Early Prevention of Diabetes Complications in people with Pre-Diabetes in Europe

• Register: EUCTR
• Last refreshed on: 6 January 2015
• Main ID: EUCTR2013-000418-39-AT
• Date of registration: 20/11/2014
• Prospective Registration: Yes
• Primary sponsor: FUNDACION DE INVESTIGACION EN RED EN ENFERMEDADES
• Public title: Early Prevention of Diabetes Complications in people with Pre-Diabetes in Europe
• Scientific title: Early Prevention of Diabetes Complications in people with Hyperglycaemia in Europe - e-PREDICE
• Target sample size: 3000
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000418-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: yes Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: yes Other specify the comparator: lifestyle intervention Number of treatment arms in the trial: 4

Countries of recruitment

Australia, Austria, Bulgaria, Germany, Greece, Italy, Lithuania, Poland, Serbia, Spain, Switzerland, Turkey

Contacts

• Name: Ruy López Ridaura
• Affiliation: FUNDACION DE INVESTIGACION EN RED EN ENFERMEDADES

• Name: Ruy López Ridaura
• Affiliation: FUNDACION DE INVESTIGACION EN RED EN ENFERMEDADES

Key inclusion & exclusion criteria

Inclusion criteria:
• Men and women
• Age 45 -74 years
• Impaired Fasting Glucose (IFG): FPG 6.1 to 6.9mmol/l and 2-h PG <7.8mmol/L; or Impaired Glucose Tolerance (IGT): FPG <7.0mmol/L and 2h PG >_7.8 and <11.1 mmol/L; or both conditions;
• Informed consent given

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 120
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 80

Exclusion criteria:
• Type 1 diabetes.
• Known* or unknown T2D (including screen detected T2D) with or without pharmacological treatment.
• Use of a GLP-1 receptor agonist (exenatide or other) or pramlintide or any dipeptidyl peptidase 4 (DPP-4) inhibitor or metformin within the 3 months prior to enrolment.
• Use of insulin or long-acting insulin analogue within 3 months prior to enrolment.
• Any previous cardiovascular or cerebrovascular clinically documented event or revascularization procedure*.
• Clinical evidence of macro-vascular complications (overt clinical cardiovascular disease) at enrolment, including angina (stable or unstable) and evidence of previous myocardial infarction in baseline EKG.
• Current renal replacement therapy.
• A previous diagnosis of liver cirrhosis or chronic hepatitis*, or an elevation of liver enzymes (AST and or ALT) >3 tiems normal ranges.
• Previous diagnosis of Chronic heart failure (NYHA class III or higher).
• A prior solid organ transplant or awaiting solid organ transplant.
• Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Subjects with intraepithelial squamous cell carcinoma of the skin (Bowen’s disease) treated with topical 5-fluorouracil (5FU) and subjects with basal cell skin cancer are allowed to enter the trial.
• Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures.
• 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 (all fertile women will be tested for before randomization), breast-feeding or intend to become pregnant.
• Presence of cataract that impedes the retinal evaluation of both eyes.
• Other previously diagnosed retinal diseases.
• Any diseases that would prevent the measurement of primary endpoints
• Dementia, mental disorder or evident cognitive impairment unable to give informed consent.
• End-stage or metastatic cancer.
• Institutionalization.
• Renal function impairment: GFR <60 ml/min/1.73m2.
• Contraindication to any of the study drugs (metformin or linagliptin). This includes: ALT > 3 times the upper limit of normal, history of cirrhosis or hepatitis, suspected renal artery stenosis, recent gastrointestinal bleeding (within the last year), pregnant, breastfeeding or a female of child-bearing potential not on reliable contraception and also any circumstance where ongoing medication might lead to potential adverse drug interaction with components of the trial medications.
• Any other reason, medical condition, ongoing medication or significant disability that would prevent the participant complying with trial consent, treatment and follow-up procedures or potentially jeopardise her/his medical care.
* Previous diagnosis should be documented after medical record review.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non diabetic hyperglycaemia: Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG) or both
MedDRA version: 17.1 Level: LLT Classification code 10065542 Term: Prediabetes System Organ Class: 100000004861

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Intervention(s)

Trade Name: Gluocophage 850 mg film-coated tablets
Product Name: GLUCOPHAGE/GLUCOPHAGE FORTE/DIANBEN/RISIDON 850mg film-coated tablet
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: METFORMIN HYDROCHLORIDE
CAS Number: 657-24-9
Other descriptive name: METFORMIN HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 850-

Trade Name: Trajenta 5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Linagliptin
CAS Number: 668270-12-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Jentadueto 2.5 mg/850 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: METFORMIN HYDROCHLORIDE
CAS Number: 657-24-9
Other descriptive name: METFORMIN HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 850-
INN or Proposed INN: Linagliptin
CAS Number: 668270-12-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 36 and 60 months after randomization

Secondary Objective: 1- To identify among people with hyperglycaemia who are most likely to develop early diabetic complication
2- To determine the extent to which the compliance to the interventions affect the rate on early diabetic complications prevention
3- To evaluate the effect of the different treatment regimes applied in this study on quality of life and neuropsychological functions
4- To assess the efficacy of treatment with linagliptin, metformin and the combination of sitagliptin with metformin plus lifestyle intervention in comparison to lifestyle intervention alone with regard to surrogate parameters of vascular function and structure, and novel biomarkers of microvascular damage in adults with hyperglycaemia (IGT, IFG or IFG plus IGT)
5- To determine the safety of linagliptin or metformin and the combination of sitagliptin with metformin plus lifestyle intervention in people with non diabetic hyperglycaemia with regard to severe adverse effects and clinically important events

Primary end point(s): The primary endpoint is a combined continuous variable, "the microvascular complication índex" (MCI), composed by the linear combination of the Early Treatment Diabetic Retinopathy Study Scale (ETDRS) score, the level of urinary albumin to creatinine ratio, and sudomotor test (SUDOSCAN) score, measured during the 36th and 60th month visits.

Main Objective: To assess the effect of treatment with linagliptin, metformin or the combination of linagliptin with metformin, plus lifestyle intervention (diet and physical activity), compared to lifestyle intervention alone, for at least 3 years, and up to 5 years, on different microvascular parameters (retinal, renal and neurological), as defined by the primary and secondary endpoints, in adults with non diabetic hyperglycaemia (IGT, IFG or IFG plus IGT).

Secondary Outcome(s)

Secondary end point(s): • Retinopathy score at last visit defined as 2 steps progression on the ETDRS scale between baseline and visits at months 36th and 60th .
• One standard deviation (SD) increase on the level of urinary albumin to creatinine ratio between baseline and visits at months 36th and 60th
• One SD decrease Changes in the level of hands and feet conductance in SUDOSCAN between baseline and visits at months 36th and 60th.

• Change in microvascular endothelial function (MEF) measured by the EndoPAT method (in a subset).
• Change in the Non-Alcoholic Fatty Liver (NAFL) Index (in a subset).
• Change in biomarkers of microvascular damage, endothelial function, per-oxidation, inflammation, and metabolomics (in a subset).
• Change in the insulin secretion and ß-cell function.
• Change in self-perceived Quality of Life (QoL).
• Change in symptoms of peripheral neuropathy
• Change in neuropsychological parameters: cognitive function, anxiety and depressive symptoms and indices.
• Changes in Obstructive Sleep Apnoea (OSA) indices as measured by Somnomedics (in a subset).
• Changes in ambulatory blood pressure monitoring (in a subset)
• Change in the mean common carotid intimae-media thickness (CIMT) (in a subset).
• Incidence of major cardiovascular events, defined as an expanded composite of total coronary events, total stroke events, revascularization procedures (coronary artery bypass graft, percutaneous coronary angioplasty, and peripheral revascularization), hospitalization for heart failure, transient ischaemic attack, and cardiovascular or cerebrovascular death

Timepoint(s) of evaluation of this end point: 36 and 60 months.

Secondary ID(s)

EPREDICE2013

Source(s) of Monetary Support

European Commission FP7