Adolescent type 1 diabetes cardio-renal intervention trial
| ISRCTN | ISRCTN91419926 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN91419926 |
| Secondary identifying numbers | RP06 |
- Submission date
- 30/07/2007
- Registration date
- 03/10/2007
- Last edited
- 21/02/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Type 1 diabetes mellitus (T1DM) is a lifelong condition where a person is unable to prevent their blood sugar (glucose) levels from becoming too high. When a person is suffering from TD1M, the body is unable to produce a hormone called insulin, which is responsible for breaking down glucose and turning it into energy. The only effective way of treating T1DM is by regularly injecting the insulin that the body is unable to produce. It is very important that sufferers take their insulin regularly, as otherwise it can lead to serious complications, such as damage to the heart and blood vessels (cardiovascular system) and kidneys (renal system). The risk of these complications seems to be higher in people diagnosed early in life, during childhood and adolescence when compared to people diagnosed during adulthood. The Adolescent type 1 diabetes cardio-renal intervention study (AdDIT) is a study aiming to evaluate drugs acting on blood pressure (ACE inhibitors) and lipid (fat) levels (statins) in adolescents with T1DM at risk of developing cardiovascular and renal complications. The AdDIT follow up study aims to look at the long term risk of developing these complications in adolescents who took part in the AdDIT study.
Who can participate?
Adolescents aged 10-16 who have type 1 diabetes and are at risk of developing cardiovascular or kidney disease.
What does the study involve?
In the AdDIT study, participants are randomly allocated to one of four groups who receive different drugs for 2-4 years. Those in the first group receive a statin (cholesterol-lowering drug) and placebo (dummy drug), those in the second receive a statin and an ACE inhibitor (blood pressure-lowering drug), those in the third group receive an ACE inhibitor and a placebo, and those in the fourth group receive two placebos. For all participants, at the start of the study and then yearly until the end, samples are taken to measure for signs of kidney or cardiovascular disease.
In the AdDIT follow up study, participants from the AdDIT study are followed up for a further five years in order to find out whether the drugs used are able to protect against development of cardiovascular kidney disease in the long-term.
What are the possible benefits and risks of participating?
There are no direct benefits for AdDIT participants, but the study results will help in the future in improving the management of type 1 diabetes in young people with type 1 diabetes. During the AdDIt trial period study participants mayexperience some of the sides effects associated with statins or ACE inhibitors, but close monitoring will reduce risk of any relevant risk. There are no notable benefits or risks associated with the AdDIt follow up study.
Where is the study run from?
1. University of Cambridge Addenbrookes Hospital (UK)
2. Hospital for Children, Perth (Australia)
3. The Hospital for Sick Children, Totonto (Canada)
When is the study starting and how long is it expected to run for?
August 2008 to November 2016 (AdDIT)
August 2016 to March 2022 (AdDIT follow up)
Who is funding the study?
1. Diabetes UK (UK)
2. Juvenile Diabetes Research Foundation (UK)
3. British Heart Foundation (UK)
Who is the main contact?
1. Professor David Dunger (AdDIT)
2. Ms Rowena Weighell (AdDIT follow up)
Contact information
Scientific
University Department of Paediatrics
Box 116, Addenbrooke's Hospital
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 1223 336886 |
|---|---|
| dbd25@cam.ac.uk |
Scientific
Department of Paediatrics
University of Cambridge
Box 116, Level 8
Addenbrooke’s Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 1223 762944 |
|---|---|
| rw564@medschl.cam.ac.uk |
Study information
| Study design | AdDIT: Randomised controlled double blind clinical trial AdDIT follow up: Multi-centre multi-national longitudinal observational study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Adolescent type 1 diabetes cardio-renal intervention trial |
| Study acronym | Adolescent Diabetes Intervention Trial (AdDIT) |
| Study objectives | AdDIT: To determine whether intervention with Angiotensin Converting Enzyme Inhibitors (ACEI), statins, or a combination of both, when compared with placebo, will: 1. Reduce albumin excretion as assessed by six monthly measurement of Albumin/Creatinine Ratio (ACR) in three early morning urines 2. Reduce the incidence of Microalbuminuria (MA) (ACR log mean greater than 3.5 mg/mmol (males) or greater than 4 mg/mmol [females] in two out of three urines) at the end of the study period 3. Reduce the incidence of MA during the six month run out period following the completion of intervention phase AdDIT follow up: The primary study outcomes will be to assess, at the end of the 5-year follow-up period the prevalence of vascular complications. Specifically: 1. The prevalence of Micro/macroalbuminuria 2. The prevalence of retinopathy 3. The prevalence of decline in renal function 4. The prevalence of early signs of macrovascular disease, as assessed by PWV, cIMT, FMD |
| Ethics approval(s) | AdDIT: South West Research Ethics Committee, 06/03/2008, ref: 08/HO206/4 AdDIT follow up: East of England - Cambridge South Research Ethics Committee, 20/04/2016, ref: 16/EE/0053 |
| Health condition(s) or problem(s) studied | Diabetic nephropathy and cardiovascular disease |
| Intervention | AdDIT: Eligible subjects who have provided informed consent and have completed baseline assessments are randomized using a secure internet-based service (www.sealedenvelope.com). This provides randomization with minimization. Subjects are allocated to one of the four treatment regimens after minimizing differences between arms on the following baseline characteristics: HbA1c (<7.5, 7.5-8.5, > 8.5%), log mean standardized ACR (>1.2 to <1.7, >1.7), gender, age (11-13, >13 years), duration of disease (<5 years, >5 years), total cholesterol (≥ 4.46 or < 4.46 mmol/l). Four treatment groups: 1) Statin-placebo 2) Statin-ACE inhibitor 3) Ace inhibitor-placebo 4) Placebo-placebo Statin: Atorvastatin at a single dose of 10 mg daily for oral administration with an identically labeled placebo ACE inhibitor: Quinapril available at 2 doses: 5 mg and 10 mg with appropriately matched placebo. Subjects are started on 5 mg and reviewed after two weeks; if there have been no adverse reactions in this time, the dose is increased to 10 mg daily, otherwise it will maintained at 5 mg. Any subjects experiencing apparent side effects (postural hypotension or persistent cough) have the option of changing to the lower dose at any point during the study. Drug exposure and trial duration: 2-4 years AdDIT follow up: The AdDIT follow up study will be a 5-year observational study, starting from the completion of the AdDIT trial. It will consist of 5 annual study visits and phone or email contact by the study team every 6 months. Baseline visit: 1. Consent and/or assent 2. Assessments of height, weight, waist circumference, blood pressure and collection of information about smoking status and medical history. 3. Blood sample collection to be used for investigations including: DNA extraction (epigenetic studies) where not previously collected (AdDIT Final visit or at Run-out, Intervention study), centralised measurement of HbA1c, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, lipoproteins, CVD (hsCRP, ADMA) and renal (creatinine, SDMA, Cystatin C) markers, new biomarkers through explanatory studies of proteomics/metabolomics, microRNAs 4. 3 early morning urine samples (ACR, microRNA, proteomics/ metabolomics). 12-monthly study visits with: 1. Assessments of height, weight, waist circumference, blood pressure and collection of information about smoking status and medical history. 2. Blood sample collection to be used for investigations including: centralised measurement of HbA1c, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, lipoproteins, CVD (hsCRP, ADMA) and renal (creatinine, SDMA, Cystatin C) markers 3. 3 early morning urine samples (ACR, microRNA, proteomics/ metabolomics). 6-monthly contact All Follow Up recruits will be contacted every 6 months between annual visits either by phone or email, depending on individual preference, to collect information on clinical events, glycaemic control and medications, and to ensure contact details are kept up to date. Final visit The final assessment will take place after 5 years of follow up. 1. Assessments of height, weight, waist circumference, blood pressure and collection of information about smoking status and medical history. 2. Blood sample collection to be used for investigations including: centralised measurement of HbA1c, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, lipoproteins, CVD (hsCRP, ADMA) and renal (creatinine, SDMA, Cystatin C) markers, new biomarkers through explanatory studies of proteomics/metabolomics, microRNAs and epigenetic changes recently implicated in vascular complications 3. Cardiovascular assessments: Assessments will include measurement of Carotid artery intima-media thickness (cIMT), and where facilities are available, Pulse Wave Velocity (PWV) and Endothelial Pulse Amplitude Tonometry (EndoPAT). 4. Retinal photographs taken during routine care will also be collected. Anonymised digital copies of the retinal photographs will be used for centralised grading of diabetic retinopathy and, where possible, also for detailed study of the retinal microvasculature. 5. Neuropathy assessment: The development of neuropathy will be assessed through the monitoring of clinical signs and symptoms. Long-term follow-up A longer term follow-up of the AdDIT cohort is planned through NHS systems analysis (UK) and other similar strategies in Australia and Canada Original interventions: Four arm randomisation: 1. Quinapril, 5 - 10 mg daily and placebo 2. Atorvostatin, 10 mg daily and placebo 3. Quinapril and atorvostatin 4. Placebo The duration of study will be three to four years, that is until subjects reach the age of 14 to 18 years and they will also be studied for an additional six months during the run out period. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | Quinapril, atorvostatin |
| Primary outcome measure | AdDIT: The primary endpoint is defined as the area under the curve over time of log albumin-creatinine ratio per year, with standardisation for gender, age and duration of disease. AdDIT follow up: Prevalence of vascular complications at the end of the 5 year follow-up period, specifically: 1. The prevalence of Micro/macroalbuminuria, as assessed by urinary albumin creatinine ratio (ACR) 2. The prevalence of retinopathy, as assessed by retinal imaging 3. The prevalence of decline in renal function, as assessed by markers such as cystatin C, SDMA, creatinine-based glomerular filtration rate 4. The prevalence of early signs of macrovascular disease, as assessed by direct vascular measures, such as PWV, cIMT, FMD |
| Secondary outcome measures | AdDIT: 1. Changes in carotid intimal media thickness, between baseline and the end of intervention period 2. Changes in arterial Blood Pressure (BP), lipids and other lipoproteins, CVD risk markers (high-sensitive C-Reactive Protein [hsCRP] and Asymmetric Dimethylarginine [ADMA]), assessed every six months during the intervention period 3. Changes in measures of Glomerular Filtration Rate (GFR) (plasma Symmetrical Dimethylarginine [SDMA], creatinine and cystatin C) assessed every six months during the intervention period 4. Changes in quality of life and health economics AdDIT follow up: Tracking of ACR, lipid levels, blood pressure, abnormal inflammatory markers during the 5-year follow up period, based on yearly assessments. |
| Overall study start date | 01/08/2008 |
| Completion date | 01/03/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 11 Years |
| Upper age limit | 15 Years |
| Sex | Both |
| Target number of participants | 500 |
| Key inclusion criteria | AdDIT: 1. Type 1 diabetes diagnosed for greater than one year 2. Aged 11 to 15 years 3. High risk for the development of diabetic nephropathy and Cardiovascular Disease (CVD) as predicted by albumin excretion in the upper tertile after appropriate adjustment for age, sex, age at diagnosis and duration of disease AdDIT follow-up: 1. Participants of the AdDIT Intervention and non-intervention cohort 2. Have given written informed consent to participate 3. Have completed involvement in the AdDIT study |
| Key exclusion criteria | AdDIT: 1. Non-type 1 diabetes, i.e., type 2 diabetes, insulin dependent diabetes related to monogenic disease, secondary diabetes 2. ACR based on six early morning urines deemed to be at low risk for subsequent development of CVD or diabetic nephropathy 3. Pregnancy, or unwillingness to comply with contraceptive advice and regular pregnancy testing throughout the trial 4. Severe hyperlipidaemia and family history data to support diagnosis of familial hypercholesterolaemia 5. Established hypertension unrelated to diabetic nephropathy 6. Prior exposure to the investigational products, statins and ACEI AdDIT follow-up: 1. Inability to give consent 2. Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of safety concern |
| Date of first enrolment | 01/08/2008 |
| Date of final enrolment | 31/12/2012 |
Locations
Countries of recruitment
- Australia
- Canada
- England
- United Kingdom
Study participating centre
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Hospital/treatment centre
Research Service Division
16 Mill Lane
Cambridge
CB2 1SB
England
United Kingdom
| Phone | +44 1223 330761 |
|---|---|
| helen.atkinson@rsd.cam.ac.uk | |
| Website | http://www.cam.ac.uk/ |
"ROR" |
https://ror.org/04v54gj93 |
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- DIABETES UK LIMITED, British Diabetic Association
- Location
- United Kingdom
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Juvenile Diabetes Research Foundation Ltd, JUVENILE DIABETES RESEARCH FOUNDATION LIMITED, JDRF UK, JDRF
- Location
- United Kingdom
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- the_bhf, The British Heart Foundation, BHF
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 28/02/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The AdDIT results and AdDIT follow up will be published around one year after the end of the study in high impact journals and will be presented at relevant international scientific meetings. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 17/12/2009 | Yes | No | |
| Results article | results | 01/12/2014 | Yes | No | |
| Results article | 21/02/2022 | 21/02/2022 | Yes | No | |
| HRA research summary | 26/07/2023 | No | No |
Editorial Notes
21/02/2022: Publication reference added.
28/08/2018: IPD sharing statement added.
14/08/2018: The overall trial end date was changed from 31/12/2012 to 01/03/2022.
24/10/2016: The risks and benefits of participating have been added to the plain English summary.
01/09/2016: There has been a substantial update of this record in order to include details of a follow-up phase of the study. This included added extra information to the hypothesis, ethics approval, interventions, outcome measures, inclusion/exclusion criteria, and the addition of a second study contact. The overall trial dates have been updated to include both studies: for the follow up study these dates are 14/07/2016-28/02/2022 and for the original study these are 01/08/2008-31/12/2012.
In addition, the information for the original trial has been updated to include further details regarding the interventions, trial participating centres and plain English summary.
