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

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ClinicalTrials.gov Identifier: NCT03222765
Recruitment Status : Recruiting
First Posted : July 19, 2017
Last Update Posted : July 19, 2017
Sponsor:
Collaborators:
European Commission
Boehringer Ingelheim
Merck Serono International SA
Information provided by (Responsible Party):
Evidem Consultores SL

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
PreDiabetes Drug: Placebo, metformin, linagliptin, linagliptin + metformin Not Applicable

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, parallel , single-blind, placebo controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Two groups (linagliptin vs placebo) double-blind Two groups (metformin & metformin+linagliptin) single-blind
Primary Purpose: Treatment
Official Title: Early Prevention of Diabetes Complications in People With Hyperglycaemia in Europe: e-PREDICE Study
Actual Study Start Date : March 15, 2015
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine


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



Primary Outcome Measures :
  1. Microvascular Complication Index "MIC" : [ Time Frame: 2-year ]
    linear combination of three continous variables: ETRSD score, UACR and sudomotor index

  2. Diabetic Retinopathy: Scale ETDRS [ Time Frame: 2-year ]
    ETDRS Score

  3. Urine albumin to creatinine ratio (UACR) [ Time Frame: 2-year ]
    Ratio albumin to creatinine in mg/dl

  4. Sudomotor Index [ Time Frame: 2-year ]
    SUDOSCAN sweat function


Secondary Outcome Measures :
  1. incidence of diabetes [ Time Frame: 2-year ]
    new cases of Type 2 Diabetes

  2. endothelial dysfunction [ Time Frame: 2-year ]
    ENDOPATH measurement

  3. Insulin sensitivity [ Time Frame: 2-year ]
    Insulin secretion and beta-cell function

  4. Inflammation biomarkers [ Time Frame: 2-years ]
  5. NAFLD biomarkers [ Time Frame: 2-year ]
  6. Quality of life [ Time Frame: 2-year ]
    D15 questionnaire.

  7. cognitive function [ Time Frame: 2-year ]
    MMSE questionnaire

  8. depressive symptoms [ Time Frame: 2-year ]
    WHO-MINI questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   45 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03222765


Contacts
Contact: Nisa Boukichou, Ms +34914025066 nisa@ceiis.org
Contact: Margarita Alonso, MS +34914025066 mgalonso@ceiis.org

Locations
Spain
Centro de Salud Jose Marva Recruiting
Madrid, Spain, 28030
Contact: Esther Sanchez, MD    +34629      
Contact: Ana M Santos         
Sponsors and Collaborators
Evidem Consultores SL
European Commission
Boehringer Ingelheim
Merck Serono International SA
Investigators
Principal Investigator: Rafael Gabriel, MD, PhD Evidem Consultores SL
Principal Investigator: Jaakko Tuomilehto, MD, PhD Evidem Consultores SL

Additional Information:
Study Data/Documents: Study Protocol  This link exits the ClinicalTrials.gov site
Study Protocol Version 5.0

Responsible Party: Evidem Consultores SL
ClinicalTrials.gov Identifier: NCT03222765     History of Changes
Other Study ID Numbers: EU-FP7 279074
First Posted: July 19, 2017    Key Record Dates
Last Update Posted: July 19, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Evidem Consultores SL:
prediabetes lifestyle drugs microvascular complications

Additional relevant MeSH terms:
Prediabetic State
Glucose Intolerance
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperglycemia
Metformin
Linagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action