Final Report Summary - PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria)
Executive Summary:
Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. More than 40% of new cases of renal disease in the USA are due to diabetes, mostly type 2 diabetes, and the proportion of patients with end stage disease due to diabetes has increased during the last decades.
Previous studies in unselected cohorts of normoalbuminuric patients were of limited success. If individuals with high risk for development of diabetic nephropathy are identified, it will be possible to target intervention to these patients. We have discovered a panel of biomarkers for diagnosis of chronic kidney disease, that have proven to identify, with high accuracy, patients who will develop microalbuminuria and ultimately diabetic nephropathy in different blinded studies, and to facilitate targeted intensified preventative therapy to this group. Additionally, we could demonstrate that spironolactone shows potential benefit over and in addition to standard of care, by reducing albuminuria, which is considered a surrogate for reduced risk for renal complications. The combination of a new biomarker selecting individuals at risk and targeting these individuals can be considered an example of precision medicine.
Project Context and Objectives:
Project context and objectives
Diabetes affects 9% of the European population and the expenditure on patients with diabetes accounts for 15% of the European health care budget expenditure. Almost 90% of patients have type 2 diabetes, and absolute numbers are expected to rise in parallel to the current obesity and metabolic syndrome epidemic. Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. More than 40% of new cases of renal disease in the USA are due to diabetes, mostly type 2 diabetes, and the proportion of patients with end stage disease due to diabetes has increased during the last decades. The individual risk seems to be reduced in selected centres, but the number of patients with diabetes is increasing and thus the prevalence of end stage renal disease due to diabetes continues to rise. Prevention of microalbuminuria in normoalbuminuric patients has been considered primary prevention of diabetic nephropathy.
Previous studies in unselected cohorts of normoalbuminuric patients were of limited success. If individuals with high risk for development of diabetic nephropathy are identified, it will be possible to target intervention to these patients. We have discovered a panel of biomarkers for diagnosis of chronic kidney disease, that have proven to identify, with high accuracy, patients who will develop microalbuminuria and ultimately diabetic nephropathy in different blinded studies, and to facilitate targeted intensified preventative therapy to this group. Additionally, we could demonstrate that spironolactone shows potential benefit over and in addition to standard of care, by reducing albuminuria, which is considered a surrogate for reduced risk for renal complications. The combination of a new biomarker selecting individuals at risk and targeting these individuals can be considered an example of precision medicine.
Our main objective is to develop an intervention strategy to prevent development of diabetic nephropathy based on the application of the urinary proteomics test to identify high risk patients and subsequent treatment by the use of aldosterone blockade as a means to reduce progression to microalbuminuria.
Specific aims
a) Confirm in a prospective multicentre study of normoalbuminuric type 2 diabetic patients that the urinary proteome test identifies subjects with a high risk for development of microalbuminuria.
Patients
We have screened 2276 patients and included 1811 normoalbuminuric type 2 diabetic patients, who have been stratified into low and high risk patients.
Low-risk group: Patients who are classified as being at low risk for progression to diabetic nephropathy will continue to receive usual care at their hospital diabetes clinic or GP with treatment and follow-up, and according to standard guidelines.
High-risk group: Patients who are classified as being at high risk will be randomly assigned to aldosterone blocker spironolactone 25 mg or placebo therapy on top of standard therapy.
Patients who have contraindications to renin-angiotensin-aldosterone system blockade have not been included in this part of the study and will receive standard care (which may include ACE inhibitors or angiotensin II receptor blockers) by their diabetologist or GP.
Follow-up
All participants, however stratified for risk, will be seen annually at the clinical research facility for review and measurement of albuminuria. The randomised patients from the high-risk group will be seen at quarterly visits. The study will run for three years for each patient, but follow-up beyond the study period itself would be relevant and we will try to establish a post-trial follow-up beyond the project.
Endpoints
The primary endpoint is development of confirmed microalbuminuria (>30 mg/g) in at least two out of three tests, with at least 30% increase from baseline. 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 3-year follow-up. We will compare the "low-risk" group and the conventionally treated "high-risk" group in order to assess the predictive value of the urinary proteomics test. Furthermore, we will compare, within the "high-risk" group changes in albuminuria between patients randomised to placebo or the aldosterone blocker spironolactone. The analysis will consider age and gender effects on the predictive value of the proteomics test and treatment effect.
Project Results:
The project has so far been devoted to preparations of the consortium for the clinical trial, development of the protocol for submission to regulatory authorities, preparations of study sites for the clinical trial, manufacturing of study medication, testing and optimisation of the proteomic biomarker in a pilot study, development of an eCRF and study database, and finally, screening, inclusion and follow-up of study participants. The clinical study is still ongoing.
The consortium has met at annual meetings. A website has been established for the consortium at www.eu-priority.org. Steering committees have been in contact through regular telephone conferences.
The protocol for the clinical trial, which describes the main activity of the project, was developed in collaboration with study partners. In July 2013, the clinical trial application including study protocol was submitted to VHP and was accepted after revision. Subsequently, the national competent authorities approved the clinical trial application, with the last national approval in late 2014. Three of the original partners, in Berlin, Zurich and Montpellier, have been terminated due to lack of access to suitable patients. To compensate for this, accession of new sites in Germany, Netherlands and Belgium, has been completed. In 2017 the legal entity of the coordinating partner was transferred from Steno Diabetes Center A/S to Region Hovedstaden (the Capital Region of Denmark).
The trial preparation included development of an electronic case record form (eCRF) including database, setting up a patient randomisation system and a medication handling system. Pre-study visits were done by the academic clinical research organisation (partner HCT) at all thirteen initially planned clinical sites. Preparations for logistics, including shipment of samples and study material between sites, have taken place as well as preparations of data transfer.
As soon as sites were initiated after protocol approval, patients were invited and inclusion into the study began. Recruitment was finalized 31 August 2017, 2276 patients have been screened, 224 have been identified as high-risk patients, 1587 as low-risk patients and 463 were screening failures.
The study is delayed compared to initial timelines, mainly due to a prolonged process of manufacturing of the investigational medicinal product (study drug) and delays in approval of the study protocol. Due to this delay, the first clinical partner was initiated in December 2013. To compensate for the delays, focus has been on boosting recruitment from existing sites and inclusion of new sites. The project was extended until 31 December 2018 to allow sufficient time for patient follow-up and data analysis. The database was then locked and data analyzed in December 2018. The results will be compiled in a clinical study report, which will be presented during 2019.
A Data Monitoring Committee was established to monitor the safety of study participants and has recommended the study to continue based on annual assessments of adverse event reporting. Furthermore, HCT performed the monitoring visits at sites at which recruitment started and subsequent visits according to recruitment pace.
A pilot test of local on-site sampling of urine specimens for urinary proteomic analysis, shipment and subsequent analysis by the laboratory at MOS provided satisfactory results proving that the process as well as the analysis worked as planned.
In collaboration with another EU FP7 project on systems biology in kidney disease: “SYSKID”, we confirmed the ability of the urinary proteomic risk profile to predict progression from normoalbuminuria to microalbuminuria independently of other risk markers in a post hoc analysis of samples from the DIRECT trial involving 740 normoalbuminuric type 2 diabetic patients followed for up to 5 years. This supports our goal.
Collaboration with the EU FP7 project HOMAGE has been established to look for markers of heart failure in PRIORITY, and for renal complications in HOMAGE.
The FDA issued a Letter of Support for the employed biomarker, CKD273, http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508790.pdf.
Potential Impact:
If we are successful in fulfilling our first study aim, i.e. to demonstrate the prospective value of the urinary proteomic marker of renal disease, we will have established a new and very early marker identifying type 2 diabetic patients at risk for diabetic nephropathy which will allow intervention before renal functional deterioration and thus potentially optimal nephro-protection. This will be optimal for prevention of renal disease in type 2 diabetes, the leading cause of end stage renal disease in the Western world.
If we are also able to reduce the increased risk in high-risk patients with spironolactone, we will have a documented treatment option for early prevention or delay of progression of renal disease. In that case our project will have not only established a new and very early marker of early diabetic nephropathy but also a treatment option. This would have major implications for patients with diabetes, and would also provide a potential for reducing health related costs due to diabetes, since treatment of end stage renal disease is very costly.
The PRIORITY project will also help to establish a state of art efficient international academic clinical research network dedicated to clinical research in diabetes and nephrology.
List of Websites:
www.eu-priority.org
Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. More than 40% of new cases of renal disease in the USA are due to diabetes, mostly type 2 diabetes, and the proportion of patients with end stage disease due to diabetes has increased during the last decades.
Previous studies in unselected cohorts of normoalbuminuric patients were of limited success. If individuals with high risk for development of diabetic nephropathy are identified, it will be possible to target intervention to these patients. We have discovered a panel of biomarkers for diagnosis of chronic kidney disease, that have proven to identify, with high accuracy, patients who will develop microalbuminuria and ultimately diabetic nephropathy in different blinded studies, and to facilitate targeted intensified preventative therapy to this group. Additionally, we could demonstrate that spironolactone shows potential benefit over and in addition to standard of care, by reducing albuminuria, which is considered a surrogate for reduced risk for renal complications. The combination of a new biomarker selecting individuals at risk and targeting these individuals can be considered an example of precision medicine.
Project Context and Objectives:
Project context and objectives
Diabetes affects 9% of the European population and the expenditure on patients with diabetes accounts for 15% of the European health care budget expenditure. Almost 90% of patients have type 2 diabetes, and absolute numbers are expected to rise in parallel to the current obesity and metabolic syndrome epidemic. Diabetic nephropathy is the leading cause of end-stage renal disease in the Western world. More than 40% of new cases of renal disease in the USA are due to diabetes, mostly type 2 diabetes, and the proportion of patients with end stage disease due to diabetes has increased during the last decades. The individual risk seems to be reduced in selected centres, but the number of patients with diabetes is increasing and thus the prevalence of end stage renal disease due to diabetes continues to rise. Prevention of microalbuminuria in normoalbuminuric patients has been considered primary prevention of diabetic nephropathy.
Previous studies in unselected cohorts of normoalbuminuric patients were of limited success. If individuals with high risk for development of diabetic nephropathy are identified, it will be possible to target intervention to these patients. We have discovered a panel of biomarkers for diagnosis of chronic kidney disease, that have proven to identify, with high accuracy, patients who will develop microalbuminuria and ultimately diabetic nephropathy in different blinded studies, and to facilitate targeted intensified preventative therapy to this group. Additionally, we could demonstrate that spironolactone shows potential benefit over and in addition to standard of care, by reducing albuminuria, which is considered a surrogate for reduced risk for renal complications. The combination of a new biomarker selecting individuals at risk and targeting these individuals can be considered an example of precision medicine.
Our main objective is to develop an intervention strategy to prevent development of diabetic nephropathy based on the application of the urinary proteomics test to identify high risk patients and subsequent treatment by the use of aldosterone blockade as a means to reduce progression to microalbuminuria.
Specific aims
a) Confirm in a prospective multicentre study of normoalbuminuric type 2 diabetic patients that the urinary proteome test identifies subjects with a high risk for development of microalbuminuria.
Patients
We have screened 2276 patients and included 1811 normoalbuminuric type 2 diabetic patients, who have been stratified into low and high risk patients.
Low-risk group: Patients who are classified as being at low risk for progression to diabetic nephropathy will continue to receive usual care at their hospital diabetes clinic or GP with treatment and follow-up, and according to standard guidelines.
High-risk group: Patients who are classified as being at high risk will be randomly assigned to aldosterone blocker spironolactone 25 mg or placebo therapy on top of standard therapy.
Patients who have contraindications to renin-angiotensin-aldosterone system blockade have not been included in this part of the study and will receive standard care (which may include ACE inhibitors or angiotensin II receptor blockers) by their diabetologist or GP.
Follow-up
All participants, however stratified for risk, will be seen annually at the clinical research facility for review and measurement of albuminuria. The randomised patients from the high-risk group will be seen at quarterly visits. The study will run for three years for each patient, but follow-up beyond the study period itself would be relevant and we will try to establish a post-trial follow-up beyond the project.
Endpoints
The primary endpoint is development of confirmed microalbuminuria (>30 mg/g) in at least two out of three tests, with at least 30% increase from baseline. 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 3-year follow-up. We will compare the "low-risk" group and the conventionally treated "high-risk" group in order to assess the predictive value of the urinary proteomics test. Furthermore, we will compare, within the "high-risk" group changes in albuminuria between patients randomised to placebo or the aldosterone blocker spironolactone. The analysis will consider age and gender effects on the predictive value of the proteomics test and treatment effect.
Project Results:
The project has so far been devoted to preparations of the consortium for the clinical trial, development of the protocol for submission to regulatory authorities, preparations of study sites for the clinical trial, manufacturing of study medication, testing and optimisation of the proteomic biomarker in a pilot study, development of an eCRF and study database, and finally, screening, inclusion and follow-up of study participants. The clinical study is still ongoing.
The consortium has met at annual meetings. A website has been established for the consortium at www.eu-priority.org. Steering committees have been in contact through regular telephone conferences.
The protocol for the clinical trial, which describes the main activity of the project, was developed in collaboration with study partners. In July 2013, the clinical trial application including study protocol was submitted to VHP and was accepted after revision. Subsequently, the national competent authorities approved the clinical trial application, with the last national approval in late 2014. Three of the original partners, in Berlin, Zurich and Montpellier, have been terminated due to lack of access to suitable patients. To compensate for this, accession of new sites in Germany, Netherlands and Belgium, has been completed. In 2017 the legal entity of the coordinating partner was transferred from Steno Diabetes Center A/S to Region Hovedstaden (the Capital Region of Denmark).
The trial preparation included development of an electronic case record form (eCRF) including database, setting up a patient randomisation system and a medication handling system. Pre-study visits were done by the academic clinical research organisation (partner HCT) at all thirteen initially planned clinical sites. Preparations for logistics, including shipment of samples and study material between sites, have taken place as well as preparations of data transfer.
As soon as sites were initiated after protocol approval, patients were invited and inclusion into the study began. Recruitment was finalized 31 August 2017, 2276 patients have been screened, 224 have been identified as high-risk patients, 1587 as low-risk patients and 463 were screening failures.
The study is delayed compared to initial timelines, mainly due to a prolonged process of manufacturing of the investigational medicinal product (study drug) and delays in approval of the study protocol. Due to this delay, the first clinical partner was initiated in December 2013. To compensate for the delays, focus has been on boosting recruitment from existing sites and inclusion of new sites. The project was extended until 31 December 2018 to allow sufficient time for patient follow-up and data analysis. The database was then locked and data analyzed in December 2018. The results will be compiled in a clinical study report, which will be presented during 2019.
A Data Monitoring Committee was established to monitor the safety of study participants and has recommended the study to continue based on annual assessments of adverse event reporting. Furthermore, HCT performed the monitoring visits at sites at which recruitment started and subsequent visits according to recruitment pace.
A pilot test of local on-site sampling of urine specimens for urinary proteomic analysis, shipment and subsequent analysis by the laboratory at MOS provided satisfactory results proving that the process as well as the analysis worked as planned.
In collaboration with another EU FP7 project on systems biology in kidney disease: “SYSKID”, we confirmed the ability of the urinary proteomic risk profile to predict progression from normoalbuminuria to microalbuminuria independently of other risk markers in a post hoc analysis of samples from the DIRECT trial involving 740 normoalbuminuric type 2 diabetic patients followed for up to 5 years. This supports our goal.
Collaboration with the EU FP7 project HOMAGE has been established to look for markers of heart failure in PRIORITY, and for renal complications in HOMAGE.
The FDA issued a Letter of Support for the employed biomarker, CKD273, http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508790.pdf.
Potential Impact:
If we are successful in fulfilling our first study aim, i.e. to demonstrate the prospective value of the urinary proteomic marker of renal disease, we will have established a new and very early marker identifying type 2 diabetic patients at risk for diabetic nephropathy which will allow intervention before renal functional deterioration and thus potentially optimal nephro-protection. This will be optimal for prevention of renal disease in type 2 diabetes, the leading cause of end stage renal disease in the Western world.
If we are also able to reduce the increased risk in high-risk patients with spironolactone, we will have a documented treatment option for early prevention or delay of progression of renal disease. In that case our project will have not only established a new and very early marker of early diabetic nephropathy but also a treatment option. This would have major implications for patients with diabetes, and would also provide a potential for reducing health related costs due to diabetes, since treatment of end stage renal disease is very costly.
The PRIORITY project will also help to establish a state of art efficient international academic clinical research network dedicated to clinical research in diabetes and nephrology.
List of Websites:
www.eu-priority.org