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CompletedNCT03274752CARE-AMIUpdated Jun 1, 2022

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

A Phase 2 interventional study of Paroxetine and Placebo oral capsule in Cardiac Remodeling and Myocardial Infarction, sponsored by Insel Gruppe AG, University Hospital Bern. Completed at 1 site in Switzerland. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-06-01.

Sponsored by Insel Gruppe AG, University Hospital Bern · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
50
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Cardiac Remodeling
  • Myocardial Infarction

Keywords

  • Paroxetine
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
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Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
50 participants (actual)

Study arms

  • Experimental
    Paroxetine

    Paroxetine 20mg QD per os for 12 weeks followed by 10mg for one additional week

    Drug: Paroxetine

  • Placebo comparator
    Placebo

    Placebo oral capsule QD per os for 13 weeks

    Drug: Placebo oral capsule

Interventions

  • DrugParoxetine

    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.

    Also known as: Deroxat

  • DrugPlacebo 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.

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What researchers measure

Primary outcomes

  1. Difference in the change of left ventricular ejection fraction (LVEF)

    Assessment by cardiac magnetic resonance imaging

    Time frame: 12 weeks after randomization

Secondary outcomes

  1. Difference in change in left left-ventricular end-diastolic volume (LVEDV)

    Assessment by cardiac magnetic resonance imaging

    Time frame: 12 weeks after randomization

  2. Difference in change in left left-ventricular end-systolic volume (LVESV)

    Assessment by cardiac magnetic resonance imaging

    Time frame: 12 weeks after randomization

  3. Difference in late-enhancement

    Assessment by cardiac magnetic resonance imaging

    Time frame: 12 weeks after randomization

  4. Difference in LVEF between baseline and 12 weeks, and 12 months, respectively

    Assessment by transthoracic echocardiography

    Time frame: 12 months after randomization

  5. Major adverse cardiac events

    Cardiac death, myocardial infarction, repeat hospitalization for heart failure

    Time frame: 12 weeks and 12 months after randomization

  6. Clinical symptoms of heart failure

    Assessed by New York Heart Association (NYHA) categorization

    Time frame: 12 weeks and 12 months after randomization

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Study locations

1 site
  • Bern University Hospital, Department of Cardiology
    Bern, 3010, Switzerland
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References and documents

Publications

  • 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. PubMed 25739765 ↗
  • 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. PubMed 10869273 ↗
  • 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. PubMed 36000427 ↗
  • 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 Oct 1;6(10):1223. doi: 10.1001/jamacardio.2021.3329. PubMed 34259826 ↗

Individual participant data

Plan to share: No

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Registry details

Key details

Study ID
NCT03274752
Lead sponsor
Insel Gruppe AG, University Hospital Bern
Responsible party
Sponsor
First posted
Sep 7, 2017
Start date
Oct 26, 2017
Primary completion
Jan 1, 2021
Completion
Mar 1, 2022
Last update
Jun 1, 2022

Study contacts

Thomas Pilgrim, MD
principal investigator · Bern University Hospital, Department of Cardiology, Freiburgstrasse 10, CH-3010 Bern, Switzerland

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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