Acute Respiratory Distress SyndromePhase 2PREMIERNCT04760821
Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for COVID-19
A Phase 2 study testing Trimetazidine in people with Acute Respiratory Distress Syndrome and Covid19, run by Ministry of Health, Brazil at 1 site in Brazil.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Respiratory Distress Syndrome, Covid19, Myocardial Injury
- What is being tested?
- Trimetazidine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 1 siteBrazil
- Study dates
- 10 Dec 2020to 30 Apr 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
- Inclusion Criteria:
- 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:
- Polymerase chain reaction assay (+) for SARS-CoV2
- Serology (+) for SARS-CoV2
- SARS-CoV2 antigen diagnostic tests (+)
- 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
- Signature of the Informed Consent Form
- Exclusion Criteria:
- Chronic renal dysfunction stage 4 (GFR <30mL / min / 1.73m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
- Patient on renal replacement therapy by dialysis
- Pregnant and lactating women
- Previous use of trimetazidine less than two weeks before hospital admission
- Any clinical condition at the investigator´s discretion likely to be associated with elevation of baseline hs-troponin >99th percentile
Trial locations and contacts
1 site in 1 country.
Brazil1 site, 1 recruiting
- Recruiting
Heart Institute (InCor-HCFMUSP)
São Paulo, São Paulo, 05403-000
Felipe Gallego Lima, MD, +55-11-26615000 ext. 5810, felipeglima@yahoo.com.br
About this study
Official title: 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.
Read more
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.
Read the 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).
- Being tested
- Trimetazidine
- Keywords
- Acute Respiratory Distress Syndrome, Coronavirus, Myocardial Injury, Troponin, Trimetazidine
- Medical subject headings
- Respiratory Distress Syndrome, COVID-19, Coronavirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TrimetazidineDrug
Trimetazidine 35mg bid in patients with GFR above 60mL/min. Trimetazidine 35mg od in patients with GFR between 30 and 60mL/min.
| Study group | Role | What they receive |
|---|---|---|
| Usual Care | No intervention | 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. |
| Trimetazidine | Experimental | 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. Receives: Drug: Trimetazidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
High-sensitivity cardiac troponin
Concentration levels of plasma high-sensitivity cardiac troponin
Measured: 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 outcomes (5)
All-cause mortality assessed at 30 days following randomization
Percentage of patients who died from all causes during hospitalization
Measured: 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
Measured: 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
Measured: From the first 30 days after randomization
ICU-free days assessed at 30 days following randomization
Time (in days) out of the ICU
Measured: From the first 30 days after randomization
Hospital-free days assessed at 30 days following randomization
Time (in days) out of the hospital
Measured: From the first 30 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2021
- Study start10 Dec 2020
- Primary completion30 Apr 2021 (estimated)
- Study completion30 Apr 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Respiratory Distress SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients admitted for moderate to severe acute respiratory distress syndrome caused by the SARS-CoV2 will be randomized to usual care or usual care + trimetazidine.
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ministry of Health, Brazil
- Sponsor type
- Other government
- Collaborators
- InCor Heart Institute
- Responsible party
- Principal investigator, Luis Henrique W Gowdak, MD, PhD, InCor Heart Institute
- Investigators
- Luis Henrique Wolff Gowdak, MD, PhD, Study chair, InCor (HC-FMUSP)Felipe Gallego Lima, MD, Principal investigator, InCor (HC-FMUSP)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04760821
- Sponsor's protocol ID
- SDC5100/20/129
- Acronym
- PREMIER
- Status last verified
- Feb 2021
- First submitted
- 17 Feb 2021
- Last updated
- 21 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for Moderate to Severe Acute Respiratory Syndrome Caused by SARS-CoV-2
- ClinicalTrials.gov ID
- NCT04760821
- Acronym / sponsor ID
- PREMIER / SDC5100/20/129
- Keywords
- Acute Respiratory Distress Syndrome, Coronavirus, Myocardial Injury, Troponin, Trimetazidine
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Ministry of Health, BrazilOther government
- Collaborators
- InCor Heart Institute
- Study start
- 10 Dec 2020 (actual)
- Primary completion
- 30 Apr 2021 (estimated)
- Study completion
- 30 Apr 2021 (estimated)
- First posted
- 18 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Patients admitted for moderate to severe acute respiratory distress syndrome caused by the SARS-CoV2 will be randomized to usual care or usual care + trimetazidine.
| Arm | Type | Receives |
|---|---|---|
| Usual Care | No intervention | –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. |
| Trimetazidine | Experimental | Drug: TrimetazidinePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TrimetazidineTrimetazidine 35mg bid in patients with GFR above 60mL/min. Trimetazidine 35mg od in patients with GFR between 30 and 60mL/min. | Drug | Trimetazidine |
Primary outcome
High-sensitivity cardiac troponin
Time frame: 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.
Concentration levels of plasma high-sensitivity cardiac troponin
5 secondary outcomes
All-cause mortality assessed at 30 days following randomization
Time frame: From the first 30 days after randomization
Admission in ICU assessed at 30 days following randomization
Time frame: From the first 30 days after randomization
Mechanical respiratory support assessed at 30 days following randomization
Time frame: From the first 30 days after randomization
ICU-free days assessed at 30 days following randomization
Time frame: From the first 30 days after randomization
Hospital-free days assessed at 30 days following randomization
Time frame: From the first 30 days after randomization
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Luis Henrique Wolff Gowdak, MD, PhD study chair
InCor (HC-FMUSP)
Felipe Gallego Lima, MD principal investigator
InCor (HC-FMUSP)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Trimetazidine in people with Acute Respiratory Distress Syndrome and Covid19, run by Ministry of Health, Brazil at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Luis Henrique Wolff Gowdak, MD, PhD (+55-11-2661-5000 ext. 5929, luis.gowdak@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
High-sensitivity cardiac troponin (time frame: 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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2021.