Ignite Creation Date:
2024-05-06 @ 8:12 PM
Last Modification Date:
2024-10-26 @ 3:22 PM
Study NCT ID:
NCT06286878
Status:
RECRUITING
Last Update Posted:
2024-02-29
First Post:
2022-01-04
Brief Title:
Pleiotropic Effects of Dapagliflozin in Patients With Acute Coronary Syndromes
Sponsor:
University of Sao Paulo
Organization:
University of Sao Paulo
Study Overview
Official Title:
Pleiotropic Effects of Dapagliflozin in Patients With Acute Coronary Syndromes
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Type 2 diabetes mellitus T2DM is one of the most important risk factors for atherosclerotic heart disease Strategies focused solely on glycemic control have failed to demonstrate vascular events reduction in this population On the other hand new antidiabetic drugs recently have demonstrated significant decrease of cardiovascular mortality raising the hypothesis that possible effects beyond glycemia control could explain this benefit Aim This study is intended to evaluate possible pleiothropic effects of dapaglifozin a SGLT-2 sodium glucose cotransporter 2 inhibitor in individuals admitted with a diagnosis of Acute Myocardial Infarction AMI Methods This is a prospective randomized double-blind placebo controlled trial Individuals presenting with AMI whithin the first seven days of evolution will be randomized to dapaglifozin or placebo The investigatorss goal is to analyze platelet aggregability 48 hours after randomization primary endpoint as well as glycemic control cardiac biomarkers corrected QT interval electrocardiographic analysis autonomic modulation through spectral analysis of the RR interval and inflammatory biomarkers at inclusion and 30 days after starting study drug secondary endpoints Sample size calculation resulted in 80 individuals 40 per group Expected results This study will seek to aggregate new insights to the current knowledge about this new antidiabetic drug class Previous randomized clinical trials have demonstrated that SGLT-2 inhibitors significantly reduced the composite endpoint of cardiovascular death AMI or stroke as well as Heart Failure HF hospitalization Therefore this study is supposed to clarify possible mechanisms that could explain these results aforementioned
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 dapagliflozinplacebo 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
1 compare B-type natriuretic peptide BNP and troponin biomarkers between dapagliflozin and placebo groups at 30 5 days after randomization
2 Correlation between levels of ultrasensitive C-reactive protein us-CRP and platelet aggregability
3 Compare hsCRP levels in dapagliflozin and placebo groups at 30 5 days
4 Compare the size of the AMI assessed by peak CK-MB mass and troponin in the dapagliflozin and placebo groups
5 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 mgdl and severe hypoglycemia glycemia below 40 mgdl during hospitalization calculation of the average insulin used during 48 hours after randomization
6 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
7 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 002 dextran sulfate 50000 MW and 03 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
8 Compare the diuresis obtained during 48 hours after randomization in the Coronary Intensive Care Unit in the dapagliflozin and placebo groups
9 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
1 obese BMI 30 Kgm2 and non-obese
2 male and female sex
3 elderly 65 years and non-elderly
4 smokers and non-smokers
5 time since diagnosis of diabetes or 10 years
6 basal blood glucose 125 mgdL and 125 mgdL
7 glycated hemoglobin HbA1c 90 and 90
8 use of clopidogrel or ticagrelor
9 treatment performed for the acute coronary event percutaneous coronary intervention or clinical treatment
10 ejection fraction 40 and 40
11 Diabetics and non-diabetics
12 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 institutions 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 mgdL 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 mgdL will receive the intravenous insulin protocol also in accordance with the institutional routines summary belowThe HbA1c target will be of 75
Inclusion criteria
1 Men and women aged 18 years women of childbearing age must have a negative pregnancy test
2 In routine use of dual antiplatelet therapy with ASA plus an ADP receptor antagonist according to institutional routines
3 Acute myocardial infarction with or without ST-segment elevation STEMINSTEMI defined according to the 4th Universal Definition of Acute Myocardial Infarction with up to 7 days of evolution from the onset of symptoms
4 Signature of the Free and Informed Consent Term
Exclusion criteria
1 Current or recent within 24 months treatment with pioglitazone andor use of pioglitazone for a total of 2 years or more during a lifetime at any time
2 Current or recent within 12 months treatment with rosiglitazone
3 Chronic use 15 consecutive days of any SGLT2 inhibitor at the time of hospitalization
4 Chronic use 30 consecutive days with an oral steroid at a dose equivalent to prednisolone 10 mg eg betamethasone 12 mg dexamethasone 15 mg hydrocortisone 40 mg per day
5 systolic BP 180 or diastolic BP 100 mmHg at randomization
6 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
7 History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
8 History of any other malignancy within 5 years with the exception of skin cancers successfully treated non-melanoma
9 Chronic cystitis andor recurrent urinary tract infections 3 or more in the last year
10 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 IIarecurrent ventricular arrhythmias or non cardiovascular eg active malignancy other than basal cell carcinoma cirrhosis chronic lung disease severe autoimmune disease
