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Effect Of Semaglutide In Coronary Atheroma Plaque (SEPLA)

Primary Purpose

Atheroscleroses, Coronary

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Semaglutide
Sponsored by
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atheroscleroses, Coronary

Eligibility Criteria

35 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men and women ≥35 and ≤ 65 years
  • Absence of previous history of clinical cardiovascular events
  • Subjects already taking therapy for diabetes on stable doses for 3 months or more.
  • Subjects must have HbA1c at the initial screening visit between 8 and 10%
  • Coronary CT performed less than 3 months before starting study medication

Exclusion Criteria:

  • Clinically significant heart disease
  • New York Heart Association (NYHA) class >II
  • Known stroke or transient ischemic accident
  • Uncontrolled hypertension at randomization, defined as a resting systolic blood pressure of 180 mm Hg at rest
  • Personal or family history of hereditary muscular disorders
  • Fasting triglyceride level > 250 mg/dL at screening
  • Type 1 diabetes
  • Known thyroid disease or subject taking thyroid replacement therapy
  • Estimated glomerular filtration rate < 60 ml/min/1.73m2
  • History of malignancy
  • Known major active infection, or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction
  • Baseline coronary CT does not meet Core Lab technical standards
  • Cardiac rhythm different to normal sinus rhythm.
  • Female subjects cannot be pregnant or breastfeeding, planning to become pregnant or planning to breastfeed during the entire study
  • Premenopausal females of childbearing potential must be willing to use an acceptable method(s) of birth control during treatment and for an additional 15 weeks after the end of treatment

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Semaglutide

    Arm Description

    Patients on semaglutide

    Outcomes

    Primary Outcome Measures

    Plaque burden modification assessed by coronary CT and plaque quantification
    The main objective of this trial is to evaluate the effect of Semaglutide on the burden of coronary atherosclerosis, based on the change in Percent Atheroma Volume (PAV) by quantifying atheroma plaque throughout the coronary tree based on the analysis of CCTA in asymptomatic subjects with T2D in optimized and stable treatment with Semaglutide

    Secondary Outcome Measures

    Atheroma volume modification assessed by coronary CT and plaque quantification
    Evaluate the effect of Semaglutide on the change in normalized total atheroma volume
    Percentage of patients with significant plaque regresion assessed by coronary CT
    Percentage of patients who demonstrated significant plaque regression
    Changes in composition of artery wall assessed by coronary CT and plaque quantification
    Effect of Semaglutide on the composition and architecture of the coronary artery wall
    Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
    Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
    Incidence of cardiovascular events
    Incidence and type of cardiovascular events (cardiovascular death, Acute coronary syndrome and stroke) during treatment with Semaglutide.

    Full Information

    First Posted
    August 5, 2021
    Last Updated
    September 27, 2021
    Sponsor
    Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05071417
    Brief Title
    Effect Of Semaglutide In Coronary Atheroma Plaque
    Acronym
    SEPLA
    Official Title
    Effect Of Semaglutide In Coronary Atherosclerotic Plaqus Assessed by Coronay CT
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2021
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 2021 (Anticipated)
    Primary Completion Date
    December 2024 (Anticipated)
    Study Completion Date
    December 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The main objective of this trial is to evaluate the effect of Semaglutide on the burden of coronary atherosclerosis, based on the change in Percent Atheroma Volume (PAV) by quantifying atheroma plaque throughout the coronary tree based on the analysis of CCTA in asymptomatic subjects with T2D in optimized and stable treatment with Semaglutide.
    Detailed Description
    Patients with type 2 diabetes mellitus (DM2) are considered to be at high vascular risk (VR). However, the VR risk may vary, depending on the presence of other cardiovascular risk factors (CVRFs), particularly dyslipidemia, smoking habit, hypertension, and obesity. High blood glucose levels are part of the etiopathogenic basis of atherosclerosis, whose vascular complications are the leading cause of death and disability in developed countries. Atherosclerosis is considered a chronic immunoinflammatory process with a polygenic and multifactorial origin that begins early due to vascular endothelial dysfunction. Atherosclerosis is a dynamic process that develops intermittently over time; periods of inactivity and rapid evolution are interspersed and modulated by environmental and genetic factors. As a result of a series of etiopathogenic and environmental factors, lesions (plaques) develop with greater or lesser lipid content, collagen, elastic fibers, and calcium. The location and degree of development of atherosclerotic plaques give rise to different forms of atherosclerotic disease, which is characterized by symptoms and signs that correspond to the obstruction of the vascular lumen with decreased flow and the consequent occurrence of (possibly chronic) ischemia. Atherosclerotic disease can also be characterized by the rupture of the plaque and the appearance of thrombotic phenomena (because the lipid nucleus of the plaque is highly thrombogenic and triggers the activation of the coagulation and platelet adhesion and aggregation cascades), with manifestations of acute ischemia. The relationship between the composition of the atheroma plaque and the occurrence of cardiovascular events, revealed the need for imaging techniques that could identify not only the degree of stenosis of atherosclerotic lesions, but also their volume, composition and levels of inflammation, and thus being able to identify the possible high-risk plaques (vulnerable plaques). Within imaging techniques, there are invasive ones such as coronary angiography or coronary angiography, ultrasound or intravascular ultrasound (IVUS) and optical coherence tomography (OCT); and non-invasive, such as magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography. Invasive coronary angiography has traditionally been the reference imaging test to determine the degree of stenosis and continues to be the procedure of choice for the evaluation of coronary anatomy and the identification of atherosclerotic lesions. Angiography provides information on the number and size of vascular stenosis but does not allow to know the plaque composition. Provides Simply an image of the internal arterial lumen but lacks the ability to adequately represent the vessel wall with its developing atherosclerotic plaque. Intravascular ultrasound (IVUS) is considered the reference method for the evaluation of atherosclerotic plaque burden and plaque characteristics. However, IVUS is an invasive method that has risks, cannot be used to study the entire coronary tree, only in one segment of the arterial tree and is not indicated for asymptomatic individuals. The IVUS technique plus virtual histology allows the identification of atheroma plaques in the vascular tree, and can quantify the size, volume, composition and distribution of the plaque. However, a limitation of this technique is the ability of the ultrasound signal to penetrate the calcified tissue, resulting in an acoustic shadow after the calcified tissue. Currently, with the new advances in the development of cardiac imaging techniques, coronary computed tomographic angiography (CCTA) has been incorporated as a non-invasive and easily applied method for direct visualization of coronary arteries without the need to introduce a catheter The image study of the coronary vessels by CCTA has been proposed as a suitable method for the qualitative detection of changes in the vessel wall, allowing the evaluation of the coronary arteries and the characterization of the atherosclerotic plaque. In the last decade, several advances have been seen in CCTA that have made it one of the key diagnostic instruments for the non-invasive evaluation of coronary atherosclerosis in patients with a low to intermediate probability of coronary heart disease. CCTA may be useful for prognostic classification together with classic CVRF in patients with intermediate cardiovascular risk, for more accurate reclassification and as a screening for the early diagnosis of coronary atherosclerotic disease in certain groups of patients at special risk. Previous studies have shown that CCTA is comparable to IVUS for the classification of atheroma plaques. CCTA, therefore, emerges as a non-invasive alternative for plaque characterization compared to other techniques such as IVUS. Coronary CCTA has established itself as a reliable and accurate tool for the detection of coronary atherosclerotic plaque and stenosis. Since CCTA provides information about plaque burden and the characteristics of high-risk plaques, the addition of these parameters to the traditional interpretation of CCTA, which is limited to the detection of stenosis, could improve the efficiency of this method for the early detection of coronary heart disease. Plaque characteristics are usually analyzed in a qualitative (subjective) way. This limitation can be solved through the use of new analytical platforms that allow automated quantification of the characteristics of the coronary plaque with high accuracy and reproducibility. In this context, software tools have been developed for the automated quantification of atheroma plaques in CCTA images. In this area, the QAngio CT (Medis medical imaging system, the netherlans) stands out, a software tool designed to perform quantitative analysis of images in CCTA data sets. In the CCTA data sets, the software is able to detect the contours of the vessel wall and the lumen, which are used for automated quantitative evaluations of coronary plaques. As for the characterization of the atherosclerotic plaque, the software is able to analyze virtual histology, differentiating between what is the mean, fibrous plaque, fibro-fatty, necrotic and calcified, with its consequent prognostic implication. The parameters of the entire coronary tree are obtained independently: vessel length, plaque burden, plaque volume, maximum thickness of the plaque, volume and percentage of fibrous plaque, fibro-fatty plaque, necrotic plaque and calcium plaque, maximum stenosis by area and by diameter. This software tool has a number of advantages over the analysis based on the IVUS. First, the non-invasiveness of the CCTA technique based on which this tool performs quantitative plaque analysis allows a consecutive analysis with a lower risk than that of IVUS. In addition, previous studies have demonstrated the correlation between QAngio CT and IVUS-based analysis regarding the area of lumen stenosis, plaque burden and remodeling index. On the other hand, although IVUS is the reference method for plaque quantification, it has the limitation of analyzing only a specific segment of the coronary tree, while QAngio CT allows the complete analysis of the coronary tree. In an evaluation study of atheroma plaque, this method could provide information not only on the size of the plaque, but also on the characteristics of the plaque. The change in plaque volume has been used successfully to monitor plaque progression in studies with IVUS. Using IVUS, plaque volumes are calculated as the difference between the area of the outer elastic membrane and the lumen area for successive cross sections of a coronary artery. The difference between the volume of the vessel and the volume of the lumen constitutes the total volume of the plaque. From these volumes, other parameters such as the plaque burden or percentage of atheroma volume (PVA) or the total volume of atheroma (VTA) can be derived, being PVA the most reproducible and the molt related to cardiovascular prognosis. Furthermore, recent studies have correlated the evaluation of the radiographic characteristics of plaque (Virtual histology) with the patient's prognosis. The QAngio CT provides an automated evaluation of the characteristics of the complete coronary tree plate based on radiological densities. The prevention and treatment of DM2 should be considered an essential part of atherosclerotic disease. Throughout numerous and extensive clinical trials, it has been shown that reductions in blood glucose and HbA1c levels lead to reductions in cardiovascular risks. This knowledge suggests that atherosclerosis can be influenced by DM2 treatment. Numerous studies have shown the beneficial effects of Glucagon-like peptide-1 (GLP-1) in the control of different cardiovascular pathologies and other effects beyond glycemic control, such as high blood pressure, weight control, and lipid metabolism. In addition to effects that are tangible in clinical practice, drugs that affect GLP-1 have been shown to have anti-atherosclerotic effects, due to the control of VR factors, or direct effects at the endothelial level. GLP-1-mediated decreases in atherosclerosis biomarkers, e.g., B-type natriuretic peptide (BNP), plasminogen activator inhibitor (PAI-1) and C- reactive protein (PCR), among others, have been observed. One of the parameters studied to validate this improvement in the progression of atherosclerosis has been the improvement in the control of the thickness of the carotid intima, which has clear benefits; however, studies in other vascular beds, such as the coronary, are more limited in terms of both numbers of participants and results. The effect of semaglutide, a GLP-1 agonist, on the progression of atheroma plaque lesions has been published. Studies in animal models have shown that semaglutide treatment reduced progression by anti-inflammatory mechanisms, independent of weight loss and glycemic control. Semaglutide treatment in SUSTAIN6, as well as liraglutide treatment in LEADER, showed a benefit against placebo in major adverse cardiac events (MACE) (HR [95% confidence interval (CI)]: 0.87 [0.78; 0.97] LEADER and 0.74 [0.58; 0.95] SUSTAIN 6) in patients with atherosclerotic disease with or without previous ischemic events. The authors can affirm, after reviewing the literature, that the effect of GLP-1 on atheroma plaque is not definitively known but instead speculated on based on results in animal models and derived, to a large extent, from cardiovascular findings in clinical trials.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Atheroscleroses, Coronary

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Model Description
    Phase IV low-intervention, double-blind, multicenter clinical trial to evaluate the effects of 18 months of semaglutide treatment on the volume, architecture, and composition of coronary atheroma plaques in subjects with DM2 for at least 10 years and without clinical cardiovascular disease. Patients with DM2 will be included if their previously prescribed treatment was insufficient to achieve adequate control of glycemic and glycosylated hemoglobin levels (HBA1c) to reach their therapeutic objective and the researcher has considered semaglutide treatment to be appropriate according to its clinical criteria and based on the indication of this treatment in this patient profile. The study treatment will therefore be the same treatment that the patient would receive even if they did not participate in the study; this condition is the basic norm for the inclusion of the patient in the study.
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    120 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Semaglutide
    Arm Type
    Experimental
    Arm Description
    Patients on semaglutide
    Intervention Type
    Drug
    Intervention Name(s)
    Semaglutide
    Intervention Description
    Usual treatment with semaglutide. Dose 0.5 - 1mg weekly, subcutaneous, weekly
    Primary Outcome Measure Information:
    Title
    Plaque burden modification assessed by coronary CT and plaque quantification
    Description
    The main objective of this trial is to evaluate the effect of Semaglutide on the burden of coronary atherosclerosis, based on the change in Percent Atheroma Volume (PAV) by quantifying atheroma plaque throughout the coronary tree based on the analysis of CCTA in asymptomatic subjects with T2D in optimized and stable treatment with Semaglutide
    Time Frame
    18 months
    Secondary Outcome Measure Information:
    Title
    Atheroma volume modification assessed by coronary CT and plaque quantification
    Description
    Evaluate the effect of Semaglutide on the change in normalized total atheroma volume
    Time Frame
    18 months
    Title
    Percentage of patients with significant plaque regresion assessed by coronary CT
    Description
    Percentage of patients who demonstrated significant plaque regression
    Time Frame
    10 months
    Title
    Changes in composition of artery wall assessed by coronary CT and plaque quantification
    Description
    Effect of Semaglutide on the composition and architecture of the coronary artery wall
    Time Frame
    18 months
    Title
    Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
    Description
    Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
    Time Frame
    18 months
    Title
    Incidence of cardiovascular events
    Description
    Incidence and type of cardiovascular events (cardiovascular death, Acute coronary syndrome and stroke) during treatment with Semaglutide.
    Time Frame
    18 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    35 Years
    Maximum Age & Unit of Time
    65 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Men and women ≥35 and ≤ 65 years Absence of previous history of clinical cardiovascular events Subjects already taking therapy for diabetes on stable doses for 3 months or more. Subjects must have HbA1c at the initial screening visit between 8 and 10% Coronary CT performed less than 3 months before starting study medication Exclusion Criteria: Clinically significant heart disease New York Heart Association (NYHA) class >II Known stroke or transient ischemic accident Uncontrolled hypertension at randomization, defined as a resting systolic blood pressure of 180 mm Hg at rest Personal or family history of hereditary muscular disorders Fasting triglyceride level > 250 mg/dL at screening Type 1 diabetes Known thyroid disease or subject taking thyroid replacement therapy Estimated glomerular filtration rate < 60 ml/min/1.73m2 History of malignancy Known major active infection, or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction Baseline coronary CT does not meet Core Lab technical standards Cardiac rhythm different to normal sinus rhythm. Female subjects cannot be pregnant or breastfeeding, planning to become pregnant or planning to breastfeed during the entire study Premenopausal females of childbearing potential must be willing to use an acceptable method(s) of birth control during treatment and for an additional 15 weeks after the end of treatment
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Leopoldo Pérez de Isla, MD
    Phone
    +34609084225
    Email
    leopisla@hotmail.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Leopoldo Pérez de Isla
    Organizational Affiliation
    Hospital Clínico San Carlos. Madrid. Spain.
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Undecided

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    Effect Of Semaglutide In Coronary Atheroma Plaque

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