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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02040441
Recruitment Status : Active, not recruiting
First Posted : January 20, 2014
Last Update Posted : February 21, 2018
Sponsor:
Collaborators:
Mosaiques Diagnostics GmbH
University Medical Center Groningen
University of Glasgow
Istituto Di Ricerche Farmacologiche Mario Negri
Univerzita Karlova v Praze
Geniko Nosokomeio Athinas Ippokrateio
Institut Klinické a Experimentální Mediciny Praze
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Klinikum St. Georg Leipzig
Cyril and Methodius University in Skopje
Hannover Clinical Trial Center
European Commission
Diabetes Vascular Research Foundation Hoogeveen
Universitair Ziekenhuis Gent
Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
Stichting VUMC
Diabetologen Hessen
Information provided by (Responsible Party):
Peter Rossing, Steno Diabetes Center

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. 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. 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.

Condition or disease Intervention/treatment Phase
Diabetic Nephropathy Diabetic Retinopathy Drug: Spironolactone Drug: Placebo Drug: Standard care Phase 2 Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1777 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
Actual Study Start Date : March 2014
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Spironolactone
High-risk pattern: Spironolactone 25 mg once daily + Standard care
Drug: Spironolactone Drug: Standard care
Standard diabetes care
Placebo Comparator: Placebo
High-risk pattern: One placebo tablet once daily + Standard care
Drug: Placebo Drug: Standard care
Standard diabetes care
Observational
Low-risk pattern: Standard care
Drug: Standard care
Standard diabetes care



Primary Outcome Measures :
  1. Albuminuria [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    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).


Secondary Outcome Measures :
  1. Cardiovascular disease and mortality [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    Comparison of composite fatal and non-fatal cardiovascular outcome (myocardial infarction, stroke, coronary artery bypass, coronary re-vascularisation, hospitalization for heart failure and cardiovascular death), and all-cause mortality during the study.

  2. Retinopathy [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from self-reported adverse events.

  3. Change in albuminuria [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    In addition to the categorical analysis of urinary albumin excretion, an analysis will be performed with changes in geometric mean albuminuria throughout the study period in all patients by assessing the slope of albuminuria changes and absolute changes from inclusion to end of trial

  4. Microalbuminuria [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    Development of microalbuminuria (UACR >30 mg/g) in at least one morn-ing void urine sample will be used as a secondary outcome instead of con-firmed microalbuminuria

  5. Macroalbuminuria [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void urine samples)

  6. Change in CKD class [ Time Frame: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156) ]
    For patients with estimated GFR ≥ 60 at baseline, development of estimated GFR<60 ml/min/1.73m2. Estimated GFR will be measured from serum creatinine (standard-ized traceable method) on blood samples tested in local laboratories.

  7. Slope of estimated GFR [ Time Frame: 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 estimated GFR (slope and absolute from baseline and from 3 month post-baseline to end of study)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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
  2. Male or female patients ≥ 18 years and < 75 years of age at Screening visit
  3. Type 2 DM (WHO criteria)
  4. Persistent normoalbuminuria (at least 2 of 3 UACR < 30 mg/g samples from "run in"-period)
  5. Estimated GFR >45 ml/min/1.73m2 (MDRD formula) at Screening visit
  6. The patient must be willing and able to comply with the protocol for the duration of the study
  7. Female without child-bearing potential at the screening visit. Defined as one or more of following:

7.1) Female patients ≥ 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year 7.2) Female patients < 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year and serum follicle stimulating hormone levels > 40 milli International unit / mL as well as serum estrogen levels < 30 pg/ml or a negative estrogen test.

7.3) 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:

7.4) 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.

7.5) 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.

7.6) Having only female sexual partners. 7.7) Sexual relationship with sterile male partners only

Exclusion Criteria:

  1. Average of systolic BP< 110 or >160 mm Hg at baseline
  2. Average of diastolic BP > 100 mm Hg at baseline
  3. Type 1 DM (WHO criteria)
  4. 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.
  5. Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)
  6. Current lithium treatment
  7. Known or suspected hypersensitivity to Spironolactone or to any of its excipients.
  8. Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or Amiloride etc.
  9. Screening (week -6) plasma (or serum) potassium level >5.0 mmol/L
  10. Low plasma sodium determine by the investigator
  11. Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)
  12. 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
  13. 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
  14. Diagnosis of non-Diabetic CKD current or in the past
  15. Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.
  16. Diagnosis of Addison's disease.
  17. Being lactating.
  18. Intend to become pregnant within the duration of the study or not use adequate birth control.
  19. Known or suspected abuse of alcohol or narcotics
  20. Not able to understand informed consent form
  21. Participation in any other intervention trial than PRIORITY or a related sub-study is not allowed within 30 days before inclusion or concurrent to this study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02040441


Locations
Belgium
Universitair Ziekenhuis
Gent, Belgium
Czechia
Institut Klinické a Experimentální Mediciny
Prague, Czechia
Universita Karlova v Praze
Prague, Czechia
Denmark
Steno Diabets Center Copenhagen
Gentofte, Denmark, 2820
Germany
Universitätsklinikum Carl Gustav Carus, Technischen Universität Dresden
Dresden, Germany
Diabetologen Hessen
Hessen, Germany
Klinikum St. Georg gGmbH
Leipzig, Germany
Greece
Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center
Athens, Greece
Italy
Instituto de Ricerche Farmacologiche Mario Negri
Bergamo, Italy, 24020
Macedonia, The Former Yugoslav Republic of
Department of Nephrology, University of Skopje
Skopje, Macedonia, The Former Yugoslav Republic of
Netherlands
University Medical Center Groningen
Groningen, Netherlands
Diabetes Vascular Research Foundation
Hoogeveen, Netherlands
Stichting VUMC
Hoorn, Netherlands
Spain
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Madrid, Spain, 28040
United Kingdom
University of Glasgow
Glasgow, United Kingdom, G12 8TA
Sponsors and Collaborators
Peter Rossing
Mosaiques Diagnostics GmbH
University Medical Center Groningen
University of Glasgow
Istituto Di Ricerche Farmacologiche Mario Negri
Univerzita Karlova v Praze
Geniko Nosokomeio Athinas Ippokrateio
Institut Klinické a Experimentální Mediciny Praze
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Klinikum St. Georg Leipzig
Cyril and Methodius University in Skopje
Hannover Clinical Trial Center
European Commission
Diabetes Vascular Research Foundation Hoogeveen
Universitair Ziekenhuis Gent
Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
Stichting VUMC
Diabetologen Hessen
Investigators
Study Chair: Peter Rossing, Prof. MD Steno Diabetes Center
Principal Investigator: 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 Universitair Ziekenhuis Gent
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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Peter Rossing, Professor, Chief Physician, MD, DMSc, Steno Diabetes Center
ClinicalTrials.gov Identifier: NCT02040441     History of Changes
Other Study ID Numbers: 2012-000452-34
2012-000452-34 ( EudraCT Number )
First Posted: January 20, 2014    Key Record Dates
Last Update Posted: February 21, 2018
Last Verified: February 2018

Keywords provided by Peter Rossing, Steno Diabetes Center:
Proteomics
Diabetes
Chronic kidney disease
Diabetic nephropathy
Diabetic retinopathy
Mineralocorticoid receptor antagonists
Spironolactone
Microalbuminuria

Additional relevant MeSH terms:
Kidney Diseases
Retinal Diseases
Diabetic Retinopathy
Diabetic Nephropathies
Urologic Diseases
Eye Diseases
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents