Prevention of Microvascular Complications in Prediabetes e-PREDICE Study

Study Overview
=================
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.

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

Conditions
-----------------
PreDiabetes

Intervention / Treatment
-----------------
* Drug: Placebo, metformin, linagliptin, linagliptin + metformin


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, parallel , single-blind, placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo Lifestyle modification (diet and physical activity recommendations) | Drug: Placebo, metformin, linagliptin, linagliptin + metformin<br> <br> |
| Experimental: Metformin<br>Metformin Lifestyle modification (diet and physical activity recommendations) | Drug: Placebo, metformin, linagliptin, linagliptin + metformin<br> <br> |
| Experimental: Linagliptin<br>Linagliptin Lifestyle modification (diet and physical activity recommendations) | Drug: Placebo, metformin, linagliptin, linagliptin + metformin<br> <br> |
| Experimental: Linagliptin and Metformin<br>Fixed dose combination of Linagliptin and metformin Lifestyle modification (diet and physical activity recommendations) | Drug: Placebo, metformin, linagliptin, linagliptin + metformin<br> <br> |

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prediabetes lifestyle drugs microvascular complications