An observational study in Giant Cell Arteritis, Temporal Arteritis and Clonal Hematopoiesis of Indeterminate Potential, sponsored by ASST Fatebenefratelli Sacco. Not yet recruiting. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-02-06.
Sponsored by ASST Fatebenefratelli Sacco · Observational
The goal of this clinical trial is to verify whether CHIP is correlated with the clinical, instrumental, and histological characteristics of GCA, and to characterize the pathogenetic effects of clonal hemopoiesis on vasculitis. The main objective of this study is to verify if clonal hematopoiesis of indeterminate potential (CHIP) affects GCA manifestations, course/response to therapies, and pathogenesis.
Patients who are going to be diagnosed with GCA and for which a fast track is available for a rapid diagnostic work-up including pre-treatment temporal artery biopsy. Patients with CHIP will be identified and characterized by using whole exome sequencing from the peripheral blood samples. The presence and characteristics of CHIP will be correlated with baseline clinical, instrumental, and histologic GCA features.
GCA is the most frequent idiopathic vasculitis in the elderly, characterized by significant morbidity, with possible formation of aneurysms and arterial dissections and with possible evolution into ischemic tissue events, such as irreversible blindness or stroke. Arterial inflammation is maintained by a leukocyte infiltrate infiltrating the vessel wall through vasa vasorum, composed primarily of macrophages (sometimes structured into granulomas with multinucleated giant cells) and Cluster of Differentiation (CD) 4+ T cells, but also from Cluster of Differentiation (CD) 8+ and dendritic cells. However, there are heterogeneous clinical pictures, in correlation to the spatial distribution of arterial lesions, to the finding of arterial ischemia, aneurysms or any relapses. Even today, there is a need to understand the pathogenetic mechanisms underlying clinical and prognostic differences in GCA and to identify patients with different clinical outcomes and response to therapies in advance.
Clonal hemopoiesis is instead characterized by the presence in the bloodstream of a hematopoietic clone with a selective advantage following somatic mutations, in the absence of other obvious hematological conditions: in fact, it cannot be detected by standard diagnostic tools, but requires a genetic assessment of blood mosaicism or the presence of known relevant mutations. Mutated leukocytes have a more intense inflammatory and atherogenic response with inflammatory stimuli, both infectious and non-infectious, favoring a proinflammatory microenvironment in elderly patients, underlying the concept of "age-related inflammation". One study identified CHIP in 33% of patients with GCA. The investigators hypothesize that specific mutations responsible for the hematopoietic clone could favor a proinflammatory dysregulation of leukocytes within vasculitic lesions, affecting the activity of arterial injury. The purpose of this study is to verify whether CHIP is correlated with the clinical, instrumental and histological characteristics of GCA, and to characterize the pathophysiologic effects of clonal hemopoiesis on vasculitis.
147 studies on the registry are indexed under Giant Cell Arteritis; 49 are open to participants now.
This study's planned enrollment of 326 is above the median of 128 across 78 observational studies indexed under Giant Cell Arteritis.
Browse Giant Cell Arteritis studies →ASST Fatebenefratelli Sacco is the lead sponsor of 38 studies on the registry; 12 are open to participants now.
Counted across the registry records on this site, refreshed daily.
The study will rely on the patients with GCA enrolled in referral centers for vasculitis, All centers have a fast-track for suspected GCA, mainly from their Emergency Departments. This allows clinical evaluation of patients with multi-dimensional disease characterization, comprising ultrasonography of the temporal, axillary and carotid arteries, temporal artery biopsies, and screening for large vessels involvement with a combination of ultrasonography and Position Emission Tomography/Computed Tomography within five days from clinical evaluation. Temporal artery biopsy will be performed in all patients with cranial symptoms for GCA or in the case of diagnostic uncertainty.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis B tests
Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.
Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Child-Pugh class
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
NYHA class (heart failure)
The New York Heart Association’s four classes of how much heart failure limits physical activity.
Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients who are going to be diagnosed with GCA and for which a fast track is available for a rapid diagnostic work-up including pre-treatment temporal artery biopsy. The main biopsy specimen will be sent for histopathology for clinical diagnosis or final validation, while the remaining specimen (at least 5 mm in length) will be digested to use for research purposes. In the fast-track, patients should rapidly receive a multi-dimensional diagnostic assessment including ultrasonography of the temporal and axillary arteries. Screening for large vessels involvement should be performed according to the local practice by a combination of ultrasonography, Position Emission Tomography (PET) and Magnetic Resonance (MR). Ideally, this assessment should be performed within five days from clinical evaluation.
Diagnostic Test: Temporal arterial biopsy · Diagnostic Test: Whole exome sequencing · Diagnostic Test: Single cell transcriptomics
Healthy controls matched with GCA patients for age, sex, smoking status, previous cardiovascular events, BMI, history of cancer and cytotoxic chemo/radiotherapy.
Collection of 30 ml of peripheral blood in ethylenediaminetetraacetic acid (EDTA) tubes performed at baseline, 6 months, 12 months and in case of flare before month 12. In addition, the temporal artery specimen (at least 5 mm in length) exceeding that used for clinical activity (at least 10 mm in length in accordance with current clinical recommendations) will be digested to use for research purposes (about protocols for collecting, processing, storing and sending biopsy, refer to Standard Operating Procedures, SOP).
Patients with CHIP will be identified and characterized by using whole exome sequencing from the peripheral blood samples. M-CHIP will be further characterized by: i) clone dimension as defined by Variant Allele Fraction (VAF); ii) mutations in specific genes such as DNMT3A, Tet methylcytosine dioxygenase 2 (TET2), Additional Sex combs (ASXL1), or Janus kinase 2 (JAK2); iii) multiple mutations. L-CHIP will be further characterized by: i) clone dimension as defined by the VAF; ii) mutations in specific genes such as Dual Specificity Phosphatase 22 (DUSP22), FAT atypical cadherin 1 (FAT1), (Histone-lysine N-methyltransferase 2D (KMT2D); iii) multiple mutations; iv) co-occurrence of mutations heralding M- and L-CHIP.
Also known as: Genetic analysis for CHIP
The investigators will identify actively inflamed arterial biopsies from three treatment-naïve patients without CHIP, and three treatment-naïve patients with CHIP driven by the most relevant gene mutation. Arterial wall Cluster of Differentiation (CD) 45+ leukocytes will be isolated after digestion of arterial tissue and characterized by single cell transcriptomics, with a specific focus on wall infiltrating T cells and macrophages and their subsets (eg: Vascular dendritic cells, Th1, Th2, Th17, Treg, M1- and M2-like,...). Frequencies of these subsets and their genetic expression will be compared between wall-infiltrating leukocytes from GCA patients with or without CH, focusing on histological events supposed to be pathogenic in GCA, or known to be dysfunctional in CHIP.
Correlation of GCA with M-CHIP-driven by DNMT3A mutations
Patients with M-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of DNMT3A-driven M-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of GCA with M-CHIP-driven by TET2, ASXL1 and JAK2 mutations
Patients with M-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of TET2, ASXL1 or JAK2-driven M-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of GCA with L-CHIP-driven by DUSP22, FAT1 and KMT2D mutations
Patients with L-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of DUSP22, FAT1 or KMT2D-driven L-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of GCA with M-CHIP and L-CHIP clone dimension
Patients with M-CHIP or L-CHIP will be characterized for the dimension of the mutated clone in the peripheral blood by assessing the Variant Allele Fraction (VAF) at whole exome sequencing. The VAF will be compared between the GCA group and the matched controls by an unmatched non-parametric test (Mann-Whitney U test).
