Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2, Diabetes Mellitus, Diabetes, High blood sugar, Blood sugar, Blood glucose, Glucose
Brief summary
The purpose of this study is to assess the safety and tolerability of MSDC-0602 and to evaluate the reduction in fasting plasma glucose in patients with Type 2 diabetes.
Interventions
DRUGPlacebo
Placebo Capsules
DRUGMSDC-0602 100 mg
MSDC-0602 100 mg Capsules
DRUGMSDC-0602 250 mg
MSDC-0602 250 mg Capsules
DRUGPioglitazone
Pioglitazone 45 mg Capsules
Sponsors
Metabolic Solutions Development Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: Inclusion Criteria: 1. Males and females with Type 2 diabetes (fasting plasma glucose ≥126 mg/dL at screening, glycosylated hemoglobin \[HbA1c\] \>7 and ≤10%, and Insulin C-peptide \>1 ng/mL). Patients can be naïve to diabetes therapy or if taking metformin should be on a stable dose level for a period of at least 3 months prior to screening visit (no dose limit). 2. Between the ages of 18-75 years, inclusive. 3. Females should be either postmenopausal (at least 12 months since last menses) or surgically sterilized (bilateral tubal ligation or hysterectomy). Menopausal status will be verified by a follicle-stimulating hormone (FSH) test. If FSH levels are below 40 mIU/mL, some method of birth control must be used. Those with bilateral tubal ligation must also use a barrier method of birth control. In addition, all females must have a negative pregnancy test at Screen and Day 15 regardless of childbearing potential. For postmenopausal women only, if FSH levels are above 40 mIU/mL and serum pregnancy results are indeterminant, the subject will be assessed as not pregnant. Males with female partners of child-bearing potential must agree to use adequate contraceptive methods (including a condom, plus one other form of contraception) if engaging in sexual intercourse. 4. Body Mass Index (BMI) ≥ 25 kg/m2 and ≤ 45 kg/m2 (inclusive). 5. Willing and able to make a screening visit to the clinic and six visits over a 10 week period. 6. Willing and able to sign an informed consent document indicating understanding the purpose of and procedures required for the study and willingness to participate in the study. Subject
Exclusion criteria
1. Use of TZDs or diabetes medications other than metformin (generic or Glucophage®) 3 months prior to screening. 2. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma. 3. Fasting plasma glucose in excess of 240 mg/dl at screening 4. History of heart failure (including CHF) or previous cardiovascular event (myocardial infarct, by-pass surgery, or PTCA) within the past 6 months prior to screening. 5. ALT and/or AST levels that equal or exceed twice the upper limit of normal; bilirubin levels that exceed 2 mg/dL; serum creatinine \>1.5 mg/dL in men or \> 1.4 mg/dL in women. 6. History of nephropathy, neuropathy, or retinopathy within 6 months of screening. 7. Use of glucocorticoids (oral, injectible, intraarticular, or chronic inhaled) or weight-loss drugs within 3 months of randomization. 8. Current or recurrent disease that may affect the action, absorption or disposition of the study treatment, or clinical or laboratory assessments. 9. Current or history of severe or unstable disorder (medical or psychiatric) requiring treatment that may make the patient unlikely to complete the study. 10. Febrile illness within the 5 days prior to Visit 1. 11. Known history of HIV, hepatitis B, or hepatitis C. 12. Clinically significant findings on physical examination, including BP, pulse rate and 12-lead ECG. 13. Blood pressure greater than 160/100 mmHg. Patients with elevated BP (\<160/100 mmHg) with or without current treatment will be allowed at the discretion of the Principal Investigator (PI) and primary care physician. Individuals with hypertension must have been stabilized to the current treatment regimen for at least 6 weeks prior to screening. 14. Change in BP or lipid-lowering medication within 6 weeks or change in dose of metformin or thyroid replacement within 3 months prior to screening. 15. Known or suspected intolerance or hypersensitivity to the study drugs, closely related compounds or any of their stated ingredients. 16. History of alcohol or drug abuse within 6 months of Screening. 17. Have participated in an investigational study or received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to study drug administration. 18. Blood donation of 1 pint or more within 56 days of screening. 19. Plasmapheresis or plasma donation within 30 days of screening. 20. Single 12-lead ECG demonstrating a QTcB \>450 msec at Screening. A single repeat ECG may be done at the Investigator's discretion. 21. Any surgical or medical condition which may significantly alter the absorption of any drug substance including, but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active inflammatory bowel syndrome. 22. Evidence of clinically relevant pathology that could interfere with the study results or put the patient's safety at risk. 23. Malignancy, including leukemia and lymphoma (not including basal cell skin cancer) within the last 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose | Baseline and 28 days | To characterize the reduction in fasting plasma glucose in response to three different doses of MSDC-0602 Tablets as compared to placebo following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c | Baseline and 28 days | To explore the drug effect difference in the reduction in hemoglobin A1c in response to three different doses of MSDC-0602 and pioglitazone (45 mg Actos®) as compared to placebo following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes. |
| Change From Baseline in Body Weight | Baseline and 28 days | To characterize the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo on hematocrit, body weight, and edema following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes. |
| Change From Baseline in Hematocrit | Baseline and 28 days | To characterize the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo in hematocrit following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes. |
| Change in Fasting Plasma Insulin | Baseline and 28 days | To characterize the effects of 3 different doses of MSDC-0602 and pioglitazone as compared to placebo on insulin following once-daily dosing for 28 consecutive days |
| Change From Baseline in High Molecular Weight Adiponectin | Baseline and 28 days | To evaluate the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo on biomarkers of inflammatory status (high molecular weight adiponectin) following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 15 investigational sites between February 15, 2011 and July 6, 2011.
Pre-assignment details
This study consisted of a 14-day placebo lead-in period and a 28-day double-blind treatment period. Eligible patients were randomized following the lead-in period based on a stratification criterion of current metformin use (yes, no) to one of the 5 treatments: MSDC 0602 100 mg, MSDC-0602 250 mg, MSDC-0602 500 mg, pioglitazone 45 mg, or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo capsule once daily | 26 |
| MSDC-0602 100 mg MSDC-0602 capsule 100 mg once daily | 25 |
| MSDC-0602 250 mg MSDC-0602 capsule 250 mg once daily | 26 |
| MSDC-0602 500 mg MSDC-0602 capsule 500 mg once daily | 26 |
| Pioglitazone 45 mg Pioglitazone capsule 45 mg once daily | 26 |
| Total | 129 |
Baseline characteristics
| Characteristic | Placebo | MSDC-0602 100 mg | MSDC-0602 250 mg | MSDC-0602 500 mg | Pioglitazone 45 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 8.87 | 57.6 years STANDARD_DEVIATION 8.07 | 57.7 years STANDARD_DEVIATION 7.35 | 55.5 years STANDARD_DEVIATION 8.59 | 55.7 years STANDARD_DEVIATION 8.01 | 56.7 years STANDARD_DEVIATION 8.12 |
| Region of Enrollment United States | 26 participants | 25 participants | 26 participants | 26 participants | 26 participants | 129 participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 13 Participants | 10 Participants | 14 Participants | 52 Participants |
| Sex: Female, Male Male | 20 Participants | 16 Participants | 13 Participants | 16 Participants | 12 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 26 | 0 / 25 | 1 / 26 | 5 / 26 | 4 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 | 0 / 26 | 0 / 26 | 0 / 26 |
Outcome results
Primary
Change From Baseline in Fasting Plasma Glucose
To characterize the reduction in fasting plasma glucose in response to three different doses of MSDC-0602 Tablets as compared to placebo following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes.
Time frame: Baseline and 28 days
Population: Per-Protocol Population:Included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures. The Per-Protocol Population was used for all efficacy measurements.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose | 6.0 mg/dL | Inter-Quartile Range 8.9 |
| MSDC-0602 100 mg | Change From Baseline in Fasting Plasma Glucose | -0.5 mg/dL | Inter-Quartile Range 9.77 |
| MSDC-0602 250 mg | Change From Baseline in Fasting Plasma Glucose | -20.0 mg/dL | Inter-Quartile Range 10.06 |
| MSDC-0602 500 mg | Change From Baseline in Fasting Plasma Glucose | -16.0 mg/dL | Inter-Quartile Range 9.68 |
| Pioglitazone 45 mg | Change From Baseline in Fasting Plasma Glucose | -22.0 mg/dL | Inter-Quartile Range 9.38 |
p-value: 0.419595% CI: [-34, 14]Wilcoxon (Mann-Whitney)
p-value: 0.081195% CI: [-38, 4]Wilcoxon (Mann-Whitney)
p-value: 0.063995% CI: [-38, 1]Wilcoxon (Mann-Whitney)
p-value: 0.002295% CI: [-50, -12]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Body Weight
To characterize the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo on hematocrit, body weight, and edema following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes.
Time frame: Baseline and 28 days
Population: The Per-Protocol Population included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | 0.12 kg | Standard Error 0.267 |
| MSDC-0602 100 mg | Change From Baseline in Body Weight | 0.25 kg | Standard Error 0.291 |
| MSDC-0602 250 mg | Change From Baseline in Body Weight | -0.07 kg | Standard Error 0.297 |
| MSDC-0602 500 mg | Change From Baseline in Body Weight | 0.17 kg | Standard Error 0.29 |
| Pioglitazone 45 mg | Change From Baseline in Body Weight | 0.54 kg | Standard Error 0.284 |
Secondary
Change From Baseline in HbA1c
To explore the drug effect difference in the reduction in hemoglobin A1c in response to three different doses of MSDC-0602 and pioglitazone (45 mg Actos®) as compared to placebo following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes.
Time frame: Baseline and 28 days
Population: The Per-Protocol Population included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c | 0.14 percentage of hemoglobin | Standard Error 0.081 |
| MSDC-0602 100 mg | Change From Baseline in HbA1c | 0.09 percentage of hemoglobin | Standard Error 0.088 |
| MSDC-0602 250 mg | Change From Baseline in HbA1c | -0.10 percentage of hemoglobin | Standard Error 0.09 |
| MSDC-0602 500 mg | Change From Baseline in HbA1c | -0.17 percentage of hemoglobin | Standard Error 0.088 |
| Pioglitazone 45 mg | Change From Baseline in HbA1c | -0.14 percentage of hemoglobin | Standard Error 0.086 |
Secondary
Change From Baseline in Hematocrit
To characterize the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo in hematocrit following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes.
Time frame: Baseline and 28 days
Population: The Per-Protocol Population included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematocrit | -0.9 Change from baseline | Standard Error 0.36 |
| MSDC-0602 100 mg | Change From Baseline in Hematocrit | -0.9 Change from baseline | Standard Error 0.39 |
| MSDC-0602 250 mg | Change From Baseline in Hematocrit | -1.2 Change from baseline | Standard Error 0.4 |
| MSDC-0602 500 mg | Change From Baseline in Hematocrit | -1.7 Change from baseline | Standard Error 0.39 |
| Pioglitazone 45 mg | Change From Baseline in Hematocrit | -1.4 Change from baseline | Standard Error 0.38 |
Secondary
Change From Baseline in High Molecular Weight Adiponectin
To evaluate the effects of three different doses of MSDC-0602 and pioglitazone as compared to placebo on biomarkers of inflammatory status (high molecular weight adiponectin) following once-daily dosing for 28 consecutive days in patients with Type 2 diabetes.
Time frame: Baseline and 28 days
Population: The Per-Protocol Population included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in High Molecular Weight Adiponectin | 3.6 ng/mL | Standard Error 15.28 |
| MSDC-0602 100 mg | Change From Baseline in High Molecular Weight Adiponectin | 44.1 ng/mL | Standard Error 17.3 |
| MSDC-0602 250 mg | Change From Baseline in High Molecular Weight Adiponectin | 101.6 ng/mL | Standard Error 17 |
| MSDC-0602 500 mg | Change From Baseline in High Molecular Weight Adiponectin | 139.2 ng/mL | Standard Error 16.62 |
| Pioglitazone 45 mg | Change From Baseline in High Molecular Weight Adiponectin | 206.0 ng/mL | Standard Error 16.35 |
Secondary
Change in Fasting Plasma Insulin
To characterize the effects of 3 different doses of MSDC-0602 and pioglitazone as compared to placebo on insulin following once-daily dosing for 28 consecutive days
Time frame: Baseline and 28 days
Population: The Per-Protocol population included all patients who completed the 4-week, double blind treatment period without any major deviations from the protocol procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Plasma Insulin | 3.06 µIU/mL | Standard Deviation 1.434 |
| MSDC-0602 100 mg | Change in Fasting Plasma Insulin | -1.70 µIU/mL | Standard Deviation 1.561 |
| MSDC-0602 250 mg | Change in Fasting Plasma Insulin | -1.11 µIU/mL | Standard Deviation 1.601 |
| MSDC-0602 500 mg | Change in Fasting Plasma Insulin | -2.13 µIU/mL | Standard Deviation 1.564 |
| Pioglitazone 45 mg | Change in Fasting Plasma Insulin | -3.21 µIU/mL | Standard Deviation 1.523 |