- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06286878
Pleiotropic Effects of Dapagliflozin in Patients With Acute Coronary Syndromes
Study Overview
Status
Intervention / Treatment
Detailed Description
Study design: Single-center, prospective, randomized, double-blind, placebo-controlled, parallel-group clinical study.
Primary Outcome: To compare platelet aggregation in the dapagliflozin and placebo groups by the Multiplate Analyzer® test (using ADP as an agonist) in hospitalized patients with a diagnosis of AMI within seven days of evolution, using dual antiplatelet therapy with acetylsalicylic acid (ASA) and an anti-platelet ADP, 48 ± 12 hours after starting dapagliflozin/placebo treatment. Due to the rapid oral absorption of the medication, reaching maximum plasma concentration after 2 hours and as its pharmacokinetics does not change with food or other concomitant medications, our hypothesis is that there may be an antiplatelet effect that can be detected early
Other exploratory analyses:
- compare B-type natriuretic peptide (BNP) and troponin biomarkers between dapagliflozin and placebo groups at 30 (± 5) days after randomization;
- Correlation between levels of ultrasensitive C-reactive protein (us-CRP) and platelet aggregability;
- Compare hsCRP levels in dapagliflozin and placebo groups at 30 (± 5) days;
- Compare the size of the AMI assessed by peak CK-MB mass and troponin in the dapagliflozin and placebo groups;
- Compare the behavior of glycemia in the dapagliflozin and placebo groups, taking into account the following parameters: calculation of the glycemic mean (±SD) of capillary blood glucose tests (remote laboratory tests) during 48 hours after randomization; incidence of hypoglycemia (blood glucose below 70 mg/dl) and severe hypoglycemia (glycemia below 40 mg/dl) during hospitalization; calculation of the average insulin used during 48 hours after randomization;
- Compare, in the dapagliflozin and placebo groups, the levels of creatinine, urea and hematocrit analyzed immediately after randomization and before starting treatment, and 30 (± 5) days after randomization;
- Test of lipid transfer from artificial nanoemulsion to HDL in dapagliflozin and placebo groups at inclusion and at 30 (± 5) days after randomization: EDTA plasma samples in a volume of 200 μL will be incubated with 50 μL nanoemulsion artificial in 3H-cholesteryl-esters and 14C-phospholipids or with free 14C-cholesterol and 3H-triglycerides. After 1h in agitation of the bath at 37 ºC, the precipitation reagent consisting of 250 μL of the solution with 0.02% dextran sulfate (50,000 MW) and 0.3 mol / L of MgCl2 will be added to the incubation, which will then be mixed for 30 seconds and centrifuged for 10 min (3000g). Finally, 250 μL of the supernatant is transferred to counting vials containing 5 μL of scintillation solution (Packard BioScience, Groeningen, The Netherlands) and the radioactivity measured with a Packard model TR 1600 liquid scintillation analyzer (Palo Alto, CA). Blank plasma samples will be replaced by 200 μL of TRIS solution. The radioactive transfer results from the nanoemulsion to HDL will be expressed as % of the total incubated radioactivity found in the supernatant containing HDL.
- Compare the diuresis obtained during 48 hours after randomization in the Coronary Intensive Care Unit, in the dapagliflozin and placebo groups.
- Compare, in the dapagliflozin and placebo groups, autonomic modulation, vascular autonomic control and assessment of baroreflex control by means of a 10-minute electrocardiogram, after inclusion and before the start of treatment, and 30 (± 5) days after randomization .
Analyze the primary objective of the study in the following pre-specified subgroups:
- obese (BMI ≥ 30 Kg/m2) and non-obese;
- male and female sex;
- elderly (≥ 65 years) and non-elderly;
- smokers and non-smokers;
- time since diagnosis of diabetes (≥ or < 10 years);
- basal blood glucose ≥ 125 mg/dL and < 125 mg/dL;
- glycated hemoglobin (HbA1c) ≤ 9.0% and > 9.0%;
- use of clopidogrel or ticagrelor;
- treatment performed for the acute coronary event: percutaneous coronary intervention or clinical treatment;
- ejection fraction ≤ 40% and > 40%.
