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Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects (Rebuild)

Primary Purpose

Atherosclerosis, Diabetes, Restenosis

Status

Completed

Phase

Phase 4

Locations

Sweden

Study Type

Interventional

Intervention

Bydureon

Humulin kwickpen

Metformin

About this trial

This is an interventional treatment trial for Atherosclerosis focused on measuring Glucagon-like peptide-1, Endothelialization, Cardiac Function, Exenatide, Optical Coherence Tomography

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients eligible for PCI with application of DES, due to ACS.
Patients with known or newly diagnosed T2D (type 2 diabetes is diagnosed according to current WHO criteria or by the use of anti-diabetic drugs)
Male and female subjects 18-80 years.
HbA1c (accordingly to IFCC) 47 mmol/mol - 110 mmol/mol.
Signed informed consent form.

Exclusion Criteria:

Type 1 diabetes (autoantibody positive).
Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors within 6 months
Known severe heart failure, classified as NYHA 4.
Active myocarditis; malfunctioning artificial heart valve.
History of ventricular tachycardia within 3 months before study entry; second- or third-degree atrioventricular block.
Supine systolic blood pressure <85 mm Hg or >200 mm Hg at screening.
Primary renal impairment, creatinine clearance < 45 ml/min if treated with metformin.
Uncorrected hypokalemia or hyperkalemia (potassium <3.5 mmol/l or >5.5 mmol/l).
Significant anemia (Hb < 90 g/l)
Severe gastrointestinal disease, including gastroparesis. As judged by the Investigator.
Body mass index (BMI) > 45 kg/m2.
Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial.
Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant.
Current drug and alcohol abuse.
History of acute or chronic pancreatitis
Subjects considered by the Investigator to be unsuitable for the study.

Sites / Locations

Dept of clinical science and education Karolinska Institutet Södersjukhuset

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Bydureon 2 mg Once Weekly

Humulin kwickpen

Arm Description

Patients randomised to Bydureon will be treated with Metformin 1g BID, and only receive 10U of Humulin kwickpen QD at bedtime, with no more up-titration of insulin during the study.

Patients randomised to the comparator group will be treated with Meformin 1g BID and Humulin kwickpen to reach a fP-glucose level of 6 mmol/l. For that reason patients will be instructed to increase the bedtime Insulin dose of 2-4U every third day until this goal is reached.

Outcomes

Primary Outcome Measures

The degree of non-covered stent struts by Bydureon add on to Insulin over that of Insulin as analyzed by optical coherence tomography (OCT).

Secondary Outcome Measures

Fractional Flow Reserve (FFR)

FFR is a unitless index calculated as the ratio between distal coronary and aortic pressure during maximum hyperemia.

Coronary Flow velocity Reserve (CRF)

CFR is a unitless index calculated as the ratio between the the mean transit time recorded at maximum hyperemia and at baseline using the thermodilution.

Index of Microcirculatory Resistance (IMR)

IMR is a unitless index calculated by dividing the mean distal coronary pressure by the inverse of the mean transit time recorded using the thermodilution technique during maximum hyperemia

Fractional flow reserve positive re-stenosis

Target lesion failure

Need of unplanned PCI in the treated stenosis or significant re-stenosis in the follow-up

Acute coronary syndrome (ACS) and/or repeat revascularization

Late lumen loss/neointima thickness measured with OCT

Change in minimal lumen area by OCT

Left ventricular systolic and diastolic function assessed by echocardiography

Recovery from endothelial damage, measured by high resolution ultrasound, after PCI

Non-invasive ultrasound over the radialis artery after the PCI procedure using Standard 6-7F guiding catheters.

Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels

Plasma markers of inflammation i.e., CRP, IL-1β, IL-6 and IL-8.

Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9

Circulating endothelial progenitor cells

Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS)

Full Information

NCT ID

NCT02621489

First Posted

November 22, 2015

Last Updated

April 19, 2023

Sponsor

Karolinska Institutet

1. Study Identification

Unique Protocol Identification Number

NCT02621489

Brief Title

Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects

Acronym

Rebuild

Official Title

Effects on Re-endothelialisation With Bydureon Treatment Add on to Insulin Versus Insulin Alone, Both in Combination With Metformin in Type 2 Diabetic Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

December 2015 (undefined)

Primary Completion Date

August 2022 (Actual)

Study Completion Date

October 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Karolinska Institutet

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The aim of the study is to use Exenatide long-acting release (LAR) [Bydureon] to minimize vascular remodeling and neointima formation after Percutaneous Coronary Intervention (PCI) and to accelerate stent endothelialisation.

