Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for COVID-19 (PREMIER)

Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for Moderate to Severe Acute Respiratory Syndrome Caused by SARS-CoV-2

Acute myocardial injury has been a finding of variable frequency among patients diagnosed with COVID-19. It is now recognized that cTnI levels are strongly associated with increased mortality. The mechanisms underlying the myocardial injury remain unknown, and it is not clear whether they reflect local/systemic inflammatory process and/or cellular ischemia.

Both myocardial ischemia and ventricular dysfunction result in dramatic changes in mitochondrial oxidative metabolism. These changes involve an increase in the rate of cytoplasmic anaerobic glycolysis to compensate for the decrease in mitochondrial adenosine triphosphate (ATP) production. The rest of the mitochondrial oxidative metabolism originates mainly from the β-oxidation of free fatty acids, which occurs at the expense of glucose oxidation.

Trimetazidine is a competitive inhibitor of the enzyme 3-ketoacyl coenzyme A (CoA) long-chain thiolase (3-KAT), the last enzyme involved in the oxidation of fatty acids. Stimulation of glucose oxidation by trimetazidine results in a better coupling between glycolysis and glucose oxidation, with a consequent decrease in lactate production and intracellular acidosis, present in situations of myocardial ischemia or heart failure.

Thus, the PREMIER-COVID-19 study was designed to test the hypothesis that the use of trimetazidine associated with usual therapy in patients admitted with a diagnosis of moderate to severe acute respiratory syndrome by SARS-CoV2 infection reduces the extent of acute myocardial injury assessed by the peak release of ultra-sensitive troponin compared to usual therapy.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Injury; Covid19; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Trimetazidine

Detailed Description

Acute myocardial injury, defined by increased levels of high-sensitivity cardiac troponin I (cTnI), has been a finding of variable frequency among patients diagnosed with COVID-19. This myocardial impairment can occur in the form of acute myocarditis or an injury secondary to the imbalance between oxygen supply and demand (type 2 myocardial infarction). It is now recognized that cTnI levels are strongly associated with increased mortality. The mechanisms underlying the myocardial injury remain unknown, and it is not clear whether they reflect local/systemic inflammatory process and/or cellular ischemia.

Both myocardial ischemia and ventricular dysfunction result in dramatic changes in mitochondrial oxidative metabolism. These changes involve an increase in cytoplasmic anaerobic glycolysis rate to compensate for the decrease in mitochondrial ATP production. Unfortunately, the increase in glycolysis exceeds the subsequent mitochondrial oxidation capacity of pyruvate (glucose oxidation) derived from glycolysis, resulting in the intracellular accumulation of lactate and protons. The protons produced from this decoupling between glycolysis and glucose oxidation contribute to a rupture in ionic homeostasis and myocardial cells, resulting in lower cardiac efficiency. In both the ischemic heart and the insufficient heart, the rest of the mitochondrial oxidative metabolism originates mainly from the β-oxidation of free fatty acids, which occurs at the expense of glucose oxidation.

Trimetazidine is a competitive inhibitor of the enzyme 3-ketoacyl CoA long-chain thiolase (3-KAT), the last enzyme involved in the oxidation of fatty acids. Stimulation of glucose oxidation by trimetazidine results in a better coupling between glycolysis and glucose oxidation, with a consequent decrease in lactate production and intracellular acidosis present in situations of myocardial ischemia or heart failure.

Thus, the PREMIER-COVID-19 study (open and randomized) was designed to test the hypothesis that the use of trimetazidine associated with usual therapy in patients admitted with a diagnosis of moderate to severe acute respiratory syndrome by SARS-CoV2 infection reduces the extent of acute myocardial injury assessed by the peak release of ultra-sensitive troponin compared to usual therapy. Investigators will also assess, as secondary outcomes, the impact on clinical evolution to more severe forms (admission to the intensive care unit or the need for mechanical ventilatory support, length of stay in hospital and in-hospital mortality).

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Luis Henrique Wolff Gowdak, MD, PhD; Phone Number: 5929 +55-11-2661-5000; Email: luis.gowdak@gmail.com
• Study Contact Backup: Name: Felipe Gallego Lima, MD; Phone Number: +55-11-2661-5000; Email: felipeglima@yahoo.com.br

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 05403-000
      • Recruiting
      • Heart Institute (InCor-HCFMUSP)
      • Contact: Felipe Gallego Lima, MD; Phone Number: 5810 +55-11-26615000; Email: felipeglima@yahoo.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

A. Inclusion Criteria:

1. Clinical diagnosis of moderate to severe acute respiratory syndrome due to SARS-CoV2 defined as:

   1.1. Tachypnea: > 24 breaths per minute 1.2. Hypoxemia: arterial oxygen saturation <94% in room air by pulse oximetry 1.3. Presumptive (or confirmed) diagnosis of SARS-Cov2 infection by at least one of the following criteria:

   1. Polymerase chain reaction assay (+) for SARS-CoV2
   2. Serology (+) for SARS-CoV2
   3. SARS-CoV2 antigen diagnostic tests (+)
   4. Chest CT with findings suggestive of the diagnosis of COVID-19 in the presence of medical history or clinical signs compatible with the diagnosis of COVID-19
2. Signature of the Informed Consent Form

B. Exclusion Criteria:

1. Chronic renal dysfunction stage 4 (GFR <30mL / min / 1.73m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
2. Patient on renal replacement therapy by dialysis
3. Pregnant and lactating women
4. Previous use of trimetazidine less than two weeks before hospital admission
5. Any clinical condition at the investigator´s discretion likely to be associated with elevation of baseline hs-troponin >99th percentile

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Usual Care; Patients ascribed to the Usual Care group will receive the standard of care for the management of patients admitted with moderate to severe acute respiratory distress syndrome due to SARS-CoV2. Usual Care means the clinical protocol approved by the enrolling center.
Experimental: Trimetazidine; Patients ascribed to the Usual Care group will receive the standard of care for the management of patients admitted with moderate to severe acute respiratory distress syndrome due to SARS-CoV2 plus trimetazidine.Usual Care means the clinical protocol approved by the enrolling center.	Drug: Trimetazidine; Trimetazidine 35mg bid in patients with GFR above 60mL/min. Trimetazidine 35mg od in patients with GFR between 30 and 60mL/min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
High-sensitivity cardiac troponin	Concentration levels of plasma high-sensitivity cardiac troponin	From enrollment until at least ten days (moderate cases) or twenty days (severe cases) after the beginning of symptoms AND 24 hours without fever AND with improvement in symptoms.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality assessed at 30 days following randomization	Percentage of patients who died from all causes during hospitalization	From the first 30 days after randomization
Admission in ICU assessed at 30 days following randomization	Percentage of patients admitted to the Intensive Care Unit	From the first 30 days after randomization
Mechanical respiratory support assessed at 30 days following randomization	Percentage of patients admitted to the Intensive Care Unit who needed mechanical respiratory support	From the first 30 days after randomization
ICU-free days assessed at 30 days following randomization	Time (in days) out of the ICU	From the first 30 days after randomization
Hospital-free days assessed at 30 days following randomization	Time (in days) out of the hospital	From the first 30 days after randomization

Collaborators and Investigators

• Sponsor: Ministry of Health, Brazil
• Collaborators: InCor Heart Institute
• Investigators: Study Chair: Luis Henrique Wolff Gowdak, MD, PhD, InCor (HC-FMUSP); Principal Investigator: Felipe Gallego Lima, MD, InCor (HC-FMUSP)

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2020
• Primary Completion (Anticipated): April 30, 2021
• Study Completion (Anticipated): April 30, 2021

Study Registration Dates

• First Submitted: February 17, 2021
• First Submitted That Met QC Criteria: February 17, 2021
• First Posted (Actual): February 18, 2021

Study Record Updates

• Last Update Posted (Actual): February 21, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Coronavirus; Acute Respiratory Distress Syndrome; Myocardial Injury; Troponin; Trimetazidine
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Syndrome; Wounds and Injuries; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Vasodilator Agents; Trimetazidine
• Other Study ID Numbers: SDC5100/20/129

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No