Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will evaluate how EFB0027 and EFB0026 behave in subjects with type 2 diabetes mellitus. In addition, this study will compare the effects of EFB0027 and EFB0026 on circulating concentrations of glucose and gastrointestinal hormones in subjects with type 2 diabetes mellitus.
Interventions
DRUGEFB0027 (metformin delayed release)
Comparison of enteric-coating to assess effect on PK
DRUGEFB0026 (metformin immediate-release)
Active comparator
Sponsors
Elcelyx Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
19 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Is 19 to 70 (inclusive) years old at Visit 1 (Screening). 2. Is diagnosed with Type 2 Diabetes Mellitus with * HbA1c between 6.0 to 9.5% (inclusive) for subjects managing their diabetes with: i. Diet and exercise alone, or ii. A stable regimen (minimum of 2 months at Visit 1) of metformin alone, or iii. A stable regimen (minimum of 2 months at Visit 1) of DPP-4 inhibitor alone, OR * HbA1c between 6.0 to 8.5% (inclusive) for subjects managing their diabetes with a stable (minimum of 2 months at Visit 1) combination regimen of metformin and DPP-4 inhibitors. 3. Has serum creatinine below the upper limit of normal at Visit 1 and an estimated creatinine clearance above 80 using the Crockroft and Gault equation (CrCl = \[(140 - age) x body weight in kg\] / (serum creatinine x 72) x (0.85 for females) \[ref. 3\]. 4. Has a body mass index (BMI) of 25.0 to 40.0 kg/m\^2 (inclusive) at Screening. 5. Is male, or is female and meets all of the following criteria: * Not breastfeeding * Negative pregnancy test result (human chorionic gonadotropin, beta subunit) at Visit 1 (Screening) (not applicable to hysterectomized females) * Surgically sterile, postmenopausal, or if of childbearing potential, must practice and be willing to continue to practice appropriate birth control during the entire duration of the study 6. Has a physical examination with no clinically significant abnormalities as judged by the investigator. 7. Ability to understand and willingness to adhere to protocol requirements. 8. If on chronic thyroid pharmacologic therapy, the dose must be stable for at least 3 months prior to Visit 1 (Screening), and must have thyroid-stimulating hormone (TSH) test result in normal range at Visit 1 (Screening).
Exclusion criteria
1. Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the investigator, including but not limited to the following conditions: * Hepatic disease * Renal disease * Gastrointestinal disease * Endocrine disorder except diabetes * Cardiovascular disease * Seizure disorder * Organ transplantation * Chronic infection 2. Has any chronic disease requiring medication that has been adjusted in the past 90 days (subjects may take acute intermittent over-the-counter medications such as Tylenol, if needed). 3. Has any drug treatment that affects gastric pH (prescription or over-the-counter), including any antacids or medications such as Rolaids or Pepcid within 2 days of Visit 1 (Screening). 4. Has had major surgery of any kind within 6 months of Visit 1 (Screening). 5. Has received a blood transfusion within 6 months of Visit 1 (Screening). 6. Has a history of \>5 kg weight change within 3 months of Visit 1 (Screening). 7. Has clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities other than those expected in subjects with diabetes and judged by the investigator to be clinically significant at Visit 1 (Screening). 8. Has physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study. 9. Currently abuses drugs or alcohol or has a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures. 10. Has donated blood within 2 months of Visit 1 (Screening) or is planning to donate blood during the study. 11. Has used insulin within 3 months of Visit 1 (Screening). 12. Has received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening). 13. Has known intolerance to metformin. 