Clinical Trials Register

Summary
EudraCT Number:	2013-000418-39
Sponsor's Protocol Code Number:	EPREDICE2013
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-12-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Lithuania - SMCA

A.2

EudraCT number

2013-000418-39

A.3

Full title of the trial

Early Prevention of Diabetes Complications in people with Hyperglycaemia in Europe

Ankstyvoji cukrinio diabeto komplikacijų profilaktika Europoje žmonėms, kuriems nustatytas padidėjęs gliukozės kiekis kraujyje.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

Ankstyvoji cukrinio diabeto komplikacijų profilaktika Europoje žmonėms, kuriems nustatytas padidėjęs gliukozės kiekis kraujyje.

A.3.2

Name or abbreviated title of the trial where available

e-PREDICE

A.4.1

Sponsor's protocol code number

EPREDICE2013

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	FUNDACION DE INVESTIGACION EN RED EN ENFERMEDADES CARDIOVASCULARES (FIRCAVA)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Commission FP7
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FUNDACION DE INVESTIGACION EN RED EN ENFERMEDADES CARDIOVASCULARES (FIRCAVA)
B.5.2	Functional name of contact point	Jaakko Tuomilehto
B.5.3	Address:
B.5.3.1	Street Address	Avda. de Europa 19, Parque Empresarial La Moraleja,
B.5.3.2	Town/ city	Alcobendas/Madrid
B.5.3.3	Post code	28108
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34917932244
B.5.6	E-mail	jaakko@ceiis.org

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Glucophage 850 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sante s.a.s.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	GLUCOPHAGE/GLUCOPHAGE FORTE/DIANBEN/RISIDON 850 mg film-coated tablet
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	657-24-9
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03200MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	850
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Trajenta 5 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Linagliptin
D.3.9.1	CAS number	668270-12-0
D.3.9.3	Other descriptive name	LINAGLIPTIN
D.3.9.4	EV Substance Code	SUB31340
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Jentadueto 2.5 mg/850 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN
D.3.9.1	CAS number	657-24-9
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03200MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	850
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Linagliptin
D.3.9.1	CAS number	668270-12-0
D.3.9.3	Other descriptive name	LINAGLIPTIN
D.3.9.4	EV Substance Code	SUB31340
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non diabetic hyperglycaemia:
Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG) or both

Prediabetas t.y. ne diabetinio lygmens hiperglikemija (sutrikusi glikemija nevalgius (SGN) ar gliukozės tolerancijos sutrikimas (GTS) arba abu sutrikimai kartu.

E.1.1.1

Medical condition in easily understood language

Pre-Diabetes

Pre-diabetas

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10065542
E.1.2	Term	Prediabetes
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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).

Įvertinti gydymo metforminu, linagliptinu ar jų kombinacija kartu su gyvensenos keitimu efektyvumą mikrovaskulinių komplikacijų (tokių kaip retinopatija, nefropatija, neuropatija) vystymuisi 3-5 metų laikotarpiu lyginant tik su gyvensenos keitimu, asmenims, kuriems diagnozuota GTS, SGN ar abu sutrikimai.

E.2.2

Secondary objectives of the trial

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 linagliptin 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 non-diabetic hyperglycaemia (IGT, IFG or IFG plus IGT)
5-To determine the safety of linagliptin, metformin and of the combination of linagliptin with metformin plus lifestyle intervention in people with non diabetic hyperglycaemia with regard to severe adverse effects and clinically important events

1. Nustatyti asmenis, kuriems yra didžiausia tikimybė kad išsivystys ankstyvos diabeto komplikacijos.
2. Išaiškinti, kurios intervencijos laikymasis labiausiai įtakoja prevenciją ankstyvoms diabetinėms komplikacijoms.
3. Įvertinti skirtingų gydymo metodų įtaką yvenimo kokybei ir neuropsichologinėms funkcijoms.
4.Įvertinti gydymo linagliptinu, metforminu ir linagliptino bei metformino deriniu kartu su su gyvenimo būdo intervencija įtaką kraujagyslių funkcijai ir struktūrai bei naujų mikrokraujagyslinių komplikacijų biologiniiams žymenims asmenims , kuriems patvirtintas pre-diabetas, lyginant tik su gyvenimo būdo intervencijos taikymu.
5.Nustatyti linagliptino, metformino ir linagliptino bei metformino derinio, drauge su gyvenimo būdo intervencijos, saugumą, vertinant pagal nepageidaujamas reakcijas ir kliniškai svarbius įvykius.

E.2.3

Trial contains a sub-study

E.3

Principal 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

•Vyrai ir moterys
•45-74 metų amžiaus
•Sutrikusi glikemija nevalgius (SGN): nevalgius 6,1 - 6,9 mmol/l ir 2 val. po krūvio (valgio)<7,8mmol/L; arba sutrikusi gliukozės tolerancija (GTS): nevalgius <7,0mmol/L ir 2 val. po krūvio (valgio)>7,8 ir <11,1 mmol/L; arba abu sutrikimai;
•Tiriamasis sutinka dalyvauti tyrime, pasirašydamas informuoto asmens sutikimo formą

E.4

Principal 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 or previous myocardial infarction in baselina EKG.
- Current renal replacement therapy
- Previous diagnosis of liver cirrhosis or chronic hepatitis*, or an elevation of liver enzymes (AST and or AST) >3 times normal ranges
- Previous diagnosis of Chronic Heart Failure (NYHA class III or higher)
- A prior solid organ transplant or waiting for 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

• Diagnozuotas 1 tipo cukrinis diabetas.
• Diagnozuotas 2 tipo cukrinis diabetas (įskaitant ir nustatytą atrankos vizito metu) nepriklausomai nuo to netaikomas medikamentinis gydymas, ar ne.
• GLP-1 receptorių agonistų ar pramlintido ar bet kurio dipetidilpeptidazės 4 (DPP-4) inhibitorių ar metformino vartojimas per paskutinius 3 mėnesius iki įtraukimo į tyrimą.
• Insulino ar ilgo veikimo insulino analogų vartojimas per paskutinius 3 mėnesius iki įtraukimo į tyrimą.
• Bet koks ankstesnis kardiovaskulinis ar cerebrovaskulinis kliniškai dokumentuotas atvejis ar revaskuliarizacijos procedūra*.
• Kliniškai patvirtinta makrovaskulinė komplikacija (akivaizdi kardiovaskulinė liga) įtraukimo metu, įskaitant krūtinės anginą (stabilią ar nestabilią) ir ankščiau buvusį miokardo infarktą, patvirtintą pradinėje EKG.
• Taikoma pakaitinė inkstų terapija.
• Ankščiau diagnozuota kepenų cirozė ar lėtinis hepatitas*, ar daugiau kaip 3 kartus virš normos ribos padidėję kepenų fermentai (ALTar AST)
• Ankščiau diagnozuota lėtinė širdies liga (III ar aukštesnė NYHA kl.)
• Atlikta vidaus organų transplantacija arba planuojama.
• Piktybinis susirgimas, po taikyto chirurginio gydymo, chemoterapijos, radioterapijos ar paliatyvios terapijos per pastaruosius 5 metus. Asmenims su intraepiteline plokščialąsteline odos karcinoma (Bowen’o liga), skiriant 5-fluorouracilą (5FU) vietiškai ir asmenims su bazinių odos ląstelių vėžiu yra leidžiama dalyvauti klinikiniame tyrime.
• Bet kokia ūminė būklė ar lėtinės ligos paūmėjimas, tyrėjo nuomone, galintis trukdyti pradinio bandomojo vizito darbotvarkę ir procedūras.
• Žinomas ar įtariamas jautrumas klinikinio tyrimo bandomiems produktams ar susijusiems produktams.
• narkotinių medžaigų vartojimas ar priklasomybė vaistams.
• Dalyvavimas kitame klinikiniame tyrime.
• Nėštumas, maitinimas krūtimi ar ketinimas pastoti. (Visos moterys, vaisingo amžiaus, bus tikrinamos dėl galimo neštumo iki randomizacijos)
• Katarakta, trukdanti abiejų akių tinklainės įvertinimui. Operuotiems dėl kataraktos leidžiama dalyvauti, jei jie pilnai pasveiko nuo jos.
• Diagnozuotos kitos tinklainės ligos.
• Bet kokios kitos ligos, trikdančios pagrindinių duomenų vertinimą
• Demencija, psichinis sutrikimas ar akivaizdus kognityvinis sutrikimas, dėl ko negalima būtų duoti informuoto asmens sutikimo formos.
• Išeičių stadijos arba metastazavęs vėžys.
• Gyvenantys slaugos namuose, kalėjime
• Inkstų funkcijos sutrikimas: GFG <60 ml/min/1.73m2.
• Kontraindikacija bet kokiam klinikinio tyrimo metu skiriamam medikamentui (metforminui ar sitagliptinui). Tai yra: ALT >3 kartus padidėjęs nei viršutinė normos riba, kepenų cirozė ar hepatitas, įtariama inkstų arterijos stenozė, nesenas (per praėjusius metus) kraujavimas iš skrandžio ar žarnyno, nėštumas, maitinimas krūtimi, vaisingo amžiaus moteris, vartojanti nepatikimą kontracepciją ir taip pat bet kokios aplinkybės, dėl kurių nuolatinis vaistų vartojimas kartu su klinikinio tyrimo metu skiriamais vaistais gali sąlygoti nepageidaujamą tarpusavio sąveiką.
• Bet kokia kita priežastis, medicininė būklė, vartojami vaistai ar akivaizdi negalia, neleidžianti laikytis klinikinio tyrimo susitarimo, gydymo ir tolimesnio stebėjimo procedūrų ar galimai kelti grėsmę jo/jos sveikatai.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is a combined continuous variable: the microvascular complication índex" (MCI) composed by a 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

Pagrinidnis vertinimo rodiklis bus mikrokraujagyslinių komplikacijų indeksas, kurį sudaro dedamosios Diabetinės Retinopatijos Ankstyvo Gydymo Studijos (DRAGS) skalės, albumino ir kreatinino santykio šlapime lygmens ir sudomotorinės funkcijos (SUDOSCAN) lygmuo, įvertinti vizitų 36 ir 60 mėn. metu.

E.5.1.1

Timepoint(s) of evaluation of this end point

36 and 60 months after randomization

36 ir 60 mėnuo

E.5.2

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 Endo-PAT 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 beta-cell function
- Change in self-perceived Quality of Life (QoL).
- Change in symptoms of peripheral neuropathy
- Change in neuropsychological parameters: cognitive function, 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 ischemic attack, and cardiovascular or cerebrovascular death

•Retinopatijos rezultatas galutiniame vizite apibrėžtas kaip 2 progrseijos laipsniai vertinant pagal DRAGS skalę tarp pradinio vizito ir 36 bei 60 mėnesio vizitų.
•Albumino ir kreatinino santykio šlapime lygio padidėjimas vienas SN tarp pradinio vizito ir 36 bei 60 mėnesio vizitų.
•Rankų ir kojų laidumo lygio, matuojant SUDOSCAN, pakitimų sumažėjimas 1vienas SN tarp pradinio vizito ir 36 bei 60 mėnesio.
• Mikrokraujagyslių endotelio funkcijos (MEF) pakitimai išmatuoti EndoPAT metodu (sub- tyrimas).
• Suriebėjusių kepenų ligos indekso pasikeitimas (pogrupyje).
• Obstrukcinės Miego Apnėjos (OMA) indekso pasikeitimai (sub- tyrimas) išmatuoti Somnomedics.
•Arterinio kraujo spaudimo pasikeitimai matuojant ambulatoriškai (sub- tyrimas).
•Bendrosios miego arterijos intimos storio (MAIS) vidurkio pasikeitimas (pogrupyje).
• Mikrokraujagyslių pažeidimo, endotelio funkcijos, peroksidacijos, uždegimo ir metabolitų biologinių žymenų pasikeitimas (sub- tyrimas).
• Insulino sekrecijos ir β ląstelės funkcijos pasikeitimas.
•Gyvenimo kokybės pasikeitimas.
•Periferinės neuropatijos simptomų pasikeitimas.
•Neuropsichologinių parametrų, kognityvinės funkcijos, nerimo ir depresijos simptomų, pasikeitimas.
•Didieji kardiovaskuliniai įvykiai ir kardiovaskulinės mirtys.

E.5.2.1

Timepoint(s) of evaluation of this end point

36 and 60 months

30 ir 60 mėnuo

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Gyvensenimo būdo keitimas

Lifestyle intervention

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Bulgaria

Germany

Greece

Italy

Lithuania

Poland

Serbia

Spain

Switzerland

Turkey

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last Visit Last Subject (LVLS)

Paskutinis paskutinio tiriamojo vizitas

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

2500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

500

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2400

F.4.2.2

In the whole clinical trial

3000

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Gydymas nenumatytas.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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Orphan Designation Number:
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