Diabetes Mellitus, Type 2
Conditions
Brief summary
This is a double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK and PD of DA-1241 in healthy male subjects and subjects with T2DM
Interventions
DRUGDA-1241
\[Part1\] Administration once daily for 28 days; Dose strength for each cohort (Cohort 1, 2 and 3) is planned as 50mg, 100mg and 200mg, respectively. \[Part2\] Administration once daily for 56 days; Dose strength for each cohort (Cohort 4, 5 and 6) is planned as 25mg, 50mg and 100mg, respectively. (Dose escalation and dose level decisions for subsequent cohorts will be made via interim dose escalation review meetings.)
DRUGPlacebo
\[Part1\] Administration once daily for 28 days. \[Part2\] Administration once daily for 56 days.
DRUGSitagliptin
\[Part2\] Administration of Sitagliptin 100mg once daily for 56 days.
Sponsors
Dong-A ST Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
\<Part 1\> Inclusion Criteria: 1. Healthy male subjects 2. Age ≥ 18 to ≤ 70 years of age. 3. Body mass index (BMI) ≥ 18.5 to ≤ 29.9 kg/m2. 4. Non-diabetic, fasting plasma glucose (FPG) of \< 100 mg/dL (measured with YSI at site; one repeat test is allowed) 5. HbA1c \< 5.7 % 6. Non-smoker smoker, defined as: Non-smoker for \>12 months (ie, subject has not smoked or used any tobacco product for the 12 months prior to the start of the study) confirmed by a negative nicotine/cotinine test. 7. Male subjects must be surgically sterile, or engaged with partners of non-childbearing potential, or if engaged with partners of childbearing potential, the subject and his partner must be willing to use contraceptive methods until 3 months after the last day of IP administration. Males must not donate sperms during the study and until 3 months after the last day of IP administration. 8. Upon review, agree to participate and sign informed consent
Exclusion criteria
1. Resting blood pressure (BP) \> 140/90 mmHg or \< 90/60 mmHg. Subjects BP may be re-checked. 2. Participation in an investigational drug/device study within 30 days or 5 half-lives within the last dose of any study drug, whichever is longer. 3. History of any serious adverse reaction or hypersensitivity to any of the investigational product components or medicinal products with similar chemical structure. 4. Have significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders or abnormalities, or other major systemic disease that, according to the investigator, would unduly risk the subject's safety or may impact the conduct of the study. 5. History of or acute significant gastrointestinal disorder (eg, peptic ulcers, severe GERD), gastric surgery, including surgical treatment for obesity (eg, bariatric surgery, gastric banding), gastric bypass or antrectomy or small bowel resection \>20cm or any disorder that would interfere with the swallowing, absorption, distribution, metabolism and excretion of the investigational product. Surgery for appendicitis is acceptable. 6. Subject shows evidence of significant active neuropsychiatric disease, including taking prescription medication for such diseases (including anti-depressant /anti-anxiety medication), 7. Presence of clinically significant physical, laboratory, or ECG findings at Screening that, in the opinion of the Investigator, may interfere with any aspect of study conduct or interpretation of results, or may present a safety issue to that particular subject. (Laboratory results may be re-checked once on a separate day per Investigator discretion) 8. Long QT syndrome or family history of long QT syndrome or corrected QT interval (QTcF) \> 450 ms at screening. 9. Liver function test results of AST and/or ALT ≥ 1.5 upper limit of normal (ULN). 10. Subject had a history of vaso-vagal syncope within 5 years. 11. History of any major surgery within 6 months. 12. History of any active infection, other than mild viral illness within 30 days prior to dosing. 13. Known history or positive test of hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus type 1 (HIV-1) or 2 (HIV-2) antibody. 14. Subjects with a positive urine nicotine/cotinine dipstick test. 15. History of alcohol abuse as judged by the Investigator within approximately 1 year. Average weekly alcohol intake \> 21 units/week or are unwilling to stop alcohol consumption from 24 hours prior to each dosing until discharged from the clinical research unit (CRU). Positive alcohol test at Screening. (One unit of alcohol equals about 250 mL of beer or lager, 100 mL of wine, or 35 mL of spirits). 