and Trail making test Part A), verbal fluency (letter FAS and category animals subtest), learning and memory (Rey Auditory 2.- Verbal Learning Test (RAVLT) and Rey Copy Figure(RCF)), motor functioning (Grooved Pegboard) and executive functions (Tower of London, Trail making test Part B and Stroop color-word test). - MRI scanning: Imaging data will be acquired at the neurorradiology section of the Hospital Marques de Valdecilla, on a 3T MRI scanner (Achieva, Philips Medical Systems, Best, The Netherlands) at the Neuroradiology Department of Marques de Valdecilla University Hospital. Subjects will undergo a 30 minutes protocol that will include a high resolution T1- weighted image, a 64 directions DWI sequence and A BOLD resting state fMRI sequence. - MRI data analysis: It will involve structural, diffusion and functional MRI analyses. These analyses will be conducted by Neuroimaging Platform at the IDIVAL. 3.1.- Structural MRI: we will use the software FreeSurfer (http://freesurfer.net/) to quantify the volume of subcortical structures (amygdala, hippocampus, thalamus, putamen, globus pallidus, and caudate nucleus) and the area, thickness, and volume of 34 cortical structures (Desikan-Killiany atlas). 3.2.- Diffusion MRI: we will use FSL's TBSS and Probtracx tools http://www.fmrib.ox.ac.uk/fsl/index.html) to compare fractional anisotropy values (a measure based on restricted movement of water molecules) in whole brain voxelwise analysis and identify regions (clusters) where white matter is more disorganized. Also we will perform fiber tracking and study connectivity between different brain areas. 3.3.- Functional MRI (fMRI): resting state fmri will be used to evaluate regional interactions that occur when non performing and specific task. This analysis will be carried out with using SPM software http://www.fil.ion.ucl.ac.uk/spm/) and the toolbox PRONTO (http://www.mlnl.cs.ucl.ac.uk/pronto ).

Official Title
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Personalized Medicine in HCV Infection: Cognitive Impairments and Brain Anomalies in Chronic Hepatitis C Infected Individuals. Characterization and Potential Reversibility With Direct Antiviral Agents.

Conditions
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Hepatitis C

Intervention / Treatment
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* Other: Neuropsychological evaluation and Brain MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CHC patients 18-75 years old Liver fibrosis ≤ F3 in Fibroscan/liver biopsy Naive or previous failure to a treatment Accept the study and sign the CI Exclusion Criteria: Does not meet the above criteria VIH or other viral coinfection Hepatocarcinoma Other systemic inflammatory diseases (i.e. RA, etc) Neurodegenerative diseases

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cognitive evaluation in HCV patients<br>Neuropsychological evaluation and Brain MRI Intervention: The only intervention to be carried out along the study will consist of complete neuro-psychological tests and MRI studies performed at different times. Chronic HCV patients who are going to be treated with new DAAs according to current guidelines will be studied: A neuro-psychological battery of tests and brain MRI studies will be performed at different times before and after the end of the treatment. The participation in the study will not influence neither the indication to treat nor the treatment used. Anti-HCV regimens will be used according to clinical practice as indicated into the current guidelines | Other: Neuropsychological evaluation and Brain MRI<br>* This is a prospective study. The only intervention planned will consist of performing neuropsychological tests and cerebral MRI that will be carried out on a single group cohort at different times. Notwithstanding, we will record the exposure to DAA to assess any change in neurocognitive function and MRI imaging. Anti-HCV regimens will be used according to clinical practice as indicated into the current guidelines (1) (1)European Association for Study of Liver. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol. 2015 Jul;63(1):199-236. doi: 10.1016/j.jhep.2015.03.025. Epub 2015 Apr 21. PubMed PMID: 25911336.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Continuous Performance Test (CPT) score | Neuropsychological test to assess Cognitive impairment, particularly Attention and reaction time | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Digits forward and backward WAIS-III subtest scores | Neuropsychological test to assess Cognitive impairment, particularly Working memory | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Digit symbol WAIS-III subtest score | Neuropsychological test to assess Information processing speed | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Trail Making Test (TMT) Parts A & B scores | Neuropsychological test to assess Information processing speed | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Letter FAS score | Neuropsychological test to assess Verbal fluency | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in animal category subtest score | Neuropsychological test to assess Verbal fluency | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Rey Auditory Verbal Learning Test (RAVLT) scores | Neuropsychological test to assess Learning and memory | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Rey Copy Figure(RCF) scores | Neuropsychological test to assess Learning and memory | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Grooved Pegboard score | Neuropsychological test to assess Motor functioning | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Tower of London score | Neuropsychological test to assess Executive functions | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in Stroop color-word test scores | Neuropsychological test to assess Executive functions | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in cortical thickness | Basal Neuroimaging findings in HCV infected patients and changes after DAA treatment (Assesed through structural, diffusion and functional MRI). | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in cortical surface área assessed by MRI | Basal Neuroimaging findings in HCV infected patients and changes after DAA treatment (Assesed through structural, diffusion and functional MRI). | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Changes in cortical surface volumen assessed by MRI | Basal Neuroimaging findings in HCV infected patients and changes after DAA treatment (Assesed through structural, diffusion and functional MRI). | Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Sustained Viral Response | Data on efficacy of treatments | 3, 6 and 12 months after the end of treatment (Sustained Viral Response) | 
| Advers events | Data on safety | up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic, Cognition Disorders, Neurocognition Disorders, Cognitive Impairments, Diffusion Magnetic Resonance Imaging, MRI functional, Verbal fluency