14. Has received any investigational drug within 1 month (or five half-lives of the investigational drug, whichever is greater) of Visit 1 (Screening). 15. Has known allergies or hypersensitivity to any component of study treatment. 16. Is employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company). 17. Smokes more than 10 cigarettes per day, 2 cigars per day, or uses more than 1 can of smokeless tobacco per week.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (0-t) of Plasma Metformin | Time points at which data were collected to create the area under the curve (0-t) for plasma metformin were: t = -0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 11 h relative to the start time of the standardized breakfast. | Measures from the time of dosing (0 h) to the time of the last quantifiable concentration following dose administration. The dose of study medication was administered at t = -1 min relative to the start time of the standardized breakfast. |
| Change in Fasting Plasma Glucose | Change from Baseline (Day 1) to Day 5 | LS mean difference from Baseline (Day 1) to Day 5 |
| Within Treatment Comparison Based on Ratios of AUCs of GLP-1 | Ratio of Day 5 to Baseline | — |
| Within Treatment Comparison Based on Ratios of AUCs of PYY | Ratio of Day 5 to Baseline | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence BCAD A = 1000 mg EFB0026 BID B = 1000 mg EFB0027 BID C = 500 mg EFB0027 BID D = 500 mg EFB0026 BID plus 1000 mg EFB0027 BID | 6 |
| Sequence ABDC A = 1000 mg EFB0026 BID B = 1000 mg EFB0027 BID C = 500 mg EFB0027 BID D = 500 mg EFB0026 BID plus 1000 mg EFB0027 BID | 6 |
| Sequence CDBA A = 1000 mg EFB0026 BID B = 1000 mg EFB0027 BID C = 500 mg EFB0027 BID D = 500 mg EFB0026 BID plus 1000 mg EFB0027 BID | 6 |
| Sequence DACB A = 1000 mg EFB0026 BID B = 1000 mg EFB0027 BID C = 500 mg EFB0027 BID D = 500 mg EFB0026 BID plus 1000 mg EFB0027 BID | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Sequence DACB | Sequence CDBA | Sequence ABDC | Sequence BCAD |
|---|---|---|---|---|---|
| Age, Continuous | 51.3 years STANDARD_DEVIATION 9.98 | 55.3 years STANDARD_DEVIATION 7.79 | 49.7 years STANDARD_DEVIATION 13.92 | 56.8 years STANDARD_DEVIATION 7.22 | 43.2 years STANDARD_DEVIATION 3.54 |
| BMI | 33.33 kg/mˆ2 STANDARD_DEVIATION 4.05 | 32.87 kg/mˆ2 STANDARD_DEVIATION 3.644 | 35.65 kg/mˆ2 STANDARD_DEVIATION 2.935 | 30.67 kg/mˆ2 STANDARD_DEVIATION 2.793 | 34.13 kg/mˆ2 STANDARD_DEVIATION 5.455 |
| eGFR | 108.39 mL/min/1.73 mˆ2 STANDARD_DEVIATION 21.161 | 93.43 mL/min/1.73 mˆ2 STANDARD_DEVIATION 20.354 | 107.54 mL/min/1.73 mˆ2 STANDARD_DEVIATION 16.644 | 114.65 mL/min/1.73 mˆ2 STANDARD_DEVIATION 21.348 | 117.94 mL/min/1.73 mˆ2 STANDARD_DEVIATION 22.065 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 2 Participants | 5 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 4 Participants | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FPG | 161 mg/dL STANDARD_DEVIATION 56.34 | 124.3 mg/dL STANDARD_DEVIATION 15.03 | 179 mg/dL STANDARD_DEVIATION 69.59 | 158 mg/dL STANDARD_DEVIATION 42.96 | 182.5 mg/dL STANDARD_DEVIATION 71.55 |
| HbA1c | 7.35 % STANDARD_DEVIATION 1.108 | 6.37 % STANDARD_DEVIATION 0.339 | 8.07 % STANDARD_DEVIATION 1.102 | 7.33 % STANDARD_DEVIATION 0.965 | 7.62 % STANDARD_DEVIATION 1.234 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 5 Participants | 6 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United States | 24 participants | 6 participants | 6 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 12 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 22 | 5 / 20 | 4 / 20 | 10 / 21 |
| serious Total, serious adverse events | 0 / 22 | 1 / 20 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Area Under the Curve (0-t) of Plasma Metformin
Measures from the time of dosing (0 h) to the time of the last quantifiable concentration following dose administration. The dose of study medication was administered at t = -1 min relative to the start time of the standardized breakfast.
Time frame: Time points at which data were collected to create the area under the curve (0-t) for plasma metformin were: t = -0.08, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 11 h relative to the start time of the standardized breakfast.
Population: Evaluable Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg EFB0026 | Area Under the Curve (0-t) of Plasma Metformin | 8672 ng*h/mL | Standard Deviation 29.7 |
| 1000 mg EFB0027 | Area Under the Curve (0-t) of Plasma Metformin | 4774 ng*h/mL | Standard Deviation 29.9 |
| 500 mg EFB0027 | Area Under the Curve (0-t) of Plasma Metformin | 3842 ng*h/mL | Standard Deviation 37.6 |
| 500 mg EFB0026 + 1000 mg EFB0027 | Area Under the Curve (0-t) of Plasma Metformin | 8075 ng*h/mL | Standard Deviation 38.6 |
Primary
Change in Fasting Plasma Glucose
LS mean difference from Baseline (Day 1) to Day 5
Time frame: Change from Baseline (Day 1) to Day 5
Population: Evaluable Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg EFB0026 | Change in Fasting Plasma Glucose | -22.5 mg/dL | Standard Error 6.8 |
| 1000 mg EFB0027 | Change in Fasting Plasma Glucose | -19.9 mg/dL | Standard Error 5 |
| 500 mg EFB0027 | Change in Fasting Plasma Glucose | -16.4 mg/dL | Standard Error 3.8 |
| 500 mg EFB0026 + 1000 mg EFB0027 | Change in Fasting Plasma Glucose | -21.2 mg/dL | Standard Error 4.7 |
p-value: <0.0595% CI: [-37, -8]Mixed Models Analysis
p-value: <0.0595% CI: [-30, -9]Mixed Models Analysis
p-value: <0.0595% CI: [-24, -8]Mixed Models Analysis
p-value: <0.0595% CI: [-31, -11]Mixed Models Analysis
Primary
Within Treatment Comparison Based on Ratios of AUCs of GLP-1
Time frame: Ratio of Day 5 to Baseline
Population: Evaluable
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg EFB0026 | Within Treatment Comparison Based on Ratios of AUCs of GLP-1 | 1.87 none (values are ratios) | Standard Error 0.18 |
| 1000 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of GLP-1 | 1.62 none (values are ratios) | Standard Error 0.11 |
| 500 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of GLP-1 | 1.69 none (values are ratios) | Standard Error 0.15 |
| 500 mg EFB0026 + 1000 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of GLP-1 | 1.88 none (values are ratios) | Standard Error 0.19 |
p-value: <0.0595% CI: [1.4, 1.9]Mixed Models Analysis
p-value: <0.0595% CI: [1.5, 2.3]Mixed Models Analysis
p-value: <0.0595% CI: [1.4, 2]Mixed Models Analysis
p-value: <0.0595% CI: [1.5, 2.3]Mixed Models Analysis
Primary
Within Treatment Comparison Based on Ratios of AUCs of PYY
Time frame: Ratio of Day 5 to Baseline
Population: Evaluable Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1000 mg EFB0026 | Within Treatment Comparison Based on Ratios of AUCs of PYY | 1.55 none (values are ratios) | Standard Error 0.09 |
| 1000 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of PYY | 1.38 none (values are ratios) | Standard Error 0.09 |
| 500 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of PYY | 1.46 none (values are ratios) | Standard Error 0.06 |
| 500 mg EFB0026 + 1000 mg EFB0027 | Within Treatment Comparison Based on Ratios of AUCs of PYY | 1.49 none (values are ratios) | Standard Error 0.06 |
p-value: <0.0595% CI: [1.4, 1.8]Mixed Models Analysis
p-value: <0.0595% CI: [1.2, 1.6]Mixed Models Analysis
p-value: <0.0595% CI: [1.3, 1.6]Mixed Models Analysis
p-value: <0.0595% CI: [1.4, 1.6]Mixed Models Analysis