Type 2 Diabetes Mellitus
Conditions
Brief summary
This study compared the effects of delayed-release metformin (Met DR, EFB0027) administered once daily in the morning (qAM), administered once daily in the evening (qPM), and administered twice daily (BID) on circulating glucose concentrations and metformin pharmacokinetics (PK) in subjects with type 2 diabetes mellitus (T2DM).
Interventions
DRUGMet DR
metformin delayed-release tablets
Sponsors
Elcelyx Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. 18 to 70 (inclusive) years old at Visit 1 (Screening) 2. Was 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. Had normal renal function with an estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m\^2 based on the Modification of Diet in Renal Disease (MDRD) equation 4. Body mass index (BMI) of 25.0 to 40.0 kg/m\^2 (inclusive) at Screening 5. Male, or if female and met 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, practiced and was willing to continue to practice appropriate birth control during the entire duration of the study 6. Had 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 have been 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. Had 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 * Central nervous system diseases * Psychiatric or neurological disorders * Organ transplantation * Chronic or acute infection * Orthostatic hypotension, fainting spells or blackouts * Allergy or hypersensitivity 2. Had any chronic disease requiring medication that was adjusted in the past 90 days (subjects could take acute intermittent over-the-counter medications such as Tylenol, if needed) 3. Had 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. Had major surgery of any kind within 6 months of Visit 1 (Screening) 5. Had received a blood transfusion within 6 months of Visit 1 (Screening) 6. Had a history of \>5 kg weight change within 3 months of Visit 1 (Screening) 7. Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities other than those expected in subjects with type 2 diabetes and judged by the investigator to be clinically significant at Visit 1 (Screening) 8. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study 9. Abused drugs or alcohol or had a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures 10. Had donated blood within 3 months of the date of the first dose of randomized study medication, or was planning to donate blood during the study 11. Used insulin within 3 months of Visit 1 (Screening) 12. Had received GLP-1 receptor agonists and/or thiazolidinedione treatment within 6 months of Visit 1 (Screening) 13. Had known intolerance to metformin 14. Had received any investigational drug within 2 months (or five half-lives of the investigational drug, whichever was greater) of Visit 1 (Screening) 15. Had known allergies or hypersensitivity to any component of study treatment 16. Was employed by Elcelyx Therapeutics, Inc. (that is an employee, temporary contract worker, or designee of the company) 17. Smoked more than 10 cigarettes per day, 3 cigars per day, 3 pipes per day, used more than 1 can of smokeless tobacco per week, or used a combination of tobacco products that approximate nicotine doses equivalent to 10 cigarettes per day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-24) of Plasma Metformin | Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. | AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. |
| Cmax of Plasma Metformin | Times points to determine Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. | Cmax = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. |
| AUC (0-24) of Plasma Glucose | Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the time of the standardized dinner. | AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. |
| Rmax (0-24) of Plasma Glucose | Times points to determine Rmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. | Rmax (0-24) = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1: ABC Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID | 9 |
| Sequence 2: BCA Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID | 8 |
| Sequence 3: CAB Treatment A = 1000 mg Met DR qAM Treatment B = 1000 mg Met DR qPM Treatment C = 500 mg Met DR BID | 9 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Non-Compliance | 1 | 1 | 0 |
| Overall Study | Personal Reason | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence 2: BCA | Total | Sequence 1: ABC | Sequence 3: CAB |
|---|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 13.47 | 50.9 years STANDARD_DEVIATION 10.9 | 51.2 years STANDARD_DEVIATION 11.73 | 49.7 years STANDARD_DEVIATION 8.49 |
| BMI | 31.6 kg/m^2 STANDARD_DEVIATION 3.93 | 31.5 kg/m^2 STANDARD_DEVIATION 3.17 | 32.3 kg/m^2 STANDARD_DEVIATION 3.73 | 30.7 kg/m^2 STANDARD_DEVIATION 1.58 |
| Diabetes Management Diet and Exercise Only | 4 participants | 7 participants | 1 participants | 2 participants |
| Diabetes Management Metformin Alone | 3 participants | 17 participants | 7 participants | 7 participants |
| Diabetes Management Metformin and DPP-4 Inhibitors | 1 participants | 2 participants | 1 participants | 0 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 18 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 8 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Serum Glucose | 177.6 mg/dL STANDARD_DEVIATION 84.17 | 167.6 mg/dL STANDARD_DEVIATION 57.04 | 161.2 mg/dL STANDARD_DEVIATION 29.94 | 165.0 mg/dL STANDARD_DEVIATION 54.02 |
| HbA1c | 7.13 % STANDARD_DEVIATION 1.107 | 7.28 % STANDARD_DEVIATION 1.017 | 7.34 % STANDARD_DEVIATION 1.038 | 7.36 % STANDARD_DEVIATION 1.022 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 24 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Female | 6 Participants | 16 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 10 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 23 | 5 / 24 | 7 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 23 |
Outcome results
Primary
AUC (0-24) of Plasma Glucose
AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.
Time frame: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the time of the standardized dinner.
Population: Evaluable Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 500 mg Met DR BID | AUC (0-24) of Plasma Glucose | Pre-Treatment | 4668 mg*h/dL | Standard Error 581 |
| 500 mg Met DR BID | AUC (0-24) of Plasma Glucose | On-Treatment | 4438 mg*h/dL | Standard Error 552 |
| 1000 mg Met DR qAM | AUC (0-24) of Plasma Glucose | Pre-Treatment | 4947 mg*h/dL | Standard Error 615 |
| 1000 mg Met DR qAM | AUC (0-24) of Plasma Glucose | On-Treatment | 4503 mg*h/dL | Standard Error 560 |
| 1000 mg Met DR qPM | AUC (0-24) of Plasma Glucose | Pre-Treatment | 4961 mg*h/dL | Standard Error 617 |
| 1000 mg Met DR qPM | AUC (0-24) of Plasma Glucose | On-Treatment | 4509 mg*h/dL | Standard Error 561 |
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.002895% CI: [85.7, 96.67]ANOVA
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.002495% CI: [85.58, 96.53]ANOVA
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.099295% CI: [89.54, 100.99]ANOVA
Primary
AUC (0-24) of Plasma Metformin
AUC (0-24) = Area under the curve from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.
Time frame: Times points to create the AUC (0-24) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.
Population: Evaluable Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 500 mg Met DR BID | AUC (0-24) of Plasma Metformin | 7771 ng*h/mL | Standard Error 619 |
| 1000 mg Met DR qAM | AUC (0-24) of Plasma Metformin | 5559 ng*h/mL | Standard Error 433 |
| 1000 mg Met DR qPM | AUC (0-24) of Plasma Metformin | 7757 ng*h/mL | Standard Error 604 |
Comparison: 1000 mg Met DR qPM is the denominator for the % ratio of least squares (LS) means and the comparator for the p-values.p-value: 0.001890% CI: [61.14, 84.01]ANOVA
Comparison: 500 mg Met DR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.00290% CI: [60.85, 84.09]ANOVA
Comparison: 500 mg Met DR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.984490% CI: [84.91, 117.33]ANOVA
Primary
Cmax of Plasma Metformin
Cmax = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.
Time frame: Times points to determine Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.
Population: Evaluable Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 500 mg Met DR BID | Cmax of Plasma Metformin | 780 ng/mL | Standard Error 71.7 |
| 1000 mg Met DR qAM | Cmax of Plasma Metformin | 868 ng/mL | Standard Error 79.8 |
| 1000 mg Met DR qPM | Cmax of Plasma Metformin | 1035 ng/mL | Standard Error 95.2 |
Comparison: 1000 mg Met DR qPM is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.159590% CI: [68.1, 103.23]ANOVA
Comparison: 500 mg Met DR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.386790% CI: [90.37, 136.99]ANOVA
Comparison: 500 mg Met DR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.029490% CI: [107.78, 163.39]ANOVA
Primary
Rmax (0-24) of Plasma Glucose
Rmax (0-24) = maximum response from the start time of the standardized dinner (0 h) to 24 hours after the standardized dinner. Study medication was administered at t = 0 hours for Treatments B and C and at t = 12 hours for Treatments A and C.
Time frame: Times points to determine Rmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.75, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 18.5, 19, 19.5, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner.
Population: Evaluable Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 500 mg Met DR BID | Rmax (0-24) of Plasma Glucose | Pre-Treatment | 279 mg/dL | Standard Error 29.9 |
| 500 mg Met DR BID | Rmax (0-24) of Plasma Glucose | On-Treatment | 263 mg/dL | Standard Error 28.2 |
| 1000 mg Met DR qAM | Rmax (0-24) of Plasma Glucose | Pre-Treatment | 290 mg/dL | Standard Error 31.1 |
| 1000 mg Met DR qAM | Rmax (0-24) of Plasma Glucose | On-Treatment | 262 mg/dL | Standard Error 28.1 |
| 1000 mg Met DR qPM | Rmax (0-24) of Plasma Glucose | Pre-Treatment | 302 mg/dL | Standard Error 32.4 |
| 1000 mg Met DR qPM | Rmax (0-24) of Plasma Glucose | On-Treatment | 273 mg/dL | Standard Error 29.4 |
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.000695% CI: [85.55, 95.56]ANOVA
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.000795% CI: [85.65, 95.67]ANOVA
Comparison: Pretreatment value is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.038995% CI: [89.24, 99.69]ANOVA