16. History of illicit drug abuse, within approximately 1 year or evidence of current use as judged by the Investigator. Positive drug test, including marijuana, at Screening. 17. Donation or loss of \> 500 mL of blood within 56 days. 18. Chronic use of over-the-counter or prescription medication within 7 or 14 days prior to dosing per Investigator's discretion (apart from vitamin/mineral supplements, occasional paracetamol, or birth control methods). 19. Unable to comply with the safety monitoring requirements of this clinical study or is considered by the investigator to be an unsuitable candidate for the study. \<Part 2\> Inclusion Criteria: 1. Male and female subjects with T2DM \> 6 months. 2. Age ≥ 18 to ≤ 70 years of age. 3. Body mass index (BMI) ≤ 35 kg/m2. 4. On stable therapy with metformin monotherapy or metformin in combination with other oral antidiabetic drugs (OADs) ≥ 1 month. (OADs except metformin will be washed-out prior to the first dosing) 5. HbA1c ≥ 6.5 to ≤ 10% 6. Female and male subjects must agree to use highly effective methods of birth control until 120 days after the last day of IP administration, or must be surgically sterile or postmenopausal. Males must not donate sperm during the study and until 120 days after the last day of IP administration. 7. Upon review, agree to participate and sign informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse event | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Incidence and severity of adverse event |
| 12-lead ECGs | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Change from baseline in QTcF (msec) |
| Blood pressure | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Change from baseline in blood pressure (mmHg) |
| Heart rate | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Change from baseline in heart rate (bpm) |
| Body temperature | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Change from baseline in oral body temperature (°C) |
| Respiratory rate | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Change from baseline in respiratory rate (bpm) |
| Physical examination | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Incidence and severity of clinical findings on physical examination |
| Clinical laboratory testing | Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively | Incidence and severity of clinical laboratory abnormality |
Secondary
| Measure | Time frame |
|---|---|
| Amount of DA-1241 excreted unchanged in the urine in each collection interval(Ae) | Through the treatment period; 7 days |
| Cumulative amount of DA-1241 excreted unchanged in the urine (Cum Ae) | Through the treatment period; 7 days |
| Percentage fraction of DA-1241 excreted unchanged in the urine in each collection interval(Fe) | Through the treatment period; 7 days |
| Cumulative percentage fraction of DA-1241 excreted unchanged in the urine (Cum Fe) | Through the treatment period; 7 days |
| Renal clearance (CLR) | Through the treatment period; 7 days |
| Fasting Plasma Glucose (FPG) | Through the treatment period; 62 days |
| 2h-Postprandial glucose | Through the treatment period; 56 days |
| Incremental AUEs after meal (iAUE) | Through the treatment period; 56 days |
| Weighted mean glucose (WMG) | Through the treatment period; 56 days |
| Incremental WMG (iWMG) | Through the treatment period; 56 days |
| Fasting Insulin | Through the treatment period; 56 days |
| Glycated albumin | Through the treatment period; 56 days |
| HbA1c | Through the treatment period; 56 days |
| Area under the measurements versus (vs) time curve(AUE) | Through the treatment period; 56 days |
| Maximum concentration of DA-1241 (Cmax) | Through the treatment period; 24 hours |
| Time of maximum plasma DA-1241 concentration (Tmax) | Through the treatment period; 24 hours |
| Area under the concentration-time curve (AUC) | Through the treatment period; 9 days |
| Apparent terminal elimination half-life (t½) | Through the treatment period; 9 days |
| Apparent total systemic clearance after oral administration (CL/F) | Through the treatment period; 9 days |
| Apparent volume of distribution (Vz/F) | Through the treatment period; 9 days |
| Accumulation ratio (Last dosing day AUCtau / First dosing day AUCtau) | Through the treatment period; 9 days |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessment of key metabolite(s) of DA-1241 | Through the treatment period; 41 days | Key metabolite(s) of DA-1241 will be assessed in blood and urine. |
Countries
United States
Outcome results
None listed