Safety, Tolerability and Preliminary Efficacy of Sublingual Liraglutide in Patients With Type 2 Diabetes Mellitus

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.
• •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.