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Effect of Colchicine on MMP-9, NOX2, and TGF-β1 in Myocardial Infarct

Primary Purpose

ST Elevation Myocardial Infarction, Colchicine, Cardiac Remodeling, Ventricular

Status
Recruiting
Phase
Phase 4
Locations
Indonesia
Study Type
Interventional
Intervention
Colchicine
Percutaneous Coronary Intervention
Optimal medical treatment including statin, aspirin, P2Y12 inhibitor, and nitrate.
Sponsored by
RSD dr. Soebandi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ST Elevation Myocardial Infarction focused on measuring STEMI, Colchicine, MMP-9, NOX2, TGF-beta 1

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Subjects who presenting with STEMI more than 12 hours from the onset of chest pain Aged 40-70 years Agreed with the informed consent Exclusion Criteria: aged <40 or >70 years subjects that have unstable condition such as comorbid disease (infection, inflammation, malignancy, severe renal failure (EGFR <30), a history of hepatic cirrhosis, acute exacerbation of hepatitis, or severe liver disease, alcoholic patient, cardiac arrest, ventricular fibrillation or cardiogenic shock, unstable hemodynamic) subjects that have colchicine hypersensitivity pregnancy or breastfeed

Sites / Locations

  • RSD dr SoebandiRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Late PCI + Colchicine

Late PCI + Optimal Medical Treatment

Optimal Medical Treatment + Colchicine

Optimal Medical Treatment

Arm Description

Subjects that undergo late PCI (12-48 hours after STEMI), received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate), and colchicine

Subjects that undergo late PCI (12-48 hours after STEMI) and received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate)

Subjects that received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate) and colchicine

Subjects that received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate)

Outcomes

Primary Outcome Measures

The change between 24 hours MMP-9 to day 5
Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix.
The change between 24 hours NOX2 to day 5
NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene (also called CYBB gene). The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).
The change between 24 hours TGF-β1 to day 5
Transforming growth factor β1 (TGFB1) is a multifunctional secreted protein that generally regulates immune function,544 as well as cell survival and migration, through the Sma- and Mad-related proteins (SMAD) signaling pathway.
Left ventricular end-diastolic volume (LVEDV)
The volume of blood in the left ventricle at the end of ventricular filling is called the end-diastolic volume (EDV), which is about 120 mL in the adult human.

Secondary Outcome Measures

Number of subjects with hypertension
Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or more, or a diastolic blood pressure (DBP) of 90 mm Hg or more
Number of subjects with diabetes
History of diabetes is defined as having fasting blood glucose 126 mg/dL or HBA1c >6.5%
Smoking status among the subjects
Smoking or Ex-smoking
Number of subjects with dyslipidemia
Dyslipidemia is the imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol, (LDL-C), triglycerides, and high-density lipoprotein (HDL)
Type of infark among the subjects
Type of infark (large or small) that happen to the subjects

Full Information

First Posted
January 12, 2023
Last Updated
April 9, 2023
Sponsor
RSD dr. Soebandi
Collaborators
Universitas Jember, University of Brawijaya
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1. Study Identification

Unique Protocol Identification Number
NCT05709509
Brief Title
Effect of Colchicine on MMP-9, NOX2, and TGF-β1 in Myocardial Infarct
Official Title
Effect of Colchicine in Regulating MMP-9, NOX-2, and TGF- β1 After Myocardial Infraction in Stable Patients
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2022 (Actual)
Primary Completion Date
May 1, 2023 (Anticipated)
Study Completion Date
May 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
RSD dr. Soebandi
Collaborators
Universitas Jember, University of Brawijaya

4. Oversight

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.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Reducing NOX-2, MMP-9, and TGF-β1 Expression in Preventing Ventricular Remodelling Post Acute ST-Segment Elevation Myocardial Infarction using Colchicine (Post Late Reperfusion Percutaneous Coronary Intervention and Non-Reperfusion and In Vitro Study on Ischemic Rat Cardiomyocyte Culture Model). Coronary heart disease (CHD) is the most common cause of mortality and disability worldwide. The handling of reperfusion in Indonesia is still far below the required standard. Most STEMI patients in Indonesia arrive late to a health facility with symptoms that have been present for more than 12 hours (late-onset). Heart failure following a myocardial infarction is one of the long-term complications of STEMI. Patients with STEMU who do not receive reperfusion were more likely to develop this consequence. According to several studies, microtubules in cardiomyocytes have been identified as an essential regulator of cardiomyocytes' ability to respond to shear stress, which offers compression resistance and facilitates mitochondrial energy production. Microtubule densification, which occurs due to remodelling in heart failure, disrupts the microtubule network. The role of reactive oxygen species (ROS) produced by ischemic myocardium in this remodelling is thus inextricably linked. NADPH oxidase is one of the enzymes involved (NOX). NOX-2 levels have been reported to be higher in myocardial infarction and cardiac remodelling, and it has a close interaction with microtubule network, with damage of microtubule tissue increasing NOX-2 generation of reactive oxygen species. By eroding the ECM and triggering cytokines and chemokines to recruit inflammatory cells to eliminate necrotic cardiomyocytes, matrix metalloproteinase 9 (MMP-9) aids tissue rebuilding. Induction and activation of endogenous TGF-signaling pathways after myocardial infarction have also been discovered to play a function. TGF-β may play a role in the resolution of the inflammatory response in the early stages of infarct repair by inactivating macrophages and decreasing endothelial cell chemokine and cytokine production. TGF-β stimulates the fibrogenic pathway by causing extracellular matrix deposition and fibrosis later. Colchicine is a commonly prescribed anti-inflammatory medication with a low cost. the mechanism of colchicine is tubulin binding, which prevents microtubule assembly and polymerization. Colchicine inhibits microtubule development at low concentrations and promotes microtubule depolymerization at higher concentrations. Several studies have demonstrated that low-dose colchicine can help reduce severe cardiac outcomes such as cardiovascular mortality, stroke, and cardiac arrest following myocardial infarction. Colchicine is known to cause partial restoration of microtubule tissue in the perinuclear region. Colchicine has also been shown in earlier research to reduce the expression of MMP-9, NOX2, and TGF-β This study aims to evaluate whether colchicine could prevent ventricular remodelling in STEMI patients with delayed reperfusion and non reperfusion. The minor hypothesis of this study was colchicine can lower NOX-2, MMP-9, and TGF-β expression in the clinical situation of patients with delayed and non-reperfusion STEMI following PCI. Randomization with 1:1 allocation were used to classify the patients, each group include 41 patients with one group receiving colchicine therapy and standard therapy and the other receiving standard therapy only. Colchicine administration was the independent variable. STEMI patients with delayed and non-reperfusion IKP who met the inclusion criteria are included in this randomized clinical trial. Left ventricular end-diastolic volume (LVEDV) was the dependent variable while serum MMP-9, NOX-2, and TGF-β were the intermediate variables. In the treatment group, colchicine 1 mg is administered before PCI or admission to the ICCU, and colchicine is continued at 0.5 mg/day for a month. Within 24 to 36 hours of treatment initiation, the patient had echocardiography, NOX-2, MMP-9, and TGF-β levels evaluated. On days 4-5, a second NOX-2, MMP-9, and TGF-β screening were performed. The follow up two months after treatment initiation includes an assessment of drug compliance, symptoms, and echocardiography. Depending on the normality of the data distribution, the difference between groups is performed using the unpaired T-test or the Mann-Whitney test. The significant difference between the treatment groups is indicated by a p-value of 0.05.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ST Elevation Myocardial Infarction, Colchicine, Cardiac Remodeling, Ventricular
Keywords
STEMI, Colchicine, MMP-9, NOX2, TGF-beta 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
