Proteomic Prediction and Renin Angiotensin Aldosterone System Inhibition Prevention Of Early Diabetic nephRopathy In TYpe 2 Diabetic Patients With Normoalbuminuria
Phase: PHASE2
Conditions: Diabetic Nephropathy, Diabetic Retinopathy
Sponsor: Peter Rossing

Clinical Study Protocol - PRIORITY 
 
EudraCT No. 2012-000452-34  
Version 3.0, dated 12.10.2015 
Page 1 of 62 
 
 
 
 
Clinical Study Protocol 
 
Proteomic prediction and Renin angiotensin aldosterone 
system Inhibition prevention Of early diabetic nephRopathy 
In TYpe 2 diabetic patients with normoalbuminuria 
 
- PRIORITY - 
 
 
Study Design: 
Prospective, multicenter, double-blind, randomized, placebo-
controlled, phase II-III study 
 
 
Version: 
3.0, dated 12.10.2015  
 
Study Code of the Sponsor:  
3004 
 
EudraCT-Number: 
2012-000452-34  
 
Sponsor:  
Steno Diabetes Center 
 
Niels Steensens Vej 2 
 
DK-2820 Gentofte 
 
Denmark 
 
International Coordinating 
Investigator: 
Senior Investigator, Chief Physician,  
 
Prof., Peter Rossing, MD, DMSc 
 
Steno Diabetes Center 
 
Niels Steensens Vej 2 
 
DK-2820 Gentofte 
 
Denmark 
 
 
Study Centers: 
PRIORITY investigators:  
 
Approx. 17 centers throughout Europe 
 
- Confidential - 

Clinical Study Protocol - PRIORITY 
 
EudraCT No. 2012-000452-34  
Version 3.0, dated 12.10.2015 
Page 2 of 62 
STATEMENT OF COMPLIANCE/ CONFIDENTIALITY 
 
This study protocol is property of the sponsor. Property rights are regulated according to the new Eu-
ropean Union Directive on Copyrights as passed in summer of 2001.No person is authorized to make 
it public without written permission of the sponsor. The information may be disclosed to and used by 
investigators and their staff and associates as may be necessary to conduct the clinical study. 
 
 
THIS DOCUMENT IS PROVIDED "AS IS," AND COPYRIGHT HOLDERS MAKE NO REPRESENTA-
TIONS OR WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, WAR-
RANTIES 
OF 
MERCHANTABILITY, 
FITNESS 
FOR 
A 
PARTICULAR 
PURPOSE, 
NON-
INFRINGEMENT, OR TITLE; THAT THE CONTENTS OF THE DOCUMENT ARE SUITABLE FOR 
ANY PURPOSE; NOR THAT THE IMPLEMENTATION OF SUCH CONTENTS WILL NOT INFRINGE 
ANY THIRD PARTY PATENTS, COPYRIGHTS, TRADEMARKS OR OTHER RIGHTS. 
 
COPYRIGHT HOLDERS WILL NOT BE LIABLE FOR ANY DIRECT, INDIRECT, SPECIAL 
OR CONSEQUENTIAL DAMAGES ARISING OUT OF ANY USE OF THE DOCUMENT OR 
THE PERFORMANCE OR IMPLEMENTATION OF THE CONTENTS THEREOF. 
 

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STUDY PERSONNEL 
Sponsor: 
 Steno Diabetes Center 
Senior Investigator, Prof. Peter Rossing MD. DMSc 
Niels Steensens Vej 2 
DK-2820 Gentofte, Denmark  
Tel.: +45 4443 7310 
Fax: +45 4443 8160 
Email: pro@steno.dk  
International Coordinating 
Investigator: 
 Senior Investigator, Prof. Peter Rossing MD. DMSc 
Steno Diabetes Center 
Niels Steensens Vej 2 
DK-2820 Gentofte, Denmark 
Tel.: +45 4443 7310 
Fax: +45 4443 8160 
Email: pro@steno.dk 
Steering committe on Science:  
 
 
 
 
Steering commitee on 
Samples, data and ethics: 
 
 
 
Steering commitee IPR and 
dissemination: 
 
 
 
SAE-Reporting/ 
Pharmacovigilance: 
 Christian Delles (Chairman) 
All partners involved in scientific issues are member of this 
Steering Committee, represented by one dedicated person, 
and Morten Lindhardt. 
 
Heiko von der Leyen (Chairman) 
All partners involved in ethics issues are member of this 
Steering Committee, represented by one dedicated person, 
and Morten Lindhardt. 
 
Harald Mischak (Chairman) 
Heiko von der Leyen, Peter Rossing, Gerjan Navis, Christian 
Delles, Piero Luigi Ruggenenti. 
 
 
Institute of Clinical Pharmacology 
Prof. Dr. Jens Jordan MD, Ph.D. 
Hannover Medical School 
Carl-Neuberg-Str. 1 
D-30625 Hannover, Germany 
Tel.: +49 (0) 511 532 3959 
Fax: +49 (0) 511 532 162794 
Email: sae-reporting@mh-hannover.de 
Study Statistics: 
 
 
 
 
 
 
 
Data Management: 
 
 
 
 
 
 
 
Steno Diabetes Center 
Tine Willum Hansen MD, Ph.D. 
Niels Steensens Vej 2 
DK-2820 Gentofte, Denmark  
Tel.: +45  4443 7310 
Fax.: +45 4443 8160 
Email: twih@steno.dk  
 
Hannover Clinical Trial Center GmbH 
Managing Director Prof. Heiko von der Leyen 
Carl-Neuberg-Str. 1 / K27 OE 9751 
DE-30625 Hannover, Germany 
Tel.: +49 (0) 511 533 333 0 
Fax: +49 (0) 511 533 333 99 
Email: priority@clinical-trial-center.de  
 

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Contract Research Organisation / 
Monitoring: 
 
 
 
 
 
 
Central Laboratory:  
 
 
 
 
 
Proteomic Laboratory: 
 
 
 
 
 
 
IMP management: 
 
 
 
 
 
 
 
IWRS Provider: 
 
 
 
 
 
 
IMP Manufacturer: 
Hannover Clinical Trial Center GmbH 
Managing Director Prof. Dr. Heiko von der Leyen 
Carl-Neuberg-Str. 1 / K27 OE 9751 
DE-30625 Hannover, Germany 
Tel.: +49 511 533 333 0 
Fax: +49 511 533 333 99 
Email: priority@clinical-trial-center.de 
 
Steno Diabetes Center  
Niels Steensens Vej 2 
DK-2820 Gentofte, Denmark 
Tel.: +45 4443 9970 
Email: Priority-lab@steno.dk 
 
Julia Raad 
Diapat GmbH, Rotenburger Str. 20  
DE-30659Hannover, Germany 
Tel.: +49 (0) 511 554744 39 
Fax.: +49 (0) 511 554744 31 
Email: raad@mosaiques-diagnostics.com  
 
Elizabeth Douglas or Pamela Surtees 
Research & Development 
NHS Greater Glasgow & Clyde 
1st Floor Tennent Institute, Western Infirmary 
Church Street, Glasgow, UK G11 6NT 
Tel:    
+44 (0) 141 211 8554  
E-mail:  Elizabeth.Douglas@ggc.scot.nhs.uk 
 
Sharon Kean 
Director Information Systems 
Robertson Centre for Biostatistics 
University of Glasgow 
Phone: +44 (0) 141 330 4744 
E-mail: Sharon.Kean@glasgow.ac.uk 
 
Amie Louise Lake or Emma Thomson (QP) 
MAWDSLEYS Clinical Services,  
Unit 22, Quest Park, Wheatley Hall Road,  
Doncaster, DN2 4LT, United Kingdom. 
Tel.: +44 (0) 1302 553022 
Fax.: +44 (0) 1302 553013 
Email: amie.louise@mawdsleys.co.uk 
Email: emma.thomson@mawdsleys.co.uk  
 

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TABLE OF CONTENTS 
1 
List of Abbreviations ............................................................................................................................ 8 
2 
Synopsis ............................................................................................................................................ 10 
3 
Summary............................................................................................................................................ 15 
4 
Backgrund Information and Scientific Rationale ................................................................................ 16 
4.1 
Background Information ..................................................................................................... 16 
4.2 
Rationale ............................................................................................................................ 17 
5 
Objectives And Endpoints .................................................................................................................. 18 
5.1 
Primary objective ............................................................................................................... 18 
5.2 
Secondary objectives ......................................................................................................... 18 
5.3 
Additional scientific objectives ........................................................................................... 18 
5.4 
Primary endpoint ................................................................................................................ 18 
5.5 
Secondary endpoints ......................................................................................................... 18 
5.5.1 
In the total population: ....................................................................................................... 18 
5.5.2 
In the intervention group (group B) / High-risk population: ................................................ 19 
5.6 
Assessment of Safety ........................................................................................................ 19 
5.7 
Calculation of eGFR........................................................................................................... 19 
6 
Study Design ..................................................................................................................................... 21 
6.1 
Overall study design / Total study population .................................................................... 22 
6.2 
Observation group (group A) / Low-risk population ........................................................... 22 
6.3 
Intervention group (group B) / High-risk population ........................................................... 22 
6.4 
Long-term follow-up ........................................................................................................... 23 
6.5 
Biobank .............................................................................................................................. 23 
6.6 
Study visit description ........................................................................................................ 23 
7 
Study Population ................................................................................................................................ 26 
7.1 
Inclusion Criteria ................................................................................................................ 26 
7.2 
Exclusion criteria ................................................................................................................ 26 
7.3 
Screening failures .............................................................................................................. 27 
7.4 
Replacement of participants .............................................................................................. 27 
8 
Randomization/Blinding and Unblinding Procedures ........................................................................ 28 
8.1 
Patient Identification .......................................................................................................... 28 
8.2 
Randomization ................................................................................................................... 28 
8.3 
Assignment to treatment .................................................................................................... 28 
8.4 
Blinding procedure ............................................................................................................. 28 
8.5 
Unblinding procedures ....................................................................................................... 28 
8.5.1 
Emergency unblinding ....................................................................................................... 28 
8.5.2 
Planned unblinding ............................................................................................................ 28 
9 
Study Schedule .................................................................................................................................. 29 
9.1 
Involvement of patient ........................................................................................................ 29 
9.1.1 
Recruitment period............................................................................................................. 29 
9.1.2 
Patients .............................................................................................................................. 29 
9.2 
Data management and statistics ....................................................................................... 29 
9.3 
Publication ......................................................................................................................... 29 
10 
Study Procedures .............................................................................................................................. 30 
10.1 
Informed consent ............................................................................................................... 30 
10.2 
Medical history ................................................................................................................... 30 
10.3 
Concomitant medication .................................................................................................... 30 
10.4 
Physical examination ......................................................................................................... 30 
10.5 
Vital signs ........................................................................................................................... 30 
10.6 
Dispensing of investigational medicinal products .............................................................. 31 
10.7 
Laboratory examination ..................................................................................................... 31 
10.7.1 
Labelling of samples .......................................................................................................... 31 
10.8 
Blood samples ................................................................................................................... 31 
10.9 
Urine samples for albuminuria ........................................................................................... 31 
10.10 
Urine samples for proteomic analysis ................................................................................ 32 
10.11 
Biobank .............................................................................................................................. 32 
10.12 
Randomization ................................................................................................................... 33 

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10.13 
Adverse Events .................................................................................................................. 33 
10.14 
Significant medical event ................................................................................................... 33 
10.15 
Urine dipstick test............................................................................................................... 33 
10.16 
Pregnancy test ................................................................................................................... 33 
10.17 
Final assessment ............................................................................................................... 33 
10.18 
Clinical procedure after end of the study/ Early termination .............................................. 33 
10.19 
Unscheduled visit ............................................................................................................... 33 
11 
Investigal medical products ............................................................................................................... 34 
11.1 
IMPS .................................................................................................................................. 34 
11.1.1 
Formulation and preparation .............................................................................................. 34 
11.1.2 
Administration .................................................................................................................... 34 
11.1.3 
Packaging .......................................................................................................................... 34 
11.1.4 
Labeling ............................................................................................................................. 34 
11.1.5 
Storage and stability .......................................................................................................... 34 
11.2 
Accountability procedures for the IMP ............................................................................... 34 
11.3 
Main side effects of spironolactone ................................................................................... 35 
11.4 
Overdose ........................................................................................................................... 35 
11.5 
Risks in connection with the investigation procedures ...................................................... 36 
12 
ConMedication and Treatment .......................................................................................................... 37 
12.1 
Treatment in general .......................................................................................................... 37 
12.2 
Prohibited medication ........................................................................................................ 37 
12.3 
Hypertension treatment ..................................................................................................... 37 
12.4 
Albuminuria treatment ........................................................................................................ 37 
13 
Adverse Event Monitoring and Reporting .......................................................................................... 38 
13.1 
Definitions .......................................................................................................................... 38 
13.1.1 
Adverse Events .................................................................................................................. 38 
13.1.2 
Adverse Reaction............................................................................................................... 38 
13.1.3 
Serious Adverse Events/ Reaction .................................................................................... 38 
13.1.4 
Suspected Unexpected Serious Adverse Reaction ........................................................... 39 
13.2 
Reference document / Applicable product information ...................................................... 39 
13.3 
Documentation and reporting of AE................................................................................... 39 
13.3.1 
Documentation requirements ............................................................................................. 39 
13.3.2 
Reporting requirements ..................................................................................................... 40 
13.4 
Data monitoring committee and stopping rules ................................................................. 42 
14 
Risk assessment and Withdrawal rules ............................................................................................. 43 
14.1 
Potential risks ..................................................................................................................... 43 
14.2 
Known potential benefits .................................................................................................... 43 
14.3 
Potential benefits ............................................................................................................... 43 
14.4 
In concurrent illness ........................................................................................................... 43 
14.5 
Patient withdrawal .............................................................................................................. 43 
14.6 
Criteria for discontinuation ................................................................................................. 44 
15 
Statistical Considerations .................................................................................................................. 45 
15.1 
Sample size considerations ............................................................................................... 45 
15.1.1 
Considerations of risk stratification .................................................................................... 45 
15.2 
Study hypotheses .............................................................................................................. 45 
15.3 
Patient enrollment  ............................................................................................................. 45 
15.4 
Planned interim analyses ................................................................................................... 46 
15.4.1 
Safety review ..................................................................................................................... 46 
15.4.2 
Efficacy review ................................................................................................................... 46 
15.5 
Final analysis plan ............................................................................................................. 46 
15.6 
Analysis of primary endpoint .............................................................................................. 46 
15.7 
Analysis of secondary endpoints ....................................................................................... 47 
15.8 
Analysis of safety endpoints .............................................................................................. 47 
16 
Quality Assurance .............................................................................................................................. 49 
16.1 
Site monitoring ................................................................................................................... 49 
16.2 
Site audit an inspections .................................................................................................... 49 
17 
Ethical, Regulatory and administrative aspects ................................................................................. 50 
17.1 
Investigator responsibilities ................................................................................................ 50 
17.2 
Regulatory requirements ................................................................................................... 50 

