| Eligibility |
<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.
Exclusion Criteria :
1. A subject who has acute proliferative retinopathy or maculopathy, severe
gastroparesis, and/or severe neuropathy, especially autonomic neuropathy, as judged by
the Investigator.
2. Recurrent major hypoglycemia or hypoglycemic unawareness or recent ketoacidosis, as
judged by the Investigator.
3. Persistent blood pressure (BP) systolic or diastolic > 160/90 mmHg or < 90/60 mmHg.
Subjects BP may be re-checked per site SOP. Treatment with stable doses of
antihypertensive medication for 2 months prior to screening are allowed.
4. Pregnant or lactating women.
5. 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.
6. History of any serious adverse reaction or hypersensitivity to any of the
investigational product components or medicinal products with similar chemical
structure.
7. Current use of any prescribed or non-prescribed drugs (other than current treatment
for diabetes mellitus or birth control methods) that are known to interfere with
glucose or insulin metabolism, including but not limited to oral corticosteroids,
GLP-1 receptor agonists, monoamine oxidase (MAO) inhibitors, growth hormone,
non-selective ß-blockers and lipid lowering medication. Lipid lowering medications
will be washed-out prior to the first dosing if subjects take medication for primary
prevention.
8. History of administration or current use of thiazolidinediones (TZDs).
9. Chronic use of acetaminophen, as acetaminophen is not allowed during the CGMS periods
in the study.
10. Unable to tolerate tape adhesive in the area of sensor placement.
11. Subject has any unresolved adverse skin condition in the area of sensor placement (eg,
psoriasis, rash, Staphylococcus infection).
12. History of or acute significant gastrointestinal disorder (eg, peptic ulcers, severe
GERD), gastric surgery, gastric bypass or antrectomy or small bowel resection or any
disorder that would interfere with the swallowing, absorption, distribution,
metabolism and excretion of the investigational product. Surgery for appendicitis is
acceptable.
13. History of renal disease or abnormal kidney function tests at Screening (eGFR < 60
mL/min/1.73m2 as estimated using the MDRD equation).
14. Clinically significant abnormal laboratory test, in particular, elevated liver enzymes
(alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 2 times
the upper limit of normal (ULN)). (Laboratory results may be re-checked once on a
separate day per Investigator discretion)
15. Any history of heart disease, defined as symptomatic heart failure (New York Heart
Association class III or IV), myocardial infarction, coronary artery bypass graft
surgery, or angioplasty, unstable angina requiring medication, transient ischemic
attack, cerebral infarct, or cerebral hemorrhage.
16. History of any clinically or active significant gastrointestinal, cardiovascular,
hematological, psychiatric, renal, hepatic, pancreatic or neurological abnormality
that could interfere with the safety or results of this study as judged by the
Investigator.
17. Subject shows evidence of significant active neuropsychiatric disease. Subjects that
are stable and controlled by stable doses of selective serotonin reuptake inhibitors
(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), antipsychotics and
lithium for = 6 months prior to screening are allowed.
18. Presence of clinically significant physical or ECG findings (eg, QTcF > 450 msec for
males, QTcF > 470 msec for females, left bundle branch block (LBBB)) 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.
19. History of any major surgery within 6 months.
20. History of any active infection, other than mild viral illness within 30 days prior to
the first dosing.
21. 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.
22. Smoking > 10 cigarettes per day or equivalent use of any tobacco product (eg, nicotine
patch) within 6 months prior to Screening. Subjects must be able to refrain from
smoking during each in-house period.
23. History of alcohol abuse as judged by the Investigator within approximately 1 year.
Average weekly alcohol intake > 21 units/week (males) and > 14 units/week (females) or
are unwilling to stop alcohol consumption from 24 hours prior to each check-in for
in-house and outpatient visits and throughout the in-house periods until discharged
from the clinical research unit (CRU) and are unwilling to limit alcohol consumption
during outpatient periods. 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).
24. 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.
25. Donation or loss of > 500 mL of blood within 56 days.
26. 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.
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