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Endothelial Dysfunction and Subclinical Atheromatosis in Chronic HCV Infection. Response to DAA Agents. (C-Endys)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02802280
Recruitment Status : Unknown
Verified June 2016 by Instituto de Investigación Marqués de Valdecilla.
Recruitment status was:  Recruiting
First Posted : June 16, 2016
Last Update Posted : June 17, 2016
Sponsor:
Collaborator:
Ministerio de Economía y Competitividad, Spain
Information provided by (Responsible Party):
Instituto de Investigación Marqués de Valdecilla

Tracking Information
First Submitted Date  ICMJE June 13, 2016
First Posted Date  ICMJE June 16, 2016
Last Update Posted Date June 17, 2016
Study Start Date  ICMJE October 2015
Estimated Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2016)
Changes in Flow mediated dilatation (FMD) [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
FMD: Vasodilation mediated by ultrasound brachial flow through the rate of increase of brachial artery diameter (d2) as compared to baseline (d1) after a ischemia time (300 mmHg) for 4 minutes (FMD = (d2-d1) / d1 (x 100).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2016)
  • Changes in cIMT (Carotid intima-media thickness) [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    cIMT (Carotid intima-media thickness) will be assessed by carotid ultrasound. It is defined as the distance between the interface of the carotid lumen with arterial intima and the interface of medium with adventitia of the distal arterial wall. They will be measured on the back wall in a free-plaque area in the common carotid (cIMT CC) in the carotid bulb (cIMT -B), and internal carotid (cIMT -CI).
  • Changes in the presence of carotid plaques [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Presence of carotid plaques in these territories (common carotid, carotid bulb and internal carotid). Plaque will be defined following the Mannheim criteria. It will be assessed by carotid ultrasound image.
  • Changes in ICAM-1 serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of ICAM-1 (Intercellular Adhesion Molecule 1) serum levels at different times (see time frame)
  • Changes in VCAM-1 serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of Vascular cell adhesion molecule 1 (VCAM-1) serum levels at different times (see time frame)
  • Changes in E-selectin serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of E-selectin serum levels at different times (see time frame)
  • Changes in P-selectin serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of P-selectin serum levels at different times (see time frame)
  • Changes in MCP-1 serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of monocyte chemoattractant protein 1 (MCP-1) serum levels at different times (see time frame)
  • Changes in galectin-3-binding protein serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of galectin-3-binding protein serum levels at different times (see time frame)
  • Changes in CD163 serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of CD163 (Cluster of Differentiation 163) serum levels at different times (see time frame)
  • Changes in hs-PCR serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of hs-PCR serum levels at different times (see time frame)
  • Changes in Lp(a) serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of Lipoprotein(a) (Lp(a)) serum levels at different times (see time frame)
  • Changes in VLDL serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of VLDL serum levels at different times (see time frame)
  • Changes in LDL serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of LDL serum levels at different times (see time frame)
  • Changes in HDL serum levels [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of HDL serum levels at different times (see time frame)
  • Changes in HOMA [ Time Frame: Basal and 3, 12 and 24 months after the end of treatment ]
    Measurement of HOMA (homeostasis model assessment) index at different times (see time frame)
  • Presence of Sustained Viral Response [ Time Frame: 3, 6 and 12 months after the end of treatment ]
    Data on efficacy of treatment
  • Adverse events [ Time Frame: up to 24 weeks ]
    Data on safety of treatments
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Endothelial Dysfunction and Subclinical Atheromatosis in Chronic HCV Infection. Response to DAA Agents.
Official Title  ICMJE Personalized Medicine in HCV Chronic Infection. Endothelial Dysfunction and Subclinical Atheromatosis in Patients With HCV Infection. Characterization and Potential Reversibility With Direct Antiviral Agents.
Brief Summary

Hypothesis: In addition to the liver deleterious effects, Chronic Hepatitis C (CHC) can cause changes in other organs highlighting the increased cardiovascular risk (CVR) through accelerated atherosclerosis, whose consequences may persist even after healing infection with new antiviral treatments. This can have major impact on the health system. Obtaining a Sustained Virological Response (SVR) with a free Interferon (IFN) antiviral treatment is probably able to reverse, at least partially, increased vascular risk induced by Hepatitis C virus (HCV) and perhaps ultimately reverse the subclinical atherosclerosis.

Aims: To study the presence of early-subclinical atherosclerotic disease (endothelial dysfunction and subclinical atherosclerosis) in patients with CHC and evaluate the influence of treatment in the short and medium term on the CVR derived. Studying these same issues but in patients with established atherosclerotic disease.

Detailed Description

Design:

Prospective interventional study.

Patients and methods:

Tracked on a population of 80 patients with CHC (estimated fibrosis F2-F3),

An evaluation of the CVR will be performed by determining biomarkers of endothelial activation and macrophage activation, measuring flow-mediated vasodilation and atherosclerotic damage.

All evaluations will take place prior (at baseline) and after antiviral treatment. Particularly, all determinations will be performed immediately before and 3, 12 and 24 months after the end of antiviral treatment.

In order to improve the diagnostic accuracy in terms of discriminating liver damage associated to Non Alcoholic Fatty Liver Disease (NAFLD) from HCV infection, the investigators will use the owl-liver® technique in all patients before and after treatment.

