Healthy Subjects
Conditions
Brief summary
This study compared the pharmacokinetics (PK) and assessed the safety of delayed-release metformin (Met DR, EFB0027) at two dosage levels, immediate-release metformin (Met IR, ETB0015), and extended-release metformin (Met XR, ETB0014) in healthy subjects.
Interventions
Sponsors
Elcelyx Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
19 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. 19 to 65 (inclusive) years old at Visit 1 (Screening) 2. Male, or if female and met all of the following criteria: 1. Not breastfeeding 2. Negative pregnancy test result at Visit 1 (Screening) (not applicable to hysterectomized females) 3. 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 3. Body mass index (BMI) of 25.0 to 35.0 kg/m² (inclusive) at Visit 1 (Screening) 4. Had a physical examination with no clinically significant abnormalities as judged by the investigator 5. Had normal renal function with an estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation 6. Ability to understand and willingness to adhere to protocol requirements
Exclusion criteria
1. Had a clinically significant medical condition as judged by the investigator that could potentially affect study participation and/or personal well-being, including but not limited to the following conditions: 1. Hepatic disease 2. Gastrointestinal disease 3. Endocrine disorder (including diabetes and impaired glucose tolerance) 4. Cardiovascular disease 5. Central nervous system diseases 6. Psychiatric or neurological disorders 7. Organ transplantation 8. Chronic or acute infection 9. Orthostatic hypotension, fainting spells or blackouts 10. 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 major surgery of any kind within 6 months of Visit 1 (Screening) 4. Had a history of \>6 kg weight change within 3 months of Visit 1 (Screening) 5. Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities judged by the investigator to be clinically significant at Visit 1 (Screening) 6. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study 7. 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) 8. Currently 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 9. 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 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. Had received any investigational drug within 2 months (or five half-lives of the investigational drug, whichever was greater) of the date of the first dose of randomized study medication 12. Had known allergies or hypersensitivity to any component of study treatment 13. Was employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-t) of Plasma Metformin | Time points to create AUC (0-t) 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-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration after the standardized dinner. Doses were administered 1 min prior to 0 h (standardized dinner) for once daily in the evening (qPM) and twice daily (BID) dosing and 1 min prior to 12 h (standardized breakfast) for once daily in the morning (qAM) and BID dosing. |
| Cmax of Plasma Metformin | Time points to create 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 concentration from the first dose of study medication administration (0 h) to the time of the last quantifiable concentration following dose administration. Doses were administered 1 min prior to 0 h (standardized dinner) for qPM and BID dosing and 1 min prior to 12 h (standardized breakfast) for qAM and BID dosing. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1: ABDC Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD | 5 |
| Sequence 2: BCAD Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD | 5 |
| Sequence 3: CDBA Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD | 5 |
| Sequence 4: DACB Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD | 5 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence 1: ABDC | Sequence 2: BCAD | Sequence 3: CDBA | Sequence 4: DACB | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 13.6 | 34.8 years STANDARD_DEVIATION 13.1 | 33.8 years STANDARD_DEVIATION 9.2 | 25.8 years STANDARD_DEVIATION 5 | 32.2 years STANDARD_DEVIATION 10.6 |
| Body Mass Index (BMI) | 30.1 kg/m^2 STANDARD_DEVIATION 4 | 29.5 kg/m^2 STANDARD_DEVIATION 2.8 | 28.7 kg/m^2 STANDARD_DEVIATION 2.8 | 30.0 kg/m^2 STANDARD_DEVIATION 1.8 | 29.6 kg/m^2 STANDARD_DEVIATION 2.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 5 Participants | 5 Participants | 3 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 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 | 4 Participants | 3 Participants | 4 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 4 Participants | 1 Participants | 14 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 / 19 | 3 / 19 | 5 / 20 | 10 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 20 | 0 / 20 |
Outcome results
Primary
AUC (0-t) of Plasma Metformin
AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration after the standardized dinner. Doses were administered 1 min prior to 0 h (standardized dinner) for once daily in the evening (qPM) and twice daily (BID) dosing and 1 min prior to 12 h (standardized breakfast) for once daily in the morning (qAM) and BID dosing.
Time frame: Time points to create AUC (0-t) 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 (MEAN) | Dispersion |
|---|---|---|---|
| 500 mg Met DR BID | AUC (0-t) of Plasma Metformin | 6164 ng*h/mL | Standard Error 465 |
| 1000 mg Met DR BID | AUC (0-t) of Plasma Metformin | 9014 ng*h/mL | Standard Error 610 |
| 1000 mg Met IR BID | AUC (0-t) of Plasma Metformin | 18709 ng*h/mL | Standard Error 1044 |
| 2000 mg Met XR QD | AUC (0-t) of Plasma Metformin | 16989 ng*h/mL | Standard Error 968 |
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of least squares (LS) means and the comparator for the p-values.p-value: <0.00190% CI: [32.27, 38.74]ANOVA
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [47.77, 57.36]ANOVA
Comparison: 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [29.3, 35.18]ANOVA
Comparison: 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [43.38, 52.09]ANOVA
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.083290% CI: [100.5, 120.68]ANOVA
Primary
Cmax of Plasma Metformin
Cmax = Maximum concentration from the first dose of study medication administration (0 h) to the time of the last quantifiable concentration following dose administration. Doses were administered 1 min prior to 0 h (standardized dinner) for qPM and BID dosing and 1 min prior to 12 h (standardized breakfast) for qAM and BID dosing.
Time frame: Time points to create 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 (MEAN) | Dispersion |
|---|---|---|---|
| 500 mg Met DR BID | Cmax of Plasma Metformin | 607 ng/mL | Standard Error 33 |
| 1000 mg Met DR BID | Cmax of Plasma Metformin | 905 ng/mL | Standard Error 56 |
| 1000 mg Met IR BID | Cmax of Plasma Metformin | 1328 ng/mL | Standard Error 63 |
| 2000 mg Met XR QD | Cmax of Plasma Metformin | 1688 ng/mL | Standard Error 97 |
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [32.43, 39.77]ANOVA
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [47.88, 58.71]ANOVA
Comparison: 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [40.88, 50.13]ANOVA
Comparison: 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: <0.00190% CI: [60.34, 74]ANOVA
Comparison: 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.000490% CI: [71.65, 87.86]ANOVA