Time frame: From beginning of study for 11 months
Correlation of GCA with M-CHIP and L-CHIP multiple mutations
The prevalence of M-CHIP and L-CHIP driven by multiple mutations as assessed by whole exome sequencing will be compared between the GCA group and the matched controls by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of ischemic features in GCA with specific CHIP mutations
The prevalence of specific CHIP mutations (assessed and defined as above) will be compared between GCA patients with vs without ischemic features (claudicatio mandibularis, soft tissue necrosis, ischemic optic neuropathy) by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of ischemic features in GCA with CHIP clone dimension
The clone dimension as assessed by VAF (see above) will be compared between GCA patients with vs without ischemic features by the Mann-Whitney U test.
Time frame: From beginning of study for 11 months
Correlation of rate of complications with specific CHIP mutations
GCA patients will be followed prospectively; the prevalence of specific CHIP mutations (assessed and defined as above) will be compared between GCA patients with vs without complications at 12 months (disease relapse, venous thromboembolism, acute coronary syndromes/strokes, infection) by Chi-squared test or Fisher test.
Time frame: From patients' enrollment for 12 months
Correlation of rate of complications with CHIP clone dimension
GCA patients will be followed prospectively; the clone dimension as assessed by VAF (see above) will be compared between GCA patients with vs without complications at 12 months (disease relapse, venous thromboembolism, acute coronary syndromes/strokes, infection) by the Mann-Whitney U test.
Time frame: From patients' enrollment for 12 months
Correlation of vascular quantitative score in GCA with specific CHIP mutations
The prevalence of specific CHIP mutations (assessed and defined as above) will be compared between GCA patients with vs without incidence of large vessel involvement and burden of arterial stenosis and dilatation using quantitative activity scores such as Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), using the Mann-Whitney U test.
Time frame: From beginning of study for 11 months
Correlation of vascular quantitative score in GCA with CHIP clone dimension
The clone dimension as assessed by VAF (see above) will be compared between GCA patients with incidence of large vessel involvement and burden of arterial stenosis and dilatation using quantitative activity scores such as Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), using Spearman's rank correlation coefficient.
Time frame: From beginning of study for 11 months
Correlation of histologic features in GCA with specific CHIP mutations
The prevalence of specific CHIP mutations (assessed and defined as above) will be compared between GCA patients with histologic features such as intimal hyperplasia, fragmentation of internal elastic membrane, transmural inflammation, vasa-vasorum neoangiogenesis, and presence of giant cells by Chi-squared test or Fisher test.
Time frame: From beginning of study for 11 months
Correlation of histologic features in GCA with CHIP clone dimension
The clone dimension as assessed by VAF (see above) will be compared between GCA patients with histologic features such as intimal hyperplasia, fragmentation of internal elastic membrane, transmural inflammation, vasa-vasorum neoangiogenesis, and presence of giant cells, by the Mann-Whitney U test.
Time frame: From beginning of study for 11 months
Demonstration of the impact of CHIP on single-cell transcriptomics of arterial wall-infiltrating leukocytes
Arterial wall Cluster of Differentiation (CD) 45+ leukocytes will be isolated after digestion of arterial tissue and characterized by single-cell transcriptomics, with a specific focus on wall infiltrating T cells and macrophages and their subsets (eg: Vascular dendritic cells, Th1, Th2, Th17, Treg, M1- and M2-like,...). Frequencies of these subsets and their genetic expression will be compared between wall-infiltrating leukocytes from GCA patients with or without CH, focusing on events supposed to be pathogenic in GCA, or known to be dysfunctional in CHIP: cytokine production, inflammasome activation and apoptosis, lymphocyte exhaustion, neoangiogenesis, tissue remodeling (fibrosis or matrix protease production), mitochondrial function and production of reactive oxygen species (ROS), neoangiogenesis, T-Cell receptor and B-cell receptor and costimulatory pathways.
Time frame: From 11th month of study to 18th month
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Plan to share: Undecided
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