Prevention of Microvascular Complications in Prediabetes e-PREDICE Study (ePREDICE)

July 18, 2017 updated by: Evidem Consultores SL

Early Prevention of Diabetes Complications in People With Hyperglycaemia in Europe: e-PREDICE Study

Background: A significant proportion of pre-diabetics, show macro and micro vascular complications associated with hyperglycaemia. Although many trials have demonstrated the efficacy of lifestyle and pharmaceutical interventions in diabetes prevention, no trial has evaluated the extent to which mid- and long-term complications can be prevented by early interventions on hyperglycaemia.

Aims: To assess the long-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: Investigator initiated (non-commercial), long-term, multi-centre, randomised, partially double blinded, placebo controlled, phase-IIIb clinical trial with prospective blinded outcome evaluation. Participants will be 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.

Setting and population: Males and Females with pre-diabetes (IFG, IGT or both) aged 45 to 74 years selected from primary care screening programs in 14 clinical centres from 10 countries: Australia, Austria, Bulgaria, Greece, Italy, Kuwait, Poland, Serbia, Spain and Turkey and . (N=1000)

Main Outcomes: The primary endpoint is a combined continous variable: "the microvascular complication índex" (MCI) composed by a linear combination of the Early Treatment Diabetic Retinopathy Study Scale (ETDRS) 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 and 48th month visits after randomisation. In addition, serological biomarkers of inflammation, vascular damage, non-alcoholic fatty liver disease, insulin secretion, measures of quality of life, sleep quality, neuropsychological evaluation and endothelial function will be also evaluated in a subset of participants.

Study Overview




Study Type


Enrollment (Anticipated)



  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Nisa Boukichou, Ms
  • Phone Number: +34914025066
  • Email:

Study Contact Backup

Study Locations

      • Madrid, Spain, 28030
        • Recruiting
        • Centro de Salud Jose Marva
        • Contact:
          • Esther Sanchez, MD
          • Phone Number: +34629
        • Contact:
          • Ana M Santos

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 74 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers


Genders Eligible for Study



Inclusion criteria

  • Impaired Fasting Glucose (IFG): Fasting Plasma Glucose (FPG) 6.1 to 6.9mmol/l and 2-hour Plasma Glucose (2-h PG): <7.8mmol/L;
  • Impaired Glucose Tolerance (IGT): FPG <7.0mmol/L and 2h PG >_7.8 and <11.1 mmol/L -Informed consent given

Exclusion Criteria:

  • Type 1 diabetes (T1D)
  • known or screen-detected Type 2 diabetes (T2D).
  • Use of any anti-diabetic drug within the 3 months prior to inclusion.
  • Previous cardiovascular event, stroke or revascularization procedure of any arterial territory
  • Morbid obesity (BMI>45)
  • Current renal replacement therapy.
  • Renal function impairment: GFR <60 ml/min/1.73m2.
  • Previous diagnosis of liver cirrhosis or chronic hepatitis
  • Elevation of liver enzymes (AST/AST) >3 times of the upper normal ranges** (6m or BL).
  • Previous diagnosis of acute or chronic pancreatitis
  • Elevation of pancreatic enzymes (Amylase/Lipase) >3 times of the upper normal ranges (6m or BL).
  • Previous diagnosis of Chronic Heart Failure (NYHA class III or higher).
  • Organ transplant or waiting for organ transplant.
  • Diagnosis of malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years.
  • End-stage or metastatic cancer.
  • Known or suspected hypersensitivity to trial products or related products.
  • Known use of non prescribed narcotics or illicit drugs.
  • Simultaneous participation in any other clinical trial of an investigational agent.
  • Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant.
  • Cataract that impedes the retinal evaluation of both eyes.
  • Ocular surgery planned in the next 6 months
  • Concomitant intraocular treatment (retina or choroid).
  • Tropicamide allergy
  • Participants with screen retinogram not optimal for retinal assessment
  • Complete amputation of one/ both hands or one/both feet.
  • Dementia, mental disorder or evident cognitive impairment unable to give informed consent.
  • Institutionalization (nursing/mental health home, hospital, prison, etc).
  • Suspected renal artery stenosis Recent gastrointestinal bleeding (within the last year)
  • Any circumstance where ongoing medication might lead to potential adverse drug effect.
  • Any other acute condition or exacerbation of chronic condition that in the investigator's opinion would interfere with the trial initiation or visit schedules or procedures.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
  • Placebo
  • Lifestyle modification (diet and physical activity recommendations)
  • Metformin
  • Lifestyle modification (diet and physical activity recommendations)
  • Linagliptin
  • Lifestyle modification (diet and physical activity recommendations)
EXPERIMENTAL: Linagliptin and Metformin
  • Fixed dose combination of Linagliptin and metformin
  • Lifestyle modification (diet and physical activity recommendations)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Microvascular Complication Index "MIC" :
Time Frame: 2-year
linear combination of three continous variables: ETRSD score, UACR and sudomotor index
Diabetic Retinopathy: Scale ETDRS
Time Frame: 2-year
Urine albumin to creatinine ratio (UACR)
Time Frame: 2-year
Ratio albumin to creatinine in mg/dl
Sudomotor Index
Time Frame: 2-year
SUDOSCAN sweat function

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
incidence of diabetes
Time Frame: 2-year
new cases of Type 2 Diabetes
endothelial dysfunction
Time Frame: 2-year
ENDOPATH measurement
Insulin sensitivity
Time Frame: 2-year
Insulin secretion and beta-cell function
Inflammation biomarkers
Time Frame: 2-years
NAFLD biomarkers
Time Frame: 2-year
Quality of life
Time Frame: 2-year
D15 questionnaire.
cognitive function
Time Frame: 2-year
MMSE questionnaire
depressive symptoms
Time Frame: 2-year
WHO-MINI questionnaire

Collaborators and Investigators

This is where you will find people and organizations involved with this study.


  • Principal Investigator: Rafael Gabriel, MD, PhD, Evidem Consultores SL
  • Principal Investigator: Jaakko Tuomilehto, MD, PhD, Evidem Consultores SL

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 15, 2015

Primary Completion (ANTICIPATED)

December 31, 2018

Study Completion (ANTICIPATED)

December 31, 2019

Study Registration Dates

First Submitted

June 20, 2017

First Submitted That Met QC Criteria

July 18, 2017

First Posted (ACTUAL)

July 19, 2017

Study Record Updates

Last Update Posted (ACTUAL)

July 19, 2017

Last Update Submitted That Met QC Criteria

July 18, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?


Drug and device information, study documents

Studies a U.S. FDA-regulated drug product


Studies a U.S. FDA-regulated device product


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