Diabetes Mellitus, Type 2
Conditions
Keywords
DBPR108, DPP4, Diabetes, GLP-1, Incretins
Brief summary
The study is being performed to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of single oral doses of DBPR108 in healthy male subjects.
Detailed description
This study represents the first administration of dipeptidyl peptidase 4 (DPP4) inhibitor DBPR108 to humans to evaluate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties following single oral doses in healthy subjects. DPP4 is a validated drug target for the treatment of human type 2 diabetes. Objectives of the study will be to characterize the safety and tolerability of single doses of DBPR108; to characterize the single dose PK of DBPR108 in plasma and urine; to characterize the single dose PD of DBPR108 on glucose, glucagon, dipeptidyl peptidase 4 activity, and total and active forms of glucagon-like peptide-1 (GLP-1) in plasma levels and insulin and C-peptide in serum levels.
Interventions
DRUGDBPR108
DBPR108 capsules in four doses beginning at 25 mg and rising to 600 mg.
DRUGmatching placebo
Matching placebo capsules in four doses beginning at 25 mg and rising to 600 mg.
Sponsors
National Health Research Institutes, Taiwan
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Male with suitable veins for cannulation or repeated venipuncture, and must be able to swallow the study drug intact; * Aged between 20 and 45 years (inclusive) at the screening visit; and * Able to provide written informed consent and willing to comply with the study protocol procedures and restrictions.
Exclusion criteria
* Has a body weight less than 50 kg and/or body mass index (BMI) less than 18 kg/m2 or greater than 30 kg/m2 at the screening visit; * Has a creatinine clearance (Ccr) less than 80 mL/min at screening; * Is not in good general health as judged by the Investigator based on routine medical history, vital signs, physical examination, ECG, laboratory tests, and urinalysis at the screening visit or at admission for the residential period; * Is not normoglycemic defined as fasting glucose at less than 70 mg/dL (3.9 mmol/L) and greater than 100 mg/dL (5.5 mmol/L); * Has a platelet count less than 150,000/µL; * Uses any antihyperglycemic agents at screening or at admission for the residential period; * Has a history or presence of any disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs at the screening visit or at admission for the residential period; * Has a clinically significant psychiatric, renal, hepatic, cardiovascular, gastrointestinal, or neurologic disease at screening or at admission for the residential period; * Is a smoker and/or has used nicotine-containing products within the last 6 months prior to the screening for the current study and/or has a history of alcohol abuse; * Has donated blood or participated in another clinical study within 8 weeks preceding the day of admission; * Excessive intake of caffeine-containing drinks or food (ie, coffee, tea, chocolate, PAOLYTA B Liq, WHISBIH Liq, or cola \[more than 6 units of caffeine per day\]); * Use of drugs with enzyme-inducing properties such as St. John's Wort within 4 weeks prior to the first administration of investigational product; * Has used prescription or nonprescription medication (except for occasional use of paracetamol or nasal spray) or herbal remedies or vitamins or minerals within 2 weeks or 5 half-lives of the drug, whichever is longer, prior to dosing until end of study; * Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of investigational product; * Male subjects who are unwilling to use barrier contraception in addition to having their partner use another method of contraception, for the duration of the study and for 3 months after dosing; * Has a positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCVAb), or human immunodeficiency virus (HIV); * Has received a blood transfusion and/or has HCV infection; * Positive result on screening for drugs of abuse, alcohol, or cotinine (nicotine) at screening or admission; or * Involved in the planning or conduct of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Adverse events were collected from Day -1 (baseline) through the end of the study, up to Day 7. | There were 4 mild adverse events observed during the course of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity) | predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose | Plasma samples were used to determine the AUC from time 0 to infinity for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups. |
| Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax) | predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose | Plasma samples were used to determine the Cmax for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups. |
| Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax) | predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose | Plasma samples were used to determine the Time of Maximum Plasma Concentration for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups. |
| Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | predose (0 hr) and 48 hrs post dose | Change of plasma DPP4 activity at 48 hrs post dose from predose (0 hr). The values were computed as areas under the DPP4 activity-time curve using ANCOVA model, in which the unit of the activity is pmol/min. |
Countries
Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received either a single oral dose of matching placebo to DBPR108 25 mg, 100 mg, 300 mg, or 600 mg | 8 |
| DBPR108 25 mg Participants received a single oral dose of DBPR108 25 mg | 6 |
| DBPR108 100 mg Participants received a single oral dose of DBPR108 100 mg | 6 |
| DBPR108 300 mg Participants received a single oral dose of DBPR108 300 mg | 6 |
| DBPR108 600 mg Participants received a single oral dose of DBPR108 600 mg | 6 |
| Total | 32 |
Baseline characteristics
| Characteristic | Placebo | DBPR108 25 mg | DBPR108 100 mg | DBPR108 300 mg | DBPR108 600 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 31 years STANDARD_DEVIATION 8 | 26 years STANDARD_DEVIATION 2 | 24 years STANDARD_DEVIATION 2 | 27 years STANDARD_DEVIATION 5 | 26 years STANDARD_DEVIATION 6 | 27 years STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 32 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 | 0 / 8 | 0 / 6 | 0 / 6 | 1 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
There were 4 mild adverse events observed during the course of study.
Time frame: Adverse events were collected from Day -1 (baseline) through the end of the study, up to Day 7.
Population: All enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 0 participants |
| DBPR108 25 mg | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 0 participants |
| DBPR108 100 mg | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 0 participants |
| DBPR108 300 mg | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 1 participants |
| DBPR108 600 mg | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 2 participants |
Secondary
Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose
Change of plasma DPP4 activity at 48 hrs post dose from predose (0 hr). The values were computed as areas under the DPP4 activity-time curve using ANCOVA model, in which the unit of the activity is pmol/min.
Time frame: predose (0 hr) and 48 hrs post dose
Population: All enrolled participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | -114 h*pmol/min | Standard Deviation 371 |
| DBPR108 25 mg | Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | -925 h*pmol/min | Standard Deviation 464 |
| DBPR108 100 mg | Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | -1510 h*pmol/min | Standard Deviation 556 |
| DBPR108 300 mg | Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | -2170 h*pmol/min | Standard Deviation 458 |
| DBPR108 600 mg | Change of Dipeptidyl Peptidase 4 (DPP4) Activities Between 48 Hrs Post Dose and 0 hr Predose | -2350 h*pmol/min | Standard Deviation 671 |
Secondary
Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity)
Plasma samples were used to determine the AUC from time 0 to infinity for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups.
Time frame: predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose
Population: All participants who received a single dose of DBPR108 25 mg, 100 mg, 300 mg, or 600 mg.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity) | 236 ng*h/mL | Standard Deviation 66.9 |
| DBPR108 25 mg | Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity) | 1310 ng*h/mL | Standard Deviation 290 |
| DBPR108 100 mg | Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity) | 3910 ng*h/mL | Standard Deviation 1200 |
| DBPR108 300 mg | Profile of Pharmacokinetics - Area Under the Plasma Concentration-Time Curve (AUC From 0 to Infinity) | 10500 ng*h/mL | Standard Deviation 2400 |
Secondary
Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax)
Plasma samples were used to determine the Cmax for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups.
Time frame: predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose
Population: All participants who received a single dose of DBPR108 25 mg, 100 mg, 300 mg, or 600 mg.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax) | 47.2 ng/mL | Standard Deviation 23.8 |
| DBPR108 25 mg | Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax) | 187 ng/mL | Standard Deviation 33.3 |
| DBPR108 100 mg | Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax) | 571 ng/mL | Standard Deviation 158 |
| DBPR108 300 mg | Profile of Pharmacokinetics - Observed Maximum Plasma Concentration (Cmax) | 1370 ng/mL | Standard Deviation 235 |
Secondary
Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax)
Plasma samples were used to determine the Time of Maximum Plasma Concentration for DBPR108. The placebo group is not included in the table below; this outcome measure only evaluated the DBPR108 groups.
Time frame: predose (0 hr), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs post dose
Population: All participants who received a single dose of DBPR108 25 mg, 100 mg, 300 mg, or 600 mg.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax) | 1.50 hrs |
| DBPR108 25 mg | Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax) | 4.02 hrs |
| DBPR108 100 mg | Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax) | 4.00 hrs |
| DBPR108 300 mg | Profile of Pharmacokinetics - Time of Maximum Plasma Concentration (Tmax) | 4.01 hrs |