title: Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial.
abstract: BACKGROUND
  Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy.
  
  
  METHODS
  Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years.The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples.
  
  
  BACKGROUND
  The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications.
  
  
  BACKGROUND
  NCT02040441; Pre-results.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Lindhardt
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Frederik
authors.identifier: http://orcid.org/0000-0001-6242-6638
authors.initials: F
authors.lastname: Persson
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Currie
authors.affiliation: Mosaiques Diagnostics, Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pontillo
authors.affiliation: Klinikum St. Georg, Nephrology and KfH Renal Unit, Leipzig, Germany Martin-Luther-University Halle, Wittenberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Beige
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.affiliation: Hannover Clinical Trial Center, Hannover, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: von der Leyen
authors.affiliation: Mosaiques Diagnostics, Hannover, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Diabetes Center, Geniko Nosokomeio Athinas Ippokrateio, Athens, Greece.
authors.forename: Marina
authors.initials: M
authors.lastname: Noutsou
authors.affiliation: Instituto de Investigacion Sanitaria de la Fundacion Jimenez D¡az (IIS-FJD UAM), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Istituto di Richerche Farmacologiche Mario Negri, Bergamo, Italy.
authors.forename: Piero Luigi
authors.initials: PL
authors.lastname: Ruggenenti
authors.affiliation: 2nd Department of Medicine, 3rd Faculty of Medicine, Universita Karlova v Praze, Prague, Czech Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rychlik
authors.affiliation: Department of Nephrology, Cyril and Methodius University in Skopje, Skopje, Former Yugoslav Republic of Macedonia.
authors.forename: Goce
authors.initials: G
authors.lastname: Spasovski
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D015415:Biomarkers; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000517:prevention & control; D018450:Disease Progression; D004311:Double-Blind Method; D005060:Europe; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods; D012084:Renin-Angiotensin System; D012107:Research Design; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic
chemical_list: D015415:Biomarkers