Insulin Resistance, Type 2 Diabetes Mellitus
Conditions
Keywords
type 2 diabetes mellitus, insulin resistance, mifepristone, glucocorticoids
Brief summary
Randomized, double blind, placebo-controlled clinical trial examining the efficacy and safety of mifepristone 600 mg daily in male subjects with type 2 diabetes mellitus, not associated with Cushing's syndrome
Detailed description
Randomized, double blind, placebo-controlled clinical trial examining the efficacy and safety of mifepristone 600 mg daily in male subjects with type 2 diabetes mellitus, not associated with Cushing's syndrome, and sub-optimally controlled on basal insulin, with or without prandial insulin and/or maximally-tolerated doses of metformin.
Interventions
DRUGMifepristone 600 mg daily
Glucocorticoid receptor antagonist
DRUGPlacebo
Matching placebo
Sponsors
Charles Drew University of Medicine and Science
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males * Age 18-65 inclusive * Established T2DM for ≥ 1 year * Taking stable doses (≤ 20% change in total daily insulin dose within 2 months prior to screening) of basal insulin, with or without prandial insulin (total daily dose must be ≤ 200 units) * Baseline hemoglobin A1c (HbA1c) 8.0%-10.5%
Exclusion criteria
* No use of any anti-hyperglycemic agents (oral or injectable) other than metformin or insulin * No history or clinical suspicion of type 1 diabetes mellitus * No concurrent chronic use of any corticosteroids by any route and for any indication, or concurrent conditions that may require the initiation of glucocorticoids during the study * No concurrent lipid-lowering medications whose levels are dependent on CYP3A pathway clearance (e.g., simvastatin, lovastatin, atorvastatin, fluvastatin and rosuvastatin) should either be washed out for at least one month prior to enrollment and/or switched to alternative LDL-cholesterol lowering agents (e.g., pravastatin or ezetimibe) for at least one month. * No contraindications or known intolerance to mifepristone * No concurrent use of strong CYP3A inhibitors (e.g., cyclosporine, ergotamine, fentanyl, quinidine, sirolimus, tacrolimus, imidazole antifungals, HIV protease inhibitors, certain macrolide antibiotics) * No concurrent use of CYP3A inducers (e.g., phenytoin, phenobarbital, carbamazepine, rifampin) * No concurrent use of medications that may prolong the QT interval (e.g., selected antipsychotics and antidepressants, quinolone antibiotics) * No daily use of warfarin or non-steroidal anti-inflammatory agents * Baseline K+ and Mg+2 within the laboratory normal ranges, with or without oral K+ and/or Mg+2 supplementation * Fasting plasma glucose (FPG) averaging \< 280 mg/dL and without polyuria or polydipsia * No symptomatic hypoglycemia averaging \> once per day * Able and willing to perform self-monitoring of blood glucose (SMBG) * Mean BP \< 140 mmHg systolic or 90 mm Hg diastolic * Baseline LDL-cholesterol \< 200 mg/dL if on lipid-lowering therapy or \< 250 mg/dL while not on lipid-lowering therapy * Fasting triglycerides ≤ 500 mg/dL if on lipid-lowering therapy * HDL-cholesterol ≥ 25 mg/dL * No known history of prostate cancer, or elevated level of prostate-specific antigen (PSA) at screening * Estimated GFR ≥ 30 mL/min * No concurrent endocrinopathies that have not been stabilized with replacement or other definitive therapies (including known adrenal insufficiency regardless of replacement therapy, cortisol \< 5 μg/dL at screening) * No active hemolytic anemias or hemoglobin variants that render the measurement of HbA1c potentially unreliable * No other clinically significant hepatic, cardiovascular (including known personal or family history of, or risk factors for long-QT syndrome, QTcF prolongation on ECG \> 500 ms), infectious (including HIV or any viral hepatitis), inflammatory, neoplastic or other systemic disease that may contraindicate the change of lipid-lowering therapy, renders mifepristone unsafe, or otherwise confounds data interpretation * Subjects not likely to start other drugs that may influence the study's outcomes (e.g., weight loss agents) * Subjects who are able and willing to comply with all components of the study protocol, attend all scheduled follow-up visits, or who do not present other foreseeable barriers that might make the implementation of the protocol problematic or confound data interpretation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin A1c | Baseline to 3 months | Glycemic lowering |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Mass Index | Baseline to 3 months | Body mass index in kg/m\^2 |
| Systolic BP | Baseline to 3 months | Systolic blood pressure |
| Diastolic BP | Baseline to 3 months | Diastolic blood pressure |
| LDL-cholesterol | Baseline to 3 months | Low-density lipoprotein cholesterol |
| Cortisol | Baseline to 3 months | Serum cortisol level (AM) |
| Weight | Baseline to 3 months | Weight in kg |
| Uric Acid | Baseline to 3 months | Serum uric acid level |
| PSA | Baseline to 3 months | Prostate-specific antigen level |
| Hypoglycemic Events | Baseline to 3 months | Symptomatic mild and severe hypoglycemic events |
| Adverse Events | Baseline to 3 months | Non-hypoglycemia-related adverse events |
| Basal Insulin Dose | Baseline to 3 months | Total daily basal insulin dosage |
| ACTH | Baseline to 3 months | Serum adrenocorticotrophic hormone level (AM) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mifepristone 600 mg Daily Mifepristone 300 mg po daily x 2 weeks, followed by mifepristone 600 mg po daily x 10 weeks
Mifepristone 600 mg daily: Glucocorticoid receptor antagonist | 3 |
| Placebo Matching, blinded placebo 1 tablet po daily x 2 weeks, followed by matching, blinded placebo 2 tablets po daily x 10 weeks
Placebo: Matching placebo | 3 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Mifepristone 600 mg Daily | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Continuous | 49.8 years STANDARD_DEVIATION 6.6 | 55.4 years STANDARD_DEVIATION 1.2 | 52.6 years STANDARD_DEVIATION 5.2 |
| Basal insulin daily dose | 73.3 Units per day STANDARD_DEVIATION 19.4 | 65.0 Units per day STANDARD_DEVIATION 39.5 | 69.2 Units per day STANDARD_DEVIATION 28.2 |
| Body mass index | 39.3 kg/m^2 STANDARD_DEVIATION 15 | 36.3 kg/m^2 STANDARD_DEVIATION 6.6 | 37.8 kg/m^2 STANDARD_DEVIATION 10.5 |
| Body weight | 107.6 kg STANDARD_DEVIATION 46.5 | 99.8 kg STANDARD_DEVIATION 4.5 | 103.7 kg STANDARD_DEVIATION 29.9 |
| Diabetes duration | 11.7 Years STANDARD_DEVIATION 8.8 | 14.0 Years STANDARD_DEVIATION 2 | 12.9 Years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c | 9.8 Percentage of hemoglobin STANDARD_DEVIATION 0.8 | 9.8 Percentage of hemoglobin STANDARD_DEVIATION 0.9 | 9.8 Percentage of hemoglobin STANDARD_DEVIATION 0.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 2 / 3 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 |
Outcome results
Primary
Hemoglobin A1c
Glycemic lowering
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Hemoglobin A1c | -2.4 Percentage of hemoglobin | Standard Deviation 1.2 |
| Placebo | Hemoglobin A1c | -1.5 Percentage of hemoglobin | Standard Deviation 1.4 |
Secondary
ACTH
Serum adrenocorticotrophic hormone level (AM)
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | ACTH | 56.0 pg/mL, change from baseline | Standard Deviation 39.8 |
| Placebo | ACTH | -8.3 pg/mL, change from baseline | Standard Deviation 11.2 |
Secondary
Adverse Events
Non-hypoglycemia-related adverse events
Time frame: Baseline to 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mifepristone 600 mg Daily | Adverse Events | 6 number of events |
| Placebo | Adverse Events | 2 number of events |
Secondary
Basal Insulin Dose
Total daily basal insulin dosage
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Basal Insulin Dose | -1.3 Units of insulin per day | Standard Deviation 16 |
| Placebo | Basal Insulin Dose | 0.7 Units of insulin per day | Standard Deviation 17.9 |
Secondary
Body Mass Index
Body mass index in kg/m\^2
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Body Mass Index | 0.6 kg/m^2, change from baseline | Standard Deviation 0.5 |
| Placebo | Body Mass Index | 0.0 kg/m^2, change from baseline | Standard Deviation 1.3 |
Secondary
Cortisol
Serum cortisol level (AM)
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Cortisol | 18.8 mg/dL, change from baseline | Standard Deviation 9 |
| Placebo | Cortisol | -0.9 mg/dL, change from baseline | Standard Deviation 0.9 |
Secondary
Diastolic BP
Diastolic blood pressure
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Diastolic BP | -4.3 mm Hg, change from baseline | Standard Deviation 8.5 |
| Placebo | Diastolic BP | -3.7 mm Hg, change from baseline | Standard Deviation 5.5 |
Secondary
Hypoglycemic Events
Symptomatic mild and severe hypoglycemic events
Time frame: Baseline to 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mifepristone 600 mg Daily | Hypoglycemic Events | 22 number of events |
| Placebo | Hypoglycemic Events | 31 number of events |
Secondary
LDL-cholesterol
Low-density lipoprotein cholesterol
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | LDL-cholesterol | -1.3 mg/dL, change from baseline | Standard Deviation 18.2 |
| Placebo | LDL-cholesterol | -9.7 mg/dL, change from baseline | Standard Deviation 19.3 |
Secondary
PSA
Prostate-specific antigen level
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | PSA | -0.3 ng/mL, change from baseline | Standard Deviation 0.2 |
| Placebo | PSA | 0.1 ng/mL, change from baseline | Standard Deviation 0.2 |
Secondary
Systolic BP
Systolic blood pressure
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Systolic BP | 3.0 mm Hg, change from baseline | Standard Deviation 8.7 |
| Placebo | Systolic BP | -3.7 mm Hg, change from baseline | Standard Deviation 1.2 |
Secondary
Uric Acid
Serum uric acid level
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Uric Acid | -0.8 mg/dL, change from baseline | Standard Deviation 0.6 |
| Placebo | Uric Acid | 1.1 mg/dL, change from baseline | Standard Deviation 0.4 |
Secondary
Weight
Weight in kg
Time frame: Baseline to 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mifepristone 600 mg Daily | Weight | 1.4 kg, change from baseline | Standard Deviation 1.4 |
| Placebo | Weight | 0.5 kg, change from baseline | Standard Deviation 3.3 |