Diabetic NephropathyPhase 2/3PRIORITYNCT02040441
Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
A Phase 2/3 study testing Spironolactone in people with Diabetic Nephropathy and Diabetic Retinopathy, run by Peter Rossing at 15 sites in 10 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Diabetic Nephropathy, Diabetic Retinopathy
- What is being tested?
- Spironolactone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,777 participants
- Where
- 15 sitesin 10 countries
- Study dates
- Mar 2014to Nov 2018
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 13Show fewer
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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.
- Diagnosis of Addison's disease.
- Being lactating.
- Intend to become pregnant within the duration of the study or not use adequate birth control.
- Known or suspected abuse of alcohol or narcotics
- Not able to understand informed consent form
- 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
Trial locations and contacts
15 sites in 10 countries.
15 sites in 10 countries
Germany3 sites
Universitätsklinikum Carl Gustav Carus, Technischen Universität Dresden
Dresden
Diabetologen Hessen
Hessen
Klinikum St. Georg gGmbH
Leipzig
Netherlands3 sites
University Medical Center Groningen
Groningen
Diabetes Vascular Research Foundation
Hoogeveen
Stichting VUMC
Hoorn
Czechia2 sites
Institut Klinické a Experimentální Mediciny
Prague
Universita Karlova v Praze
Prague
Greece1 site
Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center
Athens
North Macedonia1 site
Department of Nephrology, University of Skopje
Skopje
Spain1 site
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Madrid, 28040
About this study
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.
Read more
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:
- 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.
Read the 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:
- 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.
- 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.
- Conditions
- Diabetic Nephropathy, Diabetic Retinopathy
- Being tested
- Spironolactone, Placebo, Standard care
- Keywords
- Proteomics, Diabetes, Chronic kidney disease, Diabetic nephropathy, Diabetic retinopathy, Mineralocorticoid receptor antagonists, Spironolactone, Microalbuminuria
- Medical subject headings
- Diabetic Nephropathies, Diabetic Retinopathy, Diabetes Mellitus, Renal Insufficiency, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SpironolactoneDrug
PlaceboDrug
Standard careDrug
Standard diabetes care
| Study group | Role | What they receive |
|---|---|---|
| Spironolactone | Active comparator | High-risk pattern: Spironolactone 25 mg once daily + Standard care Receives: Drug: Spironolactone; Drug: Standard care |
| Placebo | Placebo comparator | High-risk pattern: One placebo tablet once daily + Standard care Receives: Drug: Placebo; Drug: Standard care |
| Observational | Other | Low-risk pattern: Standard care Receives: Drug: Standard care |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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
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.
Measured: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)
Retinopathy
Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from self-reported adverse events.
Measured: 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
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
Measured: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)
Microalbuminuria
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
Measured: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)
Macroalbuminuria
Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void urine samples)
Measured: 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 CKD class
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.
Measured: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)
Slope of estimated GFR
Change in estimated GFR (slope and absolute from baseline and from 3 month post-baseline to end of study)
Measured: Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2014 (estimated)
- Study startMar 2014
- Primary completionNov 2018
- Study completionNov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Diabetic NephropathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,777 participants (actual)
Sponsor and investigators
- Lead sponsor
- Peter Rossing
- Sponsor type
- University, hospital or other
- 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, Ss. Cyril and Methodius University of Skopje, Hannover Clinical Trial Center, European Commission, Diabetes Vascular Research Foundation Hoogeveen, University Ghent, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Stichting VUMC, Diabetologen Hessen
- Responsible party
- Sponsor-investigator, Peter Rossing, Steno Diabetes Center Copenhagen
- Investigators
- Peter Rossing, Prof. MD, Study chair, Steno Diabetes Center CopenhagenMatias Trillini, MD, Principal investigator, Istituto de Ricerche Farmacologiche Mario NegriAlberto Ortiz, MD, Principal investigator, Instituto de Investigación Sanitaria de la Fundación Jiménez DíazChristian Delles, MD, Principal investigator, University of GlasgowGerjan Navis, MD, Principal investigator, University Medical Center GroningenIvan Rychlik, MD, Principal investigator, Univerzita Karlova v PrazeJoachim Beige, MD, Principal investigator, Klinikum St. Georg gGmbHMarina Noutsou, MD, Principal investigator, Geniko Nosikomeico Athinas Ippokrateio, Hospital Diabetes Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02040441
- Sponsor's protocol ID
- 2012-000452-34
- Other IDs
- 2012-000452-34
- Acronym
- PRIORITY
- Status last verified
- Dec 2018
- First submitted
- 16 Dec 2013
- Last updated
- 21 Dec 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 36841085Chung 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.
