Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction

Myocardial Infarction Clinical Trial

— CARE-AMI  

Official title:

Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction (CARE-AMI): a Randomized Controlled Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03274752
• Other study ID #: 2016-00349
• Status: Completed
• Phase: Phase 2
• Start date: October 26, 2017
• Est. completion date: March 1, 2022

Study information

• Verified date: May 2022
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: March 1, 2022
• Est. primary completion date: January 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiac Remodeling
• Infarction
• Myocardial Infarction

Intervention

Drug:
• Paroxetine
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.
• Placebo oral capsule
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.

Locations

Country	Name	City	State
Switzerland	Bern University Hospital, Department of Cardiology	Bern

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne

Country where clinical trial is conducted

Switzerland, 

References & Publications (2)

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. — View Citation

Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-8. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in the change of left ventricular ejection fraction (LVEF)	Assessment by cardiac magnetic resonance imaging	12 weeks after randomization
Secondary	Difference in change in left left-ventricular end-diastolic volume (LVEDV)	Assessment by cardiac magnetic resonance imaging	12 weeks after randomization
Secondary	Difference in change in left left-ventricular end-systolic volume (LVESV)	Assessment by cardiac magnetic resonance imaging	12 weeks after randomization
Secondary	Difference in late-enhancement	Assessment by cardiac magnetic resonance imaging	12 weeks after randomization
Secondary	Difference in LVEF between baseline and 12 weeks, and 12 months, respectively	Assessment by transthoracic echocardiography	12 months after randomization
Secondary	Major adverse cardiac events	Cardiac death, myocardial infarction, repeat hospitalization for heart failure	12 weeks and 12 months after randomization
Secondary	Clinical symptoms of heart failure	Assessed by New York Heart Association (NYHA) categorization	12 weeks and 12 months after randomization