Clinical trial NCT02745132: Cognitive Impairments in Chronic Hepatitis C Patients and Potential Reversibility With New Agents (CICHepC)
Official title: Personalized Medicine in HCV Infection: Cognitive Impairments and Brain Anomalies in Chronic Hepatitis C Infected Individuals. Characterization and Potential Reversibility With Direct Antiviral Agents.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis C
Keywords: Chronic, Cognition Disorders
Neurocognition Disorders
Cognitive Impairments
Diffusion Magnetic Resonance Imaging
MRI functional
Verbal fluency
Lead sponsor: Instituto de Investigación Marqués de Valdecilla
Sponsor class: OTHER
Collaborators: name: Ministerio de Economía y Competitividad, Spain
First posted: 2016-04-20
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP

Brief summary: 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: 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:

1. - 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).
2. - 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.
3. - 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 ).

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Continuous Performance Test (CPT) score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
Secondary outcomes:
measure: Changes in Digits forward and backward WAIS-III subtest scores
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Digit symbol WAIS-III subtest score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Trail Making Test (TMT) Parts A & B scores
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Letter FAS score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in animal category subtest score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Rey Auditory Verbal Learning Test (RAVLT) scores
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Rey Copy Figure(RCF) scores
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Grooved Pegboard score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Tower of London score
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in Stroop color-word test scores
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in cortical thickness
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in cortical surface área assessed by MRI
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Changes in cortical surface volumen assessed by MRI
timeFrame: Basal and 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Sustained Viral Response
timeFrame: 3, 6 and 12 months after the end of treatment (Sustained Viral Response)
measure: Advers events
timeFrame: up to 24 weeks
Other outcomes:
Locations:
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
Study officials:
affiliation: Head of Gastroenterology and Hepatology at Hospital Universitario Marqués de Valdecilla. Professor at the Universidad de Cantabria
name: Javier Crespo García, MDPhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Head of section Of Psychiatry at University Hospital Marqués de Valdecilla. Proffesor of Psychiatry at Department of Psychiatry, School of Medicine
name: Benedicto Crespo Facorro, MDPhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Byrnes V, Miller A, Lowry D, Hill E, Weinstein C, Alsop D, Lenkinski R, Afdhal NH. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012 Mar;56(3):549-56. doi: 10.1016/j.jhep.2011.09.015. Epub 2011 Oct 23.
citation: Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez-Ramirez MA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, McKeating JA. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology. 2012 Mar;142(3):634-643.e6. doi: 10.1053/j.gastro.2011.11.028. Epub 2011 Dec 1.
citation: Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, Keicher C, Scheurlen M. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013 Aug;58(2):497-504. doi: 10.1002/hep.26229. Epub 2013 Jun 24.
citation: Bajaj JS, Forton DM. Cognitive improvement after HCV eradication: Extending the benefits. Hepatology. 2013 Aug;58(2):480-2. doi: 10.1002/hep.26481. Epub 2013 Jun 25. No abstract available.