A multiarm, randomized, open label Clinical study comparing AntiatheroSClerotic efficacy of selected Antidiabetic agents in patients with coronary artery disease and preDiabetES. A randomised clinical trial (CASCADES)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Narodowy Instytut Kardiologii Stefana Kardynala Wyszynskiego Panstwowy Instytut Badawczy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

10 Jul 2025 → ongoing

Decision date (initial)

2024-03-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Diagnosis, Efficacy

To compare anti-atherosclerotic efficacy of treatment with oral GLP-1 agonist (semaglutide) vs SGLT-2 inhibitor (dapagliflozin), as compared to metformin, atop optimal dietand lifestyle modification-based therapy in patients with coronary artery disease (CAD) and prediabetes. The diagnosis of CAD will be defined as coronary atherosclerosis confirmed in contrast coronary computed tomography angiography (CCTA). The primary outcome is the effect of treatment to the coronary plaque progression/regression assessed in CCTA over the observation time of 24 months.

Conditions and MedDRA coding

Coronary Heart Disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age 18-80
2. Diagnosed coronary artery disease (coronary artery stenosis of at least 20% with a reference diameter of >2.5 mm detected in a coronary CT scan or after percutaneous coronary revascularization)
3. Core CT scan performed <3 months after inclusion in the study, of at least good quality
4. Prediabetes defined as fasting blood glucose 100-125 mg% or Hba1c 5.70 6.49% (measurement documented during the screening/randomization visit or within 30 days before the screening/randomization visit) or a documented positive result of the oral stress test glucose (fasting blood glucose 100-125 mg% and 140-199 mg% 2 hours after an oral load of 75 g of glucose) performed within 30 days before the screening/randomization visit
5. Stable treatment and control of cardiovascular risk factors, including dietary and lifestyle management, for at least 4 weeks.
6. Willingness and ability to provide informed consent for participation in the study.
7. Capability and willingness, in the opinion of the investigator, to comply with all study requirements

Exclusion criteria 25

1. Severe valvular disease
2. History of pancreatitis or active pancreatitis
3. Body mass index (BMI) >40 kg/m2
4. A clinical condition requiring surgical treatment of coronary artery disease
5. Pregnancy/lactation
6. Other known contraindications to treatment with metformin, dapagliflozin or semaglutide
7. Condition after coronary artery bypass surgery
8. Diagnosed diabetes or Hba1c>6.5 mg% at the time of screening/randomization visit
9. Other serious illnesses requiring planned hospital treatment during the examination
10. Severe diseases of the musculoskeletal system requiring specific rehabilitation recommendations
11. Decompensated heart failure
12. Lack of consent to participate in the study
13. Severe arrhythmia/unexplained loss of consciousness
14. Other contraindications to physical exercise
15. Presence of an artificial valve, cardiac pacing system or other implantable device (e.g. cardioverter-defibrillator)
16. Use of glucose-lowering medications other than metformin
17. Use of weight loss medications
18. Condition after bariatric surgery
19. Diagnosed liver disease or ALT, AST greater than three times the upper limit of normal at the screening visit
20. Decompensated hyperthyroidism
21. History of anaphylactic shock after administration of iodine contrast
22. Chronic kidney disease (GFR <60 ml/min/1.73 m2)
23. Participation in another clinical trial
24. Medullary thyroid cancer
25. Pancreatic cancer

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The impact of GLP-1 analogue treatment on the progression of coronary artery disease (expressed as a change in the % change in the volume of non-calcified atherosclerotic plaque in CT assessed by coronary CT) in relation to routine treatment (intention-to-treat);
2. The impact of flozin treatment on the progression of coronary artery disease (expressed as a change in the % change in the volume of non-calcified atherosclerotic plaque at heart rate assessed in coronary CT) in relation to routine treatment (intention-to-treat);

