A Phase 1b, Double-Blind, Placebo-Controlled, Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability, PK and PD of DA-1241 in Healthy Male Subjects and Subjects With T2DM
Overview
- Phase
- Phase 1
- Intervention
- DA-1241
- Conditions
- Diabetes Mellitus, Type 2
- Sponsor
- Dong-A ST Co., Ltd.
- Enrollment
- 108
- Locations
- 4
- Primary Endpoint
- Heart rate
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy male subjects
- •Age ≥ 18 to ≤ 70 years of age.
- •Body mass index (BMI) ≥ 18.5 to ≤ 29.9 kg/m
- •Non-diabetic, fasting plasma glucose (FPG) of \< 100 mg/dL (measured with YSI at site; one repeat test is allowed)
- •HbA1c \< 5.7 %
- •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.
- •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.
- •Upon review, agree to participate and sign informed consent
Exclusion Criteria
- •Resting blood pressure (BP) \> 140/90 mmHg or \< 90/60 mmHg. Subjects BP may be re-checked.
- •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.
- •History of any serious adverse reaction or hypersensitivity to any of the investigational product components or medicinal products with similar chemical structure.
- •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.
- •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.
- •Subject shows evidence of significant active neuropsychiatric disease, including taking prescription medication for such diseases (including anti-depressant /anti-anxiety medication),
- •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)
- •Long QT syndrome or family history of long QT syndrome or corrected QT interval (QTcF) \> 450 ms at screening.
- •Liver function test results of AST and/or ALT ≥ 1.5 upper limit of normal (ULN).
- •Subject had a history of vaso-vagal syncope within 5 years.
Arms & Interventions
[Part1] DA-1241 : 6 subjects in each cohort(Cohort 1-3)
Subjects will participate in 1 of 3 cohorts consisting of 8 subjects per cohort. Within cohorts, subjects will be randomized to a ratio of 6:2 (DA-1241 to matching placebo).
Intervention: DA-1241
[Part1] Placebo : 2 subjects in each cohort(Cohort 1-3)
Subjects will participate in 1 of 3 cohorts consisting of 8 subjects per cohort. Within cohorts, subjects will be randomized to a ratio of 6:2 (DA-1241 to matching placebo).
Intervention: Placebo
[Part2] DA-1241 : 15 subjects in each cohort(Cohort 4-6)
Subjects will participate in 1 of 3 cohorts consisting of 25 subjects per cohort. Within cohorts, subjects will be randomized to a ratio of 3:1:1 (DA-1241 to matching placebo and active comparator).
Intervention: DA-1241
[Part2] Placebo : 5 subjects in each cohort(Cohort 4-6)
Subjects will participate in 1 of 3 cohorts consisting of 25 subjects per cohort. Within cohorts, subjects will be randomized to a ratio of 3:1:1 (DA-1241 to matching placebo and active comparator).
Intervention: Placebo
[Part2] Sitagliptin : 5 subjects in each cohort(Cohort 4-6)
Subjects will participate in 1 of 3 cohorts consisting of 25 subjects per cohort. Within cohorts, subjects will be randomized to a ratio of 3:1:1 (DA-1241 to matching placebo and active comparator).
Intervention: Sitagliptin
Outcomes
Primary Outcomes
Heart rate
Time Frame: 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
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Change from baseline in oral body temperature (°C)
Physical examination
Time Frame: 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
Blood pressure
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Change from baseline in blood pressure (mmHg)
12-lead ECGs
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Change from baseline in QTcF (msec)
Respiratory rate
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Change from baseline in respiratory rate (bpm)
Clinical laboratory testing
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Incidence and severity of clinical laboratory abnormality
Adverse event
Time Frame: Throughout study duration, i.e., about 10 weeks (Part1) and about 14-16 weeks (Part2), respectively
Incidence and severity of adverse event
Secondary Outcomes
- Fasting Insulin(Through the treatment period; 56 days)
- Percentage fraction of DA-1241 excreted unchanged in the urine in each collection interval(Fe)(Through the treatment period; 7 days)
- Incremental AUEs after meal (iAUE)(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)
- 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)
- Renal clearance (CLR)(Through the treatment period; 7 days)
- 2h-Postprandial glucose(Through the treatment period; 56 days)
- Cumulative percentage fraction of DA-1241 excreted unchanged in the urine (Cum Fe)(Through the treatment period; 7 days)
- Area under the measurements versus (vs) time curve(AUE)(Through the treatment period; 56 days)
- Weighted mean glucose (WMG)(Through the treatment period; 56 days)
- Glycated albumin(Through the treatment period; 56 days)
- HbA1c(Through the treatment period; 56 days)
- Fasting Plasma Glucose (FPG)(Through the treatment period; 62 days)
- Incremental WMG (iWMG)(Through the treatment period; 56 days)