Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial

Study Overview
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Brief Summary
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The purpose of this study is to determine whether use of blood pressure lowering drugs, Angiotensin converting enzyme inhibitors (ACEIs) and blood fat (lipid) lowering drugs (statins) may have a place in the treatment of adolescents with diabetes and can help reduce serious long-term health problems in this population.

Detailed Description
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Subjects will be recruited from a pre-screened population of 3,000 young people with T1D aged 10 to 16 years based on assessment of risk for future CVD and DN. They will be randomised to a 2 x 2 factorial design contrasting the effects of ACEI, statins, or combination therapy to placebo over a maximum four year treatment period. Minimisation of variation in albumin excretion rate, gender, age, diabetes duration, HbA1c, total cholesterol and centre site will be undertaken at randomisation. Analysis of the primary endpoint, change in albumin excretion will be undertaken on an intention to treat basis. Secondary analyses will be undertaken on the basis of 'as treated' allowing for variance in compliance and allowing for subjects who show substantial change in HbA1c levels. Additional analyses will be undertaken to assess changes in the secondary objectives and to assess the overall effect of the intervention on quality of life and health economics.

Official Title
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Randomised, Double Blind, Placebo Controlled Trial of Angiotensin Converting Enzyme Inhibitors and Statins in the Prevention of Long Term Complications in Young People With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Statin
* Drug: ACE inhibitor
* Drug: Placebo
* Drug: Combination therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 10 to 16 years. T1D diagnosed for more than 1 year or C-peptide negative. Centralised assessment of ACR based on six early morning urines deemed to be in upper tertile for risk after adjustment for age, gender, age at diagnosis and duration of disease. Exclusion Criteria: Non T1D, i.e. type 2 diabetes, insulin dependent diabetes related to monogenic disease, secondary diabetes. ACR based on six early morning urines deemed to be at low risk for subsequent development of CVD or DN. Pregnancy or unwillingness to comply with contraceptive advice and regular pregnancy testing throughout the trial. Breast feeding Severe hyperlipidaemia and family history data to support diagnosis of familial hypercholesterolaemia. Established hypertension unrelated to DN. Prior exposure to the investigational products, statins and ACEI. Unwillingness/inability to comply with the study protocol. Other co-morbidities considered unsuitable by the investigator (excluding treated hypothyroidism and coeliac disease). Proliferative retinopathy. Renal disease not associated with Type 1 Diabetes.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Statin<br>Participants receive active statin and placebo ACE Inhibitor | Drug: Statin<br>* 10mg daily for a minimum period of 2 years<br>* Other names: Atorvastatin;|
| Active Comparator: Angiotensin-converting enzyme inhibitor<br>Participants receive active ACE Inhibitor and placebo statin | Drug: ACE inhibitor<br>* Starting dose of 5mg daily rising after 14 days to 10mg daily providing it is well tolerated for a minimum period of 2 years.<br>* Other names: Quinapril;|
| Placebo Comparator: Placebo<br>Participants receive placebo ACE Inhibitor and placebo statin | Drug: Placebo<br>* Participants receive statin placebo and ACEI placebo<br>|
| Other: Combination therapy<br>Participants receive both active ACE Inhibitor and active Statin | Drug: Combination therapy<br>* Participants receive both active statin and active ACEI. Dose for Statins is 10mg daily. Dosing for ACEI starts at 5mg daily rising to 10mg after 14 days providing it is well tolerated. Both interventions last for a minimum of 2 years.<br>* Other names: Quinapril;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Albumin creatinine ratio | The area under the curve over time of log ACR per year, with standardisation for gender, age and duration of disease | 2-4 years treatment duration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in CVD risk markers | Changes in measures of: cIMT, FMD, EndoPAT and PWV between baseline and the end of intervention period; arterial BP, lipids and other lipoproteins, CVD risk markers (hsCRP and ADMA), assessed every 6 months during the intervention period. | 2-4 yrs treatment duration | 
| Changes in glomerular filtration rate (GFR) | Changes in measures of GFR (plasma SDMA, creatinine adn cystatin C levels) assessed every 6 months during intervention period. | 2-4 years treatment duration | 
| Retinopathy | Changes in retinopathy scores and retinal microvascular structure (arteriolar or venular dilation, vascular fractile dimension, branching and tortuosity) assessed annually | 2-4 years treatment duration | 
| Quality of Life and Health Economics | Changes in quality of life measures and resource usage | 2-4 years treatment duration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescence