Clinical trial NCT02802280: Endothelial Dysfunction and Subclinical Atheromatosis in Chronic HCV Infection. Response to DAA Agents.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis C
Cardiovascular Diseases
Keywords: endothelial dysfunction
Lead sponsor: Instituto de Investigación Marqués de Valdecilla
Sponsor class: OTHER
Collaborators: name: Ministerio de Economía y Competitividad, Spain
First posted: 2016-06-16
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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Flow mediated dilatation (FMD)
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
Secondary outcomes:
measure: Changes in cIMT (Carotid intima-media thickness)
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in the presence of carotid plaques
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in ICAM-1 serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in VCAM-1 serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in E-selectin serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in P-selectin serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in MCP-1 serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in galectin-3-binding protein serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in CD163 serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in hs-PCR serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in Lp(a) serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in VLDL serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in LDL serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in HDL serum levels
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Changes in HOMA
timeFrame: Basal and 3, 12 and 24 months after the end of treatment
measure: Presence of Sustained Viral Response
timeFrame: 3, 6 and 12 months after the end of treatment
measure: Adverse 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
References:
citation: 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. No abstract available.
citation: Petta S, Macaluso FS, Craxi 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. No abstract available.
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.
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.