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17.3 
Justification for selection criteria ........................................................................................ 50 
17.4 
IEC and NCA ..................................................................................................................... 50 
17.5 
Patient information and informed consent ......................................................................... 50 
17.6 
Insurance ........................................................................................................................... 51 
17.7 
Financial aspects ............................................................................................................... 51 
18 
Protocol Amendments and Deviations .............................................................................................. 52 
18.1 
Protocol amendments ........................................................................................................ 52 
18.2 
Protocol deviations............................................................................................................. 52 
19 
Data Management ............................................................................................................................. 53 
19.1 
Data retention .................................................................................................................... 53 
19.2 
Security .............................................................................................................................. 53 
19.3 
Data protection ................................................................................................................... 53 
20 
Data Handling and Record Keeping .................................................................................................. 54 
20.1 
Analyses and reporting ...................................................................................................... 54 
20.2 
Study records retention ...................................................................................................... 54 
21 
Publication Policy ............................................................................................................................... 55 
21.1 
General terms .................................................................................................................... 55 
21.2 
Study publications .............................................................................................................. 55 
21.3 
Substudy publications ........................................................................................................ 55 
22 
Substudies ......................................................................................................................................... 56 
23 
Reference .......................................................................................................................................... 57 
24 
APPENDIX 1: Treatment guidelines for hyperkalemia ...................................................................... 61 
 

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1 
LIST OF ABBREVIATIONS 
ACE 
Angiotensin converting enzyme inhibitors   
AE 
Adverse event 
ALT 
Alanine transaminase 
AR 
Adverse reaction 
ARB 
Angiotensin II receptor blocker  
ASAT 
Aspartat aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
BP 
Blood pressure  
BW 
Body weight 
CE 
Capillary electrophoresis 
CI 
Confidence interval 
CF 
Classification factor 
CABG 
Coronary artery bypass grafting  
CKD 
Chronic kidney disease 
CKD273 
Proteomic urine biomarker including 273 peptides significant for CKD 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CVD 
Cardiovascular disease 
DCCT 
The diabetes control and complications trial  
DM 
Diabetes mellitus 
DN 
Diabetic nephropathy  
DSUR 
Development safety update report 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
eGFR 
Estimated glomerular filtration rate 
EMA 
European medicines agency 
ESI-TOF 
Electrospray-ionization-time of flight   
ESRD 
End-stage renal disease  
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FP7 
Framework Program 7  
GLA 
Glasgow team 
GCP 
Good clinical practice 
GMP 
Good Manufacturing Practices 

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GFR 
Glomerular filtration rate 
GP 
General practitioner  
hCG 
Human chorionic gonadotropin  
HCTC 
Hannover Clinical Trial Center GmbH 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFCC 
International Federation of Clinical Chemistry and Laboratory Medicine 
IEC 
Independent ethics committee 
IIT 
Investigator initiated trial 
IMP 
Investigational medicinal product 
IPR 
Intellectual property rights 
IWRS 
Interactive web response system 
MARVIN 
The electronic case report form software program 
MDRD 
Modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Myocardial infarction 
MS 
Mass spectrometry 
NCA 
National competent authority 
NYHA 
The New York heart association classification for heart failure  
PI 
Principal Investigator 
PTCA 
Percutaneous transluminal coronary angioplasty 
R 
Randomization 
RAAS 
Renin angiotensin aldosterone system 
RAS 
Renin angiotensin system 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SD 
Standard deviation 
SEM 
Standard error of the mean 
SmPC 
Summary of product characteristics 
SOC 
System organ classes 
SOP 
Standard operating procedure 
SSAR 
Suspected serious adverse reaction 
SUSAR 
Suspected unexpected serious adverse reaction 
T 
Treatment 
UACR 
Urine albumin creatinine ratio 
UAER 
Urine albumin excretion rate 
WHO 
World Health Organization 
 

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2 
SYNOPSIS 
Study title 
Proteomic prediction and Renin angiotensin aldosterone system Inhibition 
prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with 
normoalbuminuria 
Short term 
PRIORITY 
Study code of the 
sponsor 
3004 
EudraCT number 
2012-000452-34 
Sponsor 
Steno Diabetes Center 
Senior Investigator, Prof. Peter Rossing MD. DMSc 
Niels Steensens Vej 2 
DK-2820 Gentofte 
Denmark  
Phone: +45 3079 5510 
Fax: +45 4443 8160 
International coordinat-
ing investigator 
Senior Investigator, Prof. Peter Rossing MD. DMSc 
Steno Diabetes Center 
Niels Steensens Vej 2  
DK-2820 Gentofte 
Denmark  
Phone: +45 4443 7310 
Fax: +45 4443 8160 
E-mail:pro@steno.dk 
Indication 
Patients with type 2 DM and normoalbuminuria 
Objectives 
Primary objective: 
To confirm that urinary proteomics can predict development of microalbu-
minuria (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 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 
Assessment of safety in the intervention group.  
Additional scientific objectives:  
To compare the rate of change in urinary albumin excretion rate 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. 

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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 spironolac-
tone. 
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 
Study design/ 
Prospective, multicenter, randomized, double blind, placebo-controlled 
phase II-III trial and a prospective observational study. 
Study centres 
Approx. 17 centres in Europe. 
Schedule 
 
Duration of the entire study (first patient in to last patient out): 
approximately 4.4 years 
Study-related: 
Recruitment period: From March 2014 to August 2016 
Patient-related: 
Duration of interventional/observational period including: 104-230 weeks 
Number of patients 
Screening: Estimated to be n = 2700 
To be included: n = 2000 
To be randomized: n = 300 
n = 300 patients will be randomized into intervention group with placebo or 
spironolactone and enter the double-blind treatment period if a CKD273 
specific (high risk) proteomic pattern is observed. Patients will be stratified 
in the two treatment arms (1:1) based on whether or not the patients is 
treated with RAS blocking agents at the time of entry (Screening).  
The remaining patients with a negative (low risk) proteomic pattern will be 
observed regarding the development of microalbuminuria and will receive 
standard of care treatment (observational group). 
Investigational medici-
nal products 
Investigational medicinal product (IMP): 
Administration: orally 
Active medication:  
Spironolactone (potassium sparing diuretic) 
Dosage: 25 mg per day (One tablet once daily) 
Placebo: 
Dosage: matched placebo (One tablet once daily) 
Study endpoints 
Primary study endpoint: 
Development of confirmed microalbuminuria (UACR>30 mg/g) in at least 
two out of three first morning voids with ≥ 30% increase (geometric mean) 

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in UACR from “run-in” period samples OR > 40 mg/g (geometric mean). 
Secondary study endpoints:  
Changes in albuminuria throughout the study period in all patients by as-
sessing the slope of albuminuria.  
Predictive value of the urinary proteomics test in regards to renal and 
cardiovascular events. 
Changes in eGFR including development of eGFR < 60 ml/min/1.73m2 
Changes in retinopathy and frequency of laser treatment. 
Additional scientific endpoints: 
The analysis will consider age and gender effects on the predictive value 
of the proteomics test and treatment effect. 
Assessment of safety in the intervention group.  
Inclusion criteria 
1) Written informed consent must be provided before participation. 
Patient information and consent form must be approved by rele-
vant independent EC. Specifically, all participating patients will be 
asked to give informed consent for long-term follow-up and collec-
tion 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) eGFR >45 ml/min/1.73m2 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. De-
fined 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 se-
rum FSH levels > 40 mIU/mL as well as serum estrogen lev-
els < 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 bar-
rier with one of the following:  barrier methods (diaphragm, 
cervical cap, Lea contraceptive, femidom or condom) AND in 
combination with a spermicide.  
7.5) General sexual abstinence from the time of screening/ base-
line, during the study until a minimum of 30 days after the 
last administration of study medication if this is already es-
tablished as the patient’s preferred and usual lifestyle. 
7.6) Having only female sexual partners. 

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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(ATC: N05AN) 
7) Known or suspected hypersensitivity to Spironolactone or to any 
of its excipients. 
8) Current use of potassium sparing diuretics (ATC: C03D, C03E), 
such as: Spironolactone, Eplerenone or Amiloride etc. 
9) Hyperkalemia at Screening: plasma potassium level >5.0 mmol/L 
or serum potassium level >5.4 mmol/L. 
10) Hyponatriemia determine by the investigator  
11) Current cancer treatment or within five years from baseline (ex-
cept 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 in-
terfere 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 MI, stroke, 
PTCA or CABG 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 re-
lated sub-study is not allowed within 30 days before inclusion or 
concurrent to this study 
Statistical rationale 
The aims of the study are to investigate the time to development of the 
primary endpoint in the included patients. The patients will based on the 
urinary proteomic test be divided into low risk patients who will enter an 
observation study without specific intervention, and high risk patients who 
will berandomized in a double blind parallel trial comparing placebo with 
active treatment with spironolactone. It is our hypothesis that high risk 
patients will develop the endpoint more frequent than low risk patients, 
and that treatment with spironolactone can mitigate the increased risk in 
high risk patients. 
The null hypotheses are that high and low risk patients develop the end-
point with the same frequency, and that the development is similar in pa-
tients treated with placebo or spironolactone 
Sample size calculation:  

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The expected relative proportions of diabetes type 2 patients develop-
ing microalbuminuriain our study population are: 24% in patients at 
high-risk for diabetic nephropathy in the treatment group, 40% in those 
patients at high-risk for diabetic nephropathy in the placebo group and 
8.5% in those therapy-naive patients at low-risk for diabetic nephropa-
thy. Using the samples size formula for two proportions test (α= 0.05 
β=0.80), randomized (1:1), n=129 in each arm of the intervention group. 
To account for drop-outs we plan to randomize 300 in all. It is expected 
that approx. 15% of the population will show a pattern of high-risk of 
CKD, therefore 2000 patients have to be included. Equal drop-out fre-
quency is expected I both groups and there will be no replacement of 
drop-out. Discontinuation prior randomization is categorized screening 
failure.   
Analysis populations: 
The primary analysis will be conducted for all patients included (intent-
to-treat population) in the observational and intervention study groups. 
In addition, all relevant efficacy endpoints will be also analyzed for the 
per protocol population in both study groups.  
Analysis of primary endpoint: 
Cox regression analysis of development of the primary endpoint ad-
justed for age, gender, study site will be conducted in both study 
groups (observational and intervention) and for study intervention in the 
interventional group. Secondly adjusted in addition for baseline UACR, 
HbA1c and BP. 
Analysis of secondary endpoints: 
Cox regression analysis of development of secondary endpoints in the 
both study groups (observational and intervention) as well within the inter-
ventional group (high- vs. low-risk), adjusted for age, gender, study site 
and study intervention with secondary adjustment for baseline UACR, 
HbA1c and BP. 
Assessment of safety: 
The assessment of safety will be based primarily on the frequency of 
eCRF-documented AEs, laboratory abnormalities, and SAEs (see section 
13.3). 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 treat-
ment groups. 
Final analysis plan: 
Statistical analysis of the data will be performed by Steno Diabetes Cen-
ter. A statistical analysis plan will be written and signed before database 
lock and unblinding of the entire treatment code.  
Methods for imputation and type of censoring will be clarified in the statis-
tical analysis plan prior to database lock and unblinding. 

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3 
SUMMARY 
This study aims to: 
1. Confirm in a prospective multicenter study of normoalbuminuric type 2 DM patients that the uri-
nary 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 pa-
tients can reduce progression to microalbuminuria in comparison to placebo, on the top of stand-
ard treatment in a randomized double-blind, placebo-controlled multicenter study.  
Patients: After screening 2700 patients, 2000 normoalbuminuric type 2 DM patients will be in-
cluded and will be stratified into an observational- and an intervention group using urinary prote-
omic test.  
Patients who have contraindications to aldosterone blockade will not be included in the study.  
Observational group: Patients who are classified as being at low risk for progression to diabetic 
nephropathy (approx. 85%) will enter observational period of at least 104 weeks, dependent on 
time of baseline visit. These patients will continue to receive usual care at their hospital diabetes 
clinic or GP with treatment according to standard guidelines  
Intervention group: Patients who are classified as being at high risk (approx. 15%) will be ran-
domly assigned to the mineralocorticoid receptor antagonist spironolactone 25 mg once daily or 
placebo therapy in addition to optimal standard therapy. These patients will enter a treatment peri-
od of at least 104 weeks, dependent on time of baseline visit. 
Endpoint: The primary endpoint will be the development of confirmed microalbuminuria (UACR 
>30 mg/g) in at least two out of three urine tests, with at least 30% increase in UACR from “run-in” 
period. We will also examine changes in albuminuria throughout the study period in all patients by 
assessing the slope of albuminuria changes and absolute changes from inclusion to the end of 
study. We will compare the observational group and the treated intervention group in order to as-
sess the predictive value of the urinary proteomics test. Furthermore, within the intervention group 
we will compare changes in albuminuria between patients randomized to placebo or the mineralo-
corticoid receptor antagonist spironolactone. The analysis will consider age and gender effects on 
the predictive value of the proteomics test and treatment effect. 

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4 
BACKGRUND INFORMATION AND SCIENTIFIC RA-
TIONALE 
4.1 
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. Almost 90% of pa-
tients have type 2 DM, and absolute numbers are expected to rise in parallel to the current obesi-
ty and metabolic syndrome epidemic. Improved treatment has reduced mortality but the pro-
longed duration of DM increases the likelihood of development of late diabetic complications 
(1;2). 
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 dis-
ease (ESRD) in the Western world (1). In clinical practice, renal impairment is diagnosed by al-
buminuria or proteinuria and/or changes in serum creatinine/creatinine clearance indicating alter-
ations of the glomerular filtration rate (GFR) (3). 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 nephropa-
thy (DN) (4).  
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 consid-
ered a risk factor and as an early indicator of future onset of DN. Microalbuminuria is regarded as 
the earliest clinical marker of renal damage (5;6). 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 cardio-
vascular disease (7;8).  
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 microvas-
cular complications (9;10). 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 microalbumi-
nuria is present (11;12). Studies aiming for earlier prevention of nephropathy by starting renin 
angiotensin aldosterone system (RAAS) blocking treatment in normoalbumuric patients have giv-
en mixed and often disappointing results (13). This might reflect that a large fraction of normoal-
buminuric patient may not be at risk for progression thereby reducing the event rate or power in 
previous studies (14). Early identification of normoalbuminuric patients at high risk for develop-
ment of diabetic nephropathy could identify patients who might benefit of intervention with in-
creased 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 anti-
hypertensive 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 (15;16). 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-

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resolution analysis of several thousand low-molecular-weight urinary proteins/peptides in about 
one hour (17). Urine holds several advantages over blood in clinical proteomics. It can be collect-
ed non-invasively and its proteome is relatively stable (18). Members of the consortium have 
successfully identified a urinary biomarker pattern including 273 peptides significantly associated 
with chronic kidney disease (CKD273) (19).  
Importantly, the biomarker panel has been validated in a multicentric approach involving >1000 
blinded samples (20;21). The accuracy was high (96% sensitivity and 98% specificity), when 
evaluating only the diabetic patients in the test-set. To test the CKD273 pattern as a tool for early 
detection of DN, we recently performed an independent longitudinal study of normoalbuminuric 
diabetic patients at inclusion (22). The urinary CKD273 pattern distinguished progressing patients 
from non-progressing patients. The corresponding receiver operating characteristic (ROC) analy-
sis 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 impair-
ment based on clinical history, creatinine, or urinary protein levels resulting in an overall specifici-
ty 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 UAER 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 (22;23). 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 (24).  
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 dur-
ing 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 pre-emptive intervention (25).  
Collectively, our existing data strongly indicate that the urinary proteomics based test appears 
ideal to identify patients who will develop microalbuminuria and ultimately DN and thereby facili-
tates targeting intensified preventative therapy to this group. 
4.2 
Rationale 
1. 
Urinary proteomics predicts development of microalbuminuria (as a surrogate 
marker for the development of overt nephropathy) in a cohort of 2000 type 2 dia-
betic patients with normal urinary albumin excretion at screening. 
2. 
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 person-
alised medicine 
 

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5 
OBJECTIVES AND ENDPOINTS 
5.1 
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 2000 type 2 diabetic patients 
with normal urinary albumin excretion. 
5.2 
Secondary objectives 
To investigate if early initiation of preventive therapy with spironolactone 25 mg once daily reduc-
es risk of transition to microalbuminuria in those patients identified by urinary proteomics to be at 
high risk. 
5.3 
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 
UACR in the intervention group. 
In addition, the objective is to study the rate of change in eGFR (26) 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. 
A research biobank will be established at Steno Diabetes Center containing biological material in 
the form of blood and urine samples.This will allow testing of additional putative markers for pro-
gression of diabetic nephropathy and development of cardiovascular events and death (such as 
but not limited to): Endothelial dysfunction (vWF, ADMA, VCAM, ICAM, E-selectin), inflammation 
(hs-CRP, IL-6, TNF-alpha, YKL40, IL-8, IL10), vascular riskmarkers (NT-proBNP, adiponectin, 
ghrelin), and bonemarkers (vitamin D, p-PTH, p-calcium, p-phosphat, p-magnesium, osteopro-
tegerin (OPG), osteopontin (OPN), RANKL, bone morphogenic protein (BMP), p-FGF23, oste-
ocalcin, bone-specific alkaline phosphatase). 
5.4 
Primary endpoint 
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).  
5.5 
Secondary endpoints 
5.5.1 
In the total population:  
In the following paragraphs patients in the intervention group, (group B) and observation 
group (group A) will be compared. 
• 
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. 

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• 
Comparison of incidence of retinopathy and frequency of laser treatment. Data 
collected from self-reported AEs 
• 
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 
• 
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 microal-
buminuria 
• 
Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void 
urine samples) 
• 
For patients with eGFR ≥ 60 at baseline, development of eGFR<60 
ml/min/1.73m2.  
• 
Change in eGFR (slope and absolute from baseline and from 3 month post-
baseline to end of study) 
5.5.2 
In the intervention group (group B) / High-risk population: 
In the following paragraphs patients receiving active medication will be compared to placebo 
treatment.  
• 
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. 
• 
Comparison of incidence of retinopathy and frequency of laser treatment. Data 
collected from AEs 
• 
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 microal-
buminuria 
• 
Development of macroalbuminuria (UACR > 300 mg/g in 2 out 3 first morning void 
urine samples) 
• 
For patients with eGFR ≥ 60 at baseline, development of eGFR <60 
ml/min/1.73m2 
• 
Change in eGFR (slope and absolute from baseline and from 3 month post-
baseline to end of study) 
5.6 
Assessment of Safety 
The assessment of safety will be based primarily on the frequency of eCRF-documented AEs, la-
boratory abnormalities, and SAEs (see section 13.2.). 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. 
5.7 
Calculation of eGFR 
Calculation is based on locally measured creatinine from a blood sample. At the time of screen-
ing the local eGFR will be used for evaluation of inclusions criteria no. 5 only.  

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Information in the eCRF is based on the creatinine measurement method in the local laboratory. 
The central calculation of eGFR will be made with CKD-EPI equation. The estimation will be 
made centrally in the eCRF after entry of creatinine data by the investigators.  
CKD-EPI equation: GFR = 141 X min(Scr/κ,1)α x max(Scr/κ,1)-1.209 x 0.993Age x 1.018 [if female] x 
1.159 [if black]. Where Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α 
is –0.329 for females and –0.411 for males, min indicates the minimum of Scr/κ or 1, and max in-
dicates the maximum of Scr/κ or 1.  
The information in the eCRF on eGFR will be used as safety measures throughout the study. 
 

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6 
STUDY DESIGN 
Figure 1: Trial flow chat 
 
Screened population 
N ~2700  
Total population 
Type 2 DM 
Normoalbuminuria 
N ~2000 
Screening failures 
N ~700 
Proteomic 
Test 
Intervention group 
(Test-positive 
High-risk population) 
N = 300  
Observational group 
(Test-negative 
Low-risk population) 
N ~1700   
Spironolactone  
 + 
Standard 
Placebo 
+ 
Standard 
Standard  
End of trial 
104-230 weeks 
A 
B 
5 years long-term follow-up  

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6.1 
Overall study design / Total study population 
Prospective, multicenter, randomized, double blind, placebo-controlled phase II-III trial and a pro-
spective observational study. With screening of approximately 2700 patients aiming to included 
2000 type 2 DM patients with normoalbuminuria. All patients included in the study will be 
screened for the presence of a CKD273-specific proteomic pattern at time of inclusion in the 
study (screening visit). All patients will be monitored for development of microalbuminuria. 
Patients with a high-risk CKD273 proteomic pattern (approx. 300 patients) will enter the interven-
tion group and randomized to receive 25 mg spironolactone once daily or placebo in a 1:1 ratio. 
These patients will enter a treatment period of at least 104 week, dependent on time of baseline 
visit.  
Patients without a low-risk proteomic pattern will not be randomized, but remain in the observa-
tional group (approx. 1700 patients). These patients will enter an observational period of at least 
104 week, dependent on time of baseline visit. 
Patients included prior to October 2016 will have a treatment/ observation period longer than 104 
week, dependent on time of baseline visit. The treatment/ observational period can’t exceed 230 
weeks (4.4 years). All patients will have final assessment performed in the period from 1st July 
2018 to 30th September 2018. 
All patients have to sign informed consent prior any study specific procedures were performed. 
6.2 
Observation group (group A) / Low-risk population 
It is expected that 85% of the total population (approx. 1700 patients) will show a low-risk pattern. 
Patients should be followed by the investigator in routine clinics or seen once yearly, for standard 
diabetes care according to local guidelines. Annual measurements of UACR, BP, medication, 
and locally measured creatinine, sodium, potassium, and lipids (cholesterol, HDL, LDL, triglycer-
ides) will be performed. HbA1c will be measured in DCCT-aligned quality control programs or 
IFCC. During the study, the medical history regarding vascular events, current retinopathy status 
(by history) and information on laser treatment, as well significant medical events (see section 
10.14.), including hospital admissions, are registered. 
Secondary endpoints and significant medical events will be registered at the annual visits. 
After the last study visit, patients will continue in the observational long-term follow-up in accord-
ance with section 6.4. 
6.3 
Intervention group (group B) / High-risk population 
Randomized, double-blind, placebo-controlled, multicenter study in the high-risk population 
based on urinary proteomic risk pattern assessment. It is estimated that 15% of the total popula-
tion (approx. 300 patients) will show a high-risk pattern.  
Patients will be invited to participate if the urinary proteomic pattern after the screening visit is 
showing a high-risk pattern, and if at least two of the three samples from the “run-in”-period show 
normoalbuminuria (UACR <30 mg/g) analyzed at the central laboratory. 
Patients in the intervention study will be randomized (1:1) to spironolactone 25 mg daily or 
matching placebo in addition to standard treatment according to the investigators discretion. Pa-
tients will be stratified in the two treatment arms (1:1) based on whether or not the patients is 
treated with RAS blocking agents at the time of entry (Screening). 
    

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Patients are seen according to Table 1, with a study visit every 13th weeks. Patients must be 
treated by the investigator for standard diabetes care according to local guidelines. Dependent on 
time of baseline the patients will be treated for at least 104 weeks with measurements of UACR, 
BP, medication, and locally measured creatinine, sodium, potassium, and lipids (cholesterol, 
HDL, LDL, triglycerides). HbA1c will be measured in DCCT-aligned quality control programs or 
IFCC. At screening and in the duration of the study, the medical history regarding vascular 
events, current retinopathy status (by history) and information on laser treatment, as well as ad-
verse events (see section 13.3), including hospital admissions, are registered. 
Potassium levels will be measured locally as indicated in table 1. 
Secondary endpoints and adverse events (see section 13.3) will be registered at the visits every 
13 weeks. 
After the last study visit patients will continue in the observational long-term follow-up in accord-
ance with section 6.4. 
6.4 
Long-term follow-up 
A long-term follow-up study will be conducted 5 years after the end of the clinical trial. The pur-
pose of this follow-up is to evaluate progression to later stages of DN (macroalbuminuria, deterio-
ration of renal function) and/or CVD and/or death based on register data.  
After the end of the clinical study no study visit will be conducted and no information will be rec-
orded in the eCRF.  
The long term follow-up will be carried out in accordance with the applicable national regulations. 
6.5 
Biobank 
A research biobank will be established at Steno Diabetes Center containing biological material in 
the form of blood and urine samples. The material will be stored in coded form for later analysis 
of markers of development and progression of nephropathy mortality and cardiovascular disease. 
Biological material from the biobank will be stored after the end of the study for 15 years if the pa-
tient accepts this. Thereafter, stored material will be destroyed.  
At least at the baseline visit (day 0), the patients will sign and date a study-specific informed con-
sent regarding participation in the research biobank with additional scientific potential. Patients 
who are not willing to participate in the additional research biobank can still participate in the 
PRIORITY-study. 
6.6 
Study visit description 
For all participants, the screening visit will be the first visit in the study. No procedures related to 
the study may be performed before the written informed consent is obtained. The screening visit 
must be performed prior to both the run-in phase and the baseline visit. In accordance with table 
1, the screening visit must be performed within a window of 4 to 12 weeks prior to baseline visit.  
The run-in phase starts after the screening visit. The study procedures related to the run-in phase 
must be at least 2 weeks before the baseline visit.  
The baseline visit can only take place after results on UACR and urinary proteomics risk assess-
ment are displayed in the eCRF.

