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Final Report Summary - E-PREDICE (Early Prevention of Diabetes Complications in people with Hyperglycaemia in Europe)

Executive Summary:
Background: Type 2 Diabetes (T2D) is a progressive chronic disease. Hyperglycaemia is related not only to macrovascular complications but also to many microvascular complications as retinopathy, nephropathy and peripheral neuropathy. According to WHO criteria `Intermediate hyperglycaemia´ or prediabetes (PD) is defined as 2-hour plasma glucose (2h PG) levels after an overload of 75g of oral glucose (OGTT) of 7.8–11.0 mmol/l (Impaired Glucose Tolerance –IGT-) or a fasting plasma glucose (FPG) of 6.1–6.9 mmol/l with 2h-PG <7.8 mmol/l (Impaired Fasting Glucose –IFG-). A significant proportion of prediabetics, show both macro- and micro- vascular complications associated with hyperglycaemia, and evidence has increasingly shown that patients with PD have microvascular dysfunction representing end-organ damage typical of diabetes. It is earlier known that early lifestyle and pharmacological interventions in people with PD can delay the onset of T2D. Although many trials have demonstrated the efficacy of lifestyle and pharmaceutical interventions in diabetes prevention, no trial has evaluated the extent to which microvascular complications can be prevented by early interventions on hyperglycaemia. Therefore, new trials combining intensive lifestyle and pharmacological treatment in PD are needed.

Aims: To assess the mid-term effects on multiple complications of hyperglycaemia of early intensive management of hyperglycaemia with linagliptin, metformin or their combination added to lifestyle intervention (LSI) (diet and physical activity), compared with LSI alone in adults with non-diabetic intermediate hyperglycaemia (IFG, IGT or both).

Study Design: The ePREDICE study is a randomized 4-arm multinational, investigator-initiated (non-commercial), partially double blinded, placebo controlled, clinical trial with prospective blinded outcome evaluation. Participants are randomised to four parallel arms: 1) LSI + 2 placebo tablets/day; 2) LSI + 2 Metformin tablets of 850 mg/day; 3) LSI + 1 Linagliptin tablets of 5 mg/day and 1 placebo; 4) LSI + 2 tablets of a fixed-dose combination of Linagliptin 2.5mg and Metformin 850 /day. Active intervention will last for at least 2 years, and additional observational follow-up two more years.
Setting and population: Males and females with prediabetes (IFG, IGT or both) aged 45 to 74 years selected from primary care screening programs in 12 clinical centres from Austria, Bulgaria, Greece, Poland, Serbia, Spain, Turkey and Australia.

Outcomes: “The Microvascular Index" (MI): a composed endpoint of three continuous variables: a) Retinal A/V score (automatic reading of digital fundus photos), b) urinary albumin to creatinine ratio (central laboratory), and c) sudomotor index measured by SUDOSCAN (automatic assessment). Secondary outcomes: biomarkers of inflammation and metabolic markers predictive of cardiovascular disease (CVD), microvascular damage, insulin secretion, NAFLD, quality of life, sleep disorders (somnogram), neuropsychological impairment, and endothelial function (EndoPAT) in a random subsample of participants. It will also give information on other diabetic complications, development of diabetes and several other outcomes.
Results: So far follow-up data exist in 942 individuals at baseline (randomization), 12 months and 24 months. At baseline patients had a mean age of 58.6 (7.6) years, 41.1 % were men, mean BMI was 30.7 (5.0), HbA1c was 5.82 (0.39) %, mean fasting glucose 6.36 (0.46) mmol/l and mean 2-hour glucose after oral glucose tolerance test 8.10 (1.75) mmol/l. As a measure of neuropathy Sudoscan showed mean values in right hand 66.4 (18.2), left hand 69.1 (17.6), right foot 78.8 (14.4) and left foot 79.3 (14.1). The Sudoscan risk index was 32.6 (11.5). As a measure of nephropathy the mean level of albumin creatinine ratio was 0.239 (0.700). Mean estimated glomerular filtration rate (eGFR), as a measure of renal function measured by CKD-EPI, was 93.7 (9.5) ml/min.
At 12 and 24 months HbA1c was 5.68 (0.38) and 5.76 (0.47) respectively. The mean Sudoscan levels in right hand was 65.6 (15.1) and 66.4 (13.9), left hand 68.7 (13.5) and 69.3 (12.5), right foot 78.1 (9.4) and 80.5 (8.1), left foot 78.2 (9.3) and 81.0 (7.7), and the Sudoscan risk index 33.5 (10.6) and 32.9 (10.0), for 12 and 24 months respectively. After 24 months the mean fasting glucose was 6.29 (0.80) mmol/l and mean 2-hour glucose after oral glucose tolerance test was 7.86 (2.42) mmol/l. The albumin creatinine ratio was at 12 and 24 months 0.253 (0.732) and 0.037 (0.066), and eGFR at the corresponding time points were 92.2 (11.0) and 89.5 (12.3).

Conclusions: After 1-year of treatment, favourable values were observed for body weight, waist circumference, total-cholesterol, HDL-cholesterol, LDL-cholesterol, HbA1c, time spent in sedentary activities per day and Sudoscan risk score. After 2-year of treatment, also favourable significant values were observed for body weight, HDL-cholesterol and HbA1c. The ePREDICE study has proceeded well so far by collecting advanced data of both demographic variables and information of complications at baseline, 12 and 24 months. It remains in the study to determine and confirm whether treatments have a different preventive effect on microvascular complications and other outcomes.

Project Context and Objectives:
The “Early Prevention of Diabetes Complications in People with Hyperglycaemia in Europe” (ePREDICE) was born as a response to FP7 call investigator-driven clinical trials to reduce diabetes complications (HEALTH 2011.2.4.3-1).

Both the incidence and prevalence of type 2 Diabetes (T2D) is increasing in Europe. According the recently published IDF-Atlas of Diabetes, the prevalence of Diabetes in the European region is 8.1% (52 million) among adult people 20-79 years. The estimated figure for 2030 is 9.1% (64.2 million). Impaired Glucose Tolerance (IGT), also known as pre-diabetes state, affects another 8.6 % (or 63 million) and although the estimate of the prevalence seems to stabilize in 8.5% by 2030, the absolute number will increase to 71.5 million. In the European region, approximately 30% of the global health expenditures are due to diabetes care with majority associated to chronic complications care. Quality of life reduces in individuals with diabetes due to chronic treatment and steadily arising disease complications, especially of microvascular origin; i.e. retinal, renal, and peripheral neural complications. Diabetic microvascular complications are the leading cause of blindness, renal end-stage disease and non-traumatic lower limb amputations in Europe.
A significant proportion of pre-diabetics, show both macro- and micro- vascular complications associated with hyperglycaemia. Although many trials have demonstrated the efficacy of both lifestyle and pharmaceutical interventions in diabetes prevention, no trial has evaluated yet to which extent microvascular complications can be delayed with early intensive intervention in people with intermediate hyperglycaemia.
The goal of ePREDICE is to prevent the development of major diabetes microvascular complications. The specific objective is to assess the mid- and long-term effects of early intensive management of hyperglycaemia with linagliptin, metformin or their combination added to lifestyle intervention (LSI) (diet and physical activity), compared with LSI alone, in adults with non-diabetic intermediate hyperglycaemia (IFG, IGT or both) on retinal, renal and peripheral nerve complications.

To achieve this, an investigator-driven, (non-commercial), multi-centre, randomised, partially blinded, placebo controlled, phase-IIIb clinical trial with prospective blinded outcome evaluation was established. Participants were randomized to four parallel arms: 1) LSI + 2 placebo tablets/day; 2) LSI + 2 Metformin tablets of 850 mg/day; 3) LSI + 1 Linagliptin tablets of 5mg in the morning and 1 matched placebo in the afternoon; 4) LSI + 2 tablets of a fixed-dose combination of Linagliptin 2.5mg and Metformin 850 /day. Active intervention will last for at least 2 years.

The study population are males and females with prediabetes (IFG, IGT or both) aged 45 to 74 years, selected from 12 clinical centres in 9 countries: Australia (1), Austria (1), Bulgaria (1), Greece (2), Poland (1), Serbia (2), Spain (3), and Turkey (1).

The primary endpoint is a combined continuous variable: “the microvascular complication índex" (MCI) composed by a linear combination of the Early Treatment Diabetic Retinopathy Study Scale score (based on retinograms), the level of urinary albumin to creatinine ratio, and a measure of distal small fibre neuropathy (sudomotor test by SUDOSCAN), measured during baseline visit and at 24th month visits after randomisation. In addition, in a subset of participant the project will evaluate novel serological biomarkers of systemic inflammation, early micro-vascular damage, insulin sensitivity, beta-cell function; self-perceived quality of life, neuropsychological (cognitive function and depressive disorder), endothelial function and sleep apnoea.

Project Results:
List of deliverables submitted for review to EC during the fourth reporting period, in line with the project´s objectives in Table 1 in attached file "Tables.pdf"
During the 4th period (July 2016 to December 2017) the project´s works focused on completion of clinical tasks (recruitment, drug and lifestyle intervention, clinical follow-up and monitoring of participants), in completing and cleaning-up of the central database, in the analysis of the information collected, and the preparation of final report with the results of these analyses.

Milestones achieved during the 4 th period.
− Last patient first visit: month 54th (completed by month 72nd December 2017)
− Last patient last visit: month 72nd (last patient in treatment has been registered in the system in December 2017)

Milestone achieved:
− All Case Record Forms (CRFs) are ready and transformed to electronic versions in the ePredice platform based on OpenClinica®. Updated in accordance with all the changes requested and approved by the European Union (Version 2.10).
− Operation Manual for each study visit updated in accordance with all the changes requested and approved by the European is ready and distributed to all clinical centres incorporating all mentioned changes (Version 4.0).
− Lifestyle intervention materials are ready and translated to the different local languages. Updated in accordance with all the mentioned changes.
− The trial is registered in the EUDRA-CT database (EUDRA-CT number 2013-000418-39) and in the Clinical Trial Gov registry (August 5, 2017), and updated in accordance with all the changes requested and approved by the European Commission.
− Submission of new clinical partners starting activities (P19 replaced by P36-MSB, P1502-UOA 2, P34-FJD) to all participating National Medicine Regulatory Agencies was completed and approved.
− The new clinical partners (P19 replaced by P36-MSB, P1502-UOA 2, P34-FJD) was sent to local ethics committees for the approval and were accepted.
− The 3rd Amendment to the technical annex was submitted during the 4th period an approved by the EC on October 25, 2017.(See annex).
− Completing training and certifications in new clinical centres (see information in WP2)
− First and second report to the EU: completed
− First patient first visit (m40): completed
− Third report issued to EU: completed
− Last patient first visit: month 54th (completed by month 72nd December 2017)
− Last patient last visit: month 72nd (last patient in treatment has been registered in the system in December 2017)

Potential Impact:
The ePREDICE results have the potential of changing the current paradigm of early management of intermediate hyperglycaemia, and will permit:
• To evaluate the effect of intensive treatment (lifestyle plus drug treatment) in prediabetes for the early prevention of diabetes complication.
• To show whether early, intensive, combined lifestyle and pharmacotherapy targeting to correct hyperglycaemia can help to delay diabetes complications.
• To characterize those individuals who will develop early complications.
• To identify which complication appear in the first place and the cumulative frequency of various complications.
• To provide evidence-based information on the most cost-effective interventions for preventing diabetes complications and to guide treatment decisions in prediabetes.
• To evaluate the efficacy of new technologies for the screening of microvascular complications in prediabetes.

Novelty and importance of this project – relevance to the specific aims of this research programme.
Microvascular complications appear at early stage of the disease, and are suitable as major outcome when trying to prevent complications of hyperglycaemia. Our hypothesis is that intensive and early treatment combining safe antidiabetic drugs with lifestyle intervention is more effective than intensive lifestyle intervention alone in preventing microvascular complications in adults with non-diabetic hyperglycaemia range. The use of a particular antidiabetic drug is based on the pharmacological capacity to control glycaemia, and the likelihood to produce long-term benefits, which is the key issue in prediabetes. We aimed to investigate if the early and intensive multifactorial treatment can challenge the current standard approach to prediabetes using pharmacological treatment, as co-adjuvant to the lifestyle interventions. We also aimed to investigate if it is possible to detect groups at higher risk of developing complications at earlier stages and, up to what extent, more intensive treatment could be prioritized to such a group.

ePREDICE is an innovative investigator- initiated, academic clinical trial, and the first assessing on a large population of prediabetics the effects of different lifestyle and glucose lowering drugs on early prevention of retinopathy, nephropathy and peripheral neuropathy. The trial is particularly innovative measuring of small nerve damage by the assessment of sudomotor function with the novel Sudoscan device.

The results and teachings from this project will be included to a practical protocol for the prevention of microvascular complications, and will contribute to the development of future European guidelines for diabetes prevention

List of Websites:
www.ePREDICE.eu

Related information

Documents and Publications

Reported by

EVIDEM CONSULTORES SL
Spain

Subjects

Life Sciences
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