Clinical Trials Register

Summary
EudraCT Number:	2019-001046-17
Sponsor's Protocol Code Number:	SMART-2019
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-03-15
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

Sweden - MPA

A.2

EudraCT number

2019-001046-17

A.3

Full title of the trial

A multicentre, register-based, randomized, controlled trial comparing dapagliflozin with metformin treatment in early stage type 2 diabetes patients by assessing mortality and macro- and microvascular complications

A.3.1

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

SGLT2 inhibitor or metformin as standard treatment in early type 2 diabetes (SMARTEST)

SGLT2-hämmare eller metformin som standardbehandling vid tidig typ 2- diabetes (SMARTEST-studien)

A.3.2

Name or abbreviated title of the trial where available

SMARTEST

A.4.1

Sponsor's protocol code number

SMART-2019

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	Uppsala University
B.1.3.4	Country	Sweden
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	Vetenskapsrådet (Swedish Research Council)
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Ögonfonden
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	ALF
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Regional Funding
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Uppsala University
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Uppsala University
B.5.2	Functional name of contact point	Jan Eriksson
B.5.3	Address:
B.5.3.1	Street Address	Dept of Medical Sciences, Clinical Diabetes and Metabolism
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	75185
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+46186114419
B.5.6	E-mail	jan.eriksson@medsci.uu.se

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	Forxiga
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
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	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	Dapagliflozin
D.3.9.1	CAS number	461432-26-8
D.3.9.4	EV Substance Code	SUB31650
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	10
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	Comparator
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	Metformin, Glucophage, Mitforgen
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	Metformin
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	Metformin
D.3.9.1	CAS number	657-24-9
D.3.9.4	EV Substance Code	SUB08831MIG
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

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

E.1.1.1

Medical condition in easily understood language

Type 2 Diabetes

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10045242
E.1.2	Term	Type II diabetes mellitus
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 determine whether SGLT2-inhibitor treatment, as compared to metformin, is beneficial in patients with early T2D in promoting
progression-free survival

E.2.2

Secondary objectives of the trial

Efficacy: To determine whether SGLT2 inhibitor treatment, as compared to metformin, is beneficial in early T2D in promoting progression-free survival when severity of events are taken into account.
Efficacy: To determine whether SGLT2 inhibitor treatment, as compared to metformin, is beneficial in early T2D in promoting progression-free survival including delay in need for insulin treatment.
Safety: To determine whether SGLT2i and metformin treatment in patients with early T2D differ with respect to serious adverse events (SAEs).
Safety: To determine whether SGLT2i and metformin treatment in patients with early T2D differ with respect to diabetes-specific SAEs

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

SMARTEST-BP-HRV (20200519, v 1.0, granted ethical approval, Dnr 2020-02824) - to investigate the effect of dapagliflozin vs metformin on heart rate variability and ambulatory blood pressure.

SMARTEST - Retinopathy and other microvascular complications (20200519, v 1.0, granted ethical approval Dnr 2020-02824) - (1) to validate assessments of fundus examinations and data from the Swedish National Diabetes Register pertaining to microvascular complications and (2) to
characterize endpoints and study variables in more detail.

SMARTEST-PRECISION (20200519, v1.0, granted ethical approval Dnr 2020-02824) - to investigate the impact of biomarkers and genetic markers on diabetes complications and the treatment-specific effect on the outcome variables in the main study.

SMARTEST - Subject's and health care staff's experience of participating in a clinical trial (2021-09-14 v 1.0, granted ethical approval Dnr 2021-06769-01) - interview of subjects and care staff at a study site in Gotland, Sweden

SMARTEST-LIVER (20221018, v1.0, planned, pending ethical approval) - to investigate the effect of dapagliflozin vs metformin on non-invasive markers of liver disease

SMARTEST-MIND (20221008 v 1.0, planned, pending ethical approval)- to investigate the effect of dapagliflozin vs metformin on measures of cognitive function and risk for development of dementia.

