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Linagliptin's Effect on CD34+ Stem Cells

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ClinicalTrials.gov Identifier: NCT02467478
Recruitment Status : Active, not recruiting
First Posted : June 10, 2015
Last Update Posted : July 30, 2019
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Sabyasachi Sen, George Washington University

Tracking Information
First Submitted Date  ICMJE June 8, 2015
First Posted Date  ICMJE June 10, 2015
Last Update Posted Date July 30, 2019
Actual Study Start Date  ICMJE April 2015
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2017)
  • Cellular Markers [ Time Frame: Up to 12 weeks post Linagliptin ]
    The investigators will use participants' peripheral blood derived CD34+ cells looking at number, function, and gene expression. This will be correlated to improvement in 24hr urinary protein estimation and creatinine clearance. Post Linagliptin will be compared to pre Linagliptin measurements.
  • Urinary Function Marker in CKD [ Time Frame: 6 to 12 weeks post Linagliptin ]
    We measure using microalbumin/creatinine ratio provided from a random spot urine sample.
Original Primary Outcome Measures  ICMJE
 (submitted: June 9, 2015)
Cellular Markers [ Time Frame: Up to 12 weeks post Linagliptin ]
We will use patient's peripheral blood derived CD34+ cells looking at number, function, and gene expression. This will be correlated to improvement in 24hr urinary protein estimation and creatinine clearance. Post Linagliptin will be compared to pre Linagliptin measurements.
Change History Complete list of historical versions of study NCT02467478 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2017)
  • Serum Endothelial Inflammatory Markers [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Serum endothelial inflammatory markers will include: high sensitivity C-reactive protein (hs-CRP), IL-6, and TNF-alpha
  • Fasting lipid profile [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Measured through serum biochemistry Lipid Panel
  • Glycemic control [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Glycemic control is evaluated by measuring fasting blood glucose, insulin, and HbA1c levels and assessing insulin resistance using homeostatic model assessment insulin resistance (HOMA-IR)
  • Adiposity [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
  • Estimation of Creatinine clearance [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Measured via blood biochemistry eGFR, and spot urine urine microalbumin/creatinine ratio
  • Vessel Health [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Vessel health is assessed by looking at systolic and diastolic blood pressure, Arterial stiffness, and central and aortic blood pressure (which are assessed using Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor).
  • Resting Metabolic Rate (RMR) [ Time Frame: 6 to 12 weeks post Linagliptin ]
    (RMR, similar to Resting Energy expenditure measurement) at baseline and post therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 9, 2015)
  • Serum Endothelial Inflammatory Markers [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Serum endothelial inflammatory markers will include: high sensitivity C-reactive protein (hs-CRP), E-selectin, ICAM-1, VCAM-1, IL-1, IL-6, IL-10, PAI-1, TNF-alpha, MCP-1
  • Fasting lipid profile including ApoA1 and ApoB. [ Time Frame: 6 to 12 weeks post Linagliptin ]
  • Glycemic control [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Evaluated by measuring fasting blood glucose, insulin, and HbA1c levels and assessing insulin resistance using HOMA-IR
  • Adiposity [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
  • Estimation of Creatinine clearance and Proteinuria [ Time Frame: 6 to 12 weeks post Linagliptin ]
  • Vessel Health [ Time Frame: 6 to 12 weeks post Linagliptin ]
    Assessed by systolic and diastolic blood pressure, Arterial stiffness, and central and aortic blood pressure assessed using Vascular Flow and wave measurement equipment, SphygmoCor CP system from ATCOR.
  • Resting Metabolic Rate [ Time Frame: 6 to 12 weeks post Linagliptin ]
    (RMR, similar to Resting Energy expenditure measurement) at baseline and post therapy.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Linagliptin's Effect on CD34+ Stem Cells
Official Title  ICMJE Role of Linagliptin in Improving Renal Failure by Improving CD34+ Stem Cell Number, Function and Gene Expression in Renal Function Impaired Type 2 Diabetes Patients.
Brief Summary

Type 2 diabetes is a national epidemic. Diabetes has undesirable effects on blood vessels which may contribute to heart disease. Endothelial Progenitor Cells (EPCs) are found in the blood. Research has shown that improving the survival of these special blood cells may decrease the harmful effects of diabetes on blood vessels and reduce or reverse heart disease. Linagliptin is an Food and Drug Administration (FDA) approved prescription medicine used along with insulin or with oral medications to lower blood sugar in people with Type 2 diabetes. It is in a class of diabetes medication called Dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors have been shown to increase EPCs in patients with Type 2 diabetes.

Hypothesis: Both type 2 diabetes and Chronic Kidney Disease (CKD) are associated with poor stem cell number and function. Poor viability and function of EPCs in CKD and diabetes The investigators hypothesize that use of Linagliptin (along with Insulin) may help reduce cardiovascular risk by improving EPC survival and function above and beyond adequate glucose metabolism control

Detailed Description

Type 2 diabetes is a national epidemic with significant macro and microvascular complications. Insulin resistance in pre-diabetes and overt diabetes are associated with endothelial dysfunction.

A few studies indicate that stem cells particularly EPCs can act as a suitable bio-marker for monitoring cardiovascular morbidity. In this proposal the investigators suggest that EPCs or CD34 positive cells (defined as CD34/vascular endothelial growth factor receptor 2 (VEGFR2+) cells) can act as a suitable cellular biomarker for estimating and following endothelial dysfunction in early type 2 diabetes patients with CKD. EPCs have been shown to be dysfunctional in both CKD patients and type 2 Diabetes Mellitus (DM) patients.