Sample size: Considering the primary endpoint the flow-mediated vasodilation (FMD), data have been reported on FMD of 7.6 ± 2.4% in healthy subjects and 5.1 ± 2.2% in subjects with risk factors (Dalli et al Rev Esp Cardiol 2002; 55: 928-35). Assuming these SD and a correlation coefficient of 0.3 between the two measurements, 80 patients will be needed to detect a change of 1% in vasodilation with an output of 90% and a significance level of 5%.

Variables and tasks:

Task 1. Assessment of endothelial function.

  1. -Vasodilation mediated by ultrasound brachial flow through the rate of increase of brachial artery diameter (d2) as compared to baseline (d1) after a ischemia time (300 mmHg) for 4 minutes (FMD = (d2-d1) / d1 (x 100).
  2. -Endothelial function biomarkers: ICAM-1, VCAM-1, E-selectin, P-selectin, MCP-1, angiopoietin-2, sTWEAK and ADMA.
  3. - Macrophage activation biomarkers: Gal-3BP, sCD163 and sCD14.

Task 2. Assessment of atherosclerotic damage. Common carotid, internal carotid and carotid bulb (bilateral) will be explored by ultrasound. The images will be electronically stored in DICOM format.

The analyzed parameters will be:

  1. cIMT (Carotid intima media thickness and carotid intima-media thickness) defined as the distance between the interface of the carotid lumen with arterial intima and the interface of medium with adventitia of the distal arterial wall. They will be measured on the back wall in a free-plaque area in the common carotid (cIMT CC) in the carotid bulb (cIMT -B), and internal carotid (cIMT -CI).
  2. Presence of carotid plaques in these territories. Plaque will be defined following the Mannheim criteria.
  3. Presence of atherosclerotic plaque: to distinguish between focal and diffuse thickening. In the focal plate area, maximum thickness and Gray Scale Median (GSM) will be quantified. In the diffuse thickening (IMT> 1.5 mm) only the GSM will be quantified.

Task 3. Assessment of vascular risk. Classic and emerging vascular risk assessment.

  1. -Study of classic risk factors: through REGICOR and Framingham Score tables. Fatty Liver Index to exclude or confirm NASH (BMI, waist circumference, triglycerides and GGT). Metabolic syndrome will be detected by the NCEP-ATPIII.
  2. - Study of emerging vascular risk factors, including proinflammatory factors. In this way, the investigators will analyze the plasma levels hcPCR, homocysteine, Lp(a), pentraxin 3, SAA, oxidized LDL, PON1, PCSK9 and elevated plasma levels of von Willebrand factor factor (VWF)
  3. - Qualitative lipoprotein changes: the total concentration of lipoprotein (VLDL, LDL, HDL) will be determined as well as their composition (total cholesterol, triglycerides, phospholipids, protein, apolipoprotein B, lipoprotein ratio / total triglyceride mass VLDL, LDL and HDL, number of VLDL, LDL and HDL, cholesterol molecules per particle and triglyceride molecules per particle).
  4. - Insulin resistance by HOMA.
  5. -HbA1c
  6. - Rx Thorax.

h)-ECG with QTc interval measurement.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Condition  ICMJE
  • Hepatitis C
  • Cardiovascular Diseases
Intervention  ICMJE Other: Cardiovascular risk in HCV patients

Cardiovascular risk assessement (through Flow-mediated vasodilatation "FMV", measurement of endothelial function biomarkers, carotid ultrasound, etc.)

This is a prospective study. The only intervention planned will consist of performing different tests that define the individual cardiovascular risk. These tests will be carried out on a single group cohort at different times.

Notwithstanding, the investigators will record the exposure to DAA to assess any change in CVR.

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.

Study Arms  ICMJE Cardiovascular risk in HCV patients

Intervention:

The only intervention to be carried out along the study will consist of a complete evaluation of cardiovascular risk of HCV patients both at baseline (pre-treatment) and after HCV treatment, through performing different tests (see below)

Chronic HCV patients who are going to be treated with new DAAs according to current guidelines will be studied 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

Intervention: Other: Cardiovascular risk in HCV patients
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 13, 2016)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2017
Estimated Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • HCV infected patients (aged 18-75 yr)
  • Naive or failure to previous treatments
  • Liver fibrosis F2-F3 in Fibroscan/liver biopsy
  • Accept the study and sign the CI

Exclusion Criteria:

  • Known cardiovascular diseases
  • Does not meet the above criteria
  • VIH or other viral coinfection
  • Hepatocarcinoma
  • Pregnancy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02802280
Other Study ID Numbers  ICMJE C-Endys PI15/02138
PI15/02138 ( Other Grant/Funding Number: Spanish Ministry of Economy and Competitiveness )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Instituto de Investigación Marqués de Valdecilla
Study Sponsor  ICMJE Instituto de Investigación Marqués de Valdecilla
Collaborators  ICMJE Ministerio de Economía y Competitividad, Spain
Investigators  ICMJE
Principal Investigator: Javier Crespo García, MDPhD Head of Gastroenterology and Hepatology at Hospital Universitario Marqués de Valdecilla. Professor at the Universidad de Cantabria
PRS Account Instituto de Investigación Marqués de Valdecilla
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP