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出境医 / 临床实验 / Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right (MITOFFA)

Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right (MITOFFA)

Study Description
Brief Summary:
Our preliminary data suggests that pharmacological inhibition of the mitochondrial fission protein, Drp1, reduced atherosclerotic plaque volume and attenuated macrophage accumulation within the plaque in an ApoE-/- mouse model of wire-induced carotid arterial injury. Furthermore, we hypothesize that modulation of mitochondrial morphology and metabolism with Drp1 inhibition prevents atherosclerosis by reducing monocyte activation and migration. In this research proposal, our overall objective will be to investigate the role of Drp1 in human monocytes and macrophages as novel therapeutic targets for preventing atherosclerosis.

Condition or disease Intervention/treatment
CAD Patients Procedure: CABG

Detailed Description:

Study 1 (tissue sample study): To investigate the changes in mitochondrial function and pro-inflammatory markers in human arterial atherosclerotic plaques.

Hypothesis: Macrophages from femoral artery atherosclerotic plaques in patients with peripheral artery disease will display upregulation of mitochondrial fission proteins and features of pro-inflammatory activation.

Study 2 (white blood cell study): To investigate the changes in mitochondrial function and pro-inflammatory markers in white blood cells from patients with stable and unstable coronary artery didease (CAD).

Hypothesis: Monocytes from patients with unstable CAD will display upregulation of Drp1 and features of pro-inflammatory activation, mitochondrial fission, impaired mitochondrial respiratory function, and perturbed metabolism, when compared to monocytes from patients with stable CAD.

Study Design
Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 200 participants
Observational Model: Other
Time Perspective: Other
Target Follow-Up Duration: 1 Year
Official Title: Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right - MITOFFA
Actual Study Start Date : October 10, 2018
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : March 31, 2020
Arms and Interventions
Group/Cohort Intervention/treatment
CABG patients Procedure: CABG
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Other Name: PCI
PAD patients Procedure: CABG
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Other Name: PCI
Healthy volunteers Procedure: CABG
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Other Name: PCI
Patients with CAD Procedure: CABG
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Other Name: PCI
Outcome Measures
Primary Outcome Measures :
  1. "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. [ Time Frame: 2 years ]

    Primary outcome analysis for aim 1:

    The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis.

    Primary outcome analysis for aim 1:

    The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis.

    The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients



Biospecimen Retention:   Samples With DNA
Tissue samples: LIMA or radial or aorta or aortic valve

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Study 1 (tissue sample study):

  • 25 adult patients undergoing coronary artery bypass graft (CABG) surgery: Control tissue will be collected from the left internal mammary artery (LIMA) or radial artery (RA) Atherosclerotic tissue will be collected from aortic root
  • 25 adult patients undergoing surgical femoral or carotid endarterectomy Endarterectomy atherosclerotic tissue will be collected

Study 2 (white blood cell study):

  • 50 healthy adult volunteers Control blood sample will be collected
  • 50 adult patients with stable CAD Stable CAD blood sample will be collected
  • 50 adult patients with unstable CAD Unstable CAD blood sample will be collected
Criteria

Inclusion Criteria:

Study 1 (tissue sample study):

CABG patients

  1. Patients aged ≥21 years old
  2. Undergoing elective CABG with aortic valve surgery

PAD patients:

  1. Patients aged ≥21 years old
  2. Undergoing either elective surgical femoral or carotid endarterectomy

Study 2 (white blood cell study):

1) Healthy volunteers aged ≥21 years old 2) Patients with stable CAD 3) Patients admitted with ACS treated by PCI in prior 24 hours.

-

Exclusion Criteria:

  1. General exclusion criteria will be a known history of leucopenia, thrombocytopenia, or severe hepatic or renal dysfunction, as well as evidence for inflammatory or malignant disease.
  2. History of haematological disorders
  3. Cardiac arrest, Cardiogenic shock, Poor pre-morbid status, Pregnancy
Contacts and Locations