Linagliptin (TRADJENTA) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. No dose adjustment is recommended for patients with renal impairment.

EPCs have been used as a regenerative tool in ischemic myocardium and diabetic wound healing. Endothelial dysfunction with associated inflammation may be a consequence of excess intra-cellular super-oxide presence in a setting of diabetes which is a pro-oxidative stress condition ultimately leading to poor EPC function and senescence.

Though lifestyle modification has been proposed as a main stay for prevention and treatment of early type 2 diabetes, several new therapies for diabetes have been developed in recent years. Incretins and incretin mimetics appear to hold promise. Mechanism of positive effect of exercise and oral hypoglycemic agents can be very different.

DPP-4 inhibitors have been shown to increase EPCs in patients with type 2 diabetes reportedly via stromal cell-derived factor 1 (SDF-1) alpha up-regulation. Interestingly, up-regulation of SDF-1 alpha and vascular endothelial growth factor (VEGF), both chemotactic factors increase mobilization and recruitment of EPCs in the face of acute ischemic injury for repair and regeneration.

Several studies have shown positive effect of incretins (Glucagon like peptide, GLP-1) and incretin receptor agonists (GLP-1 receptor agonists) on cardiovascular risk factors in type 2 diabetes patients and even in patients with chronic heart failure and left ventricular dysfunction who do not have diabetes.

DPP-4 Inhibitors may have cardio-protective effects of their own, as they increase bio-availability of endogenous GLP-1. They improve blood flow and nitric oxide production in endothelium. These are unique properties not demonstrated by other oral diabetes medications. The mechanism underlying these effects may be mediated by increased nitric oxide bioavailability but is not completely known. However these beneficial effects appear to be independent of glycemia reduction.

It is however unknown whether Linagliptin will have any positive effect on human EPC function where two prominent cardiovascular risk factors co-exist such as CKD and type 2 diabetes.

Therefore the investigators plan to investigate if Linagliptin can alter function and gene expression of CD34+ cells in a setting of CKD and type 2 diabetes. The investigators choose to look at non geriatric adult population with early type 2 diabetes (less than 10 years of duration) at an early phase of renal impairment (stages 1-3).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes
  • Impaired Renal Function
Intervention  ICMJE
  • Drug: Linagliptin
    5 mg tablet once daily for 12 weeks
    Other Name: TRADJENTA
  • Drug: Placebo
    1 tablet daily for 12 weeks
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Matching placebo 1 pill daily for 12 weeks
    Intervention: Drug: Placebo
  • Active Comparator: Linagliptin
    Linagliptin 5mg once daily for 12 weeks
    Intervention: Drug: Linagliptin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 29, 2019)
31
Original Estimated Enrollment  ICMJE
 (submitted: June 9, 2015)
40
Estimated Study Completion Date  ICMJE December 2019
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adults aged 30-70 years
  • Diagnosis of type 2 diabetes within the previous 15 years using criteria of the American Diabetes Association
  • Currently being treated with 1-2 grams/day of metformin, or insulin or both stably
  • Hemoglobin A1c (HbA1C) between 6.5% to 10.0% (both inclusive)
  • Body Mass Index (BMI) between 25 and 39.9 kg/m2 (both inclusive)
  • Chronic Kidney disease (CKD) Stages 1-3, Creatinine clearance (CrCl) less than 90 and more than 29

Exclusion Criteria:

  • Type 1 diabetes
  • History of Diabetic Ketoacidosis (DKA) or hyperosmolar nonketotic coma
  • Hemoglobinopathies with low hematocrit (Below 28 Units)
  • History of pancreatitis
  • History of cancer within the past 5 years (except basal cell carcinoma)
  • Previous cardiovascular or cerebrovascular event within 6 months of screening or active or clinically significant coronary and/or Peripheral Vascular Disease (PVD)
  • Statin use started in the last 3 month
  • Current use of oral or injectable anti-diabetic medication other than Metformin and insulin
  • Consistent use of steroids within the last 3 months
  • Any active wounds, or surgery within the past 3 months
  • Inflammatory disease, or the chronic use of anti-inflammatory drugs within the past 3 months
  • Untreated hyper/hypothyroidism
  • Contraindications to moderate exercise
  • Implanted devices that might interact with the tanita scale
  • Pre-existing liver disease and/or Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) > 2.5 times Under the Normal Limits (UNL)
  • Untreated Systolic blood pressure > 140 mmHg or diastolic blood pressure> 90 mmHg
  • Serum creatinine levels ≥ 2.0
  • CKD Stages 4 and 5 (estimated CrCl <30 mL/min)
  • Triglycerides > 450 mg/dL
  • Known allergies or hypersensitivities to Linagliptin or Dipeptidyl peptidase-4 (DDP-4) inhibitors
  • Treatment with cytochrome p450 (CYP 3A4) inhibitors
  • Women of child bearing age who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study
  • Prisoners or subjects that are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness
  • Additionally, patients who are active smokers, patients who are pregnant, nursing women, and post-menopausal women who are on hormone replacement therapy will be excluded.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02467478
Other Study ID Numbers  ICMJE 121439
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is no current plan to share IPD with other researchers.
Responsible Party Sabyasachi Sen, George Washington University
Study Sponsor  ICMJE George Washington University
Collaborators  ICMJE Boehringer Ingelheim
Investigators  ICMJE
Principal Investigator: Sabyasachi Sen, MD, PhD Medical Faculty Associates
PRS Account George Washington University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP