Clinical Trials Register

Summary
EudraCT Number:	2012-001390-88
Sponsor's Protocol Code Number:	NT13034
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-03-28
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

Czechia - SUKL

A.2

EudraCT number

2012-001390-88

A.3

Full title of the trial

Cardioprotective and metabolic effects of metformin in patients with heart failure and diabetes

Kardioprotektivní a metabolické účinky metforminu u nemocných s diabetem a srdečním selháním

A.3.1

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

Cardioprotective and metabolic effects of metformin in patients with heart failure and diabetes

Kardioprotektivní a metabolické účinky metforminu u nemocných s diabetem a srdečním selháním

A.3.2

Name or abbreviated title of the trial where available

Effects of metformin in patients with heart failure and diabetes

A.4.1

Sponsor's protocol code number

NT13034

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	Institute for Clinical and Experimental Medicine
B.1.3.4	Country	Czech Republic
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	Institute for Clinical and Experimental Medicine
B.4.2	Country	Czech Republic
B.4.1	Name of organisation providing support	Ministry of Health
B.4.2	Country	Czech Republic
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institute for Clinical and Experimental Medicine
B.5.2	Functional name of contact point	Diabetes Center
B.5.3	Address:
B.5.3.1	Street Address	Videnska 1958/9
B.5.3.2	Town/ city	Prague
B.5.3.3	Post code	140 21
B.5.3.4	Country	Czech Republic
B.5.4	Telephone number	+420 26136 4100
B.5.5	Fax number	+42026136 3183
B.5.6	E-mail	terezie.pelikanova@ikem.cz

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	Siofor 1000 potahované tbl
D.2.1.1.2	Name of the Marketing Authorisation holder	Berlin – Chemie AG Menarini Group
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Siofor 1000 potahované tbl
D.3.2	Product code	0018630
D.3.4	Pharmaceutical form	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	Each 1000 mg film-coated tablet contains 1000 mg metformin hydrochloride equivalent to metformin base 780 mg
D.3.9.1	CAS number	657-24-9
D.3.9.3	Other descriptive name	1,1-Dimethylbiguanide
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.78
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	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

type 2 diabetes mellitus, heart failure

diabetes mellitus 2.typu, srdeční selhání

E.1.1.1

Medical condition in easily understood language

type 2 diabetes mellitus, heart failure

diabetes mellitus 2.typu, srdeční selhání

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

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 evaluate the effect of metformin on myocardial function, insulin resistance and selected metabolic markers in patients with type 2 diabetes and heart failure (HF+DM+)

zjistit účinky terapie metforminem na inzulinovou rezistenci, funkci myokardu a vybrané metabolické ukazatele u pacientů s diabetem a srdečním selháním (HF+DM+)

E.2.2

Secondary objectives of the trial

to evaluate the effect of metformin on energy expenditure, endothelial function, echocardiography, spiroergometry, proton/phosphor MR spectroscopy, endocrine activity of adipose tissue (biopsy), selected cytokines in plasma and adipose tissue

zjistit účinky terapie metforminem na endotheliální funkci, na změny parametrů echokardiografie, spiroergometrie, endokrinní aktivitu tukové tkáně a vybrané cytokiny v plasmě a v tukové tkáni

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.chronic heart failure will be defined by the following criteria (all must be included):
◦diagnosis of HF known for at least 6 months
◦medical history of hospitalization for cardiac decompensation with need for parenteral therapy for congestion - X-ray findings or swelling of lower extremities
◦stable drug therapy at least 1 month
◦treatment with diuretics (thiazide or furosemide)
◦LVEF below 50%
2.the presence of diabetes will be defined by:
◦diagnosis and treatment of type 2 diabetes in the medical history
◦screening blood sample:
■the value of HbA1c(according to IFCC)≥ 4.8% + fasting glucose ≥ 7.0 mmol / l in venous plasma or
■the value of HbA1c ≥ 4.8%(according to IFCC) + random blood glucose ≥ 11.1 mmol/l in venous plasma
■or OGTT - blood glucose level at 120 min ≥ 11.1 mmol/l OGTT is indicated just in case of positivity of one of the criteria (fasting glucose + HbA1c or HbA1c + random blood glucose)
3.treatment of diabetes - by diet only
4.women and men aged 40-70 years
5.body mass index (kg/m2) in the range of 20-35
6.the range of HbA1c between 4-6,5% IFCC
7.signed informed consent

1.Chronické srdeční selhání bude definováno na základě následujících kritérií (vše musí platit):
• diagnóza HF známá alespoň 6 měsíců
• anamnéza hospitalizace pro kardiální dekompenzaci kdykoli v minulosti
(s nutností parenterální terapie pro kongesci – rtg nález či otoky dolních končetin)
• stabilní optimální farmakoterapie alespoň 1 měsíc
• léčba diuretiky (thiazidová či furosemid)
• EF LK pod 50%

2.Přítomnost diabetu bude definována na základě:
• diagnózy a léčby diabetu 2.typu v anamnéze
• nebo skríningového odběru
- při hodnotě HbA1c ≥ 4,8% dle IFCC + glykémie na lačno ≥ 7,0 mmol/l ve venózní plasmě nebo
- při hodnotě HbA1c ≥ 4,8% dle IFCC + náhodné glykémie ≥ 11,1 mmol/l ve venózní plasmě
• nebo oGTT – glykémie ve 120 min ≥ 11,1 mmol/l.
OGTT bude indikováno v případě pozitivity jen jednoho z kritérií (HbA1c + lačná glykémie, nebo HbA1c + náhodná glykémie)
3.Léčba cukrovky jen dietou
4.Ženy i muži ve věku 40-70 let
5.Body mass index (kg/m2) v rozmezí 20-35
6.Rozmezí HbA 1c mezi 4-6,5%
7.Informovaný souhlas: podepsaný, s udáním data

E.4

Principal exclusion criteria

1.the planned cardiac intervention during the study that affect the function of the heart (revascularization including PCI, heart surgery, implantation of pacemaker, RF ablation; urgent candidate for OTS
2.metabolic disease, including: 1 type diabetes, decompensated thyreopatii (Note: patients with hypothyroidism and stable substitution (the last 3 months) of normal TSH levels may participate in the study
3.treatment with insulin or PAD one month before the recruitment(patients who were temporarily treated with insulin during hospitalization may participate in the study)
4.pregnancy (positive β-HCG test), breast feeding, trying to become pregnant
5.clinically significant anemia with hemoglobin below 100 g/l
6.pacemaker or metallic implant in the body (MRI)
7.renal insufficiency with eGF below 0.7 ml/s
8.atrial fibrillation - present during screening test
9.the presence of other medical condition, which occurs during physical examination, laboratory tests, ECG, including pulmonary, neurological or inflammatory disease, which would be considered by the examiner to distort the consistency of data

1.Plánovaný kardiologický výkon během studie ovlivňující funkci srdce (revaskularizace včetně PCI, operace srdce, implantace biventrikulárního stimulátoru či ICD, RF ablace FiS či AV uzlu; urgentní kandidát OTS)
2.Metabolické onemocnění zahrnující: DM1.typu, dekompenzovanou thyreopatii (pozn. pacienti s hypotyreózou na substituci léčenou poslední 3 měsíce stabilní dávkou a s normálními hodnotami TSH se mohou studie zúčastnit)
3.Léčba inzulinem či PAD měsíc před zařazením (nemocní, kterým byl přechodně podáván inzulinu během hospitalizace, se mohou studie zúčastnit)
4.Těhotenství (pozitivní β-HCG test), kojení, snaha o otěhotnění
5.Klinicky signifikantní anémie s hemoglobinem pod 100g/l
6.Kardiostimulátor nebo kovový implantát v těle (MR vyšetření)
7.Těžší forma renální insuficience (eGF pod 0,7 ml/s)
8.Fibrilace síní přítomná při screeningovém vyšetření
9.Přítomnost jiné změny zdravotního stavu, k jejímuž zjištění se dojde během fyzikálního vyšetření, laboratorních testů, EKG, zahrnující plicní, neurologické nebo zánětlivé onemocnění, které by dle názoru vyšetřujícího mohlo zkreslit výtěžnost a konzistenci dat

E.5 End points

E.5.1

Primary end point(s)

1/Provide causal link between IR and exercise intolerance in HF
2/Improvement of chronotropic response (chronotropy index during ergometry)
3/Improvement of diastolic function
4/Improvement of cardiac energetic reserve (MRI, resting Phospho Creatine/Creatine ratio)
5/Improvement of ventriculo-vascular coupling
6/Improvement of endothelial function (Endo-PAT, ItamarMedical)

1/Zjištění souvislost mezi IR a nízkou tolerancí zátěže u HF
2/Zlepšení chronotropní reakce (chronotropy index během ergometrie)
3/Zlepšení diastolické funkce (E / E'ratio)
4/Zvýšení kardiální energetické rezervy(MRI, resting Phospho Creatine/Creatine ratio)
5/Zlepšení komorové elastance a ventricular-vascular coupling
6/Zlepšení endoteliální funkce (Endo-PAT, ItamarMedical)

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

1/humoral determinants of insulin resitance in HF
correlation with leptin, TNF alfa, norepinephrine, glucagon, adiponectin
2/to determine whether profile of effects of MET is influenced by presence of HF state

1/stanovit humorální determinanty inzulinové resitance u pacientů s HF
2/zjistit, zda je účinnost léčby metforminem ovlivněna současnou přítomností HF u pacientů s DM 2.typu

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

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

40 patients with HF and DM will be randomized into 2 groups. All participants will undergo standardized selection of metabolic and cardiovascular tests during a two-day hospitalization at the beginning and the end of each intervention period (3 times in total).

Do cross-over studie bude zařazeno 40 pacientů s diabetem a srdečním selháním. Budeme testovat účinky 3 měsíčního podávání metforminu (2 g/d) na funkci myokardu a vybrané metabolické ukazatele. Studie bude trvat 6 měsíců. Na začátku studie a na konci 3 měsíčních intervenčních period (tzn.celkem 3x) bude proveden za dvoudenní hospitalizace na Klinice diabetologie CD IKEM (KDIA) standardizovaný panel metabolických a kardiovaskulárních vyšetření.

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Institute of Physiology ASCR, Depart. of Adipose Tissue Biology
G.4.3.4	Network Country	Czech Republic

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-06-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-06-30

P. End of Trial
P.	End of Trial Status	Ongoing

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