Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria

NCT02040441 | Completed Phase 2 DMC

• 1 other identifier: 2012-000452-34
• Study Type: interventional
• Target: 1,777
• Locations: 10 countries
• Sites: 15

Brief Summary

This is a prospective, multicenter, randomized, double blind, placebo-controlled and a prospective observational study. This study will be conducted at 15 study centers in various European countries. 1777 participant between 18 to 75 years old with Type 2 diabetes mellitus and normoalbuminuria participate in the study. The study period is 2 - 4.5 years (excluding the 6 week screening period). Depending on the risk score of the urinary protein pattern, participants have been stratified into an observational group or an interventional group. Participants with the low risk pattern (observational group) attend visits annually after screening and baseline. Participants with the high risk pattern (interventional group) attend study visits every 13 weeks after screening and baseline. The interventional group has been allocated into one treatment group either receiving spironolactone or placebo. A placebo is a medicine without a pharmaceutical substance. The allocation to one of the two treatment groups has been done by a random distribution procedure established before the study start. The results of the urine sample from the Screening visit has been analysed and the urine proteomic pattern is determined to be either low- or high risk pattern and will determine the further study program. Participants with a low-risk pattern (observational group): During the study period, participants attend an annual project visit, were regular diabetes care is performed and three urine samples are analysed for albuminuria. Participants with a high-risk pattern (intervention group): Participants with a high-risk pattern have been randomized to either spironolactone treatment or placebo. The treatment is one tablet for oral use to be taken once a day for the entire study period. Four times each year (every 13th week) a study visit is conducted including examination of three urine samples for albuminuria. This study aims to:

1. 1.Confirm in a prospective multicenter study of normoalbuminuric type 2 DM patients that the urinary proteome test identifies patients with a high risk for development of microalbuminuria.
2. 2.Demonstrate the clinical utility of the test by showing that aldosterone blockade in high-risk patients can reduce progression to microalbuminuria in comparison to placebo, on the top of standard treatment in a randomized double-blind, placebo-controlled multicenter study.

Conditions

Diabetic Nephropathy; Diabetic Retinopathy

Keywords

Proteomics; Diabetes; Chronic kidney disease; Diabetic nephropathy; Diabetic retinopathy; Mineralocorticoid receptor antagonists; Spironolactone; Microalbuminuria

Outcome Measures

Primary Outcomes (1)

• Albuminuria

  Development of confirmed microalbuminuria (UACR \>30 mg/g) in at least two out of three first morning voids with ≥ 30% increase (geometric mean) in UACR from "run-in" period samples OR \> 40 mg/g (geometric mean).

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

Secondary Outcomes (7)

• Cardiovascular disease and mortality

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

• Retinopathy

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

• Change in albuminuria

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

• Microalbuminuria

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

• Macroalbuminuria

  Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)

Study Arms (3)

Spironolactone

ACTIVE COMPARATOR

High-risk pattern: Spironolactone 25 mg once daily + Standard care

Drug: Spironolactone; Drug: Standard care

Placebo

PLACEBO COMPARATOR

High-risk pattern: One placebo tablet once daily + Standard care

Drug: Placebo; Drug: Standard care

Observational

OTHER

Low-risk pattern: Standard care

Drug: Standard care

Interventions

Spironolactone DRUG

Spironolactone

Placebo DRUG

Placebo

Standard care DRUG

Standard diabetes care

Observational; Placebo; Spironolactone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent ethical committee. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data
• Male or female patients ≥ 18 years and \< 75 years of age at Screening visit
• Type 2 DM (WHO criteria)
• Persistent normoalbuminuria (at least 2 of 3 UACR \< 30 mg/g samples from "run in"-period)
• Estimated GFR \>45 ml/min/1.73m2 (MDRD formula) at Screening visit
• The patient must be willing and able to comply with the protocol for the duration of the study
• Female without child-bearing potential at the screening visit. Defined as one or more of following:
• ) 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy.
• OR a negative urine pregnancy test at the Screening visit AND one or more of following:
• ) Correct use of reliable contraception methods. This includes one or more of the following: hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring or oral) or an intrauterine device (IUD) OR correct use of double barrier with one of the following: barrier methods (diaphragm, cervical cap, Lea contraceptive or condom) AND in combination with a spermicide.
• ) General sexual abstinence from the time of screening/ baseline, during the study until a minimum of 30 days after the last administration of study medication if this is already established as the patient's preferred and usual lifestyle.
• ) Having only female sexual partners. 7.7) Sexual relationship with sterile male partners only

You may not qualify if:

• Average of systolic BP\< 110 or \>160 mm Hg at baseline
• Average of diastolic BP \> 100 mm Hg at baseline
• Type 1 DM (WHO criteria)
• HbA1c \<6.5% (48 mmo l/ mol) AND \> 5 years of known duration of diabetes type 2 AND never treated with an antidiabetic drug of any kind.
• Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)
• Current lithium treatment
• Known or suspected hypersensitivity to Spironolactone or to any of its excipients.
• Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or Amiloride etc.
• Screening (week -6) plasma (or serum) potassium level \>5.0 mmol/L
• Low plasma sodium determine by the investigator
• Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)
• Any clinically significant disorder, except for conditions associated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial
• Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or myocardial ischemia, stroke, cardiac re-vascularisation or coronary artery bypass within the last 3 months
• Diagnosis of non-Diabetic CKD current or in the past
• Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.

Sponsors & Collaborators

• Peter Rossing: lead
• Mosaiques Diagnostics GmbH: collaborator
• University Medical Center Groningen: collaborator
• University of Glasgow: collaborator
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator
• Univerzita Karlova v Praze: collaborator
• Geniko Nosokomeio Athinas Ippokrateio: collaborator
• Institut Klinické a Experimentální Mediciny Praze: collaborator
• Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz: collaborator
• Klinikum St. Georg Leipzig: collaborator
• Cyril and Methodius University in Skopje: collaborator
• Hannover Clinical Trial Center: collaborator
• European Commission: collaborator
• Diabetes Vascular Research Foundation Hoogeveen: collaborator
• University Ghent: collaborator
• Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden: collaborator
• Stichting VUMC: collaborator
• Diabetologen Hessen: collaborator

Study Sites (15)

Universitair Ziekenhuis

Ghent, Belgium

Location

Institut Klinické a Experimentální Mediciny

Prague, Czechia

Location

Universita Karlova v Praze

Prague, Czechia

Location

Steno Diabets Center Copenhagen

Gentofte Municipality, 2820, Denmark

Location

Universitätsklinikum Carl Gustav Carus, Technischen Universität Dresden

Dresden, Germany

Location

Diabetologen Hessen

Hessen, Germany

Location

Klinikum St. Georg gGmbH

Leipzig, Germany

Location

Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center

Athens, Greece

Location

Instituto de Ricerche Farmacologiche Mario Negri

Bergamo, 24020, Italy

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Diabetes Vascular Research Foundation

Hoogeveen, Netherlands

Location

Stichting VUMC

Hoorn, Netherlands

Location

Department of Nephrology, University of Skopje

Skopje, North Macedonia

Location

Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

University of Glasgow

Glasgow, G12 8TA, United Kingdom

Location

Related Publications (5)

• Rotbain Curovic V, Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, Birkenfeld AL, Currie G, Delles C, Dimos I, Francova L, Frimodt-Moller M, Girman P, Goke R, Hansen TW, Havrdova T, Kooy A, Laverman GD, Mischak H, Navis G, Nijpels G, Noutsou M, Ortiz A, Parvanova A, Persson F, Petrie JR, Ruggenenti PL, Rutters F, Rychlik I, Siwy J, Spasovski G, Speeckaert M, Trillini M, Zurbig P, von der Leyen H, Rossing P; on the behalf of the PRIORITY Study Group. Presence of retinopathy and incident kidney and cardiovascular events in type 2 diabetes with normoalbuminuria - A post-hoc analysis of the PRIORITY randomized clinical trial. J Diabetes Complications. 2023 Apr;37(4):108433. doi: 10.1016/j.jdiacomp.2023.108433. Epub 2023 Feb 18.

  PMID: 36841085 DERIVED

• Chung EY, Ruospo M, Natale P, Bolignano D, Navaneethan SD, Palmer SC, Strippoli GF. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 27;10(10):CD007004. doi: 10.1002/14651858.CD007004.pub4.

  PMID: 33107592 DERIVED

• Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, Birkenfeld AL, Currie G, Delles C, Dimos I, Francova L, Frimodt-Moller M, Girman P, Goke R, Havrdova T, Heerspink HJL, Kooy A, Laverman GD, Mischak H, Navis G, Nijpels G, Noutsou M, Ortiz A, Parvanova A, Persson F, Petrie JR, Ruggenenti PL, Rutters F, Rychlik I, Siwy J, Spasovski G, Speeckaert M, Trillini M, Zurbig P, von der Leyen H, Rossing P; PRIORITY investigators. Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2020 Apr;8(4):301-312. doi: 10.1016/S2213-8587(20)30026-7. Epub 2020 Mar 2.

  PMID: 32135136 DERIVED

• Tofte N, Lindhardt M, Adamova K, Beige J, Beulens JWJ, Birkenfeld AL, Currie G, Delles C, Dimos I, Francova L, Frimodt-Moller M, Girman P, Goke R, Havrdova T, Kooy A, Mischak H, Navis G, Nijpels G, Noutsou M, Ortiz A, Parvanova A, Persson F, Ruggenenti PL, Rutters F, Rychlik I, Spasovski G, Speeckaert M, Trillini M, von der Leyen H, Rossing P. Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes. Diabet Med. 2018 Oct;35(10):1375-1382. doi: 10.1111/dme.13669. Epub 2018 Jun 6.

  PMID: 29781558 DERIVED

• Lindhardt M, Persson F, Currie G, Pontillo C, Beige J, Delles C, von der Leyen H, Mischak H, Navis G, Noutsou M, Ortiz A, Ruggenenti PL, Rychlik I, Spasovski G, Rossing P. 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. BMJ Open. 2016 Mar 2;6(3):e010310. doi: 10.1136/bmjopen-2015-010310.

  PMID: 26936907 DERIVED

Related Links

• Official study webpage
• European Commission, The Seventh Framework Programme.

MeSH Terms

Conditions

Diabetic Nephropathies; Diabetic Retinopathy; Diabetes Mellitus; Renal Insufficiency, Chronic

Interventions

Spironolactone; Standard of Care

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Endocrine System Diseases; Retinal Diseases; Eye Diseases; Diabetic Angiopathies; Vascular Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Peter Rossing, Prof. MD

  Steno Diabetes Center Copenhagen

  STUDY CHAIR

• Matias Trillini, MD

  Istituto de Ricerche Farmacologiche Mario Negri

  PRINCIPAL INVESTIGATOR

• Alberto Ortiz, MD

  Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

  PRINCIPAL INVESTIGATOR

• Christian Delles, MD

  University of Glasgow

  PRINCIPAL INVESTIGATOR

• Gerjan Navis, MD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

• Ivan Rychlik, MD

  Univerzita Karlova v Praze

  PRINCIPAL INVESTIGATOR

• Joachim Beige, MD

  Klinikum St. Georg gGmbH

  PRINCIPAL INVESTIGATOR

• Marina Noutsou, MD

  Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center

  PRINCIPAL INVESTIGATOR

• Peter Girman, MD

  Institut Klinické a Experimentální Mediciny

  PRINCIPAL INVESTIGATOR

• Goce Spasovski, MD

  Department of Nephrology, University of Skopje

  PRINCIPAL INVESTIGATOR

• Adriaan Kooy, MD

  Diabetes Vascular Research Foundation Hoogeveen

  PRINCIPAL INVESTIGATOR

• Marjin Speeckaert, MD

  University Ghent

  PRINCIPAL INVESTIGATOR

• Joline Beulens, MD

  Stichting VUMC

  PRINCIPAL INVESTIGATOR

• Rüdiger Göke, MD

  Diabetologen Hessen

  PRINCIPAL INVESTIGATOR

• Andreas Birkenfeld, MD

  Universitätsklinikum Carl Gustav Carus, Technischen Universität Dresden

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, Chief Physician, MD, DMSc

Study Record Dates

• First Submitted: December 16, 2013
• First Posted: January 20, 2014
• Study Start: March 1, 2014
• Primary Completion: November 1, 2018
• Study Completion: November 1, 2018
• Last Updated: December 21, 2018

Record last verified: 2018-12

Locations

BE (1); CZ (2); IT (1); GR (1); GB (1); DK (1); DE (3); ES (1); NL (3); NO (1)