Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 1,777
- 试验地点
- 15
- 主要终点
- Albuminuria
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent ethical committee. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data
- •Male or female patients ≥ 18 years and < 75 years of age at Screening visit
- •Type 2 DM (WHO criteria)
- •Persistent normoalbuminuria (at least 2 of 3 UACR < 30 mg/g samples from "run in"-period)
- •Estimated GFR >45 ml/min/1.73m2 (MDRD formula) at Screening visit
- •The patient must be willing and able to comply with the protocol for the duration of the study
- •Female without child-bearing potential at the screening visit. Defined as one or more of following:
- •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
排除标准
- •Average of systolic BP< 110 or >160 mm Hg at baseline
- •Average of diastolic BP > 100 mm Hg at baseline
- •Type 1 DM (WHO criteria)
- •HbA1c <6.5% (48 mmo l/ mol) AND > 5 years of known duration of diabetes type 2 AND never treated with an antidiabetic drug of any kind.
- •Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)
- •Current lithium treatment
- •Known or suspected hypersensitivity to Spironolactone or to any of its excipients.
- •Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or Amiloride etc.
- •Screening (week -6) plasma (or serum) potassium level >5.0 mmol/L
- •Low plasma sodium determine by the investigator
- •Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)
- •Any clinically significant disorder, except for conditions associated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial
- •Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or myocardial ischemia, stroke, cardiac re-vascularisation or coronary artery bypass within the last 3 months
- •Diagnosis of non-Diabetic CKD current or in the past
- •Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.
- •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
研究组 & 干预措施
Spironolactone
High-risk pattern: Spironolactone 25 mg once daily + Standard care
干预措施: Spironolactone (Drug)
Spironolactone
High-risk pattern: Spironolactone 25 mg once daily + Standard care
干预措施: Standard care (Drug)
Placebo
High-risk pattern: One placebo tablet once daily + Standard care
干预措施: Placebo (Drug)
Placebo
High-risk pattern: One placebo tablet once daily + Standard care
干预措施: Standard care (Drug)
Observational
Low-risk pattern: Standard care
干预措施: Standard care (Drug)
结局指标
主要结局
Albuminuria
时间窗: 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).
次要结局
- Retinopathy(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Cardiovascular disease and mortality(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Change in CKD class(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Change in albuminuria(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Microalbuminuria(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Macroalbuminuria(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
- Slope of estimated GFR(Screening, (Low-risk: year 1, 2 and 3), (high-risk: week 13, 26, 39, 52, 65, 78, 91, 104, 117, 130, 143, 156))
研究者
Peter Rossing
Professor, Chief Physician, MD, DMSc
Steno Diabetes Center Copenhagen