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Table 1: Frequency of study visits at each participating center 
Assessment procedures 
 
Total Population 
Intervention Group  
(Group B,high-risk population) 
Observational Group 
(Group A,low-risk population) 
Visit 
Screening Run in -
period 
Baseline 
Visit 1 
Periodic study visits 
End of study/ 
Early Termi-
nation Visit 
Periodic 
study visits 
End of study/ Early 
Termination Visit 
Study week 
Week  
-12 to -4 
 
Week -11 
to -2 
 
Day 0 
Week 2 
(± 3 days) 
Week 13, 
26, 39, 52, 
65, 78, 91, 
104,117, 
130, 143, 
156, 169, 
182, 195, 
208 and 221 
(± 14 days) 
Week 52, 
104, 156 and 
208  (± 14 
days) 
Planned end 
(July to 
September 
2018) or 
early Termi-
nation 
Week 52, 
104, 156 and 
208  (± 14 
days) 
Planned end (July 
to September 
2018) or early 
Termination 
Informed consent 
x 
 
x1 
 
 
 
 
 
 
Inclusion/ Exclusion criteria  
x 
 
x2 
 
 
 
 
 
 
Medical history 
 
 
x 
 
 
 
 
 
 
Tobacco/alcohol usage 
 
 
x 
 
 
 
 
 
 
Concomitant medication 
X9 
 
x 
x 
x 
 
x 
x 
x 
Physical examination3 
 
 
x 
 
x 
 
x 
x 
x 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
 
x 
x 
x 
x 
Vital signs (BP/Heart rate)4 
x 
 
x 
 
x 
 
x 
x 
x 
Study medication 
 
 
x 
 
x 
 
x 
 
 
Local clinical 
laboratory 
examinations 
clinical chemis-
try (blood sam-
ples) 
Creatinine, 
sodium, 
potassium,  
x 
 
x 
x 
x 
 
 
x 
x 
x 
HbA1c 
x 
 
x10 
 
x 
 
x 
x 
x 
Cholesterol, 
LDL, HDL, 
Triglyceride 
 
 
x 
 
 
x 
x 
x 
x 
3 consecutive 
first morning 
void urine 
samples for 
albuminuria 
assessment 
Central  
Analyses 
 
x6 
 
 
x 
 
 
x 
x 
x 
Central 
Storage5 
 
x 
 
 
 
x 
x 
x 
x 
Urine sample for proteomic 
analysis 
x 
 
 
 
 
 
 
 
 
Biobank sampling (after 
informed consent) 
 
 
x 
 
 
 
x 
 
x 
Randomization 
(applicable for group B) 
 
 
(R) 
 
 
 
 
 
 
Adverse Events  
 
 
 
x 
x 
 
x 
 
 
Significant medical event 
 
 
 
 
 
 
 
x 
x 
Urine dipstick analysis7 
x 
x 
 
 
x 
 
x 
x 
x 
Pregnancy test8 
x 
 
 
 
 
 
x 
 
 
Final assessment 
 
 
 
 
 
 
x 
 
x 
1) 
Informed consent for the biobank participation. 
2) 
Only the inclusion criteria regarding UACR and exclusion criteria regarding BP will be evaluated. 

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3) 
The physical examination performed at the Baseline visit will serve as the baseline for clinical assessment. At baseline the 
examination will include: General appearance, heart, lungs, abdominal, lymph nodes and extremities. At all other visit, a 
symptom-directed physical exam will be performed. Any new clinically significant physical exam findings after the Base-
line/Randomization Visit will be recorded as adverse events.  
4) 
Blood pressure: Average of three measurements in sitting position after at least 10 min rest 
5) 
One of three samples for storage after analyses, description in section 10.9. 
6) 
Samples from excluded patients are not shipped to central laboratory. 
7) 
Test for urinary tract infections: Blood, leucocyte and nitrate. 
8) 
Pregnancy test, description in section 10.16.  
9) 
Only in regards to ACE or ARB treatment. 
10) Optional based on investigators decision.  
 

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7 
STUDY POPULATION 
All patients that are eligible according to the inclusion and exclusion criteria relevant at study entry can 
be included in the trial.  
7.1 
Inclusion Criteria 
1) 
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  
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) 
eGFR >45 ml/min/1.73m2 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 fol-
lowing: 
7.1) Female patients ≥ 50 years of age at the day of inclusion, who have been postmeno-
pausal for at least 1 year 
7.2) Female patients < 50 years of age at the day of inclusion, who have been postmeno-
pausal 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. 
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 follow-
ing:  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.  
7.5) 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. 
7.6) Having only female sexual partners. 
7.7) Sexual relationship with sterile male partners only. 
7.2 
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. 

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5) 
Current in treatment with more than one RAAS blocking agent (Angiotensin Converting En-
zyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor) 
6) 
Current lithium treatment (ATC: N05AN) 
7) 
Known or suspected hypersensitivity to Spironolactone or to any of its excipients. 
8) 
Current use of potassium sparing diuretics (ATC: C03D, C03E), such as: Spironolactone, 
Eplerenone or amiloride etc. 
9) 
Hyperkalemia at Screening: Plasma potassium level >5.0 mmol/L or serum potassium level 
>5.4 mmol/L. 
10) Hyponatriemia 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 MI, stroke, PTCA or CABG 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 con-
trol. 
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 al-
lowed within 30 days before inclusion or concurrent to this study 
7.3 
Screening failures 
Patients who discontinue prior randomization for any reason are considered screening failures. 
It is not necessary to complete all inclusion/exclusion criteria unless it is medically indicated. If a 
patient are considered a screening failure, demographic information (sex, age, onset of diabetes 
and race) are to be documented, as well as primary reason for discontinuation.  
7.4 
Replacement of participants  
Rescreening of patients is allowed with at least one week between screening visits. Any patient 
who is withdrawn from the study for any reason, after study medication has been initiated may 
not re-enter the study at any time. There will be no replacement of participants who discontinue 
the IMP or withdraw from the entire study.  
 

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8 
RANDOMIZATION/BLINDING AND UNBLINDING 
PROCEDURES 
8.1 
Patient Identification 
All patients included into the screening process will receive a consecutive patient number, start-
ing with patient number 0001. The patient identifier is the combination of the study site number 
(e.g. 01) and the patient number (e.g. 0001).  
8.2 
Randomization 
At baseline eligible patients with a high-risk proteomics pattern will be included in the intervention 
part of the study. Randomization lists will be prepared by an independent statistician at the Rob-
ertson institute, University of Glasgow, who is not involved into other tasks of the trial. 
The patients will be randomly assigned in a 1:1 ratio to one of the two treatment arms using a 
block randomization stratified by study center. 
Patients will be stratified in the two treatment arms (1:1) based on whether or not the patients is 
treated with RAS blocking agents at the time of entry (Screening) in order to have the number on 
RAS blocking agents balanced in the two treatment arms. 
8.3 
Assignment to treatment 
The IWRS will assign each patient to treatment. 
8.4 
Blinding procedure 
Placebo and active study drug will not be distinguishable from each other in terms of appearance, 
labeling or instructions for use. All IMP will be labelled with a unique pack identifier number.   
8.5 
Unblinding procedures 
8.5.1 
Emergency unblinding 
Emergency unblinding should only be done if emergencies occur that can be directly linked 
to the study medication, where it is essential to know if the patient was actually treated with 
spironolactone. If hyperkalemia occurs, it is not in all case necessary to break the code, the 
patient is to be treatment according to guidance as described in the Appendix. 
Unblinding will be performed via a telephone menu system. Several prompts in the system 
warn the user that they require to be a health professional and to record their name and oth-
er pertinent information. For each unblinding an email alert is generated to the sponsor, 
HCTC and the provider of IWRS. Requests are set at a maximum of 2-3 per 24 hours in 
case of malicious unblinding.  
In case unblinding is needed a rapport has to be filed in the TIF and patient file and docu-
mented in the eCRF and HCTC must be contacted in accordance with section 13.  
8.5.2 
Planned unblinding 
Planned unblindling will be performed by the Robertson Institute after finalizing the SAP and 
with the consent from the steering committee on science.    

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9 
STUDY SCHEDULE 
9.1 
Involvement of patient 
9.1.1 
Recruitment period 
The recruitment period will run from approval by REC and NCA in the participating countries 
and until the 31st of August 2016.  
9.1.2 
Patients 
It is intended to observe/ treat each patient for at least two years after baseline. Patients in-
cluded prior to October 2016 will be observed/ treated for more than two years dependent on 
the time of inclusion. The observation/ treatment period can’t exceed 4.4 years. All patients 
will have final assessment performed in the period from 1st July 2018 to 30th September 
2018. 
 
9.2 
Data management and statistics 
According to section 15 and 19 data management will be performed in the period from establish-
ment of protocol after end of study. 
The statistical assignment for the primary publications will be carried out after last patient visit. 
9.3 
Publication 
According to section 21 three  publications are foreseen.  

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10 
STUDY PROCEDURES 
All study data will be included in the patients’ source documentation and provided in the appropriate 
eCRF. Study procedures planned for a specific study visit must be performed in accordance with table 
1. In any case all participants must sign and date a study-specific informed consent before any study 
procedures can be performed. 
10.1 
Informed consent 
At the Screening visit the patients will sign and date a study-specific informed consent form be-
fore any study procedures are performed. Included in the informed consent will also be infor-
mation regarding the long-term follow-up in accordance with section 6.4. 
At the Baseline visit (day 0), the patient will sign and date a study-specific informed consent re-
garding participation in the research biobank with additional scientific potential. Patients who are 
not willing to participate in the additional research biobank can still participate in the PRIORITY-
study.   
10.2 
Medical history 
A complete medical history, including history of tobacco and alcohol use, will be obtained from 
each patient as indicated in Table 1. The medical history will be updated prior to randomization at 
the baseline/randomization visit and will serve as baseline for clinical assessment. 
10.3 
Concomitant medication 
At the Baseline visit and every visit thereafter, information about usage of concomitant medica-
tion will be documented for each patient. Patients are allowed to take any form of concomitant 
medication during the study except Lithium or treatment with more than one RAAS blocking 
agent. For concomitant use of ACE, ARB or Spironolactone see section 12.1.1. 
10.4 
Physical examination 
A physical examination will be performed as indicated in Table 1. Height will be measured only at 
the Screening Visit. Body weight will be measured at the Screening Visit and yearly thereafter, ,  
upon patient discontinuation or at end of study. The physical examination performed at the base-
line visit will serve as the baseline for clinical assessment. At Baseline the examination will in-
clude: General appearance, heart, lungs, abdominal, lymph nodes and extremities. At all other 
visit, a symptom-directed physical exam will be performed. Any new clinically significant physical 
exam findings after the Baseline/randomization will be recorded as adverse events. Significance 
will be adjusted by an investigator after consultation of CTCAE version 4.0 AE-intensity grading.  
10.5 
Vital signs 
Heart rate and BP will be measured as indicated in Table 1. BP and heart rate will be measured 
in the sitting position after 10 min rest, as an average of 3 measurements with a validated auto-
matic or manual device and appropriately sized cuff will be used. The vital signs measured prior 
to randomization at the Baseline/Randomization Visit will serve as the baseline for clinical as-
sessment. 

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Whenever possible, the study personnel should use the same instrument and measure BP and 
heart rate in the same arm. When the timing of these measurements coincides with a blood col-
lection, vital signs should be assessed prior to blood collection or at least 10 minutes after. 
10.6 
Dispensing of investigational medicinal products 
Study medication will be provided to the patients of the high-risk population at baseline and at 
each study visit. Prior to receiving the IMP patients will be informed orally and in writing of the 
contents of the IMP as describes in section 11.1 and the potential side effect described in section 
11.3. 
At every visit after baseline (every 13 week) patients has to return the unused IMP for accounta-
bility and destruction of unused tablets according to section 11.2. 
10.7 
Laboratory examination 
The laboratory manual holds instructions about the blood- and urine sample collection. 
10.7.1 Labelling of samples 
All samples will be labeled with the study acronym (PRIORITY), name of sponsor and the 
unique patient identifier (visit number, study site number, patient number, and the date when 
the sample was obtained). Labels will be provided by Steno Diabetes Center. 
10.8 
Blood samples 
Clinical chemistry has to be performed according to table 1 with measurement of creatinine 
(traceable standardized method), sodium, and potassium at every visit. HbA1c (DCCT-aligned 
method or IFCC) has to be measured at Screening and every periodic visit in both groups. Lipids 
(cholesterol, HDL, LDL, and triglycerides) have to be measured at least every year in all patients.  
All blood samples are to be analysed locally.  
10.9 
Urine samples for albuminuria 
Urine samples are to be analysed centrally for UACR. Three consecutive first morning void urine 
samples are collected for UACR. The samples are collected two days prior any study visit, and at 
the day of the visit as indicated in table 1. The urine samples of the “run-in”-period are collected 
the three days following the screening visit and brought or sent to the study site. Sample ship-
ment from patient to the study center is done using any authorised material for shipment of bio-
logical material in regular mail.  
Every effort should be made to ensure collection of three consecutive first morning voids for 
analysis of UACR. This is especially important in the “run in” period. If a patient attends a visit 
and has collected only one or two first morning voids, the patient must collect supplemental first 
morning voids samples on the following two mornings after the visit and send or bring these to 
the study site.  
The most recently performed morning void is tested for urinary infection with dipstick test. Sam-
ples are discarded if infection is detected and a new sample must be performed preferably within 
two weeks of the planned visit, or as soon as possible thereafter.  
Samples are frozen immediately at -20oC and are stored until shipment. Shipment to Steno Dia-
betes Center will be performed by using a local courier and samples are to be sent on dry ice. 

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Urine samples from the “run-in” period are to be sent to Steno Diabetes Center at least every 
third weeks for screening analyses. Urine samples from all other visits than the screening visit 
and the “run-in” period are to be shipped at least every sixth months. 
Urine sample from the “run-in” period and every annually visit one urine sample will be stored at 
Steno Diabetes Center. The most recently performed urine sample will be preferred. The sam-
ples will be stored at least at -20 oC upon arrival.  
10.10 Urine samples for proteomic analysis 
Urine samples for proteomic analysis will be obtained at the screening visit. Samples are tested 
for urinary infection with urine dipstick test. Samples are discarded if infection is detected and a 
new sample must be performed preferably within two weeks of the planned visit, or as soon as 
possible thereafter.  
Samples are to be frozen at -20 oC until shipment. Shipment to Steno Diabetes Center will be 
performed by using a local courier and samples are to be sent on dry ice. Urine sample from the 
screening visit is to be sent to Steno Diabetes Center at least every third weeks. From Steno Di-
abetes Center the sample will be sent for analysis at Diapat GmbH in Hannover.  
Upon arrival at Diapat GmbH the samples are catalogued, prepared for measurement and imme-
diately analyzed. The result of the analysis will be displayed in the eCRF. 
10.11 Biobank 
Samples are to be obtained at Baseline and at Final assessment visit from, all patients who 
agreed to biobank sampling.  
Urine sample for biobank will be tested for sign of infection with dipstick test. In case of infection 
this has to be treated according to national guidelines in terms of antibiotics and the patient has 
to reschedule for a new baseline visit within two weeks. If the incident occurs at the baseline it 
has to reported as medical history. If the incident occurs at the final assessment visit it must be 
reported as an AE according to section 13.3. 
At baseline and at end of study, the following samples will be stored (DNA only at Baseline) 
Material 
Collection container 
Centrifuge 
Storage container 
Freezer 
DNA Buffy-coat 
2 X 10.0 ml 
K-EDTA 
Time 
10 min. 
2 X 3.6 ml 
Cryo tubes 
-80°C 
Temp 
20°C 
RCF 
1500G 
EDTA plasma (ICE) 
1 X 4.0 ml 
K-EDTA 
Time 
10 min. 
1 X 1.8 ml 
Cryo tybe 
-80°C 
Temp 
4°C 
RCF 
1500G 
EDTA plasma 
2 X 4.0 ml 
K-EDTA 
Time 
10 min. 
2 X 1.8 ml 
Cryo tubes 
-80°C 
Temp 
20°C 
RCF 
1500G 
Serum 
3 X 6.0 ml 
Dry glass 
Time 
10 min. 
2 X 1.8 ml 
Cryo tubes 
-80°C 
Temp 
20°C 
RCF 
1500G 
Citrate Plasma (ICE) 
2 X 4.5 ml 
Na-Citrate 
Time 
10 min. 
2 X 1.8 ml 
Cryo tubes 
-80°C 
Temp 
4°C 
RCF 
1500G 
Urine (morning) 
20 ml  
plastic tubes 
 
2 X  3.6 ml 
Cryo tubes 
-80°C 
Following pre-processing and aliquoting, blood and urine samples will be stored locally, at least 
at -70 °C prior to shipping to the central laboratory at Steno Diabetes Center. Shipment to Steno 
Diabetes Center will be performed by using a local courier and samples are to be sent on dry ice. 
All samples will be stored upon arrival at -80 °C. 

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10.12 Randomization 
Randomization will be performed at the baseline visit. If the patient participates in the biobank the 
randomization will be performed after collection of samples. Only patients with a high-risk pattern 
in the proteomic analysis from the screening visit will be randomized. Patients will be randomized 
in a 1:1 ratio to either active medication or placebo in addition to standard treatment as described 
in section 8. Patients will be stratified in the two treatment arms (1:1) based on whether or not the 
patients is treated with RAS blocking agents at the time of entry (Screening). 
10.13  Adverse Events 
Documentation of all adverse events will be performed at all visits as indicated in table 1 and as 
described in section 13.1.  
10.14 Significant medical event 
Documentation of significant medical events will be conducted at the annual visit for the low-risk 
participants. Any medical untoward occurrence after baseline can be documented as a significant 
medical event. Of special interest are events described in section 5.5.1 as secondary end points.   
10.15  Urine dipstick test 
Urine dipstick test are to be performed on urine samples at the study sites to confirm that urine 
tract infection is present. Urine dipstick test is performed before the samples are frozen.  
If the patients has a urinary tract infection or menstrual bleeding at the time of a planned study 
visit, urine collection should be postponed and the visit can be rescheduled, preferably within two 
weeks of the planned visit, or as soon as possible thereafter.  
10.16  Pregnancy test 
All female patients with child-bearing potential will have a pregnancy test performed at the 
Screening visit, and at the end of study or discontinuation, as indicated in Table 1. The assess-
ment will be according to local standard based on blood or urine analysis. 
10.17  Final assessment 
At the Final assessment standard diabetic care according to local guidelines will be performed, 
as well as the study procedures indicated in table 1. 
10.18  Clinical procedure after end of the study/ Early termination 
After the end of the study or early termination, the patients will receive standard care according to 
national guidelines under the discretion of the treating physician. 
10.19  Unscheduled visit 
Unscheduled visit is possible any time after screening on the opinion of the investigator. The con-
tent of such visit is on the discretion of the investigator. The main issue for the unscheduled visit 
must be documented in the eCRF.  

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11 
INVESTIGAL MEDICAL PRODUCTS  
11.1 
IMPS 
All IMPs will be manufactured in accordance with EU Good Manufacturing Practice requirements 
and will be supplied and distributed by Mawdsleys Clinical Services UK.  
Tablets and bottles containing active IMP or placebo will be indistinguishable from each other in 
terms of taste, appearance, durability, packaging, labeling and instruction for use. 
Only patients of the intervention group will receive IMP. Only those supplies intended for use in 
the study may be dispensed to study participants.  
11.1.1 Formulation and preparation 
Spironolactone: Tablet for oral use containing spironolactone and additional excipients  
Placebo: matched placebo tablet for oral use. (Placebo tablets have the same constituents 
as the active with the exception of spironolactone content.)   
11.1.2 Administration 
Patients will be advised to take the IMP tablets once each day orally, with or just after food in 
the morning.  
Dosage Treatment: 25 mg spironolactone once daily. 
Dosage titration is prohibited.  
11.1.3 Packaging 
Packages with active or place study drug will be indistinguishable from each other.  
Primary packaging will contain IMP for 13 weeks of treatment plus a small overage (110 tab-
lets).  
11.1.4 Labeling 
Labeling will be performed according to national regulatory requirements and in accordance 
with current annex 13 EU Good Manufacturing Practice requirements.   
11.1.5 Storage and stability 
The IMPs will be provided to each participating study center from the study manufacturer in a 
blinded fashion. 
The tablets should be stored in a dry place at room temperature below 25 oC in a secure lo-
cation.   
Study supplies must be stored under the correct storage conditions at all times.   
11.2 
Accountability procedures for the IMP 
After randomization, patients of the intervention group will receive IMP from the study site they at-
tend.  

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At every 13th week after the Baseline the patients should be asked to return the IMP for account-
ability. 
Patient should take between 80-110% of IMP to be compliant. The process for capturing the 
compliance information is the assessment by tablet counts at each site. 
A record of all IMP movements including drug dispenses must be performed and documented by 
each site. 
11.3 
Main side effects of spironolactone 
Gynecomastia may develop in association with the use of spironolactone. Development appears 
to be related to both dosage level and duration of therapy and is normally reversible when the 
drug is discontinued. In rare instances some breast enlargement may persist.  
The following adverse events have been reported in association with spironolactone therapy:  
Organ system 
Side effect  
General disorders and administration site condi-
tions 
malaise 
Neoplasms benign, malignant and unspecified 
(including cysts and polyps) 
benign breast neoplasm 
Gastrointestinal disorders 
gastrointestinal disturbances, nausea 
Blood and lymphatic system disorders 
leukopenia (including agranulocytosis), throm-
bocytopenia  
Hepatobiliary disorders 
hepatic function abnormal 
Metabolism and nutrition disorders 
electrolyte disturbances, hyperkalemia 
Musculoskeletal disorders 
leg cramps 
Nervous system disorders 
dizziness 
Psychiatric disorders 
changes in libido, confusion 
Reproductive system and breast disorders 
menstrual disorders, breast pain 
Skin and subcutaneous tissue disorders 
Stevens-Johnson syndrome (SJS), toxic epi-
dermal necrolysis (TEN), drug rash with eosino-
philia and systemic symptoms (DRESS), alope-
cia, hypertrichosis, pruritus, rash, urticaria 
Renal and urinary disorders 
acute renal failure 
11.4 
Overdose 
Acute overdosage may be manifested by drowsiness, mental confusion, nausea, vomiting, dizzi-
ness or diarrhoea. Hyponatremia, or hyperkalemia may be induced, but these effects are unlikely 
to be associated with acute overdosage. Symptoms of hyperkalemia may manifest as paresthe-
sia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from 
hypokalemia. Electrocardiographic changes are the earliest specific signs of potassium disturb-
ances. No specific antidote has been identified. Improvement may be expected after withdrawal 
of the drug. General supportive measures including replacement of fluids and electrolytes may be 
indicated. For hyperkalemia, specific procedures are to be followed as described in the Appendix. 

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11.5 
Risks in connection with the investigation procedures 
The collection of the urine samples is without. The blood withdrawals for research purposes will 
be performed in relation to standard investigational procedures. As with any venepuncture, pain, 
bleeding and/or bruising may occur due to penetration of the needle; more rarely, infection can 
occur at the entry spot. Very rarely, there may be arterial puncture, nerve damage or phlebitis. 
 

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12 
CONMEDICATION AND TREATMENT 
12.1 
Treatment in general 
Treatment of any medical condition aside from hypertension, albuminuria and hyperkalemia must 
be in accordance with local guidelines. Treatment of hypertension, albuminuria and hyperkalemia 
should be carried out in accordance with the study protocol, section 12.2, 12.3 or 24. 
All participants in the trial can receive anti-diabetic treatment in accordance with local guidelines 
and standard of care. The treatment regimen can include dietary advice, oral- and/or injection of 
anti-diabetic medication.  
12.2 
Prohibited medication  
Participants are prohibited to use the following medical treatment in the duration of the study:  
ATC-code 
Drug class 
Drug example 
C03D 
Potassium-sparing diuretics 
Spironolactone, Eplerenone, Amilorid 
C03E 
Diuretics and potassium-sparing 
agents in combination 
C03D in combination with other drugs  
N05AN 
Lithium salt 
Lithium 
12.3 
Hypertension treatment 
It can be expected that the included study population will be heterogeneous at baseline in terms 
of antihypertensive treatment, as this may reflect different individual and local treatment consid-
erations. Antihypertensive treatment prior to inclusion, especially ACE or ARB treatment, should 
be continued unchanged during “run-in” period and throughout the study if possible.  
Definition: Hypertension, for the purpose of this study, is defined as systolic pressure >130 
mm HG and/or diastolic pressure >80 mm Hg.  
All patients should be treated according to local guidelines. In any case the care team should be 
encouraged to initiate or intensify treatment in case of repeated (or confirmed) blood pressure > 
140 mm Hg systolic and or diastolic > 90 mmHg. If local guidelines do not recommend a specific 
first line antihypertensive agent it is suggested to start with a calcium channel blocker or thiazide 
diuretic to reduce interference with UACR.  
In any case, choice of therapy is left to the discretion of the investigator. RAS blocking agents are 
accepted, if indicated. If blood pressure cannot be managed consideration of a secondary cause 
should be studied. If patients are assigned to IMP is started on ACE, ARB or renin-inhibitors the 
investigator is advised to measure potassium according to local guidelines, to minimize the risk of 
hyperkalemia. 
12.4 
Albuminuria treatment 
All participants included in the trial are normoalbuminuric (UACR <30 mg/g). If a participant 
reaches the primary endpoint during the course of the study, the information will be flagged in the 
eCRF and the investigator will be notified.  
Participants not in treatment with ACE or ARB at the time of screening should not start treatment 
before the primary endpoint is reached. 

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13 
ADVERSE EVENT MONITORING AND REPORTING 
13.1 
Definitions 
13.1.1 Adverse Events 
An AE as defined in this study is any untoward medical occurrence in a patient or clinical trial 
patient after baseline. The event does not necessarily have to have a causal relationship 
with that treatment. AEs can be diseases, signs of disease or symptoms. Among others, AEs 
include the following: 
• 
All suspected medication adverse reactions 
• 
Apparently unrelated illnesses, including the worsening of a preexisting illness, in-
jury or accidents 
• 
Laboratory abnormalities that require clinical intervention 
• 
Accidents and complications from diagnostic interventions 
The following events do not fulfil the definition of an AE: 
• 
An elective hospitalization during participation in a trial for an intervention or diag-
nostic procedure for a condition which was present before entering the trial 
• 
A pre-existing disease or condition which does not deteriorate during the partici-
pation in the trial 
13.1.2 Adverse Reaction 
An AR is any untoward and unintended response to the IMP related to any dose adminis-
tered. A response to the medicinal product is given when a causal relationship between the 
adverse event and one of the IMPs is at least a reasonable possibility.  
13.1.3 Serious Adverse Events/ Reaction 
A SAE or SAR is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening  
(i.e., in the opinion of the investigator, the patient is at immediate risk of death 
from the event) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity  
(i.e. a substantial disruption of a person’s ability to conduct normal life functions) 
• 
Is a congenital anomaly/birth defect 
Important AEs that may not result in death, may not be life-threatening, or do not require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
The following events do not fulfill the definition of an SAE: 
• 
Events which might have resulted in a life-threatening situation but did not 

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• 
Elective hospitalization during participation in a trial for an intervention or diagnos-
tic procedure for a condition which was present before entering the trial 
13.1.4 Suspected Unexpected Serious Adverse Reaction 
A SAE, the nature or severity of which is not consistent with the applicable product infor-
mation.  
13.2 
Reference document / Applicable product information 
The applicable product information for this trial is the summary of medicinal product characteris-
tics from http://www.medicines.org.uk/emc/medicine/9136/SPC/of 13/12/2012 respectively its up-
dates (actual version - http://www.medicines.org.uk/emc/medicine/9136/SOC/of 03/03/2015). 
13.3 
Documentation and reporting of AE 
13.3.1 Documentation requirements 
13.3.1.1 AEs 
AE will be collected by the investigator either based on the information provided sponta-
neously by the patient or evaluated by non-suggestive questions. 
The following information is necessary: 
• 
Type of AE (disease, symptoms) 
• 
Classification (serious vs. nonserious) 
• 
Start and termination date of the AE 
• 
Grading of AE-intensity (grade 1-5).The descriptions and grading scales 
found in the revised NCI CTCAE version 4.0 will be used for adverse 
event reporting.  
• 
Causality to the study drug 
• 
Measures taken with regard to study medication and treatment of the AE 
• 
Outcome of the AE 
The AE documentation period for this trial begins upon first administration of the IMP. In 
case of continuation of any AE the documentation period will be prolonged until all AEs 
are resolved or until the investigator assesses the adverse events as “chronic” or “stable”. 
Site investigator is responsible for monitoring the safety of patients enrolled into the study 
at the study sites. All AEs will be documented in the patient’s medical record and man-
aged according to standard practice. 
The following AEs will additionally be documented in the eCRF:  
• 
AEs leading to study drug discontinuation and/or withdrawal 
• 
Serious AEs (SAEs, see Section 13.1.3) 
• 
AEs related to cardiovascular and/or renal disease  
• 
AEs related to retinopathy (and corresponding laser treatment) 

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• 
Laboratory abnormalities suspected by the investigators to be related to 
the study drug including the potassium and sodium value 
At each patient visit the investigator will review the patient’s medical record and deter-
mine if there have been any serious adverse events (SAEs) and/or AEs to be document-
ed.  
All eCRF-documented AEs, SAEs and laboratory abnormalities must be graded for sever-
ity and relationship to study drug and will be coded using the MedDRA via MARVIN.  
Documentation of AEs must be performed in a timely manner on the respective AE forms 
in the eCRF. 
13.3.1.2 SAEs 
The same documentation responsibilities as described for AEs apply to SAEs as well. In 
addition, SAEs must be documented on the paper SAE-form and reported to the sponsor. 
Documentation of SAE must be as complete and detailed as possible. In case of death, 
an autopsy should be aimed for and the results should be forwarded to the principal in-
vestigator and the sponsor. 
13.3.2 Reporting requirements 
13.3.2.1 Reporting period 
The reporting period for AEs and SAEs begins with the first application end ends 30 days 
after the last application of the IMP.  
13.3.2.2 SAE reporting period by the investigator 
The investigator has to report all SAEs by faxing the SAE form immediately (within 24 
hours) to the authorized representative of the sponsor: 
Institute of Clinical Pharmacology 
Hannover Medical School 
Carl-Neuberg-Str. 1 
D-30625 Hannover 
Phone: 
+49-511-532-3959 
Fax: 
+49-511-532-16-2794 
E-Mail: 
sae-reporting@mh-hannover.de 
13.3.2.3 Exceptions to the SAE reporting requirements 
No exceptions. 
13.3.2.4 Pregnancies 
Any pregnancies occurring in the intervention group within the reporting period have to be 
reported to: 
Institute of Clinical Pharmacology 
Hannover Medical School 
Carl-Neuberg-Str. 1 
D-30625 Hannover 
Phone: 
+49-511-532-3959 
Fax: 
+49-511-532-16-2794 

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E-Mail: 
sae-reporting@mh-hannover.de 
Pregnancies have to be followed until an outcome of the pregnancy is documented with 
information about the status of both, mother and child. Any preterm termination of preg-
nancy has also to be reported.  
13.3.2.5 Events associated with pharmaceutical quality 
Any defects or events that are encountered with the IMP that may be attributed to short-
comings of pharmaceutical quality must be reported to: 
Institute of Clinical Pharmacology 
Hannover Medical School 
Carl-Neuberg-Str. 1 
D-30625 Hannover 
Phone: 
+49-511-532-3959 
Fax: 
+49-511-532-16-2794 
E-Mail: 
sae-reporting@mh-hannover.de  
And to IMP management : 
Elizabeth Douglas or Pamela Surtees 
Research & Development 
NHS Greater Glasgow & Clyde 
1st Floor Tennent Institute, Western Infirmary 
Church Street, Glasgow, UK G11 6NT 
Phone:    +44 (0) 141 211 8554  
E-mail:   
Elizabeth.Douglas@ggc.scot.nhs.uk 
13.3.2.6 Overdosing 
Significant overdosing must be reported as a SAE by the Investigator to the sponsor. 
Overdose of IMP is defined by the Sponsor as administration of > 110%. E.g. ≥ 100 tab-
lets over a period of 91 days OR > 2 tablets at any single day. 
13.3.2.7 SUSAR-Reporting by the Sponsor 
In line with the “CT-3” guideline and EU directive 2001/20/EC, it is the responsibility of the 
sponsor to report all SUSARs that occur in this trial to the respective competent authori-
ties, the leading IEC, and to all investigators of the trial. 
Fatal or life-threatening SUSARs must be reported within 7 days, all other SUSARs need 
to be reported within 15 days.  
Also, all events which can change the benefit-risk ratio of the investigational medicinal 
product have to be reported within 15 days in the same way as SUSARs. This includes: 
• 
Case reports of expected SARs with an unexpected outcome 
• 
Increased incidence of SARs which is considered clinically relevant 
• 
Cases of suspected SUSARs which occurred in patients after completion 
of the trial participation 
• 
Occurrences in relationship to the trial or the IMP which might affect the 
safety of the patients 

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13.3.2.8 Development safety update report (DSUR) 
On an annual basis throughout the clinical trial, the sponsor or his authorized representa-
tive will provide the NCA and the leading IEC with a written safety report. The safety re-
port’s format will adhere to the ICH-guideline E2F (developmental safety update report, 
DSUR) and include a listing of all suspected serious adverse reactions which have oc-
curred over this period as well as a report of the patient’s safety. 
13.4 
Data monitoring committee and stopping rules 
The sponsor has the right to terminate the study at any time for reasonable medical or adminis-
trative reasons. 
Stopping rules for the whole study: The Steering Committee on samples, data and ethics has the 
right to terminate the study at any time for reasonable medical safety reasons. The Data Monitor-
ing Committee, which has access to safety data, will provide the Steering Committee on samples, 
data and ethics with recommendations on the continuation or discontinuation of the study as well 
as on recommendations for amendments to the study protocol.  
The rules about decision finding and meeting procedures for the Data Monitoring committee will 
be laid out in a separate Data Monitoring Committee Charter. 

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14 
RISK ASSESSMENT AND WITHDRAWAL RULES 
14.1 
Potential risks 
For the patients, sample collection bare minuscule risks of infection at the venipuncture site.  
Patients in the intervention groups will be randomized to placebo or spironolactone on top of 
standard treatment with the potential common site effects like fatigue, hyperkalemia, hypo-
natremia, gynecomastia and disorder of menstruation (see section 11.3) 
14.2 
Known potential benefits 
Spironolactone has known diuretic effects and antihypertensive effects, although small in this 
dose. The applied dose has demonstrated significant beneficial effects on urinary albumin excre-
tion in patients with elevated levels, and a beneficial effect on survival in patients with heart fail-
ure. 
14.3 
Potential benefits 
The observational study will determine whether the proteomic analysis can identify patients at 
high risk of developing renal complications in patients with type 2 diabetes. The intervention 
study will determine whether spironolactone on top of conventional treatment reduces develop-
ment of renal and cardiovascular complication to diabetes in normoalbuminuric type 2 diabetic 
patients. 
14.4 
In concurrent illness 
In case of in concurrent illness or acceleration of chronic disease it will of the investigators opin-
ion to either pause or stop the IMP permanently. In case of hyperkalemia action must be taken in 
accordance with appendix 1, section 24. 
In case of hypotensive symptoms or measured BP below 100/50 consider temporary or perma-
nent reduction in antihypertensive or diuretic treatment, while taking concomitant disease or de-
hydration into consideration. 
In any case of in concurrent illness it will on the investigators opinion to pause or stop the IMP. In 
that case a rapport must be made in accordance with section 13. 
14.5 
Patient withdrawal  
Patients have the right to withdraw voluntarily from study treatment or the entire study at any time 
for any reason. The investigator also has the right to withdraw patients from the study treatment 
and the entire study if he or she considers this to be in the best interest of the patient. Should a 
patient decide to withdraw, all efforts will be made to complete and report the observations as 
thoroughly as possible. The investigator will make every reasonable attempt to contact the pa-
tient to determine as completely as possible the reason for the withdrawal. If the reason for with-
drawal of a patient from the study is an adverse event or an abnormal laboratory test result, the 
adverse event or test will be recorded in the eCRF. 
A participant must be withdrawn if any of the following is present: 
• 
Withdrawal of informed consent.  

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• 
Lack of adherence to the protocol as judged by the investigator. 
• 
Simultaneous participation in another intervention study.  
14.6 
Criteria for discontinuation 
A participant must be discontinued in the IMP treatment if any of the following is present: 
• 
Female patients in the intervention study who become pregnant, intend to become preg-
nant or do not use adequate birth control (according to inclusion criteria 7, in section 7.1). 
• 
Experience of research-related injury or unacceptable side effects to the study medication. 
• 
Safety considerations assessed by the investigator 
• 
Treatment with Lithium (ATC: N05AN). 
• 
Treatment with potassium sparing diuretics (ATC: C03D, C03E). 
• 
Confirmed eGFR below 15 ml/min/1.73 m2.  
• 
Confirmed elevated liver enzyme (ASAT and/or ALT) 3 times above normal range. 
Discontinued patients will be offered tests corresponding to the final study visit. Data on all pa-
tients will be included in the study and will be used in safety analysis.  
After discontinuation of study medication in the randomized population, observation should con-
tinue with visits as planned in the observational group (if the patient accepts), or if that is not pos-
sible/acceptable, evaluation of vital status and development of endpoints should be evaluated 
through registries, information of hospitals and GPs, or interviews with the patient as appropriate 
and possible in order to monitor development of endpoints in all included patients as thoroughly 
as possible, provided that the patient agrees. 
 

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15 
STATISTICAL CONSIDERATIONS 
15.1 
Sample size considerations 
The expected relative proportions of diabetes type 2 patients developing microalbuminuria within 
the planned study period are:  24% in patients at high-risk for diabetic nephropathy in the treat-
ment group receiving active study medication, 40% in those patients at high-risk for diabetic 
nephropathy in the placebo treated group and 8.5% in those therapy-naive patients at low-risk for 
diabetic nephropathy. Using the samples size formula for two proportions test (α= 0.05 β=0.80), 
randomized (1:1), n=129 in each arm of the intervention group.  To account for an expected drop-
out frequency of approx. 10% we plan to randomize 300 high-risk patients to double blind treat-
ment with spironolactone treatment or matched placebo. 
High-risk patients are expected to comprise 15% of the screened and included patients. In order 
to identify 300 high-risk patients the study requires 2000 patients to be included. To take screen 
failures of approx. 25% into account, we expect to screen 2700 patients.    
Recruitment will continue until a minimum of 300 high risk patients are enrolled in order to pre-
serve statistical power. Furthermore, at least 2000 patients in the overall study cohort will be in-
cluded. 
15.1.1 Considerations of risk stratification  
The study population will be stratified based on the CKD273 score at the screening visit. Pa-
tients with a CKD273 biomarker score above the level of 0.154 are classified as high-risk pa-
tients. The level of the cut-off is based on previous publications and unpublished data from 
>800 subjects with type 2 diabetes (20;22). 
15.2 
Study hypotheses 
The null hypothesis of the study is that the probability for development of microalbuminuria is 
equal in both CKD273 pattern risk populations (low and high):  
P(microalbuminuria | high-risk population) = P(microalbuminuria | low-risk population). 
The alternative hypothesis is that the probability for microalbuminuria is lower in the low-risk pop-
ulation as judged by the CKD273 urinary proteomics pattern in comparison to patients in the 
high-risk population.   
P(microalbuminuria | high risk group) > P(microalbuminuria | low risk group). 
The significance level (type I error = probability of false rejection of the null hypothesis) for estab-
lishing the superiority of the CKD273 urinary proteomics pattern is 0.05 using a two-sided 
Cochran-Mantel Haenszel test.  
15.3 
Patient enrollment  
Screening for eligible patients will be stopped, when at least 300 high-risk patients are enrolled in 
the interventions group and at least 2000 patients in the overall study.  

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15.4 
Planned interim analyses 
15.4.1 Safety review 
The SAE and cases of death during IMP treatment in both arms of the intervention group will 
be reviewed by the Institute of Clinical Pharmacology of Hannover Medical School on an on-
going basis. The Data Monitoring Committee will be provided with safety data to assess the 
overall safety of the study.  
15.4.2 Efficacy review 
No interim analysis for efficacy is planned. 
15.5 
Final analysis plan 
Statistical analysis of the data will be performed by Steno Diabetes Center. A SAP will be written 
and signed before database lock and unblinding of the entire treatment code. Methods for impu-
tation and type of censoring will be clarified in the SAP.     
The primary efficacy analysis will be performed for all patients randomized, which is the intent-to-
treat population. In addition, the primary and secondary efficacy endpoints will also be analyzed 
for the per-protocol population. The per-protocol analysis population includes all patients who 
were randomized into the double-blind study received study medication for at least 3 days.  
For all analyses a p value <0.05 is considered significant. 
Tables will be created for baseline variables, and comparisons performed between low- and high-
risk population, and in the intervention group for active vs. placebo treatment. Furthermore, ta-
bles with observations from study visits will be provided for the observational part and for the in-
tervention study. 
Analyses not described here or in the SAP will be considered exploratory/post hoc analyses. 
15.6 
Analysis of primary endpoint 
The primary endpoint is defined as time to the first occurrence of microalbuminuria (UACR >30 
mg/g and <300 mg/g) in 2 out 3 sterile first morning void urine samples with a geometric mean of 
UACR >30% above initial geometric mean UACR OR geometric mean > 40 mg/ g in three sam-
ples. The baseline urinary albumin-to-creatinine ratios are the geometric mean of three meas-
urements obtained during the “run-in" period.   
It is expected, that the number of patients who will drop out between randomization and occur-
rence of microalbuminuria will be low (<15%).  
If those cases where drop out occurs before sampling during the study period, prior to unblinding 
the treatment code it will be specified in the statistical analysis plan, whether these patients have 
to be considered as a treatment failure in the analysis of the primary endpoint. 
The predictive value of a positive and negative test, specificity and sensitivity of the test in rela-
tion to prediction of development of the primary endpoint will be evaluated. To assess whether 
CKD273 classifier (the marker) improved risk prediction of the primary outcome we determined 
the concordance statistic (c-statistic) and Integrated Discrimination Improvement (IDI). Both pa-
rameters measure the discriminative ability of a marker in a model to distinguish between people 
who will or will not develop the outcome (in case of predictive methods). 

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The primary endpoint will be analyzed in the total population with comparisons of high- vs. low-
risk pattern and active vs. placebo treatment using a Cox proportional-hazards regression model 
with treatment as a fixed effect; the baseline urinary albumin-to-creatinine ratio will be logarithmi-
cally transformed (base 10) as a covariate, and a two-tailed Wald chi-square test with an alpha 
level of less than 0.05; hazard ratios and two-sided 95 % confidence intervals will be calculated. 
Kaplan Meier plots of the groups will be made.  
Secondly, the analyses will be adjusted for age, gender, center, HbA1c and BP. Thirdly, further 
adjustment for any baseline demographic variables which are significantly different between the 
groups and related to albuminuria at baseline will be calculated. In addition adjustment will be 
made for significant changes in RAAS blockade or treatment with aldosterone receptor antago-
nist as concomitant medication during the study period.  
A third analysis will plot and compare all three groups (low, high placebo and high active treat-
ment) using a log-rank test. 
15.7 
Analysis of secondary endpoints 
All secondary endpoints as described in section 5.5 will be analyzed to test if there is a difference 
in development of endpoints over time between a) active vs. placebo treated patients, and b) 
high-risk and low-risk population based on CKD273. As described in section 15.5.1 the analyses 
will initially compare low-risk with high-risk placebo treated patients, and secondly all high-risk pa-
tients. Adjustments will be performed as for the primary endpoint. 
In addition to time to event (survival) analyses for discrete endpoints, analyses will evaluate the 
change over time in geometric mean UACR as slope analyses unadjusted as well as adjusted for 
confounders as described for the primary endpoint, comparing slope in the high-risk population 
with active vs. placebo and between low-risk and high-risk population the total population. Similar 
analyses will be performed with change in eGFR with time as the endpoint.  
In the analyses with time to cardiovascular events, only time to first event in case of more than 
one event in a patient will be included. 
In addition to the above described analyses comparing endpoints or slopes in high- vs. low-risk 
population or active vs. placebo, explorative analyses will also evaluate if the CKD 273 pattern 
and other baseline variables or changes in variables from baseline to 13 weeks visit in the high-
risk population are predictive of development of endpoints. 
Further analyses may be described in the SAP before database lock.  
15.8 
Analysis of safety endpoints 
The exposure of study treatment will be characterized by number of administrations and the cu-
mulative dose for both treatment groups.  
AEs will be coded using the MedDRA via MARVIN. 
An overview of all eCRF-documented AEs will be prepared. For all these categories of AEs (see 
section 13.3) separate frequency tables will be provided presenting the AEs by MedDRA pre-
ferred terms, SOC and treatment groups. 
In addition AEs leading to death and AEs leading to discontinuation of study medication will be 
summarized for the two treatment groups. 
Safety laboratory results will be classified by grade according to CTCAE version 4.0. The worst 
on-study grades after the first dose of study medication will be summarized. Only patients with 
post-baseline laboratory values will be included in these analyses. Furthermore, summary statis-

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tics (mean, median, SD, SEM, range) will be calculated for the laboratory values at the various 
visits and for the changes from baseline. Baseline values are defined as the last available value 
prior to start of study treatment.  
Corresponding descriptive summaries will be generated for vital signs. 
 

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16 
QUALITY ASSURANCE 
16.1 
Site monitoring 
To ensure compliance with the protocol, to legal and regulatory requirements applicable for clini-
cal trials and with the ethical principles of Declaration of Helsinki and ICH-GCP, monitoring visits 
for source data verification by members of HCTC will be scheduled to take place during the 
study.  
Before the start of the study, pre-study visits will be conducted and each participating center will 
be trained via initiation visits. Further visits during the study will be performed, according to pa-
tient recruitment rate. Finally, after the last patient has completed the study a close-out visit will 
be conducted.  
During site visits, the monitor should review drug accountability records and document retention 
(investigator’s study file) as well. Additionally, the monitor should observe clinical study proce-
dures and discuss any problems with the investigator(s) and/or the trial staff. 
All original data should be readily available for review during scheduled monitoring visits. Review-
ing the eCRFs for completeness and clarity, and cross-checking with source documents will be 
required, and the investigator assures HCTC of support at all times. 
16.2 
Site audit an inspections 
Audits (by the sponsor) and inspections (by regulatory authorities) may be performed in order to 
verify that the clinical study is performed according to the study protocol as well as to other appli-
cable regulatory requirements. The auditor or inspector is independent in regard to personnel in-
volved in the conduct of this clinical trial. This may occur at any time from start to after closure of 
the study. 

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17 
ETHICAL, REGULATORY AND ADMINISTRATIVE 
ASPECTS 
17.1 
Investigator responsibilities 
Investigator responsibilities are set out in ICH-GCP and in the Consortium Agreement (project no. 
279277). 
Investigators must enter study data in eCRFs within 2 weeks after the visit. The investigator will 
permit study-related monitoring visits and audits by the sponsor or its representatives as well as 
regulatory inspection(s). The investigator must provide direct access to the study center’s facili-
ties, to source documents, and to all other study documents. 
The investigator or a designated member of the investigators staff must be available at some 
time during monitoring visits to review data and resolve any queries and to allow direct access to 
the patient’s records (e.g., medical records, office charts, hospital charts, and study related 
charts) for source data verification. The data collection must be completed prior to each monitor-
ing visit so that the accuracy and completeness may be checked. 
The investigators reporting responsibilities regarding AEs are described in section 13. 
17.2 
Regulatory requirements 
The study will be performed under ICH-GCP requirements and national laws and regulations de-
pending on each country. 
17.3 
Justification for selection criteria 
The justification of the second inclusion criteria limiting the age of eligible patients to 75 years is 
due to the expected prevention potential of the trial. Patient included in the trial must have persis-
tent normoalbuminuria and therefor no sign of diabetic nephropathy at the time of inclusion. The 
time course of diabetic nephropathy will usually be >10 years from the onset of microalbuminuria 
to overt kidney disease. Since the aim of the study is to prevent kidney disease (onset of micro-
albuminuria) we consider it unethical to start preventive medical treatment in patient where the 
potential unset of disease is after the expected life time. 
17.4 
IEC and NCA 
This protocol and any accompanying material provided to the patient (such as patient information 
sheets or informed consent) as well as any advertising will be submitted by the sponsor to a 
country specific IEC. Written favorable opinion from the IEC must be obtained before starting the 
study in the respective country. Furthermore, written approval of the respective NCA and / or oth-
er regulatory authorities, if applicable, must be available before study-specific procedures.  
17.5 
Patient information and informed consent 
It is the responsibility of the investigator to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives and poten-
tial hazards of the study. It should be made clear that refusal to participate or withdrawal from the 
trial at any stage is without any prejudice to the patient’s subsequent care. 

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No patient should be obliged to participate in the trial.  
The patient must be given ample opportunity to enquire about details of the trial. If there is any 
doubt as to whether the patient has understood the written and verbal information, the patient 
should not enter the study. 
The patient must be made aware that the monitors, auditors and regulatory authorities will be 
granted direct access to the study patient source medical records without violating patient confi-
dentiality, and to the extent permitted by applicable regulations. 
If the patient agrees to participate in the study he will be asked to sign and date a consent form 
which will be kept by the investigator. The patient information leaflet and a copy of the signed in-
formed consent will be provided to the patient.  
The signed consent forms will be retained by the investigator and made available (for review on-
ly) to the study monitors, auditors and inspectors. 
If new safety information results in significant changes in the risk/benefit assessment, in the dura-
tion of the intervention study, the consent form should be reviewed and updated if necessary. All 
patients (including those already being treated) should be informed of the new information, given 
a copy of the revised form and asked to give their consent to continue in the study. 
17.6 
Insurance 
Every patient participating in the study will be insured according to national laws and regulations. 
All patients will be informed about their rights and obligations in regard to insurance policies be-
fore participating in the study.  
Insurance company: 
HDI-Gerling Industrial Insurance Company 
1 Great Tower Street 
London, UK, EC3 R5AA 
Contact person: Vicky Cockayne 
Tel: 020 7696 8099  
Fax: 020 7696 8444 
17.7 
Financial aspects 
The study is supported by EU under the FP7 program. This will be made clear to patients in the 
consent form. 
No financial compensation will be given to the patients for participating in the study. 

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18 
PROTOCOL AMENDMENTS AND DEVIATIONS 
18.1 
Protocol amendments 
Any amendment to this protocol must be approved by the sponsor and coordinating investigator. 
Favorable opinion of leading IEC and NCA approval will be obtained before any substantial 
amendment is implemented. 
18.2 
Protocol deviations 
When an emergency occurs that requires a deviation from the protocol for a patient, a deviation 
will be made only for that patient. A decision will be made by the PI, the coordinating investigator 
and the sponsor as soon as possible to determine whether or not the patient (for whom the devia-
tion from protocol was effected) is to continue in the study. The patient’s medical records will 
completely describe the deviation from the protocol and state the reasons for such deviation.  

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19 
DATA MANAGEMENT 
All study data will be collected by the investigator and/or other study personnel. A clinical trial data 
base is provided, in which the data are entered via an eCRF. Authorized and trained staff of the study 
centers will enter the data in the eCRF. Only SAEs will be additionally documented and notified on 
paper forms.  
Verification of the data in the eCRF occurs by monitoring as well as via range, validity, and consisten-
cy checks programmed in the system. In certain cases, queries can be detected by the study software 
or by authorized study staff. Based on the queries, the investigator can review and answer the found 
discrepancies directly in the system. All changes of data entered in the eCRF can be followed by an 
audit trail. 
A quality control will be performed before the database is closed. This procedure is documented. Fi-
nally, data transfer takes place for statistical evaluation. 
19.1 
Data retention 
We will pseudonymize (de-identify) rather than permanently (and irreversibly) anonymize data in 
the data retention process. Depersonalization means that data with identifying information is col-
lected, but the identifying information is then severed from the personal health information data in 
the research database and is stored separately. Identifying information linking to the research da-
tabase will be kept at the local site. No identifying information will be stored in an electronic way.  
 
 
 
 
 
19.2 
Security 
Data transferred between all local sites and the central data repository is encrypted. This will be 
realized with the help of HTTPS (HTTP over SSL). To prevent unauthorized access to the Re-
search Database, each user has to login with his personal user name and password. Passwords 
have to be changed in a regular manner and have to meet a defined complexity (minimum length, 
mix of characters, numbers and special characters). 
19.3 
Data protection 
All study staff has to give due consideration to data protection and medical confidentiality. The 
collection, transfer, storage and analysis of personal study-related data are performed pseudon-
ymized according to national regulations.  
Informed Consent From 
Name: John Smith 
Number: 613-737-7600 
Data of Birth: 06. jan - 1967 
Study ID: 6549 
Site ID: 08 
Blood sample sheet 
Data of collection: 14. feb. - 2013 
Sample ID: 27867 
Study ID: 6549 
Site ID: 08 
Research Data 
Study ID: 6549 
Site ID: 08 
Sample ID: 27867 

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20 
DATA HANDLING AND RECORD KEEPING 
20.1 
Analyses and reporting 
Data are captured in a web-based eCRF (MARVIN). For each patient enrolled an eCRF must be 
completed after the patients visit. This also applies to records for those patients who fail to com-
plete the study.  
The investigator should ensure the accuracy, completeness, legibility, and timelines of the data 
reported in the eCRFs and all required reports. 
Data will be analyzed and reported as soon as the data of the treatment period have been col-
lected and cleaned. 
20.2 
Study records retention 
The sponsor must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the study drug, that are source documents (original documents, data, and 
records [e.g., hospital records; clinical and office charts; laboratory notes; memoranda; patient’s 
diaries or evaluation checklists; pharmacy dispensing records; recorded data from automated in-
struments; copies or transcriptions certified after verification as being accurate copies; microfich-
es; photographic negatives, microfilm, or magnetic media; x-rays; patient files; and records kept 
at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
study; documents regarding patient treatment and study drug accountability; original signed in-
formed consents, etc.]) be retained by the investigator for as long as needed to comply with na-
tional  regulations (minimum 15 years). The investigator agrees to adhere to the docu-
ment/records retention procedures by signing the protocol. 

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21 
PUBLICATION POLICY 
21.1 
General terms 
The data of the study will be published in international, peer reviewed journals in accordance with 
Consortium Agreement section 8 and Grant Agreement section II 30. All publications related to 
the study will acknowledge the support of EU FP7 Proposal No: 279277-2 in accordance with 
Grant Agreement section II. 30.4. 
At the annual assembly of the study group, membership of the writing group will determined and 
will depend on number of patients included, or other commitment to the study. 
21.2 
Study publications 
The primary publications are foreseen, one presenting the results of the randomized study, and 
one presenting the results of the observational study. In addition two other publication will are 
foreseen. One regarding design and rationale of the study and one concerning the baseline con-
dition.  
The papers will be written by a writing group with the coordinator as chairman. Authors will be 
members of the writing group on behalf of the PRIORITY study group, with acknowledgement of 
all relevant site personnel as the PRIORITY study group. 
The trial will also be registered at the EU Clinical Trials Register according to current publication 
guidelines. 
21.3 
Substudy publications 
Any publication from a substudy must be conducted in accordance with Consortium Agreement 
section 8 and Grant Agreement section II 30. 
 

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22 
SUBSTUDIES 
Substudies are encouraged, but must not interfere with the main study. The Scientific Committee must 
approve all substudies and any additional funding (amendment fee, lab and personnel cost, monitoring 
etc.) required must be covered by the study centre(s) undertaking the substudy.  
Suggestions (1 page synopsis) should be forwarded to the Scientific Committee (Chris-
tian.Delles@glasgow.ac.uk). This also applies for suggestions regarding additional analyses of data 
available from the main study datasets. 

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23 
REFERENCE 
Scientific references are available upon request to the sponsor.  
(1)  Rossing P. Prediction, progression and prevention of diabetic nephropathy. The Minkowski 
Lecture 2005. Diabetologia 2006 Jan;49(1):11-9. 
(2)  American Diabetes Association. Standards of Medical Care in Diabetes--2009. Diabetes Care 
2009 Jan 1;32(Supplement_1):S13-S61. 
(3)  Levey AS, de Jong PE, Coresh J, El NM, Astor BC, Matsushita K, et al. The definition, 
classification, and prognosis of chronic kidney disease: a KDIGO Controversies 
Conference report. Kidney Int 2011 Jul;80(1):17-28. 
(4)  Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS. In patients with type 1 
diabetes and new-onset microalbuminuria the development of advanced chronic kidney 
disease may not require progression to proteinuria. Kidney Int 2010 Jan;77(1):57-64. 
(5)  Lambers Heerspink HJ, De ZD. Debate: PRO position. Should microalbuminuria ever be 
considered as a renal endpoint in any clinical trial? Am J Nephrol 2010;31(5):458-61. 
(6)  Glassock RJ. Debate: CON position. Should microalbuminuria ever be considered as a renal 
endpoint in any clinical trial? Am J Nephrol 2010;31(5):462-5. 
(7)  Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-
dependent diabetes mellitus. Arch Intern Med 1997;157:1413-8. 
(8)  Gaede P, Vedel P, Larsen N, Jensen GV, Parving H-H, Pedersen O. Multifactorial intervention 
and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 
2003;348(5):383-93. 
(9)  Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control 
and vascular complications in veterans with type 2 diabetes. N Engl J Med 
2009;360(2):129-39. 
(10)  
Parving H-H. Renoprotection in diabetes: genetic and non-genetic risk factors and 
treatment. Diabetologia 1998;41:745-59. 
(11)  
Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on 
diabetic microvascular complications in patients with hypertension and type 2 diabetes. 
Diabetes Care 2000;23(suppl 2):B54-B64. 
(12)  
Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving H-H, et al. Effect of candesartan 
on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a 
randomised placebo-controlled trial. lanc 2008 Oct 18;372(9647):1385-93. 
(13)  
Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving H-H. Beneficial effects of adding 
spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a 
randomized, double-masked, cross-over study. Diabetes Care 2005 Sep;28(9):2106-12. 
(14)  
Winocour PH. Microalbuminuria. BMJ 1992;304:1196-7. 
(15)  
Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, et al. Beneficial 
impact of spironolactone in diabetic nephropathy. Kidney 2005 Dec;68(6):2829-36. 

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(16)  
Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, et al. Beneficial 
impact of Spironolectone on nephrotic range albuminuria in diabetic nephropathy. Kidney 
International 2006. 
(17)  
Zurbig P, Mischak H. Capillary electrophoresis coupled to mass spectrometry for 
biomarker discovery and diagnosis of kidney diseases. Contrib Nephrol 2008;160:107-26. 
(18)  
Good DM, Thongboonkerd V, Novak J, Bascands JL, Schanstra JP, Coon JJ, et al. Body 
fluid proteomics for biomarker discovery: lessons from the past hold the key to success in 
the future. J Proteome Res 2007 Dec;6(12):4549-55. 
(19)  
Good DM, Zurbig P, Argiles A, Bauer HW, Behrens G, Coon JJ, et al. Naturally occurring 
human urinary peptides for use in diagnosis of chronic kidney disease. Mol Cell 
Proteomics 2010 Nov;9(11):2424-37. 
(20)  
Alkhalaf A, Zurbig P, Bakker SJ, Bilo HJ, Cerna M, Fischer C, et al. Multicentric validation 
of proteomic biomarkers in urine specific for diabetic nephropathy. PLoS One 
2010;5(10):e13421. 
(21)  
Rossing K, Mischak H, Dakna M, Zürbig P, Novak J, Julian BA, et al. Urinary Proteomics 
in Diabetes and CKD. J Am Soc Nephrol 2008 Apr 30;19(7):1283-90. 
(22)  
Zürbig P, Jerums G, Hovind P, MacIsaac R, Mischak H, Nielsen SE, et al. Urinary 
proteomics for ealy diagnosis in diabetic nephropathy. Unpublished 2012. 
(23)  
Roscioni SS, Zeeuw Dd, Hellemons ME, Mischak H, Zürbig P, Bakker SJL, et al. A urinary 
peptide biomarker set predicts worsening of albuminuria in type 2 diabetes. Unpublished 
2012. 
(24)  
Maahs DM, Siwy J, Argiles A, Cerna M, Delles C, Dominiczak AF, et al. Urinary collagen 
fragments are significantly altered in diabetes: a link to pathophysiology. PLoS One 
2010;5(9). 
(25)  
Andersen S, Brochner-Mortensen J, Parving HH. Kidney function during and after 
withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and 
microalbuminuria. Diabetes Care 2003 Dec;26(12):3296-302. 
(26)  
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, III, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009 May 5;150(9):604-12. 
 
 
 
 
 

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PROTOCOL SIGNATURES 
 
This protocol has been approved by the Sponsor. The following signature documents this 
approval. 
 
 
 
Prof. Peter Rossing MD, DMSc  
 
Date 
 
 
This protocol has been approved by the International Coordinating Investigator. The following 
signature documents this approval. 
 
 
This protocol has been approved by the study statistician. The following signature documents this 
approval. 
 
 
 
 
Tine Willum Hansen MD, Ph.D. 
 
 
Date 
 
 
 
Prof. Peter Rossing MD, DMSc 
 
Date 

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INVESTIGATOR STATEMENT 
By my signature, I agree to personally supervise the conduct of this study and to ensure its con-
duct in compliance with the protocol, informed consent, IEC procedures, the Declaration of Helsin-
ki, ICH-Good Clinical Practices guidelines, and the applicable parts of the European Regulations 
or local regulations governing the conduct of clinical studies. 
 
 
 
 
Name of Study Center 
 
 
 
 
 
Printed Name of (Principal) Investigator 
 
 
 
 
 
Signature of (Principal) Investigator 
 
Date 
 
 

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24 
APPENDIX 1: TREATMENT GUIDELINES FOR HY-
PERKALEMIA  
24.1 
 General principles 
Patients will have their plasma (or serum) potassium checked by a local laboratory at every visit 
and no patient can be included with hyperkalemia at Screening based on plasma potassium level 
>5.0 mmol/L or serum potassium level >5.4 mmol/L according to exclusion criteria. All patients 
not receiving IMP will be treated according to local guideline. All events of hyperkalemia must be 
recorded in the eCRF for all patients in the intervention group, in accordance with section 13. 
24.2 
 Potassium level > 0.4 and < 0.9 mmol/L above upper reference 
range 
24.2.1 Confirmation 
Confirm potassium concentration in a non-haemolysed sample.  
24.2.2 Change of dietary intake 
Patients will be given advice to lower dietary intake of potassium and restriction of 
food/drinks with high potassium content. (e.g. fruit juice, melon, bananas etc.) 
24.2.3 Review of medical treatment 
Review of medical regimens for agents known to cause hyperkalemia (including over-the-
counter medication). Consider reduction or discontinuation of these agents, only if it is clini-
cally acceptable. 
• Potassium supplements 
• Non-Steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors  
• Trimethoprim  
• Herbal supplements 
24.2.4 Additional treatment 
Consider reduction in ACE or ARB or increase in diuretics.  
24.2.5 Follow-up 
Repeat measurement of potassium within 5 days.  
If potassium remains in the level of > 0.4 and < 0.9 mmol/L above upper reference range 
regularly monitoring of plasma potassium to ensure stability shout be done. (Suggested once 
monthly).  

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24.3 
Plasma potassium level ≥ 0.9 and < 1.4 mmol/L above upper refer-
ence range 
Apply all instruction listed in section 24.2. In addition:  
24.3.1 Study medication 
Temporarily discontinue study medication.  
Evaluate continuation of the study medication after 10 days (according to section 24.5).  
24.3.2 Additional treatment 
Consider treatment with non-potassium sparing diuretics (or increased doses of ongoing 
treatment). 
Consider treatment with natriumpolystyrensulfonat. 
Reduce treatment dose of  ACE inhibitor or Angiotensin II receptor blocker (ARB) 
24.3.3 Follow-up 
Repeat measurement of potassium within 3 days. 
24.4 
 Plasma potassium level ≥ 1.4 mmol/L above upper reference range 
Apply all instruction listed in section 24.2. In addition: 
24.4.1 Study medication 
Immediately discontinue study medication.  
24.4.2 Follow-up 
Urgently evaluate the patient and treat hyperkalemia as clinically indicated.  
24.5 
 Continuation of study medication 
If the potassium level is < 0.9 mmol/L above upper reference range the patient can continue tak-
ing study medication. 
Patients who continue study medication after temporary discontinuation of study medication must 
have the potassium measured according to section 24.2.5 
In a patient who has experienced a potassium level of ≥ 1.4 mmol/L above upper reference 
range, and in whom the potassium fails to decrease to < 0.9 mmol/L above upper reference 
range after the procedures described above have been tried, the study medication must be dis-
continued permanently and it should be recorded in the eCRF. 
In case of repeated episodes of confirmed hyperkalemia after the attempt to re-start study medi-
cation following discontinuation the study medication must be discontinued permanently and it 
should be recorded in the eCRF. 
Patients, who discontinue the study medication, will remain in the study and be followed for the 
full duration of the study.