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

• Status: Completed
• Trial end date: 2018-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Peter Rossing
• Collaborators: Charite University, Berlin, Germany; Cyril and Methodius University in Skopje; Diabetes Vascular Research Foundation Hoogeveen; Diabetologen Hessen; European Commission; Geniko Nosokomeio Athinas Ippokrateio; Hannover Clinical Trial Center; Institut Klinické a Experimentální Mediciny Praze; Institut Universitaire de Recherche Clinique Montpellier; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz; Istituto Di Ricerche Farmacologiche Mario Negri; Klinikum St. Georg Leipzig; Mosaiques Diagnostics GmbH; Stichting VUMC; Universitaet Zürich; Universitair Ziekenhuis Gent; Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden; University Medical Center Groningen; University of Glasgow; Univerzita Karlova v Praze
• Treatments: Mineralocorticoid Receptor Antagonists; Spironolactone

Criteria

Inclusion Criteria:

1. Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent ethical committee. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data

2. Male or female patients ≥ 18 years and < 75 years of age at Screening visit

3. Type 2 DM (WHO criteria)

4. Persistent normoalbuminuria (at least 2 of 3 UACR < 30 mg/g samples from "run in"-period)

5. Estimated GFR >45 ml/min/1.73m2 (MDRD formula) at Screening visit

6. The patient must be willing and able to comply with the protocol for the duration of the study

7. Female without child-bearing potential at the screening visit. Defined as one or more of following:

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

7.3) 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy.

OR a negative urine pregnancy test at the Screening visit AND one or more of following:

7.4) Correct use of reliable contraception methods. This includes one or more of the following: hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring or oral) or an intrauterine device (IUD) OR correct use of double barrier with one of the following: barrier methods (diaphragm, cervical cap, Lea contraceptive or condom) AND in combination with a spermicide.

7.5) General sexual abstinence from the time of screening/ baseline, during the study until a minimum of 30 days after the last administration of study medication if this is already established as the patient's preferred and usual lifestyle.

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

Exclusion Criteria:

1. Average of systolic BP< 110 or >160 mm Hg at baseline

2. Average of diastolic BP > 100 mm Hg at baseline

3. Type 1 DM (WHO criteria)

4. HbA1c <6.5% (48 mmo l/ mol) AND > 5 years of known duration of diabetes type 2 AND never treated with an antidiabetic drug of any kind.

5. Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)

6. Current lithium treatment

7. Known or suspected hypersensitivity to Spironolactone or to any of its excipients.

8. Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or Amiloride etc.

9. Screening (week -6) plasma (or serum) potassium level >5.0 mmol/L

10. Low plasma sodium determine by the investigator

11. Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)

12. Any clinically significant disorder, except for conditions associated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial

13. Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or myocardial ischemia, stroke, cardiac re-vascularisation or coronary artery bypass within the last 3 months

14. Diagnosis of non-Diabetic CKD current or in the past

15. Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.

16. Diagnosis of Addison's disease.

17. Being lactating.

18. Intend to become pregnant within the duration of the study or not use adequate birth control.

19. Known or suspected abuse of alcohol or narcotics

20. Not able to understand informed consent form

21. Participation in any other intervention trial than PRIORITY or a related sub-study is not allowed within 30 days before inclusion or concurrent to this study