Renal Insufficiency
Conditions
Brief summary
This study evaluated how a single dose of delayed-release metformin (Met DR) behaves in subjects with normal kidney function, mild kidney dysfunction, moderate kidney dysfunction, or severe kidney dysfunction. The safety and tolerability of Met DR was also examined. In addition, this study compared the behavior of a single dose of Met DR with that of extended-release metformin (Met XR) and placebo in subjects with the varying levels of kidney function described above.
Interventions
Sponsors
Elcelyx Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
1. 18 to 80 (inclusive) years old at Visit 1 (Screening) 2. Male, or female and met all of the following criteria: * Not breastfeeding * Negative pregnancy test result at Visit 1 (Screening) (not applicable to postmenopausal or surgically sterile 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 * Body weight of ≥45 kg 3. Body mass index (BMI) of 18.0 to 40.0 kg/m² (inclusive) at Visit 1 (Screening) 4. Had type 2 diabetes mellitus and an HbA1c ≤10.0% 5. Had a physical examination with no clinically significant abnormalities as judged by the investigator 6. Estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation 7. Ability to understand and willingness to adhere to protocol requirements
Exclusion criteria
1. Had End Stage Renal Disease requiring dialysis or severe renal dysfunction with eGFR \<15 mL/min/1.73 m² 2. Was on dialysis or had been on dialysis within 12 months of Visit 1 (Screening) 3. Had received or planned to receive any iodinated contrast dye within 1 week prior to Visit 1 (Screening) or after study medication administration 4. Was taking or had taken within 1 week of Visit 1 cationic drugs that are eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) 5. 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 * Gastrointestinal disease * Endocrine disorder (type 2 diabetes mellitus was allowed) * 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 6. Had any chronic disease requiring medication that had been adjusted in the past 14 days (subjects could take acute intermittent over-the-counter medications such as Tylenol, if needed) 7. Had major surgery of any kind within 6 months of Visit 1 (Screening) 8. Had a clinically significant finding of an electrocardiogram (ECG) as assessed by the investigator at Visit 1 (Screening) 9. Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities, other than those related to diabetes or renal disease and other stable diseases, judged by the investigator to be clinically significant at Visit 1 (Screening) 10. Had a hemoglobin result \<8 g/dL or a level indicating severe anemia of renal origin 11. Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study 12. Had received Byetta® or short-acting insulin within 3 days of Visit 1 (Screening) 13. Had received metformin within 4 weeks of Visit 1 (Screening) 14. Had any drug treatment that affects gastrointestinal motility or gastric pH (prescription or over-the-counter), including any antacids or medications such as Rolaids or Pepcid, within 2 days of Visit 2 15. 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 16. Smoked more than 10 cigarettes, 3 cigars, or 3 pipes per day 17. Had donated blood within 2 months of Visit 1 (Screening) or was planning to donate blood during the study 18. Had received any investigational drug within one month (or seven half-lives of the investigational drug, whichever was greater) of Visit 1 (Screening) 19. Had known allergies or hypersensitivity to any component of study treatment 20. 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 | from the time of dosing (0 h) to 72 hours postdose | AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration following dose administration |
| Cmax of Plasma Metformin | from the time of dosing (0 h) to 72 hours postdose | Cmax = Maximum concentration from the time of dosing (0 h) to the time of the last quantifiable metformin concentration following dose administration |
| Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration | from the time of dosing (0 h) to 24 hours postdose | To determine the exposure-response relationship of metformin and plasma lactate concentrations |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Normal Normal Renal Function = eGFR ≥90 mL/min/1.73 m² | 8 |
| Mild RI Mild Renal Impairment = eGFR ≥60 to \<90 mL/min/1.73 m² | 11 |
| Moderate RI Moderate Renal Impairment = eGFR ≥30 to \<60 mL/min/1.73 m² | 12 |
| Severe RI Severe Renal Impairment = eGFR ≥15 to \<30 mL/min/1.73 m² | 8 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Mild RI | Moderate RI | Severe RI | Normal | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 6.62 | 72.6 years STANDARD_DEVIATION 3.9 | 70.5 years STANDARD_DEVIATION 5.5 | 54.5 years STANDARD_DEVIATION 11.01 | 65.1 years STANDARD_DEVIATION 9.83 |
| BMI | 31.8 kg/m² STANDARD_DEVIATION 3.79 | 30.4 kg/m² STANDARD_DEVIATION 3.33 | 33.3 kg/m² STANDARD_DEVIATION 4.09 | 32.8 kg/m² STANDARD_DEVIATION 3.81 | 31.9 kg/m² STANDARD_DEVIATION 3.75 |
| Body Weight | 94.9 kg STANDARD_DEVIATION 12.06 | 94.2 kg STANDARD_DEVIATION 14.96 | 99.8 kg STANDARD_DEVIATION 10.69 | 94.9 kg STANDARD_DEVIATION 18.02 | 95.7 kg STANDARD_DEVIATION 13.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 8 Participants | 8 Participants | 36 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 4 Participants | 1 Participants | 12 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 10 Participants | 3 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 7 Participants | 6 Participants | 32 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 | 4 / 36 | 12 / 38 | 11 / 37 |
| serious Total, serious adverse events | 0 / 36 | 0 / 38 | 0 / 37 |
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 following dose administration
Time frame: from the time of dosing (0 h) to 72 hours postdose
Population: PK Evaluable Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Met DR | AUC (0-t) of Plasma Metformin | Normal (N = 8) | 5362 ng*h/mL | Standard Error 943 |
| Met DR | AUC (0-t) of Plasma Metformin | Mild RI (N = 10) | 8705 ng*h/mL | Standard Error 1368 |
| Met DR | AUC (0-t) of Plasma Metformin | Moderate RI (N = 9) | 11477 ng*h/mL | Standard Error 1915 |
| Met DR | AUC (0-t) of Plasma Metformin | Severe RI (N = 7) | 22893 ng*h/mL | Standard Error 4307 |
| Met XR | AUC (0-t) of Plasma Metformin | Severe RI (N = 7) | 43683 ng*h/mL | Standard Error 8218 |
| Met XR | AUC (0-t) of Plasma Metformin | Normal (N = 8) | 10411 ng*h/mL | Standard Error 1831 |
| Met XR | AUC (0-t) of Plasma Metformin | Moderate RI (N = 9) | 20240 ng*h/mL | Standard Error 3377 |
| Met XR | AUC (0-t) of Plasma Metformin | Mild RI (N = 10) | 11788 ng*h/mL | Standard Error 1853 |
Comparison: For the Normal Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.001190% CI: [37.77, 70.23]ANOVA
Comparison: For the Mild RI Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.073390% CI: [55.97, 97.43]ANOVA
Comparison: For the Moderate RI Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.002890% CI: [42.25, 76.1]ANOVA
Comparison: For the Severe RI Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.002590% CI: [37.61, 73.02]ANOVA
Primary
Cmax of Plasma Metformin
Cmax = Maximum concentration from the time of dosing (0 h) to the time of the last quantifiable metformin concentration following dose administration
Time frame: from the time of dosing (0 h) to 72 hours postdose
Population: PK Evaluable Population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Met DR | Cmax of Plasma Metformin | Normal (N = 8) | 969 ng/mL | Standard Error 153 |
| Met DR | Cmax of Plasma Metformin | Mild RI (N = 10) | 1036 ng/mL | Standard Error 147 |
| Met DR | Cmax of Plasma Metformin | Moderate RI (N = 9) | 925 ng/mL | Standard Error 139 |
| Met DR | Cmax of Plasma Metformin | Severe RI (N = 7) | 1414 ng/mL | Standard Error 239 |
| Met XR | Cmax of Plasma Metformin | Severe RI (N = 7) | 2590 ng/mL | Standard Error 438 |
| Met XR | Cmax of Plasma Metformin | Normal (N = 8) | 1479 ng/mL | Standard Error 234 |
| Met XR | Cmax of Plasma Metformin | Moderate RI (N = 9) | 1634 ng/mL | Standard Error 245 |
| Met XR | Cmax of Plasma Metformin | Mild RI (N = 10) | 1340 ng/mL | Standard Error 189 |
Comparison: For the Normal Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.047490% CI: [46.32, 92.68]ANOVA
Comparison: For the Mild RI Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.169190% CI: [56.72, 105.41]ANOVA
Comparison: For the Moderate RI Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.006490% CI: [40.73, 78.63]ANOVA
Comparison: For the Severe RI Renal Function Cohort. Met XR is the denominator for the % ratio of LS means and the comparator for the p-values.p-value: 0.009790% CI: [37.68, 79.11]ANOVA
Primary
Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration
To determine the exposure-response relationship of metformin and plasma lactate concentrations
Time frame: from the time of dosing (0 h) to 24 hours postdose
Population: PD Evaluable Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Met DR | Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration | 0.000011129 R² |
| Met XR | Correlation of Placebo-adjusted Change From Pre-dose Value in Lactate Versus Metformin Concentration | 0.069527 R² |
p-value: 0.9444Pearson Correlation
p-value: <0.0001Pearson Correlation