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

Phase 1

Conditions: Type 2 diabetes mellitus
MedDRA version: 18.0Level: PTClassification code 10067585Term: Type 2 diabetes mellitusSystem Organ Class: 10027433 - Metabolism and nutrition disorders
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2013-000364-28-DE

Lead Sponsor: Profil Institut für Stoffwechselforschung GmbH

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: Not specified

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15

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: ?-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 o

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To quantify differences in GLP-1 concentrations;Secondary Objective: To quantify differences in the secretion of GIP, insulin and C-peptide;Primary end point(s): Change in active GLP-1 concentrations (incremental AUC 0-240 min and ANOVA) after oral<br>glucose ingestion after linagliptin treatment compared between Groups.;Timepoint(s) of evaluation of this end point: End of study

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): ?AUCGIP-OGTT(0-240): <br>Change in active GIP concentrations after oral<br>glucose ingestion after linagliptin treatment<br>compared between Groups.<br><br>?AUCIns-OGTT(0-240):<br>Change in insulin (Ins) concentrations after oral<br>glucose ingestion after linagliptin treatment<br>compared between groups.<br><br>?AUCGG-OGTT(0-240): <br>Change in glucagon (GG) concentrations after oral<br>glucose ingestion after linagliptin treatment<br>compared between Groups.<br><br>?InsPh1 and ?InsPh2:<br>Change in first (Ph1)- and second-phase (Ph2)<br>insulin secretion after i.v. glucose administration<br>after linagliptin treatment compared between Groups<br><br>?AUCGG-ivGTT(0-120):<br>Change in glucagon levels after i.v. glucose<br>administration after linagliptin treatment compared<br>between Groups.;Timepoint(s) of evaluation of this end point: End of study

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