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| Name | Class |
|---|---|
| Singapore General Hospital | OTHER |
| Mackay Memorial Hospital | OTHER |
| National Taiwan University Hospital | OTHER |
| Peking University People's Hospital |
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The aim of this study is to identify patients with DM at high risk of CVD using elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (>125pg/mL), and (2) intensify therapy using renin-angiotensin system (RAS) antagonists, beta-blockers and sodium glucose co-transporter-2 inhibitors (SGLT2i) for primary prevention of cardiovascular events in this high-risk DM population.
Rationale:
Cardiovascular events are the leading cause of death among patients with diabetes. Early identification of high-risk diabetic (DM) patients for intensification of preventive therapy may prevent cardiovascular events.
Aims:
Among biomarker (N-terminal pro-B-type natriuretic peptide, NT-proBNP)-identified high-risk type 2 DM patients without pre-existing cardiovascular disease, to test if intensive preventive therapy (high dose renin-angiotensin-aldosterone system inhibitors [RAASi], beta-blockade, sodium-glucose co-transporter 2 inhibitors [SGLT2i]) may be associated with reduced cardiovascular events compared to standard of care.
Design:
Prospective multinational randomized open-label, parallel group, active-controlled, two-arm, long-term morbidity and mortality trial involving 5 Asian regions (Singapore, Malaysia, China, Taiwan, India; estimated 6 sites each) with patients followed for 2 years.
Population:
Adults with type 2 DM without known cardiovascular disease (defined as known coronary stenosis > 70%, reduced left ventricular ejection fraction < 40%, or a history of myocardial infarction/coronary revascularization/heart failure hospitalization/stroke/prior non-traumatic lower limb amputation or angioplasty) and with NT-proBNP > 125 pg/mL
Duration:
The goal is to include approximately 2,400 patients. It is estimated that about 3,000 patients with NT-proBNP > 125pg/mL have to be screened. The screen failure rate, for reasons other than NT-proBNP, is anticipated to be approximately 20%. The observation period is planned to last for two years. However, the trial is event driven and will continue until predefined event rate is reached (see sample size calculation). The total trial duration is expected to last for four years (two years of recruitment and a two-year observation period after last patient in). Every patient will remain in the study for two years after randomization.
Visits:
Visit 1:
Pre- Screening
Patients who fulfil the first three pre-screening criteria will proceed for NT-proBNP Point-of-Care (POC) testing:
Full- Screening
Interim visits for the treatment group Visit 1-4 is mandatory for all patients, interim visits (between Visits 1-2) only for the intensive treatment group for up-titration of RAASi and beta-blockers and initiation/continuation of SGLT2i. The frequency is up to the treating physician and titration steps. A visit is not mandatory for each titration step.
Visit 2 (3 months ± 1 week)
Visit 3 (12 months ± 2 weeks)
Visit 4: End of Study (24 months ± 2 weeks)
Long-term follow-up (LTFU) (36 and 48 months ± 3 weeks)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intensive Treatment Group | Other | High dose of RAASi and beta-blockers (unless contraindicated) as well as preferential use of SGLT2i as per local drug label guidelines on top of standard therapy. |
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| Control Group | No Intervention | Standard therapy where the use of SGLT2i at randomization is not encouraged but RAASi and beta-blockers (except for maximal dosage) are allowed. Prescription or up-titration of the study drugs listed under Intensive Treatment is not encouraged. If investigators/treating physicians feel that further prescription or up-titration is required, a thorough justification is mandatory. Unless there is clinically irrefutable reason, every attempt should be made to use other blood pressure lowering drugs than RAASi or beta-blockers, as well as glucose lowering drugs than SGLT2i, in the control group. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Renin-angiotensin-aldosterone system inhibitors | Drug | Research participants in the intensive therapy arm should be strongly encouraged to follow the intensive treatment strategy. Every attempt should be made to up-titrate RAS-antagonists and beta-blockers (max dosage, unless contraindicated) as well as preferentially use SGLT2i (standard dosage, as required) throughout the trial. |
| Measure | Description | Time Frame |
|---|---|---|
| Combined endpoint based on the first occurrence of cardiovascular death or major adverse cardiovascular event | Stroke/myocardial infarction/heart failures events | 48 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Serene Ng Miss | Contact | 67042232 | serene.ng.b.l@singhealth.com.sg | |
| Salma Asali Miss | Contact | 67042303 | asali.salma@singhealth.com.sg |
| Name | Affiliation | Role |
|---|---|---|
| Carolyn Lam Prof | National Heart Centre Singapore | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Singapore General Hospital (SGH) | Recruiting | Singapore | 169608 | Singapore |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D002318 | Cardiovascular Diseases |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000806 | Angiotensin-Converting Enzyme Inhibitors |
| D057911 | Angiotensin Receptor Antagonists |
| D000319 | Adrenergic beta-Antagonists |
| D000077203 | Sodium-Glucose Transporter 2 Inhibitors |
| ID | Term |
|---|---|
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
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| OTHER |
| Medanta, The Medicity, India | OTHER |
| Public Health Foundation of India | OTHER |
| Putrajaya Hospital, Malaysia | UNKNOWN |
| Universiti Teknologi Mara | OTHER |
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| Beta blocker | Drug | Research participants in the intensive therapy arm should be strongly encouraged to follow the intensive treatment strategy. Every attempt should be made to up-titrate RAS-antagonists and beta-blockers (max dosage, unless contraindicated) as well as preferentially use SGLT2i (standard dosage, as required) throughout the trial. |
|
| SGLT2 Inhibitor - Sodium Glucose Cotransporter Subtype 2 Inhibitor Product | Drug | Research participants in the intensive therapy arm should be strongly encouraged to follow the intensive treatment strategy. Every attempt should be made to up-titrate RAS-antagonists and beta-blockers (max dosage, unless contraindicated) as well as preferentially use SGLT2i (standard dosage, as required) throughout the trial. |
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| D020164 | Chemical Actions and Uses |
| D018674 | Adrenergic Antagonists |
| D018663 | Adrenergic Agents |
| D018377 | Neurotransmitter Agents |
| D045505 | Physiological Effects of Drugs |
| D007004 | Hypoglycemic Agents |