Secondary endpoints 21

1. The effect of each of the tested drugs vs. the control group on the progression of coronary artery disease (expressed as a change in the % change in the volume of uncalcified atherosclerotic plaque in t.w. assessed in coronary CT) (as treated);
2. Comparison of the effect of semaglutide vs. flozin on the progression of coronary artery disease (expressed as a change in the % change in the volume of uncalcified atherosclerotic plaque at heart rate assessed by coronary CT scan)(intention to treat/as treated);
3. The effect of each of the tested drugs vs. the control group/comparison of the effect of semaglutide vs. flozin on the progression of coronary artery disease (expressed as a % change in the volume of the entire atherosclerotic plaque in t.w. assessed in coronary CT); (intention to treat/as treated)
4. The effect of each of the tested drugs vs. the control group/comparison of the effect of semaglutide vs. flozin on the progression of coronary artery disease (expressed as a % change in the volume of individual components of the atherosclerotic plaque in CT assessed in coronary CT); (intention to treat/as treated);
5. Assessment of the effect of each of the studied drugs vs. the control group/comparison of the effect of semaglutide vs. flozin on the progression of coronary artery disease (expressed as the conversion of non-calcified plaque into calcified plaque in CT assessed in coronary CT); (intention to treat/as treated);
6. Assessment of the impact of individual tested drugs vs. the control group/comparison of the effect of semaglutide vs. flozin on the risk of SN expressed as the dynamics of high-risk features 1. Change in the number of high-risk atherosclerotic lesions defined as the presence of at least 2 high-risk features among: spotty calcifications, low attenuation plaque, i.e. plaque density < 30 HU, positive remodeling, napkin ring sign assessed in koro-CT 2. Change in Pericoronary FAI assessed in koro-CT
7. Evaluation of weight change, including body composition, in patients treated with semaglutide vs. patients treated with flozin - weight - body mass index (BMI). - fat mass - skeletal muscle mass - Fat-To-Muscle Ratio (FMR). - Body Cell Mass (BCM) - Visceral Fat Area (VFA
8. Evaluation of waist-to-hip index (WHI) change in patients treated with semaglutide vs. patients treated with phlorizin
9. Evaluation of change in inflammatory parameters in patients treated with semaglutide vs. patients treated with phlorizin. Concentration of hsCRP
10. Evaluation of change in lipid levels in patients treated with semaglutide vs. patients treated with flozin. - total cholesterol - low-density lipoproteins (LDL) - high-density lipoproteins (HDL) - non-HDL cholesterol - triglycerides - lipoprotein A
11. Evaluation of change in the percentage of glycated hemoglobin (HBA1c) in patients treated with semaglutide vs. patients treated with flozin
12. Evaluation of change in the percentage of patients with normal blood pressure in patients treated with semaglutide vs. patients treated with flozin. Change in percentage of patients with normal blood pressure defined as systolic pressure <140 mmHg and diastolic pressure <90 mmHg
13. Change in the percentage of patients who smoke tobacco
14. Evaluation of compliance with physical activity recommendations in patients treated with semaglutide vs. patients treated with flozin. - Percentage of patients classified in the "high" physical activity category; - Percentage of patients classified in the "sufficient" physical activity category; - Percentage of patients classified in the "insufficient" physical activity category
15. Evaluation of dietary compliance in patients treated with semaglutide vs. patients treated with flozin. Change in the DASH Index between baseline and end of study
16. Diagnosis of diabetes based on the criteria of the Polish Diabetes Association
17. Evaluation of the onset of heart failure requiring hospitalization. Hospitalization for heart failure.
18. Number of unplanned hospitalizations
19. Number of major cardiovascular events and strokes (MACCE: death/myocardial infarction/revascularization/stroke) separately and combined.
20. Homeostatic Model Change Assessment – Insulin Resistance (HOMA-IR).
21. Assessment of changes in the concentration of selected oxidative stress markers.Change in concentration of selected oxidative stress markers: catalase, superoxide dismutase (SOD), Oxygen Radical Absorbance Capacity (ORAC), total antioxidant capacity (TAC)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Narodowy Instytut Kardiologii Stefana Kardynala Wyszynskiego Panstwowy Instytut Badawczy

Sponsor organisation

Narodowy Instytut Kardiologii Stefana Kardynala Wyszynskiego Panstwowy Instytut Badawczy

Address

Alpejska 42

City

Warsaw

Postcode

04-628

Country

Poland

Scientific contact point

Organisation

Narodowy Instytut Kardiologii Stefana Kardynala Wyszynskiego Panstwowy Instytut Badawczy

Contact name

Principal Investigator

Public contact point

Organisation

Narodowy Instytut Kardiologii Stefana Kardynala Wyszynskiego Panstwowy Instytut Badawczy

Contact name

Principal Investigator

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications