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

Primary Purpose

PreDiabetes

Status

Unknown status

Phase

Not Applicable

Locations

Spain

Study Type

Interventional

Intervention

Placebo, metformin, linagliptin, linagliptin + metformin

About this trial

This is an interventional treatment trial for PreDiabetes focused on measuring prediabetes lifestyle drugs microvascular complications

Eligibility Criteria

45 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Centro de Salud Jose MarvaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Metformin

Linagliptin

Linagliptin and Metformin

Arm Description

Placebo Lifestyle modification (diet and physical activity recommendations)

Metformin Lifestyle modification (diet and physical activity recommendations)

Linagliptin Lifestyle modification (diet and physical activity recommendations)

Fixed dose combination of Linagliptin and metformin Lifestyle modification (diet and physical activity recommendations)

Outcomes

Primary Outcome Measures

Microvascular Complication Index "MIC" :

linear combination of three continous variables: ETRSD score, UACR and sudomotor index

Diabetic Retinopathy: Scale ETDRS

ETDRS Score

Urine albumin to creatinine ratio (UACR)

Ratio albumin to creatinine in mg/dl

Sudomotor Index

SUDOSCAN sweat function

Secondary Outcome Measures

incidence of diabetes

new cases of Type 2 Diabetes

endothelial dysfunction

ENDOPATH measurement

Insulin sensitivity

Insulin secretion and beta-cell function

Inflammation biomarkers

NAFLD biomarkers

Quality of life

D15 questionnaire.

cognitive function

MMSE questionnaire

depressive symptoms

WHO-MINI questionnaire

Full Information

NCT ID

NCT03222765

First Posted

June 20, 2017

Last Updated

July 18, 2017

Sponsor

Evidem Consultores SL

Collaborators

European Commission, Boehringer Ingelheim, Merck Serono International SA

1. Study Identification

Unique Protocol Identification Number

NCT03222765

Brief Title

Prevention of Microvascular Complications in Prediabetes e-PREDICE Study

Acronym

ePREDICE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Unknown status

Study Start Date

March 15, 2015 (Actual)

Primary Completion Date

December 31, 2018 (Anticipated)

Study Completion Date

December 31, 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Evidem Consultores SL

Collaborators

European Commission, Boehringer Ingelheim, Merck Serono International SA

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

PreDiabetes

Keywords

prediabetes lifestyle drugs microvascular complications

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Randomized, parallel , single-blind, placebo controlled

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Two groups (linagliptin vs placebo) double-blind Two groups (metformin & metformin+linagliptin) single-blind

Allocation

Randomized

Enrollment

1000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo Lifestyle modification (diet and physical activity recommendations)

Arm Title

Metformin

Arm Type

Experimental

Arm Description

Metformin Lifestyle modification (diet and physical activity recommendations)

Arm Title

Linagliptin

Arm Type

Experimental

Arm Description

Linagliptin Lifestyle modification (diet and physical activity recommendations)

Arm Title

Linagliptin and Metformin

Arm Type

Experimental

Arm Description

Fixed dose combination of Linagliptin and metformin Lifestyle modification (diet and physical activity recommendations)

Intervention Type

Drug

Intervention Name(s)

Placebo, metformin, linagliptin, linagliptin + metformin

Primary Outcome Measure Information:

Title

Microvascular Complication Index "MIC" :

Description

linear combination of three continous variables: ETRSD score, UACR and sudomotor index

Time Frame

2-year

Title

Diabetic Retinopathy: Scale ETDRS

Description

ETDRS Score

Time Frame

2-year

Title

Urine albumin to creatinine ratio (UACR)

Description

Ratio albumin to creatinine in mg/dl

Time Frame

2-year

Title

Sudomotor Index

Description

SUDOSCAN sweat function

Time Frame

2-year

Secondary Outcome Measure Information:

Title

incidence of diabetes

Description

new cases of Type 2 Diabetes

Time Frame

2-year

Title

endothelial dysfunction

Description

ENDOPATH measurement

Time Frame

2-year

Title

Insulin sensitivity

Description

Insulin secretion and beta-cell function

Time Frame

2-year

Title

Inflammation biomarkers

Time Frame

2-years

Title

NAFLD biomarkers

Time Frame

2-year

Title

Quality of life

Description

D15 questionnaire.

Time Frame

2-year

Title

cognitive function

Description

MMSE questionnaire

Time Frame

2-year

Title

depressive symptoms

Description

WHO-MINI questionnaire

Time Frame

2-year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

Eligibility 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Nisa Boukichou, Ms

Phone

+34914025066

nisa@ceiis.org

First Name & Middle Initial & Last Name or Official Title & Degree

Margarita Alonso, MS

Phone

+34914025066

mgalonso@ceiis.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rafael Gabriel, MD, PhD

Organizational Affiliation

Evidem Consultores SL

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Jaakko Tuomilehto, MD, PhD

Organizational Affiliation

Evidem Consultores SL

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centro de Salud Jose Marva

City

Madrid

ZIP/Postal Code

28030

Country

Spain

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Esther Sanchez, MD

Phone

+34629

First Name & Middle Initial & Last Name & Degree

Ana M Santos

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32282852

Citation

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.

Results Reference

derived

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Prevention of Microvascular Complications in Prediabetes e-PREDICE Study

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