Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction (CARE-AMI)
Primary Purpose
Cardiac Remodeling, Myocardial Infarction
Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Paroxetine
Placebo oral capsule
Sponsored by
About this trial
This is an interventional treatment trial for Cardiac Remodeling focused on measuring Paroxetine
Eligibility Criteria
Inclusion Criteria:
- Anterior wall ST-segment elevation myocardial infarction
- Primary percutaneous coronary intervention (PCI) within 24 hours of symptom onset
- Left ventricular ejection fraction ≤ 45% within 48-96 hours after primary PCI (transthoracic echocardiography)
Exclusion Criteria:
- Female patients at reproductive age (<50 years)
- Known intolerance to paroxetine
- Inability to provide informed consent
- Currently participating in another trial before reaching first endpoint
- Current medical therapy with MAO-blocker (during, 14 days before, and 14 days after treatment with MAO-blocker), lithium, thioridazide, or pimozide
- Concomitant tamoxifen intake
- Previous myocardial infarction
- Previous revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting).
- Contraindication to cardiac magnetic resonance imaging
- Obvious or questionable inability to appropriately cooperate (alcohol, drugs etc.)
- Relevant nephropathy or hepatopathy
Sites / Locations
- Bern University Hospital, Department of Cardiology
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Paroxetine
Placebo
Arm Description
Paroxetine 20mg QD per os for 12 weeks followed by 10mg for one additional week
Placebo oral capsule QD per os for 13 weeks
Outcomes
Primary Outcome Measures
Difference in the change of left ventricular ejection fraction (LVEF)
Assessment by cardiac magnetic resonance imaging
Secondary Outcome Measures
Difference in change in left left-ventricular end-diastolic volume (LVEDV)
Assessment by cardiac magnetic resonance imaging
Difference in change in left left-ventricular end-systolic volume (LVESV)
Assessment by cardiac magnetic resonance imaging
Difference in late-enhancement
Assessment by cardiac magnetic resonance imaging
Difference in LVEF between baseline and 12 weeks, and 12 months, respectively
Assessment by transthoracic echocardiography
Major adverse cardiac events
Cardiac death, myocardial infarction, repeat hospitalization for heart failure
Clinical symptoms of heart failure
Assessed by New York Heart Association (NYHA) categorization
Full Information
NCT ID
NCT03274752
First Posted
August 29, 2017
Last Updated
May 29, 2022
Sponsor
Insel Gruppe AG, University Hospital Bern
1. Study Identification
Unique Protocol Identification Number
NCT03274752
Brief Title
Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction
Acronym
CARE-AMI
Official Title
Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction (CARE-AMI): a Randomized Controlled Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
October 26, 2017 (Actual)
Primary Completion Date
January 1, 2021 (Actual)
Study Completion Date
March 1, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Insel Gruppe AG, University Hospital Bern
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study evaluates the off-target effect of paroxetine to reverse cardiac remodeling and improve left ventricular ejection fraction in patients after acute myocardial infarction. Half of the participants will receive paroxetine, while the other half will receive placebo treatment.
Detailed Description
Cardiac remodeling is characterized by a composite of structural, geometric, molecular, and functional changes of the myocardium, and is an important determinant of heart failure and cardiovascular outcome in survivors of acute myocardial infarction. Progression of heart failure secondary to the remodeling process results from dysregulation of the G protein-coupled receptor (GPCR). Excessive adrenergic drive in patients with heart failure results in an enhanced activation of GPCR kinases (GRKs) that is considered to have a central role in adverse cardiac remodeling after ischemic injury. The selective Serotonin reuptake inhibitor paroxetine specifically binds to the catalytic domain of GRK2 as an off-target effect, and has been shown to reverse cardiac remodeling and increase left ventricular ejection fraction in a mouse model. The effect was observed at serum levels achieved with standard dosages of paroxetine, and was robust in mice with and without concomitant heart failure treatment, respectively.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiac Remodeling, Myocardial Infarction
Keywords
Paroxetine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Paroxetine
Arm Type
Experimental
Arm Description
Paroxetine 20mg QD per os for 12 weeks followed by 10mg for one additional week
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo oral capsule QD per os for 13 weeks
Intervention Type
Drug
Intervention Name(s)
Paroxetine
Other Intervention Name(s)
Deroxat
Intervention Description
Paroxetine (Deroxat) will be administered in a dosage of 20mg q.d. per os continuously for 12 weeks after primary PCI. In week 13, Paroxetine (Deroxat) will be administered in a dosage of 10mg q.d. per os.
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
Placebo will be given q.d. per os continuously for 12 weeks after primary PCI. In addition, a placebo will be given q.d. per os in week 13 as well.
Primary Outcome Measure Information:
Title
Difference in the change of left ventricular ejection fraction (LVEF)
Description
Assessment by cardiac magnetic resonance imaging
Time Frame
12 weeks after randomization
Secondary Outcome Measure Information:
Title
Difference in change in left left-ventricular end-diastolic volume (LVEDV)
Description
Assessment by cardiac magnetic resonance imaging
Time Frame
12 weeks after randomization
Title
Difference in change in left left-ventricular end-systolic volume (LVESV)
Description
Assessment by cardiac magnetic resonance imaging
Time Frame
12 weeks after randomization
Title
Difference in late-enhancement
Description
Assessment by cardiac magnetic resonance imaging
Time Frame
12 weeks after randomization
Title
Difference in LVEF between baseline and 12 weeks, and 12 months, respectively
Description
Assessment by transthoracic echocardiography
Time Frame
12 months after randomization
Title
Major adverse cardiac events
Description
Cardiac death, myocardial infarction, repeat hospitalization for heart failure
Time Frame
12 weeks and 12 months after randomization
Title
Clinical symptoms of heart failure
Description
Assessed by New York Heart Association (NYHA) categorization
Time Frame
12 weeks and 12 months after randomization
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Anterior wall ST-segment elevation myocardial infarction
Primary percutaneous coronary intervention (PCI) within 24 hours of symptom onset
Left ventricular ejection fraction ≤ 45% within 48-96 hours after primary PCI (transthoracic echocardiography)
Exclusion Criteria:
Female patients at reproductive age (<50 years)
Known intolerance to paroxetine
Inability to provide informed consent
Currently participating in another trial before reaching first endpoint
Current medical therapy with MAO-blocker (during, 14 days before, and 14 days after treatment with MAO-blocker), lithium, thioridazide, or pimozide
Concomitant tamoxifen intake
Previous myocardial infarction
Previous revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting).
Contraindication to cardiac magnetic resonance imaging
Obvious or questionable inability to appropriately cooperate (alcohol, drugs etc.)
Relevant nephropathy or hepatopathy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Pilgrim, MD
Organizational Affiliation
Bern University Hospital, Department of Cardiology, Freiburgstrasse 10, CH-3010 Bern, Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Bern University Hospital, Department of Cardiology
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
25739765
Citation
Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. doi: 10.1126/scitranslmed.aaa0154.
Results Reference
background
PubMed Identifier
10869273
Citation
Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-8. doi: 10.1161/01.cir.101.25.2981. No abstract available.
Results Reference
background
PubMed Identifier
36000427
Citation
Pilgrim T, Bernhard B, Furholz M, Vollenbroich R, Babongo Bosombo F, Losdat S, Reusser N, Windecker S, Stortecky S, Siontis GCM, Hunziker L, Lanz J, Dobner S. Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition in Patients With Acute Anterior Myocardial Infarction: Final 1-Year Outcomes of the Randomized CARE-AMI Trial. J Am Heart Assoc. 2022 Sep 6;11(17):e026362. doi: 10.1161/JAHA.122.026362. Epub 2022 Aug 24. No abstract available.
Results Reference
derived
PubMed Identifier
34259826
Citation
Pilgrim T, Vollenbroich R, Deckarm S, Grani C, Dobner S, Stark AW, Erne SA, Babongo Bosombo F, Fischer K, Stortecky S, Reusser N, Furholz M, Siontis GCM, Heg D, Hunziker L, Windecker S, Lanz J. Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction: A Randomized Clinical Trial. JAMA Cardiol. 2021 Oct 1;6(10):1171-1176. doi: 10.1001/jamacardio.2021.2247. Erratum In: JAMA Cardiol. 2021 Aug 18;:null.
Results Reference
derived
Learn more about this trial
Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction
We'll reach out to this number within 24 hrs