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

• ClinicalTrials.gov Identifier: NCT05641753
• Recruitment Status: Recruiting
• First Posted: December 8, 2022
• Last Update Posted: December 8, 2022
• Sponsor: NYU Langone Health
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes	Drug: Evolocumab Cartridge; Drug: Atorvastatin Calcium Tablets; Drug: Ezetimibe Tablets; Drug: 18F-FDG; Device: Angiocatheter 20IV; Device: J-Wire; Device: GlycoCheck Glycocalyx Measurement Software	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 125 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: CHORD1 - CHOlesterol Lowering and Residual Risk in Diabetes, Type 1
• Actual Study Start Date: November 16, 2022
• Estimated Primary Completion Date: January 2027
• Estimated Study Completion Date: January 2027

Arms and Interventions

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 Name: REPATHA; Drug: Atorvastatin Calcium Tablets; HMG-CoA reductase inhibitor for oral use.; Other Name: 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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Change in Monocyte Platelet Aggregation (MPA) from Baseline [ Time Frame: Baseline, Week 4 ]
   Measurement of platelet activity. Assessed via patient blood sample.
2. Change in Light Transmission Aggregation (LTA) from Baseline [ Time Frame: Baseline, Week 4 ]
   Measurement of platelet activity. Assessed via patient blood sample.

Secondary Outcome Measures :

1. Percent Change in Natural Killer (NK) Cell Population from Baseline [ Time Frame: Baseline, Week 4 ]
   Assessed via patient blood sample.
2. Percent Change in Dendritic Cell Population from Baseline [ Time Frame: Baseline, Week 4 ]
   Assessed via patient blood sample.
3. Percent Change in CD8 Cell Population from Baseline [ Time Frame: Baseline, Week 4 ]
   Assessed via patient blood sample.

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Contacts

Contact: Ira Goldberg, MD; 646-501-0589; Ira.Goldberg@nyulangone.org

Locations

United States, New York

New York VA Hospital; Recruiting

New York, New York, United States, 10010

NYC Health + Hospitals/Bellevue; Recruiting

New York, New York, United States, 10016

NYU Langone Health; Recruiting

New York, New York, United States, 10016

Sponsors and Collaborators

NYU Langone Health

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Ira Goldberg, MD; NYU Langone Health

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT05641753
• Other Study ID Numbers: 22-01095
• First Posted: December 8, 2022
• Last Update Posted: December 8, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Immediately following publication. No end date.
• 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Atorvastatin; Ezetimibe; Evolocumab; Calcium; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors