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CHOlesterol Lowering and Residual Risk in Type 2 Diabetes (CHORD)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04369664
Recruitment Status : Recruiting
First Posted : April 30, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
NYU Langone Health

Brief Summary:
The purpose of this study is to investigate why individuals with type 2 diabetes are at increased risk for heart disease and stroke. This study will investigate risk factors for heart disease and stroke, including platelet (involved in clotting) activity, inflammation, blood vessel wall function, and genetic information (blueprints of your cells), in participants with type 2 diabetes and elevated cholesterol. This study will also include a control group - subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (PCSK9 inhibitor and statin or ezetimibe) for 1 month with the same risk factors being measured following cholesterol reduction. This study will help understand why individuals with type 2 diabetes are at higher risk for heart disease and stroke before and even after cholesterol reduction.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Statin Drug: PCSK9 inhibitor Drug: Ezetimibe 10mg Not Applicable

Detailed Description:
As part of this SFRN investigating REPAIR (non-progression of clinical events or regression of atherosclerosis) in T2D, this project will reveal mechanisms behind the platelet mediated increased cardiovascular risk in patients with T2D by focusing on the platelet transcriptome in those with clinical progression and subsequent cardiovascular events versus those without clinical progression. A prospective clinical study will investigate platelet activity and transcriptome before and after significant cholesterol reduction to better understand mechanisms of increased residual risk observed in patients with T2D, even when cholesterol is not elevated. By combining prospective studies on the platelet phenotype in humans with T2D, mechanistic mouse models of diabetes-accelerated atherosclerosis in the Fisher, Basic Project, and the human plaque and genomic data available data from the Giannarelli, Population Project, the investigators believe the research will fill an important and clinically significant gap in the understanding of how diabetes attenuates cardiovascular repair and to identify new treatment and prevention strategies.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CHOlesterol Lowering and Residual Risk in Type 2 Diabetes
Actual Study Start Date : June 22, 2020
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Ezetimibe

Arm Intervention/treatment
Experimental: Type 2 Diabetes group
All participants with type 2 diabetes will be given cholesterol-lowering medicine (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Drug: Statin
Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day.
Other Name: Atorvastatin

Drug: PCSK9 inhibitor
Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home.
Other Names:
  • Evolocumab
  • Repatha

Drug: Ezetimibe 10mg
Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day.
Other Name: Zetia

Control group
The participants in the control group are subjects with elevated cholesterol who do not have diabetes. All participants will be given cholesterol-lowering medicines (evolocumab (PCSK9 inhibitor) plus atorvastatin (statin) or ezetimibe (zetia)) for 1 month with the same risk factors being measured following cholesterol reduction. They will be asked to undergo blood draw, to receive study medication, and to undergo additional optional vascular health testing including endothelial cell harvesting and glycocalyx (tongue probe).
Drug: Statin
Participants will be given up to 80 mg oral tablets daily for the entire study period preferably at the same time each day.
Other Name: Atorvastatin

Drug: PCSK9 inhibitor
Participants will receive 2 injections of 140 mg of PCSK9 inhibitor, one will be administered at baseline visit and the other will be self-administered 2 weeks later at home.
Other Names:
  • Evolocumab
  • Repatha

Drug: Ezetimibe 10mg
Participants who are not able to or not willing to take atorvastatin will be given 10 mg ezetimibe oral tablets daily for the entire study period preferably at the same time each day.
Other Name: Zetia




Primary Outcome Measures :
  1. Change in platelet activity (MPA) before and after cholesterol reduction [ Time Frame: Baseline visit, Follow up visit (4 weeks) ]
    The difference in platelet activity will be assessed by measuring changes in monocyte-platelet aggregates. Monocyte platelet aggregates (MPA) are a robust marker of platelet activity and inflammatory monocytes. The difference in platelet activity before and after cholesterol reduction will be compared using paired t-test or Wilcoxon signed-rank test. The study will also perform a linear mixed model for the multivariate analysis; the primary outcome will be the change in platelet activity (MPA) before and after cholesterol reduction. All tests will be 2-tailed, and a P <0.05 will be considered as statistically significant.

  2. Change in platelet activity (LTA) before and after cholesterol reduction [ Time Frame: Follow up visit (4 weeks) ]
    The difference in platelet activity will be assessed by using the light transmission aggregometry test (LTA). Light Transmission Aggregometry [LTA] is frequently undertaken as the first test of platelet function, as a screening test for a bleeding disorder and in addition for monitoring of anti-platelet drugs using platelet rich plasma (PRP). The difference in platelet activity before and after cholesterol reduction will be compared using paired t-test or Wilcoxon signed-rank test. We will also perform a linear mixed model for the multivariate analysis; the primary outcome will be the change in platelet activity (LTA) before and after cholesterol reduction. All tests will be 2-tailed, and a P <0.05 will be considered as statistically significant.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Subjects with type 2 diabetes:

  • Age ≥ 18 & < 90
  • LDL-C >100mg/dl
  • Able and willing to provide written informed consent for the study

Control subjects without known diabetes:

  • Age ≥ 18 & < 90
  • LDL-C >100mg/dl or lp(a) >50 mg/dl
  • Able and willing to provide written informed consent for the study

Exclusion Criteria:

Subjects with type 2 diabetes:

  • Established cardiovascular disease on antithrombotic therapy
  • Triglycerides >250mg/dl
  • Use of a PCSK9 inhibitor
  • Use of maximal intensity statin (rosuvastatin ≥20 mg/day or atorvastatin ≥40 mg/day)
  • HbA1c >10%
  • Recent infection in the past 30 days
  • Any hospitalization in the past 30 days
  • Use of Immunosuppressive therapy
  • Use of any antithrombotic therapy
  • Use of aspirin
  • Use of NSAID within the past 72 hours
  • Pregnancy
  • Anemia (hemoglobin < 9 g/dl) or thrombocytopenia (Platelet count <75), or thrombocytosis (Platelet count >600)
  • A history of severe bleeding or bleeding disorders
  • Chronic kidney disease (CrCl < 30ml/min)

Control subjects without known diabetes:

  • Diabetes (type 1 or type 2)
  • All other exclusions are identical to the type 2 diabetes group.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04369664


Contacts
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Contact: Jeffrey Berger, MD 212-263-4004 jeffrey.berger@nyulangone.org
Contact: Maja Fadzan 347-964-3380 maja.fadzan@nyulangone.org

Locations
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United States, New York
NYU Langone Health Recruiting
New York, New York, United States, 10016
Contact: Jeffrey Berger, MD    212-263-4004    jeffrey.berger@nyulangone.org   
Principal Investigator: Jeffrey Berger, MD         
Sponsors and Collaborators
NYU Langone Health
Investigators
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Principal Investigator: Jeffrey Berger, MD NYU Langone Health
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Responsible Party: NYU Langone Health
ClinicalTrials.gov Identifier: NCT04369664    
Other Study ID Numbers: 19-01964
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
Access Criteria: The investigator who proposed to use the data and upon reasonable request. Requests should be directed to jeffrey.berger@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Atorvastatin
Ezetimibe
Evolocumab
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors