Clinical trial NCT06082063: Multifactorial Intervention to Reduce Cardiovascular Disease in Type 1 Diabetes
Official title: Multifactorial Intervention to Reduce Cardiovascular Disease in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cardiovascular Diseases
Heart Failure
Type 1 Diabetes
Kidney Failure
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Steno Diabetes Center Nordjylland
name: Steno Diabetes Center Odense
name: Slagelse Hospital
name: Nykøbing Falster County Hospital
name: Zealand University Hospital
name: Hillerod Hospital, Denmark
name: Rigshospitalet, Denmark
name: Hvidovre University Hospital
name: Regionshospitalet Viborg, Skive
name: Randers Regional Hospital
name: Herning Hospital
name: Esbjerg Hospital - University Hospital of Southern Denmark
name: Regionshospitalet Silkeborg
name: Bispebjerg Hospital
name: Regionshospitalet Horsens
First posted: 2023-10-13
Enrollment: 2000
Sex: ALL
Minimum age (years): 40
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study uses a PROBE design (prospective, cluster-randomized, open, blinded endpoint evaluation). The study is a superiority trial.
Primary purpose: TREATMENT

Brief summary: A prospective, randomised, open-labelled, multi-center study. The aim of the Steno 1 study is to test multifactorial intervention in individuals with type 1 diabetes at high risk of CVD with ambitious treatment targets. We will include 2000 participants. Follow-up is 5 years.

Detailed description: Background: Individuals with type 1 diabetes (T1D) are at high risk for cardiovascular disease (CVD). Even with optimal glycemic control, the risk is doubled compared to healthy individuals. Treatment of type 2 diabetes (T2D) is based on multifactorial intervention (MFI). The development of new drug classes has had profound impact on treatment guidelines through a documented reduction in mortality and morbidity in individuals with T2D. MFI acknowledges the need for control and interventions directed towards several risk factors for CVD, and not focus merely on glucose levels. A fundamental change in risk management with a strong focus on MFIs to lower CVD risk in individuals with T1D and comorbidity of CVD, CKD, HF or obesity, has the potential to improve morbidity and survival in T1D.

Objective: The aim of the Steno 1 study is to test MFI in individuals with T1D at high risk of CVD with ambitious treatment targets. We hypothesize, that the MFI reduces major adverse cardiovascular endpoints (MACE) hospitalization for heart failure (HHF), kidney failure and mortality.

Design: This study uses a PROBE design (prospective, cluster-randomized, open, blinded endpoint evaluation), as it will not be possible to mask the MFI. The study is a superiority trial.

Patient population: High-risk individuals with T1D of \>10 years duration (\>40 years of age with presence of either CKD, CVD, HF, obesity or a \>10% 5-year CVD risk determined by the Steno T1 Risk Engine). Participants are recruited from Steno Diabetes Centres or partner clinics.

Randomization: There will be formed three clusters (large patient pool, intermediate- and small). Within each cluster, participating centers will be randomised to either group A or group B. Group A will receive current guideline-recommended standard of care and group B will receive the multifactorial risk based intensive therapy. Participants are allocated to centers based on geography and not based on phenotype.

Intervention: For the intensively treated group, the MFI will be determined by the risk profile and risk markers of each individual and the participants will be allocated to Semaglutide, sotagliflozin, finerenone, ezetimibe and/ or PCSK9-inhibitors. The intervention will also comprise more ambitious treatment targets for blood pressure and lipid levels. In addition, all participants will take aspirin 75 mg OD.

Endpoints: The primary endpoint is to determine whether MFI is superior to standard care with respect to MACE+HHF (composite of time to first non-fatal myocardial infarction, first non-fatal stroke, cardiovascular death or first hospitalization for heart failure). Secondary endpoints are to determine whether MFI is superior to standard care with respect to all-cause mortality, a composite endpoint of renal function (end-stage kidney disease (ESKD) (dialysis, renal death, transplantation) or \>50% sustained decline in eGFR) compared to standard of care and to determine whether MFI including the use of SGLT2i and GLP1RA leads to an increased frequency of diabetic ketoacidosis compared to standard of care.

Eligibility criteria: Inclusion Criteria:

1. Given written informed consent
2. Male or female patients ≥40 years old with type 1 diabetes (diagnosis before age 30 with insulin from onset or if diagnosis after 30 years of age insulin from onset and DKA or positive autoantibodies ( in accordance with local guidelines)) during \>10 years.
3. Presence of chronic kidney disease (UACR \>30 mg/g or eGFR \< 60 ml/min/1.73 m2) OR history of ischemic heart disease (previous myocardial infarction, stroke or angina) OR history of heart failure OR obesity grade 2 and 3 (BMI\>35 kg/m2) OR 10-year CVD risk \>10% according to Steno Type 1 Risk Engine.
4. Fertile females must use highly efficient chemical, hormonal and mechanical contraceptives during the whole study and at least 2 months after cessation of study drug. The following contraceptive methods are approved: IUD or hormonal contraception that inhibits ovulation, i.e. pills, implantations, transdermal patches, vaginal ring or depot injection. Alternatively, be in menopause (i.e. must not have had regular menstrual bleeding for at least one year), have undergone bilateral oophorectomy or have been surgically sterilized or hysterectomised at least 12 months prior to screening. Fertile participants will be pregnancy tested every six months with urine HCG.
5. Ability to communicate with the investigator and understand informed consent.

Exclusion Criteria:

1. Type 2 diabetes, MODY, secondary diabetes.
2. History of pancreatitis.
3. Body mass index \< 18.5 kg/m2
4. Females of childbearing potential who are pregnant, breast-feeding, intend to become pregnant or are not using adequate contraceptive methods.
5. Known or suspected abuse of alcohol or recreational drugs.
6. Participant in another intervention study.
7. CKD stage 5.

Primary outcomes:
measure: MACE + HHF
timeFrame: 5 years
Secondary outcomes:
measure: All-cause mortality
timeFrame: 5 years
measure: Renal function
timeFrame: 5 years
measure: Diabetic ketoacidosis, safety
timeFrame: 5 years
Other outcomes:
measure: Indivudual components of the primary endpoint
timeFrame: 5 years
measure: Lower extremity amputations
timeFrame: 5 years
measure: Progression of retinopathy
timeFrame: 5 years
measure: Reduction in kidney function
timeFrame: 5 years
measure: EQ5D questionnaire
timeFrame: 5 years
measure: 5- and 10-year cardiovascular risk as assessed using the Steno T1 Risk Engine
timeFrame: 5 years
measure: Urinary albumin to creatinine ratio (UACR)
timeFrame: 5 years
measure: Decline in eGFR
timeFrame: 5 years
measure: HbA1c
timeFrame: 5 years
measure: LDL cholesteerol
timeFrame: 5 years
measure: BMI
timeFrame: 5 years
measure: Biothesiometry
timeFrame: 5 years
measure: Diabetic ketoacidosis (DKA)
timeFrame: 5 years
measure: Long term risk of CVD events
timeFrame: 10 years
measure: Survival
timeFrame: 10 years
measure: Long term risk of ESKD
timeFrame: 10 years
measure: Long term risk of lower extremity amputations
timeFrame: 10 years
measure: Long term risk of DKA
timeFrame: 10 years
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Herlev
country: Denmark
facility: Steno Diabetes Center Copenhagen
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Peter Rossing, MD, DMSc, Proffessor
role: PRINCIPAL_INVESTIGATOR
References: