Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
Condition: Diabetic Nephropathy; Diabetic Retinopathy
MeSH terms: Retinal Diseases; Diabetic Retinopathy; Kidney Diseases; Diabetic Nephropathies
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Detailed description: 
      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.

      Rationale:

        1. Urinary proteomics predicts development of microalbuminuria (as a surrogate marker for
           the development of overt nephropathy) in a cohort of type 2 diabetic patients with
           normal urinary albumin excretion at screening.

        2. 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 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.
    

Intervention name(s): Spironolactone; Placebo; Standard care
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Standard diabetes care
Intervention MeSH terms: Spironolactone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: Proteomics; Diabetes; Chronic kidney disease; Diabetic nephropathy; Diabetic retinopathy; Mineralocorticoid receptor antagonists; Spironolactone; Microalbuminuria