Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial

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.

• Drug: Statin
  10mg daily for a minimum period of 2 years
  Other Name: Atorvastatin
• Drug: ACE inhibitor
  Starting dose of 5mg daily rising after 14 days to 10mg daily providing it is well tolerated for a minimum period of 2 years.
  Other Name: Quinapril
• Drug: Placebo
  Participants receive statin placebo and ACEI placebo
• Drug: Combination therapy
  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.
  Other Names:

  • Atorvastatin
  • Quinapril

• Active Comparator: Statin
  Participants receive active statin and placebo ACE Inhibitor
  Intervention: Drug: Statin
• Active Comparator: Angiotensin-converting enzyme inhibitor
  Participants receive active ACE Inhibitor and placebo statin
  Intervention: Drug: ACE inhibitor
• Placebo Comparator: Placebo
  Participants receive placebo ACE Inhibitor and placebo statin
  Intervention: Drug: Placebo
• Combination therapy
  Participants receive both active ACE Inhibitor and active Statin
  Intervention: Drug: Combination therapy

• 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.
• 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.
• 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.
• 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.
• 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 Oct 26:HYPERTENSIONAHA12015721. doi: 10.1161/HYPERTENSIONAHA.120.15721. [Epub ahead of print]
• 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.
• 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.

Inclusion Criteria:

1. Age 10 to 16 years.
2. T1D diagnosed for more than 1 year or C-peptide negative.
3. 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:

1. Non T1D, 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 DN.
3. Pregnancy or unwillingness to comply with contraceptive advice and regular pregnancy testing throughout the trial.
4. Breast feeding
5. Severe hyperlipidaemia and family history data to support diagnosis of familial hypercholesterolaemia.
6. Established hypertension unrelated to DN.
7. Prior exposure to the investigational products, statins and ACEI.
8. Unwillingness/inability to comply with the study protocol.
9. Other co-morbidities considered unsuitable by the investigator (excluding treated hypothyroidism and coeliac disease).
10. Proliferative retinopathy.
11. Renal disease not associated with Type 1 Diabetes.

• 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