Cholesterol Lowering and Residual Risk in Diabetes, Type 1 (CHORD1)

CHORD1 - CHOlesterol Lowering and Residual Risk in Diabetes, Type 1

This is a prospective, interventional, cohort study, meaning that researchers will follow and observe a group of enrolled study participants over a period of time (one to two months) to gather information and record any developments of the outcomes in question.

This study will recruit 125 participants with Type 1 Diabetes (T1D) to:

1. Analyze the effect of reducing the cholesterol levels in the blood on platelet function. (Platelets are small cells in the blood which help form blood clots to slow or stop bleeding and to help wounds heal
2. Analyze the effect of reducing the cholesterol levels in the blood on While Blood Cell (WBC) gene expression, (White Blood Cells are part of the body's immune system which help the body fight infection and other diseases) and
3. Analyze the effect of reducing the cholesterol levels in the blood on vascular or blood vessel function.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Evolocumab Cartridge; Drug: Atorvastatin Calcium Tablets; Drug: Ezetimibe Tablets; Drug: 18F-FDG; Device: Angiocatheter 20IV; Device: J-Wire; Device: GlycoCheck Glycocalyx Measurement Software

Detailed Description

Participants will receive weekly injections of PCSK9i (evolocumab) plus daily, oral pills of atorvastatin or ezetimibe for 1 month.

Participants will undergo blood draw, and optional vascular studies that include:

• Glycocalyx testing (A non-invasive test where a video microscope camera is placed under the tongue to capture images of the movement of red blood cells as they travel through the micro-blood vessels)
• PET/CT for vascular imaging - to assess any inflammation of blood vessels and to evaluate increased metabolism in related tissues, and
• Endothelial cell collection before cholesterol reduction and 1-month after cholesterol reduction to measure any genetic changes in in the endothelial cells before and after collection

Glycemic Variability (GV), the amount one's blood sugar changes throughout the day, will be analyzed from continuous glucose monitoring (CGM) data.

• Study Type: Interventional
• Enrollment (Estimated): 125
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ira Goldberg, MD; Phone Number: 646-501-0589; Email: Ira.Goldberg@nyulangone.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
    • New York, New York, United States, 10029
      • Recruiting
      • Mount Sinai School of Medicine
      • Principal Investigator: Zahi Fayad
    • New York, New York, United States, 10010
      • Recruiting
      • New York VA Hospital
    • New York, New York, United States, 10016
      • Recruiting
      • NYC Health + Hospitals/Bellevue

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants with previous diagnosis of T1D (as defined by American Diabetes Association or judgment of physician for at least 1 year)

   1. American Diabetes Association Criteria for diagnosis of diabetes (Must meet at least 1 of the following criteria):

      • i. FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours, OR;
      • ii. 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water, OR;
      • iii. A1C ≥6.5% (48 mmol/mol), OR;
      • iv. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L), AND;
   2. History of T1D (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency, including latent autoimmune diabetes of adulthood). Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (glutamic acid decarboxylase, GAD65), insulin, the tyrosine phosphatases islet antigen 2 (IA-2) and IA-2β, and zinc transporter 8, OR;
   3. Diagnosis of T1D and confirmed by review of records by 2 separate clinical members of the study team
2. Age ≥ 18 & < 90
3. LDL-C >100mg/dl
4. Able and willing to provide written informed consent for the study

Exclusion Criteria:

