Clinical Trials Register

Summary
EudraCT Number:	2012-002278-30
Sponsor's Protocol Code Number:	CRC2012LINA
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-06-14
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

Germany - BfArM

A.2

EudraCT number

2012-002278-30

A.3

Full title of the trial

Effects of Linagliptin on Renal Endothelium Function in Patients with Type 2 Diabetes.

A.3.1

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

Effects of Linagliptin on Renal Endothelium Function in Patients with Type 2 Diabetes.

A.4.1

Sponsor's protocol code number

CRC2012LINA

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	University Hospital Erlangen
B.1.3.4	Country	Germany
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	Boehringer Ingelheim International GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen
B.5.2	Functional name of contact point	Clinical Research Center
B.5.3	Address:
B.5.3.1	Street Address	Ulmenweg 18
B.5.3.2	Town/ city	Erlangen
B.5.3.3	Post code	91054
B.5.3.4	Country	Germany
B.5.4	Telephone number	004991318536245
B.5.5	Fax number	004991318539209
B.5.6	E-mail	roland.schmieder@uk-erlangen.de

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	Trajenta
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	Germany
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	Trajenta
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.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

Diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Diabetes mellitus

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10012613
E.1.2	Term	Diabetes mellitus non-insulin-dependent
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 determine the effect of linagliptin compared to placebo on basal production and release of nitric oxide (NO) from renal vasculature, as assessed by changes of renal plasma flow due to L-NMMA infusion.

E.2.2

Secondary objectives of the trial

To determine the effects of linagliptin compared to placebo on
- other renal hemodynamic parameters: RPF, GFR and FF, RVR, calculated intraglomerular pressure.

- UACR and tubular markers (e.g. NGAL).

- markers of oxidative stress (e.g. isoprostanes) and inflammation (e.g. hsCRP).

- metabolic parameters (fasting glucose, fasting insulin, triglycerides, total-, LDL- and HDL-cholesterol)

To determine the effect of linagliptin compared to baseline on
- the change of RPF due to L-NMMA-infusion

- other renal hemodynamic parameters: RPF, GFR and FF, RVR, calculated intraglomerular pressure.

- UACR and tubular markers (e.g. NGAL).

- markers of oxidative stress (e.g. isoprostanes) and inflammation (e.g. hsCRP).

- metabolic parameters (fasting glucose, fasting insulin, triglycerides, total-, LDL- and HDL-cholesterol)

To determine the relationship between changes of renal endothelial function with metabolic changes and changes of isoprostanes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age between 18 and 70 years
• Type 2 diabetes without diabetic nephropathy (definition see exclusion criteria)
• Male and Female patients are eligible. Females of child bearing potential or within two years of the menopause are only eligible if pregnancy test at the screening visit is negative and they use adequate contraceptive precautions during the trial.

E.4

Principal exclusion criteria

• Any other form of diabetes mellitus than type 2 diabetes mellitus
• Patients with more than on one blood glucose lowering medication or on one antidiabetic drug that can not be discontinued for the study period.
• Use of insulin, glitazone or gliptine within the past 3 months
• Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 6 months prior to study inclusion
• Urinary albumin excretion (UACR) > 100 mg/g (early morning spot urine)
• eGFR <45 ml/min/1.73m² (MDRD Formula)
• Uncontrolled arterial hypertension (RR ≥180/ ≥110mmHg)
• HbA1c ≥ 10%
• Fasting plasma glucose ≥ 240 mg/dl
• Body mass index ≥ 40 kg/m²
• Triglyceride levels ≥ 1000 mg/dl
• HDL-cholesterol levels <25 mg/dl
• Overt congestive heart failure (CHF) or history of CHF
• Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmakinetics of study drugs
• Significant laboratory abnormalities such as SGOT or SGPT levels more than 3 x above the upper limit of normal range, serum creatinine > 2mg/dl
• Drug or alcohol abusus
• Pregnant or breast-feeding patients
• Any patient currently receiving chronic (>30 consecutive days) treatment with an oral corticosteroid
• Patients being treated for severe auto immune disease e.g. lupus
• Participation in another clinical study within 30 days prior to visit 1
• Individuals at risk for poor protocol or medication compliance
• Subject who do not give written consent, that pseudonymous data will be transferred in line with the duty of documentation and the duty of notification according to § 12 and § 13 GCP-V

E.5 End points

E.5.1

Primary end point(s)

Absolute change of L-NMMA on renal plasma flow between placebo and linagliptin.

E.5.1.1

Timepoint(s) of evaluation of this end point

After 4 weeks treatment with placebo and linagliptin.

E.5.2

Secondary end point(s)

- the effects of linagliptin compared to placebo on other renal hemodynamic parameters:
Renal plasma flow, glomerular filtration rate and filtration fraction, renal vascular resistance, calculated intraglomerular pressure.
- the effect of linagliptin compared to placebo on urinary albumin creatinine ratio and tubular markers (e.g. NGAL).
- the effect of linagliptin compared to placebo on markers of oxidative stress (e.g. isoprostanes) and inflammation (e.g. hsCRP).
- the effect of linagliptin compared to placebo on metabolic parameters (fasting glucose, fasting insulin, triglycerides, total-, LDL- and HDL-cholesterol)
- the effect of linagliptin compared to baseline on the change of renal plasma flow due to L-NMMA-infusion
- the effects of linagliptin compared to baseline on other renal hemodynamic parameters:
Renal plasma flow, glomerular filtration rate and filtration fraction, renal vascular resistance, calculated intraglomerular pressure.
- the effect of linagliptin compared to baseline on urinary albumin creatinine ratio and tubular markers (e.g. NGAL).
- the effect of linagliptin compared to baseline on markers of oxidative stress (e.g. isoprostanes) and inflammation (e.g. hsCRP).
- the effect of linagliptin compared to baseline on metabolic parameters (fasting glucose, fasting insulin, triglycerides, total-, LDL- and HDL-cholesterol)
- the relationship between changes of renal endothelial function with metabolic changes and changes of isoprostanes.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and after 4 weeks treatment with linagliptin and placebo

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

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.8.5

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

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

LVLS

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.1.3

Elderly (>=65 years)

Yes

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.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

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

2012-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-02-06

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