Prediction and prevention of kidney disease in patients with diabetes

• Register: EUCTR
• Last refreshed on: 4 December 2018
• Main ID: EUCTR2012-000452-34-ES
• Date of registration: 05/12/2013
• Prospective Registration: Yes
• Primary sponsor: Steno Diabetes Center
• Public title: Prediction and prevention of kidney disease in patients with diabetes
• Scientific title: Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria - PRIORITY
• Date of first enrolment: 07/02/2014
• Target sample size: 3280
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-000452-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Randomized, double blind, placebo-control trial and prospective observational study; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Czech Republic, Denmark, France, Germany, Greece, Italy, Macedonia, the former Yugoslav Republic of, Netherlands, Spain, Switzerland, United Kingdom

Contacts

• Name: Prof. Peter Rossing MD. DMSc
• Affiliation: Steno Diabetes Center

• Name: Prof. Peter Rossing MD. DMSc
• Affiliation: Steno Diabetes Center

Key inclusion & exclusion criteria

Inclusion criteria:
? Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent EC. 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)
? eGFR > 45 ml/min/1.73m2 (MDRD formula) at Screening visit
? HbA1c ? 6.5% (48 mmol / mol) and < 13% (119 mmol / mol) 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:
- Female patients ? 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year
- Female patients < 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year and serum FSH levels > 40 mIU/mL as well as serum estrogen levels < 30 pg/ml or a negative estrogen test
- 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 the following:
- Correct use of reliable contraception methods. This includes one or more ofthe 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, femidom or condom) AND in combination with a spermicide
- General sexual abstinence from the time of screening, 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.
- Having only female sexual partners
- Sexual relationship with sterile male partners only
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 80
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 120

Exclusion criteria:
? 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)
? 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
? Hyponatriemia 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 as-sociated 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 MI, stroke, PTCA or CABG within the last 3 months
? Body mass index < 18.5 or > 40 kg/m2
? 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with type 2 diabetes mellitus and normoalbuminuria
MedDRA version: 14.1 Level: PT Classification code 10067585 Term: Type 2 diabetes mellitus System Organ Class: 10027433 - Metabolism and nutrition disorders

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Intervention(s)

Product Name: Espironolactona
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SPIRONOLACTONE
CAS Number: 52-01-7
Other descriptive name: SPIRONOLACTONE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Development of confirmed microalbuminuria UACR >30 mg/g in at least two out of three first morning voids with ? 30% increase in UACR from "run-in" period samples.

Timepoint(s) of evaluation of this end point: Every 13 weeks and week 156 or early termination (treatment group)
Every 52 weeks and week 156 or early termination (observational group)

Main 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 Objective: -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
-Assessment of safety in the intervention group
-To compare the rate of change in UAER in high- vs. low-risk patients (based on the proteomic test), and to compare the effect of spironolactone on rate of change in UACR in the intervention study.
-In addition, the objective is to study the rate of change in eGFR 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
-To establish a biobank that will allow testing of additional putative markers for progression of diabetic nephropathy, development of cardiovascular events and death

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1), 8) during the study
2), 9) Data collected from self-reported AEs
3), throughout the study
4), 5), 10), 11), run-in period, every 13 weeks, week 156 or early termination (treatment group), run-in period, every 52 weeks, week 156 or early termination (observational group)
6),12) screening/baseline, Visit 1, every 13 weeks, week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group)
7), 13) baseline, every 13 weeks and week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group)
14) baseline, every Visit, prolonged until all AEs are resolved or until the investigator assess the adverse events as ?chronic? or ?stable?.

Secondary end point(s): In the following paragraphs patients in the intervention group, (group B) and observation group (group A) will be compared

1) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD), and all cause mortality during the study
2) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from self-reported AEs
3) 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
4) Development of microalbuminuria (UACR >30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of confirmed microalbuminuria
5) Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void urine samples)
6) For patients with eGFR ? 60 at baseline, development of eGFR<60 ml/min/1.73m2. eGFR will be measured from serum creatinine (standardized traceable method) on blood samples tested in local laboratories. Serum creatinine (mg/dL) will be recorded on eCRFs and used to calculate estimated glomerular filtration rate using the MDRD equation [eGFR ml/min/ 1.73m2 =186 x serum creatinine-1.154 x age-0.203 x (1.210 if black) x (0.742 if female)]
7) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)


In the following paragraphs patients receiving active medication will be compared to placebo treatment.

8) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD) and all cause mortality during the study
9) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from AEs
10) Development of microalbuminuria (UACR > 30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of con-firmed microalbuminuria
11) Development of macroalbuminuria (UACR > 300 mg/g in 2 out 3 first morning void urine samples)
12) For patients with eGFR ? 60 at baseline, development of eGFR<60 ml/min/1.73m2
13) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)

14) Assessment of safety
The assessment of safety will be based primarily on the frequency of eCRF-documented AEs, laboratory abnormalities, and SAEs. Occurrence and frequency of eCRF-documented AEs, SAEs and laboratory abnormalities will be summarized by treatment group.
In addition AEs leading to death and AEs leading to discontinuation of study medication and/or withdrawal will be summarized for the two treatment groups.

Secondary ID(s)

3004

2012-000452-34-DK

Source(s) of Monetary Support

FP7 Program