Clinical trial NCT03022344: DD2-Coronary Plaque Morphology and Plaque Progression
Official title: Coronary Plaque Morphology and Plaque Progression in Patients With Newly Diagnosed Type-2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Diabetes
Plaque
Atherosclerosis
Keywords: DD2 plaque study
Coronary plaque
Type-2 diabetes mellitus
Lead sponsor: Esbjerg Hospital - University Hospital of Southern Denmark
Sponsor class: OTHER
Collaborators: name: The Danish Diabetes Academy supported by the Novo Nordisk Foundation
name: University of Southern Denmark
name: Department of Regional Health Research - Center Southwest
name: Edith and Vagn Hedegaard Jensens Foundation
name: Karola Jørgensens Foundation and Foundation for Cardiology in Southwest Denmark.
First posted: 2017-01-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: However, there is only very sparse information regarding the atherosclerotic burden and cardiovascular biomarkers in the early stages of type-2 diabetes, as the vast majority of studies have concerned diabetes populations with more than 5 years average diabetes age or high-risk subgroups, who at inclusion already had atherosclerotic disease manifestations.

Consequently, this study aims on evaluating the occurrence of early-stage subclinical atherosclerosis in newly diagnosed type-2 diabetes with special emphasis on coronary plaque characteristics by modern imaging techniques. These findings will be compared to the functional status of various peripheral arterial segments and biomarkers in the cross-sectional part of this study. The 5-year follow-up study intends to describe relationships between these selected measures for general atherosclerotic involvement and the progression of the coronary atherosclerotic burden by contemporary techniques.

Detailed description: THE AIM

The objective of this study is to:

Study I: Compare the prevalence and complexity of coronary plaques in patients with newly discovered type-2 diabetes with a healthy control group matched for age and gender, as evaluated by coronary computed tomography angiography.

Study II: Describe the relationship between morphological, functional and biochemical estimates of arteriosclerosis in newly diagnosed type-2 diabetes.

Study III: Characterize the progression of coronary plaques in patients with newly discovered type-2 diabetes in a 5-year follow-up study.

DESIGN

"Coronary plaque morphology and plaque progression in patients with newly diagnosed type-2 diabetes mellitus" (DD2-plaque study) is a prospective cohort follow up study.

The inclusion phase will run for 2 years. The follow-up phase is 5 years from inclusion.

The DD2-plaque study (diabetic patient's cohort):

Recruitment in this cohort will take place in three ways:

1. From the "Danish centers for strategic research in type 2 diabetes" (DD2) - patients who agreed to be contacted for participation in a future study.
2. Direct from outpatient clinics in The Region of Southern. Patients will either be recruited through general practitioners or from outpatient clinics in The Region of Southern Denmark. The investigators expect to be able to include 100 asymptomatic patients with newly diagnosed type-2 diabetes.

Inclusion criteria

1. Newly diagnosed (\< 1 year) diabetes patients clinically classified as type-2 diabetes patients of both sex.
2. Age 18 +.

Exclusion criteria

1. Type 1 diabetes (or have age\<30 years and C-peptid\<300pmol/l and GAD-ab titer\> 20 IU/ml).
2. Renal insufficiency (GFR \< 45 or se-creatinine \>140 micromol/l).
3. BMI \> 35 kg/m2
4. Atrial fibrillation.
5. Life expectancy below 2 years.
6. Mental disease and/or misuse of alcohol or drugs that affects patient's ability to give informed consent.
7. Pregnancy at time of or planned at inclusion.
8. Patients with a history of prior atherothrombotic disease (including acute coronary syndromes, prior revascularization, ischemic stroke or peripheral arterial disease).

The DD2-plaque study (control patients cohort):

100 controls will be recruited from the general population by advertisement in the local press. Controls with cardiovascular disease (criteria consistent with those described for patients with type-2 diabetes) and type-2 diabetes (undiagnosed type-2 diabetes in this group was excluded by fasting plasma glucose and by an oral glucose tolerance test) will be excluded. In addition, exclusion criteria are also consistent with those described for patients with type-2 diabetes.

Longitudinal measurements will be done at the screening visit and after 5 years.

1. The proxy statement.
2. Participants will fill in a questionnaire concerning:

   * Cardiovascular and diabetes hereditary
   * Medication
   * Alcohol and drugs consumption
   * Smoking habits (current, prior and never smokers)
   * Family history (cardiac events or strokes for women \< 65 years of age and men \< 55 years of age in first generation relatives)
   * Medical history
3. Physical examination will include measurement of:

   * Height, weight, BMI.
   * Waist/hip ratio
   * ECG
4. Brachial blood pressure will be measured by oscillometric technics during 24 hours using TM-2430 (A\&D CO., LTD, Saitama, Japan) or BDM Mobil-O-Graph® NG Classic (IEM GmbH, Stolberg, Germany).
5. Blood samples: Procedures for handling and shipping samples is available in the trial master and at www.DD2.nu under "blodprøvetagning".

   An exception to these procedures are that the blood samples will be frozen at site and send on ice to the biobank.

   2 x 9 ml. containers with green lid (Li-hep) 2 x 2.7 ml. containers with blue lid (Na-citrat) 2 x 9 ml. containers with purple lid (EDTA) 2 x 4 ml. containers with purple/dark purple lid (EDTA) 2 x 3 ml. containers with pink lid (Fluoridcitrat) 2 x 9 ml. containers with brown lid (Serum)

   1 container for urine with yellow lid 10 ml of morning midstream urine will be sampled. Urine sticks will be used to rule out urinary tract infection. If this is present the urine should be resembled. A total of 73.4 ml + 10 ml of blood will be drawn.

   For a subset of patients the DD2 cohort registration and the baseline visit will take place in the same day. These patients will have 146.8 ml of blood drawn on the same day. Containers will be sent to the patients.
6. Biochemical analysis: total cholesterol, S-LDL-cholesterol, S-HDL-cholesterol and S-triglycerides, HbA1c, glucose, C-reactive protein, D-dimer, creatinin and fibrinogen. All analyses are performed at our local Dept. of Clinical Biochemistry.
7. All patients will undergone:

   Carotid intima media thickness (IMT) will be measured by B-mode ultrasound (Model IE33, Koninklijke Philips Electronics N.V, Eindhoven, The Netherlands) using a linear array transducer, L11-3 with a frequency up to 11 MHz.
8. Pulse wave velocity: Using sphygmocor (ArtCor, Sydney, Australia).
9. Ankle brachial index.
10. Albumin creatinine ratio
11. Coronary atherosclerosis is evaluated by measurement of calcium in the coronary arteries and by evaluation of coronary plaques using contrast enhanced cardiac CT. Coronary artery calcifications will be estimated by the Agatston score while the evaluation of coronary plaques will be performed by a dedicated plaque-analysis tool, Auto-Plaque.

STATISTICS

Sample size estimations are performed for comparison of calcium scoring between patients with type-2 diabetes and normal controls (Un-paired evaluation) and comparison of calcium scoring between type-2 diabetes patients at inclusion and at follow-up (Paired). From previous studies on calcium scoring in the Danish Risk Score Study cohort, the standard deviation, SD, on coronary calcification is known to be 32.7 UE (Agatston Score). It is supposed that SD in the diabetic patients is equal to the figure in controls. Under the assumptions that 15% will drop-out, a MIREDIF of 20 (twice the threshold for registering the occurrence of coronary calcification in the central West Danish Heart Registry, VDH), beta= 0, 1 and alfa= 0.02 (Planned comparative analysis of 2-3 plaque-components) it is calculated, that it is needed to include 41 patients in each group for the un-paired analyses and to follow 41 diabetic patients for 5 years (Paired analysis). It is supposed, that app. 40% of type-2 diabetes patients meet the age criteria (55+/-5 years or 65+/-5 years) for comparison with the background population, which means that app. 100 type-2 diabetes patients should be included in the DD2 plaque study.

Students T-test will be used for comparison of normally distributed continuous variables and the Mann-Whitney test will be used for comparison of continuous variables that are not normally distributed. The χ2- test is performed for comparison of dichotomous variables. Continuous variables are presented as either mean or standard deviation or median and interquartile range. P-values \<0.05 will be considered statistically significant. Stepwise multivariate logistic regression will be performed for analysis of which factors are associated with coronary atherosclerosis using either presence coronary artery calcification or other plaque variables as dependant variables.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed (\< 1 year) diabetes patients clinically classified as type-2 diabetes patients of both sex.
* Age 18 +.

Exclusion Criteria:

* Type 1 diabetes (or have age\<30 years and C-peptid\<300pmol/l and GAD-ab titer\> 20 IU/ml).
* Renal insufficiency (GFR \< 45 or se-creatinine \>140 micromol/l).
* BMI \> 35.
* Atrial fibrillation.
* Life expectancy below 2 years.
* Mental disease and/or misuse of alcohol or drugs that affects patient's ability to give informed consent.
* Pregnancy at time of or planned at inclusion.
* Patients with a history of prior atherothrombotic disease (including acute coronary syndromes, prior revascularization, ischemic stroke or peripheral arterial disease).

Primary outcomes:
measure: Progression of contrast enhanced cardiac CT in relation to baseline and follow-up cardiovascular risk factors and biomarkers.
timeFrame: 5 years
Secondary outcomes:
measure: Biochemical analysis in relation to contrast enhanced cardiac CT
timeFrame: 1 year
measure: Body mass index (kg/m2)
timeFrame: 1 year
measure: Carotid intima media thickness
timeFrame: 1 year
measure: Ankle brachial index
timeFrame: 1year
measure: waist hip ratio (m)
timeFrame: 1 year
measure: Blood pressure (mmHg)
timeFrame: 1 year
Other outcomes:
Locations:
city: Esbjerg
country: Denmark
facility: Sydvestjysk sygehus
Study officials:
References: