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

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

• Status: Unknown
• Conditions: PreDiabetes
• Intervention / Treatment: Drug: Placebo, metformin, linagliptin, linagliptin + metformin

• Study Type: Interventional
• Enrollment (Anticipated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nisa Boukichou, Ms; Phone Number: +34914025066; Email: nisa@ceiis.org
• Study Contact Backup: Name: Margarita Alonso, MS; Phone Number: +34914025066; Email: mgalonso@ceiis.org

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo; Lifestyle modification (diet and physical activity recommendations)	Drug: Placebo, metformin, linagliptin, linagliptin + metformin
EXPERIMENTAL: Metformin; Metformin; Lifestyle modification (diet and physical activity recommendations)	Drug: Placebo, metformin, linagliptin, linagliptin + metformin
EXPERIMENTAL: Linagliptin; Linagliptin; Lifestyle modification (diet and physical activity recommendations)	Drug: Placebo, metformin, linagliptin, linagliptin + metformin
EXPERIMENTAL: Linagliptin and Metformin; Fixed dose combination of Linagliptin and metformin; Lifestyle modification (diet and physical activity recommendations)	Drug: Placebo, metformin, linagliptin, linagliptin + metformin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Evidem Consultores SL
• Collaborators: Boehringer Ingelheim; Merck Serono International SA; European Commission
• Investigators: Principal Investigator: Rafael Gabriel, MD, PhD, Evidem Consultores SL; Principal Investigator: Jaakko Tuomilehto, MD, PhD, Evidem Consultores SL

Publications and helpful links

General Publications

• Gabriel R, Boukichou Abdelkader N, Acosta T, Gilis-Januszewska A, Gomez-Huelgas R, Makrilakis K, Kamenov Z, Paulweber B, Satman I, Djordjevic P, Alkandari A, Mitrakou A, Lalic N, Colagiuri S, Lindstrom J, Egido J, Natali A, Pastor JC, Teuschl Y, Lind M, Silva L, Lopez-Ridaura R, Tuomilehto J; e-PREDICE Consortium. Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data. PLoS One. 2020 Apr 13;15(4):e0231196. doi: 10.1371/journal.pone.0231196. eCollection 2020.

Study record dates

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

• Keywords: prediabetes lifestyle drugs microvascular complications
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Linagliptin
• Other Study ID Numbers: EU-FP7 279074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No