PubMed 33107592Tofte 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.
PubMed 32135136Tofte 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.
PubMed 29781558Lindhardt 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.
PubMed 26936907
Study at a glance
From the registry record, last updated by the sponsor on 21 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
- ClinicalTrials.gov ID
- NCT02040441
- Acronym / sponsor ID
- PRIORITY / 2012-000452-34
- Conditions
- Diabetic Nephropathy, Diabetic Retinopathy
- Keywords
- Proteomics, Diabetes, Chronic kidney disease, Diabetic nephropathy, Diabetic retinopathy, Mineralocorticoid receptor antagonists, Spironolactone, Microalbuminuria
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,777 participants (actual)
- Lead sponsor
- Peter RossingUniversity, hospital or other
- 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, Ss. Cyril and Methodius University of Skopje, Hannover Clinical Trial Center, European Commission, Diabetes Vascular Research Foundation Hoogeveen, University Ghent, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Stichting VUMC, Diabetologen Hessen
- Study start
- Mar 2014 (actual)
- Primary completion
- Nov 2018 (actual)
- Study completion
- Nov 2018 (actual)
- First posted
- 20 Jan 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
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:
- 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.
- 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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Spironolactone | Active comparator | Drug: Spironolactone, Drug: Standard careHigh-risk pattern: Spironolactone 25 mg once daily + Standard care |
| Placebo | Placebo comparator | Drug: Placebo, Drug: Standard careHigh-risk pattern: One placebo tablet once daily + Standard care |
| Observational | Other | Drug: Standard careLow-risk pattern: Standard care |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (21 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Spironolactone | Drug | Spironolactone |
| Placebo | Drug | Placebo |
| Standard careStandard diabetes care | Drug | Observational, Placebo, Spironolactone |
Primary outcome
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).
7 secondary outcomes
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)
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)
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)
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)
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)
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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Dec 2018.
- Derived from this study: PubMed 36841085Rotbain 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.
- Derived from this study: PubMed 33107592Chung 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.
- Derived from this study: PubMed 32135136Tofte 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.
- Derived from this study: PubMed 29781558Tofte 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.
- Derived from this study: PubMed 26936907Lindhardt 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.
- Official study webpageLink provided by the sponsor.
- European Commission, The Seventh Framework Programme.Link provided by the sponsor.
Related trials for Diabetic Nephropathy
Not yet recruitingObservational study
Beta-2-Trace Protein in Diabetic Nephropathy
Diabetic Nephropathy Type 2, Type 2 Diabetes Mellitus
Active, not recruitingObservational study
Family Investigation of Nephropathy and Diabetes (F.I.N.D.)
Diabetic Nephropathy, Diabetes Mellitus
Active, not recruitingPhase 4
Pentoxifylline in Diabetic Kidney Disease
Diabetic Kidney Disease
Active, not recruitingPhase 2
A Study on the Safety and Clinical Efficacy of Guominkang in the Treatment of Diabetic Kidney Disease
Diabetic Kidney Disease (DKD), Type 2 Diabetes
Not yet recruitingObservational study
Relationship Between Insulin Dose and Complications in Type 1 Diabetes
Diabetes Mellitus, Type 1 Diabetes, Cardiovascular Diseases (CVD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Rossing, Prof. MD study chair
Steno Diabetes Center Copenhagen
Matias Trillini, MD principal investigator
Istituto de Ricerche Farmacologiche Mario Negri
Alberto Ortiz, MD principal investigator
Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
15 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Spironolactone in people with Diabetic Nephropathy and Diabetic Retinopathy, run by Peter Rossing at 15 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 15 sites in Germany, Netherlands, Czechia, Belgium, Denmark and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02040441, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Dec 2018.