Detailed Description

Exenatide LAR will be given as a once-weekly (s.c.) dose of Bydureon (2 mg) add on to Insulin in combination with Metformin. If patients are Insulin naïve (both groups) an initial dose of 10U (s.c.) at bedtime will be started, and further up-titrated to achieve a fP-glucose levels at 6 mmol/l. Standard care for post myocardial infarction will be given after PCI. Primary objectives: To test whether Bydureon, add on to Insulin Neutral Protamine Hagedorn (NPH) + Metformin, is superior vs. Insulin NPH + Metformin alone, in covered stent struts Secondary objectives: To test whether Bydureon, add on to Insulin NPH + Metformin, is superior vs. Insulin NPH + Metformin alone: in cardiac and endothelial functions

6. Conditions and Keywords

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

Atherosclerosis, Diabetes, Restenosis

Keywords

Glucagon-like peptide-1, Endothelialization, Cardiac Function, Exenatide, Optical Coherence Tomography

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

38 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bydureon 2 mg Once Weekly

Arm Type

Experimental

Arm Description

Patients randomised to Bydureon will be treated with Metformin 1g BID, and only receive 10U of Humulin kwickpen QD at bedtime, with no more up-titration of insulin during the study.

Arm Title

Humulin kwickpen

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bydureon

Other Intervention Name(s)

Exenatide

Intervention Description

2 mg Once Weekly

Intervention Type

Drug

Intervention Name(s)

Humulin kwickpen

Other Intervention Name(s)

Insulin Aspart

Intervention Description

Humulin kwickpen 10U QD at bedtime

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Biguanide

Intervention Description

Metformin 1g BID

Primary Outcome Measure Information:

Title

The degree of non-covered stent struts by Bydureon add on to Insulin over that of Insulin as analyzed by optical coherence tomography (OCT).

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Fractional Flow Reserve (FFR)

Description

FFR is a unitless index calculated as the ratio between distal coronary and aortic pressure during maximum hyperemia.

Time Frame

12 weeks

Title

Coronary Flow velocity Reserve (CRF)

Description

CFR is a unitless index calculated as the ratio between the the mean transit time recorded at maximum hyperemia and at baseline using the thermodilution.

Time Frame

12 weeks

Title

Index of Microcirculatory Resistance (IMR)

Description

IMR is a unitless index calculated by dividing the mean distal coronary pressure by the inverse of the mean transit time recorded using the thermodilution technique during maximum hyperemia

Time Frame

12 weeks

Title

Fractional flow reserve positive re-stenosis

Time Frame

12 weeks

Title

Target lesion failure

Description

Need of unplanned PCI in the treated stenosis or significant re-stenosis in the follow-up

Time Frame

12 weeks

Title

Acute coronary syndrome (ACS) and/or repeat revascularization

Time Frame

12 weeks

Title

Late lumen loss/neointima thickness measured with OCT

Time Frame

12 weeks

Title

Change in minimal lumen area by OCT

Time Frame

12 weeks

Title

Left ventricular systolic and diastolic function assessed by echocardiography

Time Frame

12 weeks

Title

Recovery from endothelial damage, measured by high resolution ultrasound, after PCI

Description

Non-invasive ultrasound over the radialis artery after the PCI procedure using Standard 6-7F guiding catheters.

Time Frame

12 weeks

Title

Plasma markers of endothelial activation i.e., E-Selectin, VCAM-1, ICAM-1, nitrotyrosine levels

Time Frame

12 weeks

Title

Plasma markers of inflammation i.e., CRP, IL-1β, IL-6 and IL-8.

Time Frame

12 weeks

Title

Plasma markers of matrix remodeling enzymes i.e., MMP-2 and MMP9

Time Frame

12 weeks

Title

Circulating endothelial progenitor cells

Time Frame

12 weeks

Title

Gene expression (Affymetrix) e.g., transcription factors of sirtuins (SIRT) and nitric oxide synthase (NOS)

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients eligible for PCI with application of DES, due to ACS. Patients with known or newly diagnosed T2D (type 2 diabetes is diagnosed according to current WHO criteria or by the use of anti-diabetic drugs) Male and female subjects 18-80 years. HbA1c (accordingly to IFCC) 47 mmol/mol - 110 mmol/mol. Signed informed consent form. Exclusion Criteria: Type 1 diabetes (autoantibody positive). Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors within 6 months Known severe heart failure, classified as NYHA 4. Active myocarditis; malfunctioning artificial heart valve. History of ventricular tachycardia within 3 months before study entry; second- or third-degree atrioventricular block. Supine systolic blood pressure <85 mm Hg or >200 mm Hg at screening. Primary renal impairment, creatinine clearance < 45 ml/min if treated with metformin. Uncorrected hypokalemia or hyperkalemia (potassium <3.5 mmol/l or >5.5 mmol/l). Significant anemia (Hb < 90 g/l) Severe gastrointestinal disease, including gastroparesis. As judged by the Investigator. Body mass index (BMI) > 45 kg/m2. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial. Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant. Current drug and alcohol abuse. History of acute or chronic pancreatitis Subjects considered by the Investigator to be unsuitable for the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Thomas Nyström

Organizational Affiliation

Karolinska Institutet

Official's Role

Principal Investigator

Facility Information:

Facility Name

Dept of clinical science and education Karolinska Institutet Södersjukhuset

City

Stockholm

State/Province

Other

ZIP/Postal Code

11883

Country

Sweden

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

25966620

Citation

Eriksson L, Saxelin R, Rohl S, Roy J, Caidahl K, Nystrom T, Hedin U, Razuvaev A. Glucagon-Like Peptide-1 Receptor Activation Does not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury. J Vasc Res. 2015;52(1):41-52. doi: 10.1159/000381097. Epub 2015 May 7.

Results Reference

result

PubMed Identifier

23343509

Citation

Erdogdu O, Eriksson L, Xu H, Sjoholm A, Zhang Q, Nystrom T. Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol. 2013 Mar 18;50(2):229-41. doi: 10.1530/JME-12-0166. Print 2013 Apr.

Results Reference

result

PubMed Identifier

20452396

Citation

Erdogdu O, Nathanson D, Sjoholm A, Nystrom T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010 Aug 30;325(1-2):26-35. doi: 10.1016/j.mce.2010.04.022. Epub 2010 May 7.

Results Reference

result

PubMed Identifier

22390929

Citation

Erdogdu O, Eriksson L, Nystrom T, Sjoholm A, Zhang Q. Exendin-4 restores glucolipotoxicity-induced gene expression in human coronary artery endothelial cells. Biochem Biophys Res Commun. 2012 Mar 23;419(4):790-5. doi: 10.1016/j.bbrc.2012.02.106. Epub 2012 Feb 27.

Results Reference

result

PubMed Identifier

15353407

Citation

Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15. doi: 10.1152/ajpendo.00237.2004. Epub 2004 Sep 7.

Results Reference

result

PubMed Identifier

23241323

Citation

Dokken BB, Piermarini CV, Teachey MK, Gura MT, Dameff CJ, Heller BD, Krate J, Ashgar AM, Querin L, Mitchell JL, Hilwig RW, Kern KB. Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects. Am J Physiol Heart Circ Physiol. 2013 Feb 15;304(4):H538-46. doi: 10.1152/ajpheart.00282.2012. Epub 2012 Dec 15. Erratum In: Am J Physiol Heart Circ Physiol. 2018 Dec 1;315(6):H1861.

Results Reference

result

PubMed Identifier

20630463

Citation

Guagliumi G, Sirbu V, Bezerra H, Biondi-Zoccai G, Fiocca L, Musumeci G, Matiashvili A, Lortkipanidze N, Tahara S, Valsecchi O, Costa M. Strut coverage and vessel wall response to zotarolimus-eluting and bare-metal stents implanted in patients with ST-segment elevation myocardial infarction: the OCTAMI (Optical Coherence Tomography in Acute Myocardial Infarction) Study. JACC Cardiovasc Interv. 2010 Jun;3(6):680-7. doi: 10.1016/j.jcin.2010.04.005.

Results Reference

result

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Effects on Re-endothelialisation With Bydureon Treatment in Type 2 Diabetes Subjects

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