E.3

Principal inclusion criteria

1. Diagnosis of T2D (according to WHO criteria) with less than 4 years duration.
2. Men and women, age > 18 years
3. BMI 18.5 - 45 kg/m2
4. Medication for type 2 diabetes:
a) drug naïve, or newly started or short temporary medication*
b) ongoing or previous monotherapy with oral GLD medication for more than 4 weeks in total**
5. Participation in the Swedish National Diabetes Register (NDR) and accepting individual data collection from this register and those of SoS/SCB.
6. Signed informed consent

*Stratum A: no GLD treatment, except for any ongoing or previous treatment for maximally 4 weeks in total. **Stratum B.

E.4

Principal exclusion criteria

Subjects will not be included in the study if any of the following exclusion criteria apply:

1. Known or suspected other form of diabetes than type 2
2. Ongoing or >4 weeks in total of any previous treatment for type 2 diabetes with: insulin, GLP-1 receptor agonists, SGLT2 inhibitors or combination of any diabetes medications
3. Medical need for any specific GLD treatment, eg. insulin due to marked hyperglycemia
4. HbA1c >70 mmol/mol for patients on monotherapy. >80 in drug naïve, but a higher HbA1c can be accepted if the current glucose levels imply a rapid trajectory towards acceptable glucose control
5. Contraindication to either metformin or dapagliflozin, or any unacceptable risk with either treatment as assessed by the investigator 6. History of established cardiovascular disease: diagnosis of myocardial infarction, angina pectoris, stroke, lower ex¬tremity arterial disease, heart failure or ongoing diabetic foot ulcers.
7. Any serious illness or other condition with short life expectancy (<4 yr)
8. Renal impairment (eGFR <60 ml/min/1,73m2)
9. Any condition, as judged by the investigator, that suggests that the patient will be non-compliant or otherwise unsuitable to study medication or study participation. For example, serious psychiatric or alcohol or substance abuse disorders.
10. Pregnancy or breastfeeding, women of childbearing potential (WOCBP; including perimenopausal women who have had a menstrual period within 1 year) without adequate anticonception during any part of the study period
11. Involvement in the planning and/or conduct of the study
12. Ongoing participation in another clinical trial

E.5 End points

E.5.1

Primary end point(s)

Time to first of:
1. All-cause death
2. Major adverse cardiovascular events (MACE; myocardial infarction, stroke, heart failure)
3. Microvascular events (occurrence or progression of retinopathy, nephropathy, or diabetic foot lesions)

E.5.1.1

Timepoint(s) of evaluation of this end point

At time of event

E.5.2

Secondary end point(s)

Modified composite endpoint with weighted components 1-3 of primary endpoint based on their individual degrees of severity (falling in that order). Ordinal analysis at 2 years of follow-up.

Time to first event among: individual components of the primary endpoint or initiation of insulin treatment.

Time to first of: non-fatal myocardial infarction, stroke, heart failure, unstable angina or cardiovascular death

Time to first of: heart failure or cardiovascular death Time to event of death

Time to first microvascular event; occurrence or progression of retinopathy, nephropathy, diabetic foot lesions

Time to initiation of insulin treatment

Time to any treatment failure, defined as add-on or switch to another GLD

Change in:
1) HbA1c 2) total cholesterol 3) LDL- cholesterol 4) HDL-cholesterol 5) Triglycerides 6) Urinary albumin/creatinine ratio 7) BMI 8) Systolic blood pressure 9) Diastolic blood pressure

Diagnosis-based (IDG) costs for all health care during study period plus medication cost

Results from RAND-36 and DTSQ questionnaires.

Occurrence of SAEs (all non-elective hospitalisations or other SAEs).

Occurrence of diabetes- and treatment-specific SAEs (hospitalisations for diabetes, severe hypoglycaemia, ketoacidosis, lactate acidosis, diabetic coma, amputations, fractures).

E.5.2.1

Timepoint(s) of evaluation of this end point

Time to event/time to SAE

At end of study for continuous variables

At specified timepoints (0-2 years after randomization) for RAND-36 and DTSQ

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

Yes

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)

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

Yes

E.8.1.3

Single blind

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

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

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

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

The duration of the main study is event-driven and it will continue until it is estimated that at least 844 events of the primary composite endpoint have occurred.

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:

1200

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1000

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

2200

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)

Post trial treatment not different from the expected normal treatment
of that condition

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

2019-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-27

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

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