All subjects were allocated to 4 different groups: Late PCI + Colchicine, Late PCI + Optimal Medical Treatment, Optimal Medical Treatment + Colchicine, and Optimal Medical Treatment Only
Masking
None (Open Label)
Allocation
Randomized
Enrollment
148 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Late PCI + Colchicine
Arm Type
Experimental
Arm Description
Subjects that undergo late PCI (12-48 hours after STEMI), received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate), and colchicine
Arm Title
Late PCI + Optimal Medical Treatment
Arm Type
Experimental
Arm Description
Subjects that undergo late PCI (12-48 hours after STEMI) and received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate)
Arm Title
Optimal Medical Treatment + Colchicine
Arm Type
Experimental
Arm Description
Subjects that received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate) and colchicine
Arm Title
Optimal Medical Treatment
Arm Type
Placebo Comparator
Arm Description
Subjects that received optimal medical treatment (statin, aspirin, P2Y12 inhibitor, and nitrate)
Intervention Type
Drug
Intervention Name(s)
Colchicine
Intervention Description
Colchicine: A major alkaloid from Colchicum autumnale L. and found also in other Colchicum species. commonly used as anti-inflammatory drugs.
Intervention Type
Procedure
Intervention Name(s)
Percutaneous Coronary Intervention
Intervention Description
Percutaneous Coronary Intervention: a family of minimally invasive procedures used to open clogged coronary arteries (those that deliver blood to the heart)
Intervention Type
Other
Intervention Name(s)
Optimal medical treatment including statin, aspirin, P2Y12 inhibitor, and nitrate.
Other Intervention Name(s)
No Intervention
Intervention Description
The subjects just received optimal medical treatment including statin, aspirin, P2Y12 inhibitor, and nitrate.
Primary Outcome Measure Information:
Title
The change between 24 hours MMP-9 to day 5
Description
Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix.
Time Frame
24 Hours, Day 5
Title
The change between 24 hours NOX2 to day 5
Description
NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene (also called CYBB gene). The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).
Time Frame
24 Hours, Day 5
Title
The change between 24 hours TGF-β1 to day 5
Description
Transforming growth factor β1 (TGFB1) is a multifunctional secreted protein that generally regulates immune function,544 as well as cell survival and migration, through the Sma- and Mad-related proteins (SMAD) signaling pathway.
Time Frame
24 Hours, Day 5
Title
Left ventricular end-diastolic volume (LVEDV)
Description
The volume of blood in the left ventricle at the end of ventricular filling is called the end-diastolic volume (EDV), which is about 120 mL in the adult human.
Time Frame
Month 1
Secondary Outcome Measure Information:
Title
Number of subjects with hypertension
Description
Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or more, or a diastolic blood pressure (DBP) of 90 mm Hg or more
Time Frame
Baseline
Title
Number of subjects with diabetes
Description
History of diabetes is defined as having fasting blood glucose 126 mg/dL or HBA1c >6.5%
Time Frame
Baseline
Title
Smoking status among the subjects
Description
Smoking or Ex-smoking
Time Frame
Baseline
Title
Number of subjects with dyslipidemia
Description
Dyslipidemia is the imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol, (LDL-C), triglycerides, and high-density lipoprotein (HDL)
Time Frame
Baseline
Title
Type of infark among the subjects
Description
Type of infark (large or small) that happen to the subjects
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects who presenting with STEMI more than 12 hours from the onset of chest pain Aged 40-70 years Agreed with the informed consent Exclusion Criteria: aged <40 or >70 years subjects that have unstable condition such as comorbid disease (infection, inflammation, malignancy, severe renal failure (EGFR <30), a history of hepatic cirrhosis, acute exacerbation of hepatitis, or severe liver disease, alcoholic patient, cardiac arrest, ventricular fibrillation or cardiogenic shock, unstable hemodynamic) subjects that have colchicine hypersensitivity pregnancy or breastfeed
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Suryono Suryono, MD (Cardiologist)
Phone
+628123514186
Email
suryonofiha@gmail.com
Facility Information:
Facility Name
RSD dr Soebandi
City
Jember
State/Province
Jawa Timur
ZIP/Postal Code
68111
Country
Indonesia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Suryono Suryono, MD (Cardiologist)
Phone
+628123514186
Email
suryonofiha@gmail.com
First Name & Middle Initial & Last Name & Degree
Suryono Suryono, MD (Cardiologist)

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Effect of Colchicine on MMP-9, NOX2, and TGF-β1 in Myocardial Infarct

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