Locations
Layout table for location information
Singapore
Hector A. Cabrera-Fuentes Recruiting
Singapore, Singapore, 169609
Contact: Tan Mui Teng    67042297    tan.mui.teng@nhcs.com.sg   
Sponsors and Collaborators
National Heart Centre Singapore
Tracking Information
First Submitted Date June 6, 2019
First Posted Date June 10, 2019
Last Update Posted Date June 10, 2019
Actual Study Start Date October 10, 2018
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 6, 2019) 		"mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. [ Time Frame: 2 years ]
Primary outcome analysis for aim 1: The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis. Primary outcome analysis for aim 1: The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients with atherosclerosis disease. The statistical analysis will be performed by 2-tailed student's T-test with the platelet "mitochondria-shaping" proteins expression as the response variable. The primary analyses will be by per protocol analysis and there will also be an intention to treat analysis. The primary endpoint is "mitochondria-shaping" proteins expression quantified on immunoblotting in patients
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right
Official Title Targeting Mitochondrial Fusion and Fission to Prevent Atherosclerosis: Getting the Balance Right - MITOFFA
Brief Summary Our preliminary data suggests that pharmacological inhibition of the mitochondrial fission protein, Drp1, reduced atherosclerotic plaque volume and attenuated macrophage accumulation within the plaque in an ApoE-/- mouse model of wire-induced carotid arterial injury. Furthermore, we hypothesize that modulation of mitochondrial morphology and metabolism with Drp1 inhibition prevents atherosclerosis by reducing monocyte activation and migration. In this research proposal, our overall objective will be to investigate the role of Drp1 in human monocytes and macrophages as novel therapeutic targets for preventing atherosclerosis.
Detailed Description

Study 1 (tissue sample study): To investigate the changes in mitochondrial function and pro-inflammatory markers in human arterial atherosclerotic plaques.

Hypothesis: Macrophages from femoral artery atherosclerotic plaques in patients with peripheral artery disease will display upregulation of mitochondrial fission proteins and features of pro-inflammatory activation.

Study 2 (white blood cell study): To investigate the changes in mitochondrial function and pro-inflammatory markers in white blood cells from patients with stable and unstable coronary artery didease (CAD).

Hypothesis: Monocytes from patients with unstable CAD will display upregulation of Drp1 and features of pro-inflammatory activation, mitochondrial fission, impaired mitochondrial respiratory function, and perturbed metabolism, when compared to monocytes from patients with stable CAD.
Study Type Observational [Patient Registry]
Study Design Observational Model: Other
Time Perspective: Other
Target Follow-Up Duration 1 Year
Biospecimen Retention:   Samples With DNA
Description:
Tissue samples: LIMA or radial or aorta or aortic valve
Sampling Method Probability Sample
Study Population

Study 1 (tissue sample study):

  • 25 adult patients undergoing coronary artery bypass graft (CABG) surgery: Control tissue will be collected from the left internal mammary artery (LIMA) or radial artery (RA) Atherosclerotic tissue will be collected from aortic root
  • 25 adult patients undergoing surgical femoral or carotid endarterectomy Endarterectomy atherosclerotic tissue will be collected

Study 2 (white blood cell study):

  • 50 healthy adult volunteers Control blood sample will be collected
  • 50 adult patients with stable CAD Stable CAD blood sample will be collected
  • 50 adult patients with unstable CAD Unstable CAD blood sample will be collected
Condition CAD Patients
Intervention Procedure: CABG
Patients undergoing coronary artery bypass graft and patient presented with ACS undergoing PCI
Other Name: PCI
Study Groups/Cohorts
  • CABG patients
    Intervention: Procedure: CABG
  • PAD patients
    Intervention: Procedure: CABG
  • Healthy volunteers
    Intervention: Procedure: CABG
  • Patients with CAD
    Intervention: Procedure: CABG
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Estimated Enrollment
 (submitted: June 6, 2019) 		200
Original Estimated Enrollment Same as current
Estimated Study Completion Date March 31, 2020
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

Study 1 (tissue sample study):

CABG patients

  1. Patients aged ≥21 years old
  2. Undergoing elective CABG with aortic valve surgery

PAD patients:

  1. Patients aged ≥21 years old
  2. Undergoing either elective surgical femoral or carotid endarterectomy

Study 2 (white blood cell study):

1) Healthy volunteers aged ≥21 years old 2) Patients with stable CAD 3) Patients admitted with ACS treated by PCI in prior 24 hours.

-

Exclusion Criteria:

  1. General exclusion criteria will be a known history of leucopenia, thrombocytopenia, or severe hepatic or renal dysfunction, as well as evidence for inflammatory or malignant disease.
  2. History of haematological disorders
  3. Cardiac arrest, Cardiogenic shock, Poor pre-morbid status, Pregnancy
Sex/Gender
Sexes Eligible for Study: All
Ages 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Singapore
Removed Location Countries  
 
Administrative Information
NCT Number NCT03980548
Other Study ID Numbers 2018/2497
SHF/FG651P/2017 ( Other Grant/Funding Number: SingHealth Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party National Heart Centre Singapore
Study Sponsor National Heart Centre Singapore
Collaborators Not Provided
Investigators Not Provided
PRS Account National Heart Centre Singapore
Verification Date August 2018

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