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Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

Primary Purpose

Diabetes Mellitus, Type 2, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG)

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Dapagliflozin
Saxagliptin
Pioglitazone
Metformin
Sponsored by
The University of Texas Health Science Center at San Antonio
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 2

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • NGT subjects will serve as controls and will be matched in age, gender, ethnicity, and BMI to IGT and IFG subjects

    1. Male or female subjects between the ages of 18 and 65 years of age, inclusive, at Screening.
    2. FPG < 100 mg/dl and 2-h PG < 140 mg/dl
    3. BMI = 24-40 kg/m2;
    4. Stable body weight (±4lbs) over the preceding 3 months
    5. Subjects with no evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
    6. Females of childbearing potential with a negative pregnancy test at Screening and Treatment visits, using one of the following forms of contraception for the duration of participation in the study (i.e., until Follow-up 7-14 days post last dose):

      • Oral contraceptive
      • Injectable progesterone
      • Subdermal implant
      • Spermicidal foam/gel/film/cream/suppository
      • Diaphragm with spermicide
      • Copper or hormonal containing IUD
      • Sterile male partner vasectomized > 6 month pre-dosing.
    7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
    8. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures.

Exclusion Criteria:

  1. Recent (i.e., within three (3) months prior to Screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, immunological, or clinically significant neurological disease.
  2. Subjects with a family history of diabetes in a first degree relative
  3. BMI of less than 24 or greater than 40 kg/m2
  4. Unstable body weight (change of greater than ±4lbs over the preceding 3 months
  5. Subjects participating in an excessively heavy exercise program
  6. Subject with a feeding/sleeping schedule different from a daytime feeding/night time sleeping schedule
  7. Subjects taking medications known to alter glucose metabolism (with the exception of metformin and/or pioglitazone) or which effect brain neurosynaptic function are excluded.
  8. Subjects with evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
  9. Pregnant subjects or subjects unwilling to use birth control during their study enrollment
  10. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening.
  11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
  12. Subjects with hematuria will be excluded.
  13. Subjects with evidence or prior history of heart failure will be excluded
  14. Subjects with family history of pancreatic, bladder, and breast cancer will be excluded.
  15. Subjects with history of pancreatitis will be excluded.
  16. Subjects with eGFR < 60 ±5 ml/min.1.73m2 will be excluded.
  17. Subjects with elevated serum creatinine (>1.5 mg/dl males/1.4 mg/dl females) will be excluded.
  18. Subjects with a history of orthostatic hypotension (>15/10 mmHg) will be excluded.
  19. Subjects with liver enzymes (ALT, AST) >3-fold above upper normal limit will be excluded.
  20. Subjects with a history of hypersensitivity to pioglitazone, dapagliflozin, or Saxagliptin will be excluded.

Sites / Locations

  • The University of Texas Health Science Center at San AntonioRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm Type

No Intervention

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Healthy normal glucose tolerance (NGT) subjects

Isolated IGT with Dapagliflozin

Isolated IGT with Saxagliptin

Isolated IGT with Pioglitazone

Isolated IGT with Metformin

Isolated IFG with Dapagliflozin

Isolated IFG with Saxagliptin

Isolated IFG with Pioglitazone

Isolated IFG with Metformin

IGT plus IFG with Dapagliflozin

IGT plus IFG with Saxagliptin

IGT plus IFG with Pioglitazone

IGT plus IFG with Metformin

Arm Description

Subjects (Fasting Plasma Glucose or FPG < 100 mg/dl and 2-h PG < 140 mg/dl) without FH (family history) of diabetes in a first degree relative

Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive dapagliflozin, 10 mg/day

Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive saxagliptin, 5 mg/day

Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive dapagloflozin, 10mg/day

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive saxagliptin, 10mg/day

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Healthy subjects with IGT plus IFG will receive dapagliflozin, 10mg/day

Healthy subjects with IGT plus IFG will receive saxagliptin, 10mg/day

Healthy subjects with IGT plus IFG will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Healthy subjects with IGT plus IFG will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Outcomes

Primary Outcome Measures

Beta cell function
Beta cell function will be measured as insulin secretion during the hyperglycemic clamp (mean plasma insulin concentration in uU/ml) multiplied by insulin sensitivity measured with the euglycemic insulin clamp (mg/kg.min).
Insulin sensitivity
Insulin sensitivity will be measured with the euglycemic insulin clamp and expressed as mg/kg.min.
Glucose tolerance status
Glucose tolerance status will be evaluated by measuring the HbA1c which is a measure of the average of the amount of glucose attached to hemoglobin over the past 3 months, expressed as a percentage.

Secondary Outcome Measures

Full Information

First Posted
March 16, 2016
Last Updated
August 2, 2023
Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
American Diabetes Association, AstraZeneca, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT02969798
Brief Title
Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)
Official Title
Preservation of Beta Cell Function in Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2014 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The University of Texas Health Science Center at San Antonio
Collaborators
American Diabetes Association, AstraZeneca, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
HYPOTHESIS: Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have distinct pathophysiologic etiologies. Therefore, therapeutic interventions designed to correct the specific underlying pathogenic abnormalities in IGT and IFG will be required to optimally prevent the progressive beta cell failure and development of overt type 2 diabetes.
Detailed Description
SPECIFIC AIMS: To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired glucose tolerance (IGT): (i) treatment with the renal Sodium-glucose co-transporter 2 (SGLT2) inhibitor inhibitor, dapagliflozin; (ii) treatment with the inhibitors of dipeptidyl peptidase 4, also DPP4, saxagliptin ; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired fasting glucose (IFG): (i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with combined impaired glucose tolerance (IGT) plus impaired fasting glucose (IFG): i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG)

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
700 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Healthy normal glucose tolerance (NGT) subjects
Arm Type
No Intervention
Arm Description
Subjects (Fasting Plasma Glucose or FPG < 100 mg/dl and 2-h PG < 140 mg/dl) without FH (family history) of diabetes in a first degree relative
Arm Title
Isolated IGT with Dapagliflozin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive dapagliflozin, 10 mg/day
Arm Title
Isolated IGT with Saxagliptin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive saxagliptin, 5 mg/day
Arm Title
Isolated IGT with Pioglitazone
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two
Arm Title
Isolated IGT with Metformin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
Arm Title
Isolated IFG with Dapagliflozin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive dapagloflozin, 10mg/day
Arm Title
Isolated IFG with Saxagliptin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive saxagliptin, 10mg/day
Arm Title
Isolated IFG with Pioglitazone
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two
Arm Title
Isolated IFG with Metformin
Arm Type
Active Comparator
Arm Description
Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
Arm Title
IGT plus IFG with Dapagliflozin
Arm Type
Active Comparator
Arm Description
Healthy subjects with IGT plus IFG will receive dapagliflozin, 10mg/day
Arm Title
IGT plus IFG with Saxagliptin
Arm Type
Active Comparator
Arm Description
Healthy subjects with IGT plus IFG will receive saxagliptin, 10mg/day
Arm Title
IGT plus IFG with Pioglitazone
Arm Type
Active Comparator
Arm Description
Healthy subjects with IGT plus IFG will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two
Arm Title
IGT plus IFG with Metformin
Arm Type
Active Comparator
Arm Description
Healthy subjects with IGT plus IFG will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Other Intervention Name(s)
farxiga
Intervention Description
10mg/day
Intervention Type
Drug
Intervention Name(s)
Saxagliptin
Other Intervention Name(s)
onglyza
Intervention Description
5mg/day
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Other Intervention Name(s)
actos
Intervention Description
the dose will increase from 15 mg/day to 30 mg/day at month two
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
glucophage
Intervention Description
starting at 1000 mg/day and increased to 2000 mg/day at month 2.
Primary Outcome Measure Information:
Title
Beta cell function
Description
Beta cell function will be measured as insulin secretion during the hyperglycemic clamp (mean plasma insulin concentration in uU/ml) multiplied by insulin sensitivity measured with the euglycemic insulin clamp (mg/kg.min).
Time Frame
24 months after treatment phase begins
Title
Insulin sensitivity
Description
Insulin sensitivity will be measured with the euglycemic insulin clamp and expressed as mg/kg.min.
Time Frame
24 months after treatment phase begins
Title
Glucose tolerance status
Description
Glucose tolerance status will be evaluated by measuring the HbA1c which is a measure of the average of the amount of glucose attached to hemoglobin over the past 3 months, expressed as a percentage.
Time Frame
24 months after treatment phase begins

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: NGT subjects will serve as controls and will be matched in age, gender, ethnicity, and BMI to IGT and IFG subjects Male or female subjects between the ages of 18 and 65 years of age, inclusive, at Screening. FPG < 100 mg/dl and 2-h PG < 140 mg/dl BMI = 24-40 kg/m2; Stable body weight (±4lbs) over the preceding 3 months Subjects with no evidence of major organ system disease as determined by physical exam, history, and screening laboratory data Females of childbearing potential with a negative pregnancy test at Screening and Treatment visits, using one of the following forms of contraception for the duration of participation in the study (i.e., until Follow-up 7-14 days post last dose): Oral contraceptive Injectable progesterone Subdermal implant Spermicidal foam/gel/film/cream/suppository Diaphragm with spermicide Copper or hormonal containing IUD Sterile male partner vasectomized > 6 month pre-dosing. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures. Exclusion Criteria: Recent (i.e., within three (3) months prior to Screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, immunological, or clinically significant neurological disease. Subjects with a family history of diabetes in a first degree relative BMI of less than 24 or greater than 40 kg/m2 Unstable body weight (change of greater than ±4lbs over the preceding 3 months Subjects participating in an excessively heavy exercise program Subject with a feeding/sleeping schedule different from a daytime feeding/night time sleeping schedule Subjects taking medications known to alter glucose metabolism (with the exception of metformin and/or pioglitazone) or which effect brain neurosynaptic function are excluded. Subjects with evidence of major organ system disease as determined by physical exam, history, and screening laboratory data Pregnant subjects or subjects unwilling to use birth control during their study enrollment Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study Subjects with hematuria will be excluded. Subjects with evidence or prior history of heart failure will be excluded Subjects with family history of pancreatic, bladder, and breast cancer will be excluded. Subjects with history of pancreatitis will be excluded. Subjects with eGFR < 60 ±5 ml/min.1.73m2 will be excluded. Subjects with elevated serum creatinine (>1.5 mg/dl males/1.4 mg/dl females) will be excluded. Subjects with a history of orthostatic hypotension (>15/10 mmHg) will be excluded. Subjects with liver enzymes (ALT, AST) >3-fold above upper normal limit will be excluded. Subjects with a history of hypersensitivity to pioglitazone, dapagliflozin, or Saxagliptin will be excluded.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ralph A DeFronzo, MD
Phone
210-567-6691
Email
defronzo@uthscsa.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Monica Palomo, BS
Phone
210-567-6710
Email
palomom@uthscsa.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ralph A DeFronzo, MD
Organizational Affiliation
The University of Texas Health Science Center at San Antonio
Official's Role
Principal Investigator
Facility Information:
Facility Name
The University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ralph A DeFronzo, MD
Phone
210-567-6691
Email
defronzo@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Monica Palomo, BS
Phone
210-567-6710
Email
palomom@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Ralph A DeFronzo, MD
First Name & Middle Initial & Last Name & Degree
Eugenio Cersosimo, MD

12. IPD Sharing Statement

Learn more about this trial

Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

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