Clinical Trials Register

Summary
EudraCT Number:	2011-000300-18
Sponsor's Protocol Code Number:	REMOVAL
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-05-25
Trial results	View 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

Denmark - DHMA

A.2

EudraCT number

2011-000300-18

A.3

Full title of the trial

Reducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes

A.3.1

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

REduction of risk for cardiovascular events by treatment with metformin in patients with type 1 diabetes

A.4.1

Sponsor's protocol code number

REMOVAL

A.5.4

Other Identifiers

Name:

clinicaltrials.gov

Number:

NCT01483560

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	NHS Greater Glasgow and Clyde Board
B.1.3.4	Country	United Kingdom
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	Juvenile Diabetes Foundation JDRF
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Steno Diabetes Center
B.5.2	Functional name of contact point	Peter Rossing
B.5.3	Address:
B.5.3.1	Street Address	Niels Steensens Vej 2
B.5.3.2	Town/ city	Gentofte
B.5.3.3	Post code	DK-2820
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4544437310
B.5.6	E-mail	pro@steno.dk
B.Sponsor: 2
B.1.1	Name of Sponsor	University of Glasgow
B.1.3.4	Country	United Kingdom
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	JDRF
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Steno Diabetes Center
B.5.2	Functional name of contact point	Peter Rossing
B.5.3	Address:
B.5.3.1	Street Address	Niels Steensen vej 2
B.5.3.2	Town/ city	Gentofte
B.5.3.3	Post code	2820
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4544437310
B.5.6	E-mail	pro@steno.dk

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 500 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Limited
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Metformin
D.3.2	Product code	AS2
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.3.9.2	Current sponsor code	none
D.3.9.3	Other descriptive name	none
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	500
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

Type 1 diabetes

E.1.1.1

Medical condition in easily understood language

diabetes type 1

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10067584
E.1.2	Term	Type 1 diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

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 in a randomized controlled trial the effects of three years metformin added to titrated insulin therapy (towards target HbA1c 7.0%/ 53 mmol/mol) on progression of atheroma as measured by progression of averaged mean far wall common carotid artery intima-media thickness (cIMT) in adults with type 1 diabetes at risk of cardiovascular disease.

E.2.2

Secondary objectives of the trial

Change in (i) HbA1c; (ii) LDL cholesterol; (iii) albuminuria and estimated glomerular filtration rate; (iv) retinopathy stage (two-field photographs); (v) weight; (vi) insulin dose; (vii) endothelial function (in 50% of participants).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Type 1 diabetes; age ≥ 40 years; 7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol)

AND three or more of the following ten CVD risk factors:
(i) BMI ≥ 27 kg/m2
(ii) current HbA1c > 8.0% (64 mmol/mol)
(iii) known CVD/ peripheral vascular disease
(iv) current smoker
(v) eGFR < 90 ml/ min/ 1.73 m2
(vi) micro- (or macro-) albuminuria [according to local assays and reference ranges]
(vii) hypertension (BP¬≥140/ 90 mmHg; or established on antihypertensive treatment)
(viii) dyslipidaemia [total cholesterol≥5.0 mmol/L (200 mg/dL); or HDL cholesterol<1.20 mmol/L (46 mg/dL) [men] HDL cholesterol<1.30 mmol/L (50 mg/dL) [women]; or fasting triglycerides≥1.7 mmol/L (150 mg/dL); or established on lipid-lowering treatment
(ix) strong family history of CVD (at least one parent or sibling with myocardial infarction or stroke aged < 60 years)
(x) duration of diabetes > 20 years.

E.4

Principal exclusion criteria

(i) eGFR < 45 ml/ min/ 1.73m2
(ii) woman of childbearing age not on effective contraception – see Appendix 4
(iii) pregnancy and/or lactation
(iv) Acute Coronary Syndrome within the last 3 months
(v) NYHA stage 3 or 4 heart failure
(vi) uncontrolled angina
(vi) suspected hypoglycaemia unawareness
(vii) impaired cognitive function/ unable to give informed consent
(viii) previous carotid surgery/ inability to capture adequte carotid images
(ix) gastroparesis
(x) history of lactic acidosis
(xi) other contraindications to metformin
- hepatic impairment
- known hypersensitivity to metformin
- acute illness (dehydration, severe infection, shock,
acute cardiac failure)
- suspected tissue hypoxia
(xii) Any coexistent life threatening condition including prior diagnosis of cancer within two years
(xii) history of alcohol problem or drug abuse

E.5 End points

E.5.1

Primary end point(s)

progression of averaged mean far wall common carotid artery IMT (CCA cIMT, measured in mm, at baseline, 12, 24 and 36 months).

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline an hereafter annually

E.5.2

Secondary end point(s)

HbA1c;
(ii) LDL cholesterol;
(iii) albuminuria & estimated glomerular filtration rate
(iv) retinopathy stage (ETDRS stage = Early Treatment Diabetic Retinopathy Study);
(v) weight
(vi) insulin dose;
(vii) endothelial function

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and Annually hereafter for (i,ii,ii,v,vi,vii)
Baseline, year 1 and year 3 for (vii)
Baseline and year 3 for (iv)

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

Yes

E.6.4

Safety

E.6.5

Efficacy

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)

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

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)

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.8.5

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

Canada

Australia

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 patient last visit

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

380

F.4.2.2

In the whole clinical trial

120

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)

followup on glycaemic control - and optimisation of treatment

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-04-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-02-17

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