Clinical Trials Register

Summary
EudraCT Number:	2013-000364-28
Sponsor's Protocol Code Number:	00/0594-LINARI
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:	2013-04-22
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

2013-000364-28

A.3

Full title of the trial

Effects of Linagliptin on active GLP-1 concentrations in subjects with renal impairment

A.3.1

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

Effects of Linagliptin on active GLP-1 concentrations in subjects with renal impairment

A.4.1

Sponsor's protocol code number

00/0594-LINARI

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	Profil Institut für Stoffwechselforschung GmbH
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	Profil Institut für Stoffwechselforschung 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	Profil Institut für Stoffwechselforschung GmbH
B.5.2	Functional name of contact point	RA
B.5.3	Address:
B.5.3.1	Street Address	Hellersbergstr. 9
B.5.3.2	Town/ city	Neuss
B.5.3.3	Post code	41460
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4921314018145
B.5.5	Fax number	+4921314018517
B.5.6	E-mail	regulatory@profil.com

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	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.3.9.4	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

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

E.1.1.1

Medical condition in easily understood language

Diabetes mellitus Type 2

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 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 quantify differences in GLP-1 concentrations

E.2.2

Secondary objectives of the trial

To quantify differences in the secretion of GIP, insulin and C-peptide

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Signed and dated written informed consent obtained before any study-related activities.
2. Have Type 2 diabetes mellitus based on the disease diagnostic criteria (WHO)
classification on ongoing insulin therapy on a stable regimen of antidiabetic treatment
other than metformin , GLP-1 agonists and DPP-4 antagonists for the previous 6 weeks
(participants using either of these therapies will be asked to stop their treatment until
the end of the study. They will be allowed a wash-out period of 6 weeks before the first
GTT will be performed).
3. Male or female subjects aged between 18 and 75 years, inclusive.
4. Have an HbA1c level between 7.0-9.5 %.
5. Medical history without major pathology (with the exception of type 2 diabetes) as judged
by the investigator.
6. Ability and willingness to abstain from grapefruit juice (and all grapefruit containing
products) throughout the study starting 12 hours prior to first study test and from alcohol,
methylxanthine-containing beverages or food (coffee, tea, Coke, chocolate, “power
drinks”), tobacco products and from engaging in strenuous physical activity from 12 hours
prior to each admission until discharge from the unit.
7.For female patients of childbearing potential: Use of acceptable method of contraception
(Pearl-Index <1). Acceptable methods of birth control include tubal ligation, transdermal
patch, intra uterine devices/systems (IUD/IUSs), oral, implantable or injectable
contraceptives, sexual abstinence, double barrier method and vasectomised partner.

E.4

Principal exclusion criteria

1. Subjects with type 1 diabetes, maturity onset diabetes of the young (MODY) or secondary
forms of diabetes such as due to pancreatitis.
2. Current or previous treatment (less than 6 weeks) with metformin, DPP-4 inhibitors or
GLP-1 analogues.
3. Have any contraindications, known allergy, or hypersensitivity to linagliptin.
4. Have participated in an interventional medical, surgical, or pharmaceutical study within
the last three months prior to entry into the study.
5. Women of child-bearing age who are pregnant, or plan a pregnancy.
6. Subjects on systemic glucocorticoid treatment (except topic or inhalative preparations) within the last 3 months prior to screening.
7. Subjects that underwent surgery of the upper gastrointestinal tract.
8. Subjects with any severe medical or surgical history of conditions likely to confound
study assessments or study endpoints, for example but not limited to
haemoglobinopathies, inflammatory bowel disease, cystic fibrosis, bariatric surgery
and/or any surgery shortening the intestine, history of galactose intolerance, lactose- or
glucose-galactose-malabsorption.
9. Subjects with a suspicion for medullar thyroid cancer or a multiple endocrine neoplasia
will undergo a calcitonine measurement.
10. Subjects with a personal or family history of medullar thyroid cancer or a multiple
endocrine neoplasia.
11. Serious and/or unstable coronary heart disease (unstable angina, myocardial infarction
within the preceding 6 months), congestive heart failure of New York Heart Association
Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary
physical activity results in fatigue, palpitation, or dyspnoea), second/third degree heart
block, superior vena cava syndrome, uncontrolled hypertension, history of congenital QTsyndrome
within family, history of stroke (within the preceding 6 months) or serious
peripheral vascular disease.
12. Marked diabetic complications with the exception of peripheral neuropathy: severe autonomic neuropathy including gastroparesis;
proliferative retinopathy as judged by the Investigator.
13. Clinically significant vital signs including known bradycardia with pulse rate < 50/min or
12-lead ECG findings including pre-treatment mean QTc > 450 msec for males or QTc >
470 msec for women (if first ECG shows increased values, 2 further ECGs will be
performed at least 2 minutes apart and values will be averaged).
14. Clinically significant abnormal haematology, biochemistry, or coagulation screening tests,
as judged by the Investigator.
15. Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence
defined as any of the following parameters: γ-GT, ALT, or AST > 3x ULN.
16. Chronic pancreatitis.
17. Uncontrolled high blood pressure (DBP > 95 mmHg and/or SBP > 160 mmHg), unless
clearly documented to be white-coat hypertension.
18. History of any psychiatric condition that might impair the subject’s ability to understand
or to comply with the requirements of the study or to provide informed consent.
19. History of relevant drug and/or food allergies or a history of severe anaphylactic reaction.
20. Not willing to abstain from any consume of tobacco containing products 12 hours prior to
each admission until discharge.
21. Currently active or history of alcohol abuse (defined as an intake of more than 24 units of
alcohol per week; one unit of alcohol equals approximately 250 mL of beer, 100 mL of
wine or 35 mL of spirits) or drug addiction (including soft drugs like cannabis products).
22. Positive alcohol test at screening.
23. Use of concomitant medication which would be likely to interact with linagliptin
(according to the subject information leaflet).
24. Malignancy within 5 years of study start, except for successfully treated local basal cell
carcinomas.
25. History of Hepatitis B surface antigen or Hepatitis C antibodies.
26. History of HIV-1 antibodies, HIV-2 antibodies or HIV-1 antigen.
27. Subject who has donated or lost more than 500 mL blood within 3 months prior to
screening.
28. Veins unsuitable for repeated venepuncture.

E.5 End points

E.5.1

Primary end point(s)

Change in active GLP-1 concentrations (incremental AUC 0-240 min and ANOVA) after oral
glucose ingestion after linagliptin treatment compared between Groups.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of study

E.5.2

Secondary end point(s)

ΔAUCGIP-OGTT(0-240):
Change in active GIP concentrations after oral
glucose ingestion after linagliptin treatment
compared between Groups.

ΔAUCIns-OGTT(0-240):
Change in insulin (Ins) concentrations after oral
glucose ingestion after linagliptin treatment
compared between groups.

ΔAUCGG-OGTT(0-240):
Change in glucagon (GG) concentrations after oral
glucose ingestion after linagliptin treatment
compared between Groups.

ΔInsPh1 and ΔInsPh2:
Change in first (Ph1)- and second-phase (Ph2)
insulin secretion after i.v. glucose administration
after linagliptin treatment compared between Groups

ΔAUCGG-ivGTT(0-120):
Change in glucagon levels after i.v. glucose
administration after linagliptin treatment compared
between Groups.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of study

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

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Proof of principle

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

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

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

E.8.2.3

Other

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

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

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

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
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

2013-04-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-04-22

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