Endothelial Dysfunction and Subclinical Atheromatosis in Chronic HCV Infection. Response to DAA Agents.

Cardiovascular Diseases Clinical Trial

— C-Endys  

Official title:

Personalized Medicine in HCV Chronic Infection. Endothelial Dysfunction and Subclinical Atheromatosis in Patients With HCV Infection. Characterization and Potential Reversibility With Direct Antiviral Agents.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02802280
• Other study ID #: C-Endys PI15/02138
• Secondary ID: PI15/02138
• Status: Recruiting
• Phase: Phase 4
• First received: June 13, 2016
• Last updated: June 15, 2016
• Start date: October 2015
• Est. completion date: March 2017

Study information

• Verified date: June 2016
• Source: Instituto de Investigación Marqués de Valdecilla
• Contact: Javier Crespo García, MDPhD
• Phone: 34 942202544
• Email: javiercrespo1991[@]gmail.com
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: March 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Atherosclerosis
• Cardiovascular Diseases
• Hepatitis C

Intervention

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.

Locations

Country	Name	City	State
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria

Sponsors (2)

Lead Sponsor	Collaborator
Instituto de Investigación Marqués de Valdecilla	Ministerio de Economía y Competitividad, Spain

Country where clinical trial is conducted

Spain, 

References & Publications (4)

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. — View Citation

Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol. 2014 Nov;61(1 Suppl):S69-78. doi: 10.1016/j.jhep.2014.08.003. Epub 2014 Nov 3. Review. — View Citation

Perticone M, Maio R, Tassone EJ, Tripepi G, Di Cello S, Miceli S, Caroleo B, Sciacqua A, Licata A, Sesti G, Perticone F. Insulin-resistance HCV infection-related affects vascular stiffness in normotensives. Atherosclerosis. 2015 Jan;238(1):108-12. doi: 10.1016/j.atherosclerosis.2014.11.025. Epub 2014 Nov 29. — View Citation

Petta S, Macaluso FS, Craxì A. Cardiovascular diseases and HCV infection: a simple association or more? Gut. 2014 Mar;63(3):369-75. doi: 10.1136/gutjnl-2013-306102. Epub 2013 Dec 2. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Flow mediated dilatation (FMD)	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).	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in cIMT (Carotid intima-media thickness)	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).	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in the presence of carotid plaques	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.	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in ICAM-1 serum levels	Measurement of ICAM-1 (Intercellular Adhesion Molecule 1) serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in VCAM-1 serum levels	Measurement of Vascular cell adhesion molecule 1 (VCAM-1) serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in E-selectin serum levels	Measurement of E-selectin serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in P-selectin serum levels	Measurement of P-selectin serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in MCP-1 serum levels	Measurement of monocyte chemoattractant protein 1 (MCP-1) serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in galectin-3-binding protein serum levels	Measurement of galectin-3-binding protein serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in CD163 serum levels	Measurement of CD163 (Cluster of Differentiation 163) serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in hs-PCR serum levels	Measurement of hs-PCR serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in Lp(a) serum levels	Measurement of Lipoprotein(a) (Lp(a)) serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in VLDL serum levels	Measurement of VLDL serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in LDL serum levels	Measurement of LDL serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in HDL serum levels	Measurement of HDL serum levels at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Changes in HOMA	Measurement of HOMA (homeostasis model assessment) index at different times (see time frame)	Basal and 3, 12 and 24 months after the end of treatment	No
Secondary	Presence of Sustained Viral Response	Data on efficacy of treatment	3, 6 and 12 months after the end of treatment	No
Secondary	Adverse events	Data on safety of treatments	up to 24 weeks	Yes