1. Established cardiovascular disease on antithrombotic therapy
2. Triglycerides >400mg/dl
3. Use of a PCSK9 inhibitor
4. Recent infection in the past 30 days
5. Any hospitalization in the past 30 days
6. Use of immunosuppressive therapy
7. Use of any antithrombotic therapy
8. Use of aspirin
9. Use of NSAID within the past 72 hours
10. Pregnancy
11. Anemia (hemoglobin < 9 g/dl) or thrombocytopenia (platelet count <75), or thrombocytosis (platelet count >600)
12. A history of hemorrhagic diathesis
13. Chronic kidney disease (CrCl < 30ml/min)
14. T2D, monogenic diabetes syndromes, or diabetes in the context of disease of the exocrine pancreas (such as pancreatitis, trauma or pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 4-Week LDL-Cholesterol (LDL-C)-Reduction Treatment; Treatment consists of: Evolocumab (140 mg; 2 injections, one administered at baseline visit and another self-administered 2 weeks later), and; Atorvastatin (up to 80mg dose; 1 tab per day for 30 days, starting at baseline visit post-assessment). Participants with statin intolerance will be provided with a 1-month supply of ezetimibe 10 mg to replace Evolocumab and Atorvastatin.; Additional procedures: Blood draws.; Optional procedures: Glycocalyx testing, PET/CT, or Endothelial Cell Collection.

Drug: Evolocumab Cartridge; Injectable PCSK9 inhibitor.; Other Names: REPATHA; Drug: Atorvastatin Calcium Tablets; HMG-CoA reductase inhibitor for oral use.; Other Names: LIPITOR; Drug: Ezetimibe Tablets; Will only be distributed to patients with statin intolerance; replacement for both Atorvastatin and Evolocumab. Inhibitor of intestinal cholesterol for oral use.; Other Names: ZETIA; Drug: 18F-FDG; Optional procedure. Positron emission tomography (PET) and computed tomography (CT) imaging to assess vascular inflammation and related anatomy requires injection of the PET tracer 18F-FDG. 18F-FDG is an FDA-approved analogue of sugar, routinely used to evaluate elevated metabolism in tissues, including increased metabolism due to inflammatory cells. A standard dose of 7.0 mSv will be administered.; Device: Angiocatheter 20IV; Optional procedure (endothelial cell harvesting). An angiocatheter ≤ 21 gauge will be inserted into a peripheral vein on the upper extremity using aseptic technique. A 0.018in. diameter J-shaped wire (Arrow, Reading, PA) will be then advanced into the angiocatheter, to a distance of 4cm beyond the end of the angiocatheter.; Other Names: BD Insyte Autoguard; Device: J-Wire; Optional procedure (endothelial cell harvesting). Either a 0.021in. diameter J-shaped wire (Daig, Minnetonka, MN) or a 0.018in. diameter J-shaped wire (Arrow, Reading, PA) will be used.; Device: GlycoCheck Glycocalyx Measurement Software; Optional procedure (assessment of vascular function). Video microscope developed by GlycoCheck.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Monocyte Platelet Aggregation (MPA) from Baseline	Measurement of platelet activity. Assessed via patient blood sample.	Baseline, Week 4
Change in Light Transmission Aggregation (LTA) from Baseline	Measurement of platelet activity. Assessed via patient blood sample.	Baseline, Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Natural Killer (NK) Cell Population from Baseline	Assessed via patient blood sample.	Baseline, Week 4
Percent Change in Dendritic Cell Population from Baseline	Assessed via patient blood sample.	Baseline, Week 4
Percent Change in CD8 Cell Population from Baseline	Assessed via patient blood sample.	Baseline, Week 4

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ira Goldberg, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2022
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: November 29, 2022
• First Posted (Actual): December 8, 2022

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Calcium-Regulating Hormones and Agents; Serine Proteinase Inhibitors; PCSK9 Inhibitors; Atorvastatin; Calcium; Evolocumab; Ezetimibe
• Other Study ID Numbers: 22-01095

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification, will be shared upon reasonable request beginning immediately following publication provided the researchers who provide a methodologically sound proposal for use of the data execute a data use agreement with NYU Langone Health. Requests should be directed to Ira.Goldberg@nyulangone.org. The protocol, statistical analysis plan, informed consent form, clinical study report, and analytic code will be made available on Clinicaltrials.gov.
• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal will have access to the data upon reasonable request. Requests should be directed to Ira.Goldberg@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes