- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01969084
The Effect of Linagliptin on Mitochondrial and Endothelial Function
November 17, 2016 updated by: Aristidis Veves, Beth Israel Deaconess Medical Center
Investigators propose to examine the effect of 12 weeks of Linagliptin, a diabetes drug, treatment on inflammation as well as vascular and mitochondrial function in diabetic patients.
Investigators hypothesize that Linagliptin will reduce the proinflammatory state, improve endothelial function, increase the blood flow at the muscle microcirculation level and improve mitochondrial function.
In this study, investigators will perform tests that evaluate the function of small and large blood vessels by employing ultrasound and laser doppler techniques.
In addition MRI scans that evaluate the mitochondrial function of the lower extremity muscles at rest and during exercise will also be employed.
Forty subjects with Type 2 diabetes will be studied for twelve weeks and half of them will be randomly assigned to receive linagliptin while the other half will receive placebo.
All tests will be performed at the beginning and the end of the study.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Study Type
Interventional
Enrollment (Actual)
45
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Beth Israel Deaconess Medical Center
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-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
30 years to 70 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Patients with T2DM whose medical or lifestyle treatment regimen is stable and not expected to be changed during the study period. Patients will be considered stable on their treatment regimen if there have not been any changes in the type of their antidiabetic medications over the past 3 months and/or there have not been any changes in their blood glucose levels that have caused them to see their health care provider more often than usual over the preceding three months. The diagnosis of T2DM will be according to the American Diabetes Association criteria. Subjects previously diagnosed with T2DM will not require confirmatory testing.
- Age 30-70 years
- Patients on insulin should be on a stable insulin regimen for at least 4 months prior to enrollment.
- Patients on antidiabetic treatment will be eligible if they are stable and no change in their treatment is planned for the next three months while they are in the study.
- HBA1c ≤ 10.0
Exclusion Criteria:
- Patient with unstable diabetes that has resulted in hyperosmolar coma, DKA, and/or documented increase or decrease in HbA1c of more than 2.0% within the previous 6 months
- Treatment with DPP4 Inhibitors or GLP-1 agonists. Patients who discontinued such treatment should be at least free for a 3-month period.
- Severe proliferative retinopathy that renders the subject legally blinded
- Previously intermittent claudication or diagnosed severe peripheral arterial disease requiring intervention.
- History of Deep Vein Thrombosis (DVT) within the past 3 months.
- Significant limb swelling due to lymphedema
- Previous diagnosis of severe gastroparesis diabeticorum due to autonomic neuropathy that has necessitated hospital admission
- Presence of non-healing foot ulceration due to severe peripheral diabetic neuropathy
- History of pancreatitis
- Documented diabetic nephropathy manifested as macro-albuminuria before enrollment in the study, (2 of 3 urine specimens collected within a 3-6 month period with urine albumin> 300 ug/mg creatinine - according to the ADA position statement)
- Smokers. Smokers will be defined as any subject who reports tobacco use during the three months before to study enrollment.
Active or uncontrolled cardiovascular disease as follows:
- Myocardial infarction, or angina within 12 months of study participation
- Arrhythmia (uncontrolled, highly symptomatic, requires treatment or life-threatening).
- Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.
- Stroke or transient ischemic attack within 12 months of study participation
- Uncontrolled hypertension: SBP> 180 mmHg or DBP> 105 mmHg (2 abnormal readings during visit)
- Liver disease (AST, ALT Alk Phos levels >2x upper normal limit) at the time of enrollment
- Renal disease (creatinine > 2 mg/dL and/or estimated GFR <30 mL/min, history of dialysis, nephrotic syndrome) at the time of enrollment.
- Severe dyslipidemia (triglycerides>600 mg/dL or cholesterol >350 mg/dL) Subjects with hypertriglyceridemia may be retested in 2-3 weeks as the values can fluctuate tremendously within a few days. In the event that the retested value allows the patient to be enrolled, a planned deviation will be submitted to the CCI.
- Any other serious chronic disease requiring active treatment.
- Pregnancy or Lactation
- Females of childbearing potential not using an effective form of birth control as determined by the investigators.
Subjects on any of the following medications:
- Systemic (not inhaled) Glucocorticoids
- Antineoplastic agents
- Rifampin
- Patient is known to have a history of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result in the past.
- History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.
- Contraindications to MRI: Medically unstable or hematologic, renal, or hepatic dysfunction, cardiac pacemaker, Intracranial clips, metal implants, or external clips within 10 mm of the head,
- Metal in eyes.
- Pregnant or nursing women -
- Claustrophobia.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Linagliptin
Subjects given Linagliptin
|
Other Names:
The endothelial function of the micro-circulation will be assessed by measuring the hyperemic response of the vessels in the superficial skin of the forearm after the iontophoresis of acetylcholine.
The endothelium independent vasodilation will be assessed by the iontophoresis of sodium nitroprusside.
Laser Doppler perfusion imaging will be used to measure relative changes in flow velocity.Visible and NIR Medical Hyperspectral Imaging (MHSI) data will be collected with a HyperMed OxyView MHSI System (HyperMed, Inc., Watertown, MA).
MHSI images will be obtained from same forearm area where the iontophoresis of acetylcholine and sodium nitroprusside will be performed, before and after the iontophoresis test.
Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).
Phosphorus-31 MRI data will be obtained during an exercise protocol.
Muscle oxygenation will be measured using the blood oxygenation level-dependent magnetic resonance imaging (BOLD MRI) technique after induced hyperemia.
|
Placebo Comparator: Sugar pill
Subjects given sugar pill/placebo
|
The endothelial function of the micro-circulation will be assessed by measuring the hyperemic response of the vessels in the superficial skin of the forearm after the iontophoresis of acetylcholine.
The endothelium independent vasodilation will be assessed by the iontophoresis of sodium nitroprusside.
Laser Doppler perfusion imaging will be used to measure relative changes in flow velocity.Visible and NIR Medical Hyperspectral Imaging (MHSI) data will be collected with a HyperMed OxyView MHSI System (HyperMed, Inc., Watertown, MA).
MHSI images will be obtained from same forearm area where the iontophoresis of acetylcholine and sodium nitroprusside will be performed, before and after the iontophoresis test.
Use ultrasound to measure brachial artery flow mediated vasodilation (FMD, endothelium-dependent vasodilation) and nitroglycerin induced dilation (NID, endothelium-independent vasodilation).
Phosphorus-31 MRI data will be obtained during an exercise protocol.
Muscle oxygenation will be measured using the blood oxygenation level-dependent magnetic resonance imaging (BOLD MRI) technique after induced hyperemia.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Phosphocreatine (PCR) Recovery Time After Exhaustive or up to 6 Minutes of Leg Exercise.
Time Frame: Baseline and 12 weeks
|
Change in the time to phosphocreatine recovery between the baseline visit and post-treatment visit following the graded exercise test.
|
Baseline and 12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Muscle Oxygenation Recovery Time
Time Frame: Baseline and 12 weeks
|
Change in muscle oxygenation after ischemia inducing occlusion for 4 minutes.
|
Baseline and 12 weeks
|
Changes in Vascular Reactivity in the Micro- and Macro-circulation.
Time Frame: Baseline and 12 weeks
|
Change in markers of macro- and microvascular function from the baseline visit to the post-treatment visit between the two groups.
|
Baseline and 12 weeks
|
Changes in SDF1-α and Substance P
Time Frame: Baseline and 12 weeks
|
Baseline and 12 weeks
|
|
Changes in Circulating Endothelial Progenitor Cell Phenotypes
Time Frame: Baseline and 12 weeks
|
The measurements of the various EPC phenotypes were performed at the Beth Israel Deaconess Flow Cytometry Core Facility.
Immunofluorescent cell staining was performed on peripheral blood with the use of the fluorescent conjugated antibodies.
1.000.000
events per sample were acquired using a FACS LSR II analyzer (Becton Dickinson, Franklin Lakes, NJ, USA) and the results were analyzed using the Beckman Coulter Kaluza analysis software (Beckman Coulter Inc., Brea, CA, USA).
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Baseline and 12 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
October 1, 2013
Primary Completion (Actual)
July 1, 2016
Study Completion (Actual)
July 1, 2016
Study Registration Dates
First Submitted
August 29, 2013
First Submitted That Met QC Criteria
October 21, 2013
First Posted (Estimate)
October 25, 2013
Study Record Updates
Last Update Posted (Estimate)
November 18, 2016
Last Update Submitted That Met QC Criteria
November 17, 2016
Last Verified
November 1, 2016
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
- 2013P-000057
- IIS trial 1218.137 (Other Grant/Funding Number: BIPI)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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