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Effects of Saxagliptin on Adipose Tissue Inflammation in Humans

Primary Purpose

Type 2 Diabetes Mellitus (T2DM)

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Saxagliptin
Placebo
Sponsored by
Phoenix VA Health Care System
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus (T2DM) focused on measuring Adipose tissue, Inflammation, .Obesity

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Signed Written Informed Consent

    1. Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel.
    2. Subjects must be able to communicate meaningfully with the investigator and legally competent to provide informed written consent.
  2. Target Population

    1. Body mass index 27.5-37.5 kg/m2
    2. Stable body weight (not varying >10% during the last 6 months)
  3. Age and Reproductive Status

    1. Men and women, ages 21 to 70 years.
    2. Women must be sterilized by hysterectomy or postmenopausal or on acceptable birth control if of childbearing potential.
    3. Women of childbearing potential (WOCBP) include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:

      • Amenorrhea ≥12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level >35 mIU/mL, or
      • Women with irregular menstrual periods and a documented serum FSH level >35 mIU/mL, or NOTE: FSH level testing is not required for women ≥62 years old with amenorrhea of ≥1 year
      • Women on hormone replacement therapy (HRT) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

Exclusion Criteria:

  1. Sex and Reproductive Status

    1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
    2. Women who are pregnant or breastfeeding
  2. Target Disease Exceptions

    1. Gastrointestinal disease (including gastrectomy, chronic pancreatitis, bariatric surgery and gastroparesis)
    2. Hepatic disease (ALT, AST >2.5 times the upper limit of normal, high sensitivity CRP ≥1 mg/L)
    3. Kidney disease (serum creatinine >1.6 mg/dl, Creatinine Clearance 50 mL/min)
    4. Hypertension (blood pressure > 150/95 mmHg) at Screening for the mean of three consecutive readings performed in a sitting position after a 5-minute resting period. If treatment for hypertension has recently been initiated, subjects must be clinically stable for 4 weeks prior to Screening
    5. Cardiac disease (myocardial infarction within past year, clinically significant arrhythmia, unstable angina, congestive heart failure, or coronary artery bypass surgery within 1 year or expected to require coronary bypass surgery within 12 months of study entry).
  3. Medical History and Concurrent Diseases

    1. Type 1 diabetes mellitus
    2. Type 2 diabetes mellitus
    3. History of diabetic ketoacidosis or hyperosmolar nonketotic coma
    4. Malignancy other than basal cell or squamous cell skin cancer
    5. Significant clinical allergic rhinitis or asthma, regularly requiring inhaled corticosteroids and/or antihistamines
  4. Additional Laboratory Test Findings

    1. Hemoglobin <12 g/dl in men, <11 g/dl in women
    2. Abnormal prothrombin or partial thromboplastin time
    3. Clinically abnormal thyroid stimulating hormone (TSH)
    4. 2 hour glucose > 170mg/dl in standard oral glucose tolerance test (OGTT)
  5. Allergies and Adverse Drug Reactions

    a. Subjects with a history of a serious hypersensitivity reaction to saxagliptin, such as anaphylaxis, angioedema,or exfoliative skin conditions.

  6. Prohibited Treatments and/or Therapies

    1. Treatment with strong systemic cytochrome P450 3A4/5 (CYP 3A4/5) inhibitors
    2. Treatment with any of the following medications during screening or their expected use during the study: recent systemic glucocorticoids (for more than 2 weeks), any anti-hyperglycemic agents, antineoplastic agents, transplant medications, drugs for weight loss, niacin, fibrates, or anti-retroviral medications
    3. Treatment with beta-blockers, antihistamines or inhaled corticosteroids within 3 months prior to screening
    4. Start or change of hormonal replacement therapy within 3 months prior to screening
  7. Other Exclusion Criteria

    1. Prisoners, or subjects who are involuntarily incarcerated
    2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
    3. Currently abusing alcohol or drugs, or have a history of alcohol or drug abuse that in the investigator's opinion could cause the subject to be non-compliant; or have a general history of non-compliance with medications
    4. Any acute febrile illness within 2 weeks of screening with a temperature 100°F

Sites / Locations

  • Carl T. Hayden VA Medical Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Saxagliptin

Placebo

Arm Description

Saxagliptin (trade-name ONGLYZA™) is used along with diet and exercise to lower blood sugar levels in patients with Type II diabetes (condition in which blood sugar is too high because the body does not produce or use insulin normally). Saxagliptin is in a class of medications called dipeptidyl peptidase-4 (DPP-4) inhibitors. It works by increasing the amount of insulin produced by the body after meals when blood sugar is high As the blood sugar returns towards normal, the medication effect on insulin is decreased.

Sugar pill

Outcomes

Primary Outcome Measures

Change from baseline in the secretion of cytokines/adipokines by adipose tissue
The primary objective is to determine whether 6 weeks of treatment with saxagliptin, compared to placebo, causes a reduction from baseline in the production and secretion of cytokines/adipokines by adipose tissue

Secondary Outcome Measures

reduction from baseline in tissue measures of inflammation
The secondary objective is to determine whether 6 weeks of treatment with saxagliptin, compared to placebo, causes a reduction from baseline in reactive oxygen production, pro-inflammatory gene expression, toll-like receptor and nuclear factor-kappa B activation, and macrophage infiltration in adipose tissue of obese individuals
change in plasma postprandial lipids
We will also compare the change in postprandial lipids following a standard meal between placebo and saxagliptin
change in reactive hyperemic index
We will use peripheral artery tonometry to measure the change in endothelial function by measuring reactive hyperemic index

Full Information

First Posted
June 17, 2014
Last Updated
March 11, 2020
Sponsor
Phoenix VA Health Care System
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT02285985
Brief Title
Effects of Saxagliptin on Adipose Tissue Inflammation in Humans
Official Title
Effects of Saxagliptin on Adipose Tissue Inflammation in Humans
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
February 2013 (Actual)
Primary Completion Date
October 12, 2019 (Actual)
Study Completion Date
October 12, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Phoenix VA Health Care System
Collaborators
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
In this research study, Investigators will be comparing the effects of a medication Saxagliptin versus placebo (a similar looking pill that contains no medication) on inflammation in the body. Research Hypothesis DPP-4 inhibition by saxagliptin (ONGLYZA™) reduces adipose tissue inflammation in obese individuals and this is characterized by decreases in a) reactive oxygen species (ROS) production, b) toll-like receptors (TLR) and NF-kappa B pathway activation, c) expression of pro-inflammatory genes, d) macrophage infiltration, and e) secretion of pro-inflammatory factors.
Detailed Description
This is a randomized, prospective, double-blind study. Randomization to Saxagliptin and placebo will be in a 2:1 fashion. Treatment duration will be approximately 6 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus (T2DM)
Keywords
Adipose tissue, Inflammation, .Obesity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
103 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Saxagliptin
Arm Type
Experimental
Arm Description
Saxagliptin (trade-name ONGLYZA™) is used along with diet and exercise to lower blood sugar levels in patients with Type II diabetes (condition in which blood sugar is too high because the body does not produce or use insulin normally). Saxagliptin is in a class of medications called dipeptidyl peptidase-4 (DPP-4) inhibitors. It works by increasing the amount of insulin produced by the body after meals when blood sugar is high As the blood sugar returns towards normal, the medication effect on insulin is decreased.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Sugar pill
Intervention Type
Drug
Intervention Name(s)
Saxagliptin
Other Intervention Name(s)
ONGLYZA™, Inhibitor
Intervention Description
Tablets: 5 mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar pill
Intervention Description
Tablets: 5mg
Primary Outcome Measure Information:
Title
Change from baseline in the secretion of cytokines/adipokines by adipose tissue
Description
The primary objective is to determine whether 6 weeks of treatment with saxagliptin, compared to placebo, causes a reduction from baseline in the production and secretion of cytokines/adipokines by adipose tissue
Time Frame
6 weeks
Secondary Outcome Measure Information:
Title
reduction from baseline in tissue measures of inflammation
Description
The secondary objective is to determine whether 6 weeks of treatment with saxagliptin, compared to placebo, causes a reduction from baseline in reactive oxygen production, pro-inflammatory gene expression, toll-like receptor and nuclear factor-kappa B activation, and macrophage infiltration in adipose tissue of obese individuals
Time Frame
6 weeks
Title
change in plasma postprandial lipids
Description
We will also compare the change in postprandial lipids following a standard meal between placebo and saxagliptin
Time Frame
6 weeks
Title
change in reactive hyperemic index
Description
We will use peripheral artery tonometry to measure the change in endothelial function by measuring reactive hyperemic index
Time Frame
6 weeks
Other Pre-specified Outcome Measures:
Title
change in percent arteriole dilation
Description
Using arterioles isolated from tissue biopsies, we will measure dose related responses to distinct dilators
Time Frame
6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed Written Informed Consent Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel. Subjects must be able to communicate meaningfully with the investigator and legally competent to provide informed written consent. Target Population Body mass index 27.5-37.5 kg/m2 Stable body weight (not varying >10% during the last 6 months) Age and Reproductive Status Men and women, ages 21 to 70 years. Women must be sterilized by hysterectomy or postmenopausal or on acceptable birth control if of childbearing potential. Women of childbearing potential (WOCBP) include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: Amenorrhea ≥12 consecutive months without another cause and a documented serum follicle stimulating hormone (FSH) level >35 mIU/mL, or Women with irregular menstrual periods and a documented serum FSH level >35 mIU/mL, or NOTE: FSH level testing is not required for women ≥62 years old with amenorrhea of ≥1 year Women on hormone replacement therapy (HRT) Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential. Exclusion Criteria: Sex and Reproductive Status WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period Women who are pregnant or breastfeeding Target Disease Exceptions Gastrointestinal disease (including gastrectomy, chronic pancreatitis, bariatric surgery and gastroparesis) Hepatic disease (ALT, AST >2.5 times the upper limit of normal, high sensitivity CRP ≥1 mg/L) Kidney disease (serum creatinine >1.6 mg/dl, Creatinine Clearance 50 mL/min) Hypertension (blood pressure > 150/95 mmHg) at Screening for the mean of three consecutive readings performed in a sitting position after a 5-minute resting period. If treatment for hypertension has recently been initiated, subjects must be clinically stable for 4 weeks prior to Screening Cardiac disease (myocardial infarction within past year, clinically significant arrhythmia, unstable angina, congestive heart failure, or coronary artery bypass surgery within 1 year or expected to require coronary bypass surgery within 12 months of study entry). Medical History and Concurrent Diseases Type 1 diabetes mellitus Type 2 diabetes mellitus History of diabetic ketoacidosis or hyperosmolar nonketotic coma Malignancy other than basal cell or squamous cell skin cancer Significant clinical allergic rhinitis or asthma, regularly requiring inhaled corticosteroids and/or antihistamines Additional Laboratory Test Findings Hemoglobin <12 g/dl in men, <11 g/dl in women Abnormal prothrombin or partial thromboplastin time Clinically abnormal thyroid stimulating hormone (TSH) 2 hour glucose > 170mg/dl in standard oral glucose tolerance test (OGTT) Allergies and Adverse Drug Reactions a. Subjects with a history of a serious hypersensitivity reaction to saxagliptin, such as anaphylaxis, angioedema,or exfoliative skin conditions. Prohibited Treatments and/or Therapies Treatment with strong systemic cytochrome P450 3A4/5 (CYP 3A4/5) inhibitors Treatment with any of the following medications during screening or their expected use during the study: recent systemic glucocorticoids (for more than 2 weeks), any anti-hyperglycemic agents, antineoplastic agents, transplant medications, drugs for weight loss, niacin, fibrates, or anti-retroviral medications Treatment with beta-blockers, antihistamines or inhaled corticosteroids within 3 months prior to screening Start or change of hormonal replacement therapy within 3 months prior to screening Other Exclusion Criteria Prisoners, or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Currently abusing alcohol or drugs, or have a history of alcohol or drug abuse that in the investigator's opinion could cause the subject to be non-compliant; or have a general history of non-compliance with medications Any acute febrile illness within 2 weeks of screening with a temperature 100°F
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter D Reaven, MD
Organizational Affiliation
Carl T. Hayden VA Medical Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Carl T. Hayden VA Medical Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85012
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Subject to VA regulation.
Citations:
PubMed Identifier
24963111
Citation
Kim SH, Liu A, Ariel D, Abbasi F, Lamendola C, Grove K, Tomasso V, Ochoa H, Reaven G. Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study. Diabetes Care. 2014 Jul;37(7):1944-50. doi: 10.2337/dc13-2977.
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Effects of Saxagliptin on Adipose Tissue Inflammation in Humans

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