- Diabetics and non-diabetics
- Onset of symptoms ≤ 72 hours and > 72 hours
Study plan: Eligible patients will be enrolled within the first seven days of symptom onset. After signing the Informed Consent Form, laboratory tests will be collected, as previously specified in the methodology. Subsequently, patients will be randomized to use dapagliflozin or placebo in a double-blind manner. Randomization will be performed using the Graphipad® program, with distribution of numbered vials containing the study medication (dapagliflozin 10 mg tablets or placebo-equivalent), randomly between the two groups. All patients must be using dual antiplatelet therapy and the results will be stratified by the type of treatment performed for AMI. Study medication, once initiated, will be maintained until the final platelet assessment, scheduled for 30 days, is performed. The other medications, including other oral antidiabetics and insulin, will be used according to the institution's routines, except for prohibited medications, as stated in the exclusion criteria. After the end of the study, the sealed envelopes will be opened to identify the blinding codes.
Glycemic control: According to institutional routines, the cut-off value of 140 mg/dL will be used in two sequential capillary blood glucose levels as the threshold for starting treatment with subcutaneous insulin. Patients whose diabetes control is not adequate, as evidenced by a capillary blood glucose value maintained greater than 250 mg/dL, will receive the intravenous insulin protocol, also in accordance with the institutional routines (summary below).The HbA1c target will be of < 7.5%.
Inclusion criteria:
- Men and women aged ≥ 18 years (women of childbearing age must have a negative pregnancy test)
- In routine use of dual antiplatelet therapy with ASA plus an ADP receptor antagonist, according to institutional routines;
- Acute myocardial infarction, with or without ST-segment elevation (STEMI/NSTEMI) defined according to the 4th Universal Definition of Acute Myocardial Infarction, with up to 7 days of evolution from the onset of symptoms;
- Signature of the Free and Informed Consent Term.
Exclusion criteria:
- Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for a total of 2 years or more during a lifetime at any time;
- Current or recent (within 12 months) treatment with rosiglitazone;
- Chronic use (>15 consecutive days) of any SGLT2 inhibitor at the time of hospitalization;
- Chronic use (>30 consecutive days) with an oral steroid at a dose equivalent to prednisolone ≥10 mg (eg, betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day;
- systolic BP > 180 or diastolic BP > 100 mmHg at randomization;
- Diagnosis of Type 1 diabetes mellitus, MODY (maturity onset diabetes of the Young) or diabetes mellitus secondary to diverse endocrinopathy, pancreatic resection, medication, pancreas neoplasia or chronic pancreatitis;
- History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time;
- History of any other malignancy within 5 years (with the exception of skin cancers successfully treated non-melanoma);
- Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year);
- Any condition that, in the opinion of the Investigator, may render the research participant unfit to complete the study, including, but not limited to, cardiovascular disease (KILLIP > 2, modified Forester > IIa,recurrent ventricular arrhythmias) or non cardiovascular (eg, active malignancy other than basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease);
- Pregnancy or lactation;
- Active participation in another clinical trial
- Patients with septic shock or severe glycemic decompensation requiring the use of IV insulin at the time of randomization;
- TGP/ALT(Alanine Amino Transferase) >3x the upper limit of normality (ULN) or total bilirubin >2.5 x ULN;
- Estimated glomerular filtration rate (GFR) < 45 ml/min/1.73m² , calculated by MDRD, or kidney transplant;
- Known thrombophilias or thrombocytosis;
- Blood dyscrasias or any disorder that causes hemolysis, previously known;
- Hematological abnormality (Hb ≤ 11g/dL or > 17g/dL, leukocytes ≤ 4500/mm³ or >11000/mm³, platelet count <150,000/mm³ or > 450,000/mm³)
Casuistry: To calculate the sample size, the following assumptions were taken into account consideration :
- Aggregability of 482.61 ± 231.82 (area under the curve AUC) in a previous study of patients with ACS using dual antiaggregation therapy with AAS and clopidogrel;
- estimated difference of 33% less in the dapagliflozin group (323.35 ± 231.82 AUC);
- alpha of 0.05 and statistical power of 80%. Based on this information, the sample size was calculated at 70 patients, and in order to compensate for any follow-up losses, 80 patients (40 in each group) will be included in this project.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Contact
- Name: Jose JN Nicolau
- Phone Number: +55 (11) 2661-5058
- Email: jose.nicolau@incor.usp.br
Study Locations
-
-
-
Sao Paulo, Brazil, 05403-900
- Recruiting
- Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo
-
Contact:
- José Carlos Nicolau
- Phone Number: 551126615058
- Email: josecarlosnicolau@gmail.com
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Men and women aged ≥ 18 years (women of childbearing age must have a negative pregnancy test);
- In routine use of dual antiplatelet therapy with ASA plus an ADP receptor antagonist, according to institutional routines;
- Acute myocardial infarction, with or without ST-segment elevation (STEMI/NSTEMI) defined according to the 4th Universal Definition of Acute Myocardial Infarction, with up to 7 days of evolution from the onset of symptoms;
- Signature of the Free and Informed Consent Term.
Exclusion criteria:
- Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for a total of 2 years or more during a lifetime at any time;
- Current or recent (within 12 months) treatment with rosiglitazone;
- Chronic use (>15 consecutive days) of any SGLT2 inhibitor at the time of hospitalization;
- Chronic use (>30 consecutive days) with an oral steroid at a dose equivalent to prednisolone ≥10 mg (eg, betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day;
- Systolic BP > 180 or diastolic BP > 100 mmHg at randomization;
- Diagnosis of Type 1 diabetes mellitus, MODY (maturity onset diabetes of the Young) or diabetes mellitus secondary to diverse endocrinopathy, pancreatic resection, medication, pancreas neoplasia or chronic pancreatitis;
- History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time;
- History of any other malignancy within 5 years (with the exception of skin cancers successfully treated non-melanoma);
- Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year);
- Any condition that, in the opinion of the Investigator, may render the research participant unfit to complete the study, including, but not limited to, cardiovascular disease (KILLIP > 2, modified Forester > IIa,35 recurrent ventricular arrhythmias) or non cardiovascular (eg, active malignancy other than basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease);
- Pregnancy or lactation;
- Active participation in another clinical trial
- Patients with septic shock or severe glycemic decompensation requiring the use of IV insulin at the time of randomization;
- TGP/ALT(Alanine Amino Transferase) >3x the upper limit of normality (ULN) or total bilirubin >2.5 x ULN;
- Estimated glomerular filtration rate (GFR) < 45 ml/min/1.73m² , calculated by MDRD, or kidney transplant;
- Known thrombophilias or thrombocytosis;
- Blood dyscrasias or any disorder that causes hemolysis, previously known;
- Hematological abnormality (Hb ≤ 11g/dL or > 17g/dL, leukocytes ≤ 4500/mm³ or >11000/mm³, platelet count <150,000/mm³ or > 450,000/mm³)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Dapagliflozin
Dapagliflozin 10 mg tablets given once daily, per oral use
|
Patients will be randomized to use dapagliflozin or placebo in a double-blind way
|
Placebo Comparator: Placebo group
Placebo tablets given once daily, per oral use
|
Patients will be randomized to use dapagliflozin or placebo in a double-blind way
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Platelet aggregation using ADP
Time Frame: 4 Years
|
To compare platelet aggregation in the dapagliflozin and placebo groups by the Multiplate Analyzer® test (using ADP as an agonist) in hospitalized patients with a diagnosis of AMI within seven days of evolution, using dual antiplatelet therapy with acetylsalicylic acid (ASA) and an anti-platelet ADP, 48 ± 12 hours after starting dapagliflozin/placebo treatment.
|
4 Years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Platelet aggregation using ADP at 30 (± 5) days after study therapy
Time Frame: 4 Years
|
Compare between the dapagliflozin and placebo groups: platelet aggregability at 30 (± 5) days after study therapy by the Multiplate Analyzer®️ test with ADP , at the same intervals of the analyzes that will be performed with the ADP.
|
4 Years
|
Platelet aggregation using ASPI at 30 (± 5) days after study therapy
Time Frame: 4 Years
|
Compare between the dapagliflozin and placebo groups: platelet aggregability at 30 (± 5) days after study therapy by the Multiplate Analyzer®️ test with ASPI, at the same intervals of the analyzes that will be performed with the ADP.
|
4 Years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Analyze the primary objective of the study in the following pre-specified subgroups:
Time Frame: 4 Years
|
|
4 Years
|
Collaborators and Investigators
Sponsor
Investigators
- Study Director: Jose JN Nicolu, University of Sao Paulo
Publications and helpful links
General Publications
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- Jackson AM, Dewan P, Anand IS, Belohlavek J, Bengtsson O, de Boer RA, Bohm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukat A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Kober L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez FA, O'Meara E, Sabatine MS, Sjostrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray JJV. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation. 2020 Sep 15;142(11):1040-1054. doi: 10.1161/CIRCULATIONAHA.120.047077. Epub 2020 Jul 16. Erratum In: Circulation. 2020 Nov 17;142(20):e369.
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Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Ischemia
- Pathologic Processes
- Necrosis
- Myocardial Ischemia
- Heart Diseases
- Cardiovascular Diseases
- Vascular Diseases
- Disease
- Myocardial Infarction
- Infarction
- Syndrome
- Acute Coronary Syndrome
- Ventricular Dysfunction
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Sodium-Glucose Transporter 2 Inhibitors
- Dapagliflozin
Other Study ID Numbers
- SDC 4620/17/120
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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