Prediction and prevention of kidney disease in patients with diabetes

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2012-000452-34-DK
• Date of registration: 18/09/2013
• 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: 19/11/2013
• Target sample size: 2000
• 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, Germany, Greece, Italy, Macedonia, the former Yugoslav Republic of, Netherlands, Spain, 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 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 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 400

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)
• HbA1c <6.5% (48 mmo l/ mol) AND > 5 years of known duration of diabetes type 2 AND never treated with a 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 (ATC: N05AN)
• Known or suspected hypersensitivity to Spironolactone or to any of its excipients
• Current use of potassium sparing diuretics (ATC: C03D, C03E), such as: Spironolactone, Eplerenone or amiloride etc
• Hyperkalemia at Screening: plasma potassium level >5.0 mmol/L or
serum potassium level >5.4 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
• 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

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

Patients with type 2 diabetes mellitus and normoalbuminuria
MedDRA version: 18.1 Level: PT Classification code 10067585 Term: Type 2 diabetes mellitus System Organ Class: 10027433 - Metabolism and nutrition disorders

Intervention(s)

Product Name: Spironolactone
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 (ge-ometric mean) in UACR from “run-in” period samples OR > 40mg/g (geometric mean).

Timepoint(s) of evaluation of this end point: Every 13 weeks and at planned end (July to September 2018) or early
termination (treatment group)
Every 52 weeks and at planned end (July to September 2018) 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 2000 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)

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.
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.

Timepoint(s) of evaluation of this end point: 1), 3), 8) during the study
2), 9) Data collected from self-reported AEs
4), 5), 10), 11) run-in period, every 13 weeks, at planned end (July to
September 2018) or early termination (treatm. group), run-in period,
every 52 weeks, at planned end (Jul to Sep 2018) or early termination
(obs. group)
6),12) screening/baseline, Visit 1, every 13 weeks, at planned end or
early termination (treatm. group); every 52 weeks and at planned end
or early termination (obs. group)
7), 13) baseline, every 13 weeks and at planned end or early termination
(treatm. group); every 52 weeks and at planned end or early
termination (obs. group)
14) baseline, every Visit, prolonged until all AEs are resolved or until the
investigator assess the adverse events as "chronic" or "stable".

Secondary ID(s)

3004

Source(s) of Monetary Support

FP7 Program

Ethics review

Status: Approved
Approval date:
Contact: