| Eligibility |
Inclusion Criteria:
1. Males and females aged 18-65 years (inclusive)
2. Body mass index (BMI) 18-35 kg/m2, inclusive
3. Normal blood pressure or well managed hypertension (systolic blood pressure <160mmHg,
diastolic blood pressure <100 mmHg)
4. Confirmed diagnosis of T2DM (by repeated laboratory findings) for at least 1 year.
5. Subjects under glycemic control on a stable dose of metformin (within the standard of
care dose range up to 2 g daily) for at least 2 months prior to enrolment or those who
manage their condition only by diet/exercise.
6. For subjects on a stable dose of concomitant metformin for at least 2 months prior to
enrolment, the subject's dose of metformin will be required to remain constant until
at least the completion of MMTT on the final dosing day. Subjects whose concomitant
glucose lowering medication changes during the dosing phase of the study will be
discontinued and may be replaced.
7. For subjects not in receipt of concomitant metformin for at least 2 months prior to
enrolment, and who manage their condition only by diet/exercise, documentation of
stable glycemic control under current condition management for at least 2 months prior
to enrolment, as confirmed by HbA1c. For subjects who meet this criterion, no change
in disease management is permitted until at least the completion of MMTT on the final
dosing day. Any subject who requires a change in disease management, including
initiation of any diabetes medication during the study, will be discontinued from the
study and may be replaced.
8. Fasting plasma glucose =5.6 mmol/L at screening
9. HbA1c =6.5% and =9.0% at screening
10. Vital signs after 10 minutes resting supine:
1. 90 mmHg <systolic blood pressure <160 mmHg
2. 40 mmHg <diastolic blood pressure <100 mmHg
3. 40 bpm <heart rate <100 bpm Duplicate assessments will be performed and the
average of the two assessments of blood pressure will be used.
11. Standard 12-lead ECG parameter results at screening, after 10 minutes resting in
supine position, within 120 ms <PR <220 ms, QRS <120 ms, QTcF =450 ms (males), QTcF
=470 ms (females).
12. No history of significant cardiovascular disease over the preceding 3 years or any
other major disease other than T2DM and well managed hypertension, unless permitted at
the discretion of the PI.
13. Negative test for selected drugs of abuse at screening (does not include alcohol) and
at admission (testing at admission does include alcohol breath test). A positive
result may be verified by re-testing (up to one false positive result permitted) and
may be followed up at the discretion of the PI.
14. Females must be non-pregnant and non-lactating, and either surgically sterile for a
minimum of 6 months (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy,
bilateral oophorectomy), or use highly effective contraceptive method (oral
contraceptives pills, long-acting implantable hormones, injectable hormones, a vaginal
ring or an intrauterine device [IUD]) from screening until study completion, or be
post-menopausal for =12 months. Post-menopausal status will be confirmed through
testing of follicle-stimulating hormone (FSH) levels (= 40 IU/mL) at screening for
amenorrheic female subjects. Females who are abstinent from heterosexual intercourse
will also be eligible.
15. Women of child-bearing potential (WOCBP) must have a negative pregnancy test at
screening and admission and be willing to have additional pregnancy tests as required
throughout the study.
16. Males must be surgically sterile (>30 days since vasectomy with no viable sperm),
abstinent, or if engaged in sexual relations with a WOCBP, the subject and his partner
must be surgically sterile (e.g. tubal occlusion, hysterectomy, bilateral
salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective
contraceptive method from screening until study completion. Acceptable methods of
contraception include the use of condoms and the use of an effective contraceptive for
the female partner (WOCBP), as per Inclusion Criterion #14. Male subjects whose female
partner is post-menopausal, and subjects who are abstinent from heterosexual
intercourse will also be eligible. Male subjects must agree to refrain from donating
sperm from screening until study completion.
Exclusion Criteria:
1. Pregnant or lactating, or intending to become pregnant within 30 days after last dose
of study drug.
2. Participation in a clinical trial within 30 days before enrolment; use of any
experimental oral therapy within 30 days or 5 half-lives prior to enrolment, whichever
is greater; or use of any biologic therapy within 12 weeks or 5 half-lives prior to
enrolment, whichever is greater. Subjects who have received an experimental therapy
that has no half-life, such as a vaccine, should have completed that therapy at least
30 days prior to enrolment.
3. Any vaccine 2 weeks prior to first study drug administration until 2 weeks after the
last dose, with the exception of current seasonal influenza vaccination.
4. Use of any weight loss agent within the preceding 4 weeks.
5. Surgery or hospitalization during the 4 weeks prior to screening.
6. Planned procedure or surgery during the study.
7. Blood transfusion within 8 weeks prior to screening.
8. Donation or loss of blood (excluding the volume of blood that will be drawn during
screening procedures) as follows: = 300 mL of blood within 30 days prior to study drug
administration.
9. Poor peripheral venous access.
10. Alcohol and/or substance abuse or dependence within the past 2 years.
11. Within the last 2 years, unstable or clinically significant cardiovascular disease
(e.g. myocardial infarction, angina pectoris, New York Heart Association Class II or
more cardiac failure).
12. History of pancreatitis
13. History or presence of an abnormal ECG that is clinically significant in the PI's
opinion and/or evidence of prior myocardial infarction within 2 years before
screening.
14. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such
as structural heart disease, coronary heart disease (symptomatic or with ischemia
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities
(e.g. hypokalemia, hypomagnesemia, hypocalcaemia), or family history of sudden
unexplained death or long QT syndrome.
15. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) = 2 x or total bilirubin = 1.5 x the upper limit of
normal (ULN), which remains above these limits if retested due to a slightly elevated
initial result or abnormalities in synthetic function tests that are judged by the PI
to be clinically significant.
16. Unstable hypo- or hyperthyroidism.
17. Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia
syndrome Type 2.
18. Current or history of bulimia or anorexia nervosa.
19. History of severe allergy (requiring hospital care), severe reaction to any drug, or
any known or suspected allergies or sensitivities to the study drug constituents.
20. Diagnosis with Type 1 Diabetes Mellitus (T1DM) or any previous episodes of diabetic
ketoacidosis.
21. History of or ongoing inflammatory bowel disease or diabetic gastroparesis.
22. Severe hypoglycaemia resulting in seizure/unconsciousness/coma/hospitalization in the
last 3 months before screening.
23. Persistent hyperglycaemia not controlled by metformin/diet/exercise.
24. Proliferative retinopathy, nephropathy or renal impairment (<60 mL/min as calculated
by the CKD-EPI equation) if deemed clinically significant by the PI.
25. Any other serious medical condition, or abnormality in clinical laboratory tests, that
would preclude the subject's safe participation in and completion of the study or
increase the expected risk of exposure to the investigational product (IP) or would be
expected to interfere with the planned evaluations, in the judgment of the PI.
26. Use of diabetes medication other than metformin at screening and between screening and
Day 1 assessments.
27. Any medication during the treatment period and within 14 days before first dosing
unless permitted by the inclusion criteria or permitted at the discretion of the PI
and when the intake is unlikely to interfere with insulin/glucose control.
28. Use of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 [GLP-1] agonists,
sodium glucose transporter 2 inhibitors, insulin, thiazolenindiones, acarbose in the 3
months prior to study enrolment will not be permitted.
29. Unwilling or unable to follow protocol requirements.
|