11 Pregnancy or lactation
12 Active participation in another clinical trial
13 Patients with septic shock or severe glycemic decompensation requiring the use of IV insulin at the time of randomization
14 TGPALTAlanine Amino Transferase 3x the upper limit of normality ULN or total bilirubin 25 x ULN
15 Estimated glomerular filtration rate GFR 45 mlmin173m² calculated by MDRD or kidney transplant
16 Known thrombophilias or thrombocytosis
17 Blood dyscrasias or any disorder that causes hemolysis previously known
18 Hematological abnormality Hb 11gdL or 17gdL leukocytes 4500mm³ or 11000mm³ platelet count 150000mm³ or 450000mm³
Casuistry To calculate the sample size the following assumptions were taken into account consideration
1 Aggregability of 48261 23182 area under the curve AUC in a previous study of patients with ACS using dual antiaggregation therapy with AAS and clopidogrel
2 estimated difference of 33 less in the dapagliflozin group 32335 23182 AUC
3 alpha of 005 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
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 dapagliflozinplacebo 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
1 compare B-type natriuretic peptide BNP and troponin biomarkers between dapagliflozin and placebo groups at 30 5 days after randomization
2 Correlation between levels of ultrasensitive C-reactive protein us-CRP and platelet aggregability
3 Compare hsCRP levels in dapagliflozin and placebo groups at 30 5 days
4 Compare the size of the AMI assessed by peak CK-MB mass and troponin in the dapagliflozin and placebo groups
5 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 mgdl and severe hypoglycemia glycemia below 40 mgdl during hospitalization calculation of the average insulin used during 48 hours after randomization
6 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
7 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 002 dextran sulfate 50000 MW and 03 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
8 Compare the diuresis obtained during 48 hours after randomization in the Coronary Intensive Care Unit in the dapagliflozin and placebo groups
9 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
1 obese BMI 30 Kgm2 and non-obese
2 male and female sex
3 elderly 65 years and non-elderly
4 smokers and non-smokers
5 time since diagnosis of diabetes or 10 years
6 basal blood glucose 125 mgdL and 125 mgdL
7 glycated hemoglobin HbA1c 90 and 90
8 use of clopidogrel or ticagrelor
9 treatment performed for the acute coronary event percutaneous coronary intervention or clinical treatment
10 ejection fraction 40 and 40
11 Diabetics and non-diabetics
12 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 institutions 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 mgdL 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 mgdL will receive the intravenous insulin protocol also in accordance with the institutional routines summary belowThe HbA1c target will be of 75
Inclusion criteria
1 Men and women aged 18 years women of childbearing age must have a negative pregnancy test
2 In routine use of dual antiplatelet therapy with ASA plus an ADP receptor antagonist according to institutional routines
3 Acute myocardial infarction with or without ST-segment elevation STEMINSTEMI defined according to the 4th Universal Definition of Acute Myocardial Infarction with up to 7 days of evolution from the onset of symptoms
4 Signature of the Free and Informed Consent Term
Exclusion criteria
1 Current or recent within 24 months treatment with pioglitazone andor use of pioglitazone for a total of 2 years or more during a lifetime at any time
2 Current or recent within 12 months treatment with rosiglitazone
3 Chronic use 15 consecutive days of any SGLT2 inhibitor at the time of hospitalization
4 Chronic use 30 consecutive days with an oral steroid at a dose equivalent to prednisolone 10 mg eg betamethasone 12 mg dexamethasone 15 mg hydrocortisone 40 mg per day
5 systolic BP 180 or diastolic BP 100 mmHg at randomization
6 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
7 History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
8 History of any other malignancy within 5 years with the exception of skin cancers successfully treated non-melanoma
9 Chronic cystitis andor recurrent urinary tract infections 3 or more in the last year
10 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 IIarecurrent ventricular arrhythmias or non cardiovascular eg active malignancy other than basal cell carcinoma cirrhosis chronic lung disease severe autoimmune disease
11 Pregnancy or lactation
12 Active participation in another clinical trial
13 Patients with septic shock or severe glycemic decompensation requiring the use of IV insulin at the time of randomization
14 TGPALTAlanine Amino Transferase 3x the upper limit of normality ULN or total bilirubin 25 x ULN
15 Estimated glomerular filtration rate GFR 45 mlmin173m² calculated by MDRD or kidney transplant
16 Known thrombophilias or thrombocytosis
17 Blood dyscrasias or any disorder that causes hemolysis previously known
18 Hematological abnormality Hb 11gdL or 17gdL leukocytes 4500mm³ or 11000mm³ platelet count 150000mm³ or 450000mm³
Casuistry To calculate the sample size the following assumptions were taken into account consideration
1 Aggregability of 48261 23182 area under the curve AUC in a previous study of patients with ACS using dual antiaggregation therapy with AAS and clopidogrel
2 estimated difference of 33 less in the dapagliflozin group 32335 23182 AUC
3 alpha of 005 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None