Linagliptin as Add on to Basal Insulin in the Elderly

A 24 Week Randomized, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Trial of Once Daily Linagliptin, 5 Milligrams Orally, as Add on to Basal Insulin in Elderly Type 2 Diabetes Mellitus Patients With Insufficient Glycaemic Control

To investigate the efficacy, safety, and tolerability of linagliptin 5 milligrams once a day compared to placebo as as add-on therapy for 24 weeks to stable basal insulin treatment in elderly patients, 60 years of age and older, with Type 2 Diabetes Mellitus and insufficient glycaemic control.Stable background therapy of metformin and/or alpha-glucosidase inhibitors is also allowed.

In addition, this trial will assess if linagliptin reduces the risk of hypoglycaemia when added to background basal insulin therapy. The treatment duration of this trial (24 weeks) will enable assessment of the clinically relevant endpoint of a decrease in glycosylated Haemoglobin, a well-accepted measurement of chronic glycaemic control.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: linagliptin; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 302
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Merewether, New South Wales, Australia, 2291
      • AIM Centre
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital-Endocrinology
  • Victoria
    • East Ringwood, Victoria, Australia, 3135
      • ECRU Maroondah
• Belgium
  • Oostham, Belgium, 3945
    • Ham - PRAC Mortelmans
• Colombia
  • Armenia, Colombia, 630004
    • CEQUIN
  • Bogotá, Colombia, 110221
    • Dexa Diabetes Servicios Médicos Ltda
  • Bogotá, Colombia, 111211
    • CAFAM Caja de Compensación Familiar
  • Manizales, Colombia, 170004
    • Asociacion IPS Medicos Internistas de Caldas
  • Medellín, Colombia, 050034
    • Hospital Pablo Tobon Uribe
• Denmark
  • Aalborg, Denmark, 9100
    • Aalborg Sygehus Syd
  • Esbjerg, Denmark, 6700
    • Sydvestjyst Sygehus Esbjerg, Endokrinologisk afdeling
  • Frederiksberg, Denmark, 2000
    • Frederiksberg Hospital, Endokrinologisk afd.
  • Hellerup, Denmark, 2900
    • Gentofte University Hospital
  • Kolding, Denmark, 6000
    • Kolding Sygehus
  • København NV, Denmark, 2400
    • Bispebjerg Hospital
  • Køge, Denmark, 4600
    • Køge Sygehus
  • Roskilde, Denmark, 4000
    • Roskilde Sygehus
• Finland
  • Kerava, Finland, 04200
    • Keravan terveyskeskus
  • Oulu, Finland, FI-90100
    • Terveystalo Oulu, Diapolis
  • Turku, Finland, FI-20520
    • TYKS
  • Turku, Finland, 20520
    • Lääkärikeskus Aava, Turku
• Germany
  • Asslar, Germany, 35614
    • Gemeinschaftspraxis, Asslar
  • Berlin, Germany, 10115
    • ikfe - Institut für klinische Forschung und Entwicklung Berlin GmbH
  • Bosenheim, Germany, 55545
    • Diabetologische Schwerpunktpraxis, Bosenheim
  • Koeln, Germany, 51069
    • Dünnwaldpraxis, Köln
  • Rodgau, Germany, 63110
    • Praxis Dr. Naudts, Rodgau
  • Unterschneidheim, Germany, 73485
    • Praxis Dr. Braun, Unterschneidheim
• Greece
  • Athens, Greece, 115 26
    • "Korgialeneio-Benakeio" Hellenic Red Cross Hospital
  • Athens, Greece, 11527
    • General Hospital of Athens "G. Gennimatas"
  • Ioannina, Greece, 45500
    • Univ. Gen. Hosp. of Ioannina
  • Kifisia, Greece, 14561
    • General Hospital of Attiki "KAT-EKA"
  • Nikaia, Greece, 18454
    • General Hospital of Nikaia
  • Thessaloniki, Greece, 57010
    • General Hospital of Thessaloniki "G. Papanikolaou"
• Ireland
  • Dublin, Ireland, Dublin 15
    • Connolly Hospital Blanchardstown
• Japan
  • Aichi, Nagoya, Japan, 462-0825
    • Daishinkai Medical Corporation Ookuma Hospital
  • Ehime, Matsuyama, Japan, 790-0067
    • Matsuyama Shimin Hospital
  • Gunma, Maebashi, Japan, 370-3573
    • Iryohojin Kikuchi Naika Clinic
  • Hokkaido, Bibai, Japan, 072-0012
    • Nakamura Digestive Organ Internal Medicine Clinic
  • Hokkaido, Hakodate, Japan, 042-0942
    • Iida Medical Clinic
  • Hokkaido, Obihiro, Japan, 080-0848
    • Jiyugaoka Yamada Clinic
  • Hokkaido, Sapporo, Japan, 062-8618
    • Japan Community Health care Organization Hokkaido Hospital
  • Hokkaido, Sapporo, Japan, 006-0811
    • Teine Keijinkai Clinic
  • Hokkaido, Sapporo, Japan, 001-0912
    • Shinkotoni Family Clinic
  • Hokkaido, Sapporo, Japan, 003-0026
    • Yoshida Memorial Hospital
  • Ibaraki, Koga, Japan, 306-0232
    • Itabashi Diabetic medicine and Dermatology Clinic
  • Ibaraki, Naka, Japan, 311-0113
    • Nakakinen clinic
  • Kanagawa, Kamakura, Japan, 247-0056
    • Takai Naika Clinic
  • Kanagawa, Sagamihara, Japan, 252-0302
    • Kaneshiro DIAB Clinic, Kanagawa, I.M.
  • Kanagawa, Yokohama, Japan, 245-8575
    • National Hospital Organization Yokohama Medical Center
  • Kanagawa, Yokohama, Japan, 221-0802
    • Asahi Med. clinic, Kanagawa, I.M.
  • Kanagawa, Yokohama, Japan, 241-0821
    • Ishikawa Med. Clinic, Kanagawa, I.M.
  • Okayama, Okayama, Japan, 700-8511
    • Okayama Saiseikai General Hospital Outpatient Center
  • Osaka, Osaka, Japan, 530-0001
    • AMC NISHI-UMEDA Clinic
  • Osaka, Osaka, Japan, 550-0012
    • Nissay Hospital Nippon Life Saiseikai Public Interest Incorporated Foundation
  • Osaka, Suita, Japan, 565-0853
    • OCROM Clinic
  • Saga, Saga, Japan, 849-0917
    • Saga Memorial Hospital
  • Saitama, Kawagoe, Japan, 350-0851
    • Asano Clinic
  • Shizuoka, Hamamatsu, Japan, 430-8525
    • Hamamatsu Rosai Hospital
  • Tokyo, Adachi-ku, Japan, 121-0064
    • Kuriyama Clinic
  • Tokyo, Chuo-ku, Japan, 103-0027
    • Tokyo-Eki Center-building Clinic
  • Tokyo, Chuo-ku, Japan, 103-0028
    • Tokyo Center Clinic
  • Tokyo, Chuo-ku, Japan, 103-0002
    • The Institute for Adult Deseases, Asahi Life Foundation
  • Tokyo, Chuo-ku, Japan, 104-0061
    • AGE Makita Medical Clinic
  • Tokyo, Koto-ku, Japan, 135-0011
    • Kobayashi Internal Medicine Clinic
  • Tokyo, Kunitachi, Japan, 186-0002
    • Kunitachi Naika Clinic
  • Tokyo, Shibuya-ku, Japan, 150-8935
    • Japanese Red Cross Medical Center
• Mexico
  • Chihuahua, Mexico, 31217
    • Investigación en Salud y Metabolismo S.C.
  • Mexico, Mexico, 06400
    • Centro de At. e Inv.en Fact.de riesgo cardiovasc.Omega, S.C.
  • Mexico, Mexico, 06760
    • CAIMED
  • México, Mexico, 06700
    • Clinstile S.A. de C.V.
  • México, Mexico, C.P. 11650
    • CEDOPEC-Ctro Esp en Diab, Obesidad y Prev de Enf Cardiovasc
  • Pachuca, Mexico, 42070
    • Asociación Mexicana para la Investigacion Clínica, A.C(AMIC)
• New Zealand
  • Auckland, New Zealand, 2025
    • Middlemore Clinical Trials
  • Auckland, New Zealand, New Zealand, 0610
    • South Pacific Clinical Trials
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
• Poland
  • Oswiecim, Poland, 32-600
    • Medicome Sp. z o.o.
  • Poznan, Poland, 60-111
    • Omedica Centrum Medyczne
  • Warszawa, Poland, 00-465
    • NBR Polska
• Romania
  • Bucharest, Romania, 010507
    • Nicodiab SRL, Bucharest
  • Oradea, Romania, 410469
    • Pelican Impex SRL, Cabinet Nr. 15
  • Tirgu Mures, Romania, 540142
    • Mediab SRL
• South Africa
  • Cape Town, South Africa, 7500
    • TREAD Research
  • Cape Town, South Africa, 7530
    • Tiervlei Trial Centre
  • Cape Town, South Africa, 7646
    • Paarl Research Centre
  • Johannesburg, South Africa, 1818
    • Soweto Clinical Trials Centre
  • Johannesburg, South Africa, 2021
    • LCS Clinical Research Unit
  • Johannesburg, South Africa, 2189
    • Resego Health Services
  • KwaMhlanga, South Africa, 1022
    • Zinakekele Medical Centre
  • Middleburg, South Africa, 1055
    • Mzansi Ethical Research Centre
  • Pretoria, South Africa, 0087
    • VX Pharma (Pty) Ltd Pretoria
• Spain
  • A Coruña, Spain, 15003
    • Hospital A Coruña
  • Alicante, Spain, 03004
    • Instituto de Ciencias Médicas
  • Barcelona, Spain, 08025
    • C.A.P. Sardenya
  • Barcelona, Spain, 08023
    • Hospital Quiron. I.C.U.
  • Barcelona, Spain, 08028
    • CAP Les Corts
  • Canet de Mar, Spain, 08360
    • Cap Canet de Mar
  • Malaga, Spain, 29010
    • Hospital Virgen de la Victoria
  • Sevilla, Spain, 41014
    • Hospital Nuestra Señora de Valme
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia
  • Vic, Spain, 08500
    • CAP El Remei
• United Kingdom
  • Burnhope, United Kingdom, DH7 0BD
    • The Haven Surgery
  • Doncaster, United Kingdom, DN9 2HY
    • South Axholme Practice
  • Fowey, United Kingdom, PL23 1DT
    • Fowey Clinical Research Company Ltd
  • Liskeard, United Kingdom, PL14 3XA
    • Oak Tree Surgery
  • Newport, United Kingdom, PO309 5TG
    • St. Mary's Hospital, Vectasearch Clinic, Newport
  • Penzance, United Kingdom, TR19 7HX
    • Mounts Bay Medical Ltd
  • Torpoint, United Kingdom, PL11 2TB
    • Rame Medical, Penntorr Health
• United States
  • Alabama
    • Sheffield, Alabama, United States, 35660
      • Syed Research Consultants, LLC
  • California
    • Chula Vista, California, United States, 91910
      • Precision Research Institute, LLC
    • Costa Mesa, California, United States, 92627
      • Aurora Care Clinic, LLC
    • Laguna Hills, California, United States, 92653
      • Prime Care Clinical Research
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute Inc.
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • Internal Medicine of the Rockies
  • Florida
    • Delray Beach, Florida, United States, 33446
      • Cohen Medical Research Associates, LLC
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Hollywood, Florida, United States, 33024
      • Clinical Research of Hollywood
    • Jacksonville, Florida, United States, 32258
      • Solutions Through Advanced Research, Inc.
    • Jacksonville, Florida, United States, 32204
      • East Coast Institute for Research LLC at NE FL Endo & Diabetes
    • Miami, Florida, United States, 33156
      • Baptist Diabetes Associates, PA
    • Miami, Florida, United States, 33183
      • International Research Associates
    • Miami Lakes, Florida, United States, 33014
      • Panax Clinical Research
    • Pembroke Pines, Florida, United States, 33026
      • South Florida Research Solutions, LLC
  • Georgia
    • Snellville, Georgia, United States, 30078
      • Georgia Clinical Research, LLC
  • Illinois
    • Crystal Lake, Illinois, United States, 60012
      • Midwest Endocrinology
  • Indiana
    • Avon, Indiana, United States, 46123
      • American Health Network
  • Nevada
    • Las Vegas, Nevada, United States, 89121
      • Clinical Research of South Nevada
    • Las Vegas, Nevada, United States, 89052
      • Accent Clinical Trials
  • New York
    • New York, New York, United States, 10016
      • Manhattan Medical Research Practice PLLC
  • Ohio
    • Wadsworth, Ohio, United States, 44281
      • Family Practice Center Of Wadsworth, Inc.
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16602
      • Clinical Research Associates of Central Pennsylvania
    • Fleetwood, Pennsylvania, United States, 19522
      • Fleetwood Clinical Research
    • Uniontown, Pennsylvania, United States, 15401
      • Preferred Primary Care Phys
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • TLM Medical Services, LLC
    • Hodges, South Carolina, United States, 29653
      • Advanced Research Associates
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Arlington, Texas, United States, 76012
      • Arlington Family Research Center, Inc.
    • Dallas, Texas, United States, 75234
      • Renaissance Clinical Research and Hypertension of Texas
    • Fort Worth, Texas, United States, 76132
      • Diabetes and Thyroid Center of Fort Worth
    • Houston, Texas, United States, 77090
      • Houston Clinical Research Associates
    • San Antonio, Texas, United States, 78229
      • Science Advancing Medicine Clinical Research Center
  • Utah
    • Bountiful, Utah, United States, 84010
      • Office of Dr. Val R. Hansen
  • Virginia
    • Arlington, Virginia, United States, 22203
      • Millennium Clinical Trials LLC
    • Norfolk, Virginia, United States, 23510
      • York Clinical Research, LLC
  • Washington
    • Spokane, Washington, United States, 99218
      • Rowan Research, Inc.
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53216
      • Family Medical Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Patients must sign and date an Informed Consent consistent with International Conference on Harmonisation and Good Clinical Practice guidelines and local regulations prior to any evaluation and participation in the trial.
• Male and female patients with a clinical diagnosis of Type 2 Diabetes Mellitus, at the time of Informed Consent, who are:
• 60 years of age or older at informed consent or Screen Visit,
• taking stable doses of basal or biosimilar basal insulin [strictly inclusive of: insulin neutral protamine Hagedorn and isophane insulin; Humalog Basal (a suspension of insulin lispro protamine); insulin degludec; insulin detemir; and insulin glargine] for at least 4 weeks prior to randomisation (Visit 3) with dose adjustments up to a maximum of plus or minus 20% of baseline being allowed,
• may or may not be taking metformin immediate release or extended release [if the patient is taking metformin, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)], and
• may or may not be taking alpha-glucosidase inhibitors [acarbose, miglitol, and voglibose; if the patient is taking alpha-glucosidase inhibitors, stable dose must be maintained for at least twelve weeks without dose adjustments prior to randomisation (Visit 3)].
• Patients must have an glycosylated Haemoglobin of 7.0% (53 millimoles per mole) to 10.0% (86 millimoles per mole) at the first visit (Screen).
• Patients must have a Body Mass Index of 45 kilogram/meter squared or less at the Screen Visit.
• In the investigator's opinion, patients must be reliable, compliant, and agree to cooperate with all planned future trial evaluations as explained in detail during the informed consent process and to be able to perform them.

Exclusion criteria:

• Impaired cognitive ability as supported by the Saint Louis University Mental Status Examination, additional assessment if necessary, and verified by the investigator at the Screen Visit.
• Depressed mood as supported by a score of 10 or more on the Patient Health Questionnaire at the Screen Visit.
• Type 1 Diabetes Mellitus as determined by past medical records and history.
• Acute coronary syndrome (non-ST Elevation Myocardial Infarction, ST Elevation Myocardial Infarction, and/or unstable angina pectoris), stroke or transient ischemic attack within 3 months prior to Screen Visit.
• Indication of liver disease determined during Screen and/or Run-In Period, defined by a serum level above 3 times the upper limit of normal in any of the following: alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase.
• Bariatric, gastric bypass, and other gastrointestinal procedures or surgeries (including all types of gastric banding, restriction, and/or LapBand) with the objective of promoting weight loss within the past two years at Screen Visit.
• Medical history of cancer (except for resected non-invasive basal or squamous cell carcinoma) and/or treatment for cancer within the last 5 years.
• Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (malaria, babesiosis, haemolytic anaemia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: linagliptin 5 mg; patient to receive a tablet of linagliptin 5 mg each day	Drug: linagliptin; 5 mg once a day
Placebo Comparator: placebo; patient to receive a tablet of placebo matching linagliptin 5 mg	Drug: placebo; placebo matching linagliptin 5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin A1c (HbA1c) After 24 Weeks of Treatment.	This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range.	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Experiencing at Least One Hypoglycaemia Accompanied by a Prespecified Glucose Value.	Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The percentage of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according American Diabetes Association definition of clinically significant hypoglycaemia.	24 weeks
Percentage of Patients With HbA1c<8.0%	This is the percentage of patients with HbA1c on treatment <8.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.	24 weeks
Percentage of Patients With HbA1c on Treatment <7.0%	This is the percentage of patients with HbA1c on treatment <7.0% after 24 weeks of treatment. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.	24 weeks
Percentage of Patients With HbA1c Lowering by at Least 0.5%.	The percentage of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in measure of dispersion are exact 95% CI by Clopper and Pearson.	24 weeks
Change From Baseline in Fasting Plasma Glucose (FPG)	This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term 'baseline' refers to the last observation prior to the administration of any randomised study medication	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Eli Lilly and Company

Publications and helpful links

General Publications

• Araki E, Unno Y, Tanaka Y, Sakamoto W, Miyamoto Y. Long-Term Efficacy and Safety of Linagliptin in a Japanese Population with Type 2 Diabetes Aged >/= 60 Years Treated with Basal Insulin: A Randomised Trial. Adv Ther. 2019 Oct;36(10):2697-2711. doi: 10.1007/s12325-019-01065-7. Epub 2019 Sep 3.

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2014
• Primary Completion (Actual): April 18, 2017
• Study Completion (Actual): April 25, 2017

Study Registration Dates

• First Submitted: September 15, 2014
• First Submitted That Met QC Criteria: September 15, 2014
• First Posted (Estimate): September 16, 2014

Study Record Updates

• Last Update Posted (Actual): July 3, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin
• Other Study ID Numbers: 1218.149; 2014-000904-88 (EudraCT Number)