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Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT)

Primary Purpose

Type 1 Diabetes

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Statin

ACE inhibitor

Placebo

Combination therapy

About this trial

This is an interventional prevention trial for Type 1 Diabetes focused on measuring Adolescence

Eligibility Criteria

10 Years - 16 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Western Australia
Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Other

Arm Label

Statin

Angiotensin-converting enzyme inhibitor

Placebo

Combination therapy

Arm Description

Participants receive active statin and placebo ACE Inhibitor

Participants receive active ACE Inhibitor and placebo statin

Participants receive placebo ACE Inhibitor and placebo statin

Participants receive both active ACE Inhibitor and active Statin

Outcomes

Primary Outcome Measures

Albumin creatinine ratio

The area under the curve over time of log ACR per year, with standardisation for gender, age and duration of disease

Secondary Outcome Measures

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.

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.

Retinopathy

Changes in retinopathy scores and retinal microvascular structure (arteriolar or venular dilation, vascular fractile dimension, branching and tortuosity) assessed annually

Quality of Life and Health Economics

Changes in quality of life measures and resource usage

Full Information

NCT ID

NCT01581476

First Posted

April 13, 2012

Last Updated

June 26, 2018

Sponsor

University of Cambridge

Collaborators

Juvenile Diabetes Research Foundation, Diabetes UK, British Heart Foundation, Pfizer, The University of Western Australia, The Hospital for Sick Children, University of Oxford, St Thomas' Hospital, London

1. Study Identification

Unique Protocol Identification Number

NCT01581476

Brief Title

Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial

Acronym

AdDIT

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2018

Overall Recruitment Status

Completed

Study Start Date

January 2009 (undefined)

Primary Completion Date

April 2017 (Actual)

Study Completion Date

June 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Cambridge

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes

Keywords

Adolescence

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

443 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Statin

Arm Type

Active Comparator

Arm Description

Participants receive active statin and placebo ACE Inhibitor

Arm Title

Angiotensin-converting enzyme inhibitor

Arm Type

Active Comparator

Arm Description

Participants receive active ACE Inhibitor and placebo statin

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants receive placebo ACE Inhibitor and placebo statin

Arm Title

Combination therapy

Arm Type

Other

Arm Description

Participants receive both active ACE Inhibitor and active Statin

Intervention Type

Drug

Intervention Name(s)

Statin

Other Intervention Name(s)

Atorvastatin

Intervention Description

10mg daily for a minimum period of 2 years

Intervention Type

Drug

Intervention Name(s)

ACE inhibitor

Other Intervention Name(s)

Quinapril

Intervention Description

Starting dose of 5mg daily rising after 14 days to 10mg daily providing it is well tolerated for a minimum period of 2 years.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Participants receive statin placebo and ACEI placebo

Intervention Type

Drug

Intervention Name(s)

Combination therapy

Other Intervention Name(s)

Atorvastatin, Quinapril

Intervention Description

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.

Primary Outcome Measure Information:

Title

Albumin creatinine ratio

Description

The area under the curve over time of log ACR per year, with standardisation for gender, age and duration of disease

Time Frame

2-4 years treatment duration

Secondary Outcome Measure Information:

Title

Changes in CVD risk markers

Description

Time Frame

2-4 yrs treatment duration

Title

Changes in glomerular filtration rate (GFR)

Description

Changes in measures of GFR (plasma SDMA, creatinine adn cystatin C levels) assessed every 6 months during intervention period.

Time Frame

2-4 years treatment duration

Title

Retinopathy

Description

Changes in retinopathy scores and retinal microvascular structure (arteriolar or venular dilation, vascular fractile dimension, branching and tortuosity) assessed annually

Time Frame

2-4 years treatment duration

Title

Quality of Life and Health Economics

Description

Changes in quality of life measures and resource usage

Time Frame

2-4 years treatment duration

10. Eligibility

Sex

All

Minimum Age & Unit of Time

10 Years

Maximum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David B Dunger, Professor

Organizational Affiliation

University of Cambridge

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Western Australia

City

Perth

Country

Australia

Facility Name

Hospital for Sick Children

City

Toronto

State/Province

Ontario

Country

Canada

12. IPD Sharing Statement

Citations:

PubMed Identifier

18349042

Citation

Amin R, Widmer B, Prevost AT, Schwarze P, Cooper J, Edge J, Marcovecchio L, Neil A, Dalton RN, Dunger DB. Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study. BMJ. 2008 Mar 29;336(7646):697-701. doi: 10.1136/bmj.39478.378241.BE. Epub 2008 Mar 18.

Results Reference

background

PubMed Identifier

17257274

Citation

Dunger DB, Schwarze CP, Cooper JD, Widmer B, Neil HA, Shield J, Edge JA, Jones TW, Daneman D, Dalton RN. Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria? Diabet Med. 2007 Feb;24(2):131-6. doi: 10.1111/j.1464-5491.2006.02047.x.

Results Reference

background

PubMed Identifier

20017932

Citation

Adolescent type 1 Diabetes cardio-renal Intervention Trial Research Group. Adolescent type 1 Diabetes Cardio-renal Intervention Trial (AdDIT). BMC Pediatr. 2009 Dec 17;9:79. doi: 10.1186/1471-2431-9-79.

Results Reference

background

PubMed Identifier

22416821

Citation

Cherney DZ, Scholey JW, Daneman D, Dunger DB, Dalton RN, Moineddin R, Mahmud FH, Dekker R, Elia Y, Sochett E, Reich HN. Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria. Diabet Med. 2012 Oct;29(10):1297-302. doi: 10.1111/j.1464-5491.2012.03651.x.

Results Reference

result

PubMed Identifier

33100044

Citation

Chiesa ST, Marcovecchio ML, Benitez-Aguirre P, Cameron FJ, Craig ME, Couper JJ, Davis EA, Dalton RN, Daneman D, Donaghue KC, Jones TW, Mahmud FH, Marshall SM, Neil HAW, Dunger DB, Deanfield JE; Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) Study Group. Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes. Hypertension. 2020 Dec;76(6):1734-1743. doi: 10.1161/HYPERTENSIONAHA.120.15721. Epub 2020 Oct 26.

Results Reference

derived

PubMed Identifier

32108022

Citation

Niechcial E, Acerini CL, Chiesa ST, Stevens T, Dalton RN, Daneman D, Deanfield JE, Jones TW, Mahmud FH, Marshall SM, Neil HAW, Dunger DB, Marcovecchio ML; Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) Study Group; Adolescent Type 1 Diabetes Cardio-renal Intervention Trial AdDIT Study Group. Medication Adherence During Adjunct Therapy With Statins and ACE Inhibitors in Adolescents With Type 1 Diabetes. Diabetes Care. 2020 May;43(5):1070-1076. doi: 10.2337/dc19-0884. Epub 2020 Feb 27.

Results Reference

derived

PubMed Identifier

29091568

Citation

Marcovecchio ML, Chiesa ST, Bond S, Daneman D, Dawson S, Donaghue KC, Jones TW, Mahmud FH, Marshall SM, Neil HAW, Dalton RN, Deanfield J, Dunger DB; AdDIT Study Group. ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes. N Engl J Med. 2017 Nov 2;377(18):1733-1745. doi: 10.1056/NEJMoa1703518.

Results Reference

derived

PubMed Identifier

25392936

Citation

Har RL, Reich HN, Scholey JW, Daneman D, Dunger DB, Moineddin R, Dalton RN, Motran L, Elia Y, Deda L, Ostrovsky M, Sochett EB, Mahmud FH, Cherney DZ. The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes. PLoS One. 2014 Nov 13;9(11):e111131. doi: 10.1371/journal.pone.0111131. eCollection 2014.

Results Reference

derived

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Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial

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