Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria (PRIORITY)
This is a prospective, multicenter, randomized, double blind, placebo-controlled and a prospective observational study.
This study will be conducted at 13 study centers in various European countries. Approximately 3500 participant between 18 to 75 years old with Type 2 diabetes mellitus and normoalbuminuria will participate in the study. The study period is 3 years (excluding the 6 week screening period). Depending on the risk score of the urinary protein pattern, participants will be stratified into an observational group or an interventional group. Either 5 (low risk pattern, observational group) or 15 (high risk pattern, interventional group) office visits of 1-3 hours duration are scheduled.
The interventional group will be 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 will be 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) (approximately 80%):
During the next three years, participants will attend an annual project visit, were regular diabetes care will be performed and three urine samples will be analysed for albuminuria.
Participants with a high-risk pattern (intervention group) (approximately 20%):
Participants with a high-risk pattern will be randomization to either spironolactone treatment or placebo. The treatment is one tablet for oral use to be ta en once a day for the next three years. Four times each year (every 13th week) a study visit will be conducted including examination of three urine samples for albuminuria.
This study aims to:
- 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.
- 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.
|Diabetic Nephropathy Diabetic Retinopathy||Drug: Spironolactone Drug: Placebo Drug: Standard care||Phase 2 Phase 3|
|Study Design:||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|
- 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).
- 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.
- 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.
- 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
- 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
- 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)
- 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.
- 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)
|Study Start Date:||November 2013|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Active Comparator: Spironolactone
High-risk pattern: Spironolactone 25 mg once daily + Standard care
Drug: Standard care
Standard diabetes care
Placebo Comparator: Placebo
High-risk pattern: One placebo tablet once daily + Standard care
Drug: Standard care
Standard diabetes care
Low-risk pattern: Standard care
Drug: Standard care
Standard diabetes care
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Background Information Diabetes mellitus (DM) affects 9% of the European population and the cost of caring for patients with DM accounts for 15% of the European health care budget expenditure. Al-most 90% of patients have type 2 DM, and absolute numbers are expected to rise in parallel to the current obesity and metabolic syndrome epidemic. Improved treatment has reduced mortality but the prolonged duration of DM increases the likelihood of development of late diabetic complications.
Diabetic nephropathy is one of the major late complications of diabetes and is associated with substantial cardiovascular morbidity and mortality and is a leading cause of end stage renal disease (ESRD) in the Western world. In clinical practice, renal impairment is diagnosed by albuminuria or proteinuria and/or changes in serum creatinine/creatinine clearance indicating alterations of the glomerular filtration rate (GFR). However, the inter-individual variability is high, and as a consequence, these standard tests have a moderate specificity and sensitivity at early stages of disease, with major limitations in the diagnosis of the early stages of diabetic nephropathy (DN).
Development of DN is generally characterized by an increase of urinary albumin excretion rate (>300 mg/24 h or 200 μg/min). Microalbuminuria (30-300 mg/24 h or 20-200 μg/min) is considered a risk factor and as an early indicator of future onset of DN. Microalbuminuria is regarded as the earliest clinical marker of renal damage. However, structural changes to the kidney have already occurred at the stage of microalbuminuria and patients with microalbuminuria have a high risk for development of renal disease, but also increased morbidity and mortality due to cardiovascular disease.
Blood pressure and glycemic control with pharmacotherapeutic intervention as well as life style interventions are the cornerstones of type 2 DM management aiming at prevention of microvascular complications. Specific therapy, particularly treatment with angiotensin converting enzyme inhibitors (ACE) and angiotensin receptor antagonists (ARB) to prevent progression to overt proteinuria and advanced stages of diabetic nephropathy is recommended if microalbuminuria is present. Studies aiming for earlier prevention of nephropathy by starting renin angiotensin aldosterone system (RAAS) blocking treatment in normoalbuminuric patients have given mixed and often disappointing results. This might reflect that a large fraction of normoalbuminuric patient may not be at risk for progression thereby reducing the event rate or power in previous studies. Early identification of normoalbuminuric patients at high risk for development of diabetic nephropathy could identify patients who might benefit of intervention with increased blockade of the RAAS. Furthermore, blockade of the RAAS with aldosterone blockade has been demonstrated to reduce urinary albumin excretion with 20-30% on top of standard antihypertensive treatment including ACE or ARB in proteinuric type 1 and 2 diabetic patients, and a 60% reduction was seen in microalbuminuric type 1 diabetic patients. Therefore, it may also hold the potential to reduce the risk of development of microalbuminuria in high risk normoalbuminuric patients.
CKD Biomarker panel Proteomics is the analysis of large number of proteins or polypeptides in tissue and body fluids. Capillary electrophoresis mass spectrometry (CE-MS) enables reproducible and robust high-resolution analysis of several thousand low-molecular-weight urinary proteins/peptides in about one hour. Urine holds several advantages over blood in clinical proteomics. It can be collected non-invasively and its proteome is relatively stable. Members of the consortium have successfully identified a urinary biomarker pattern including 273 peptides significantly associated with chronic kidney disease (CKD273).
Importantly, the biomarker panel has been validated in a multicentric approach involving >1000 blinded samples. The accuracy was high (96% sensitivity and 98% specificity), when evaluating only the diabetic patients in the test-set. To test the CKD273 pat-tern as a tool for early detection of DN, we recently performed an independent longitudinal study of normoalbuminuric diabetic patients at inclusion. The urinary CKD273 pattern distinguished progressing patients from non-progressing patients. The corresponding receiver operating characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.925 assuming a prevalence of 30% for DN. The positive predictive value was 97% and the negative predictive value was 88%. The specificity of the CKD273 pattern was further evaluated in patients without any evidence for renal impairment based on clinical history, creatinine, or urinary protein levels resulting in an overall specificity of 98%.
The used CKD273 pattern showed that these biomarkers can detect initiation and progression of DN earlier than the currently used indicators, well preceding increases in urinary albumin levels. While the CKD273 pattern detected DN with >90% accuracy four years before clinical diagnosis, serum creatinine and/or Urine albumin execration rate did not detect DN earlier than one and two years before clinical manifestation, respectively. In addition, diagnostic accuracy was significantly lower compared to the CKD273 pattern. In addition, two independent studies on type 1 and type 2 DM patients, on longitudinally collected samples over a period of 10 years demonstrate that CKD273 markers of kidney disease were altered 3 to 5 years prior to manifestation of albuminuria, and 1 to 2 years prior to development of microalbuminuria. Thus, the performance of the CKD273 pattern is better than prediction based on urinary albumin values and represents potentially a significant improvement over the current state of the art in assessing DN, enabling earlier detection with higher accuracy than urinary albumin.
Finally, the proteome analysis and application of the CKD273 pattern indicated a positive scoring for CKD in microalbuminuric type 2 diabetic patients, which showed persistent improvement during long-term renoprotective treatment with Irbesartan, while placebo treated patients showed a slight deterioration of kidney damage markers likely reflecting disease progression in the absence of preemptive intervention.
Collectively, our existing data strongly indicate that the urinary proteomics based test ap-pears ideal to identify patients who will develop microalbuminuria and ultimately DN and thereby facilitates targeting intensified preventative therapy to this group.
- Urinary proteomics predicts development of microalbuminuria (as a surrogate marker for the development of overt nephropathy) in a cohort of 3280 type 2 diabetic patients with normal urinary albumin excretion at screening.
- Early initiation of preventive therapy with spironolactone reduces risk of transition to microalbuminuria in those identified by urinary proteomics to be at high risk, and thereby delays progression to overt nephropathy. Treatment can be spared for those with low risk according to urinary proteomics, paving the way of personalised medicine
Primary Objective To confirm that urinary proteomics can predict development of microalbuminuria (as a surrogate marker for the development of overt nephropathy) in a cohort of 3280 type 2 diabetic patients with normal urinary albumin excretion.
Secondary Objectives To investigate if early initiation of preventive therapy with spironolactone 25 mg once daily reduces risk of transition to microalbuminuria in those patients identified by urinary proteomics to be at high risk.
Additional Scientific Objectives To compare the rate of change in urinary albumin excretion rate in high vs. low-risk population (based on the proteomic test), and to compare the effect of spironolactone on rate of change in urine albumin execration rate in the intervention group.
In addition, the objective is to study the rate of change in estimated GFR in relation to urinary marker pattern (CKD 273) and the intervention with spironolactone.
To study the ability of urinary proteomic patterns, to predict cardiovascular or renal events during the study as well as response to intervention, in relation to study endpoints.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02040441
|Contact: Peter Rossing, Prof, MD||+45 4443 7310||Pro@steno.dk|
|Contact: Morten Lindhardt, MD||+45 3075 firstname.lastname@example.org|
|Institut Klinické a Experimentální Mediciny||Recruiting|
|Prague, Czech Republic|
|Contact: Petr Boucek, MD|
|Universita Karlova v Praze||Recruiting|
|Prague, Czech Republic|
|Contact: Ivan Rychlik, MD|
|Steno Diabets Center||Recruiting|
|Gentofte, Denmark, 2820|
|Contact: Morten Lindhardt, MD +45 30752019 email@example.com|
|Contact: Peter Rossing, Prof. MD +45 4443 7310 firstname.lastname@example.org|
|Sub-Investigator: Morten Lindhardt, MD|
|Principal Investigator: Peter Rossing, Prof. MD|
|Klinikum St. Georg gGmbH||Recruiting|
|Contact: Joachim Beige, MD|
|Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center||Active, not recruiting|
|Instituto de Ricerche Farmacologiche Mario Negri||Recruiting|
|Bergamo, Italy, 24020|
|Contact: Matias Trillini, MD email@example.com|
|Sub-Investigator: Matias Trillini, MD|
|Principal Investigator: Piero Luigi Ruggenenti, MD|
|Macedonia, The Former Yugoslav Republic of|
|Department of Nephrology, University of Skopje||Recruiting|
|Skopje, Macedonia, The Former Yugoslav Republic of|
|Contact: Goce Spasovski, MD|
|University Medical Center Groningen||Recruiting|
|Contact: Gerjan Navis, MD|
|Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz||Active, not recruiting|
|Madrid, Spain, 28040|
|University of Glasgow||Recruiting|
|Glasgow, United Kingdom, G12 8TA|
|Contact: Christian Delles, DM Christian.Delles@glasgow.ac.uk|
|Principal Investigator: Christian Delles, MD|
|Sub-Investigator: Gemma Currie, MD|
|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:||Angel Argiles, MD||Institut Universitaire de Recherche Clinique, RD Nephrologie SAS|
|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:||Petr Boucek, MD||Institut Klinické a Experimentální Mediciny|
|Principal Investigator:||Goce Spasovski, MD||Department of Nephrology, University of Skopje|