Type 2 Diabetes Mellitus (T2DM)

Primary objective: • To evaluate the effect of multiple orally-administered doses of TTP273 tablets on glycosylated hemoglobin (HbA1c) after 12 weeks of treatment in adult patients with T2DM Secondary objectives: • To evaluate the safety and tolerability of TTP273 administered for 12 weeks in adult patients with T2DM • To evaluate the effect of TT273 administered for 12 weeks on the pharmacodynamics (PD) markers • To characterize the PK profile of TTP273 administered in adult patients with T2DM

TTP273 Table

TTP273 Table

Table

75mg/Table

Primary endpoint:
• Changes in glycated hemoglobin (HbA1c) from baseline (day 1) to Week 12 of Treatmen

Secondary endpoints:
Safety:
• Number of treatment-emergent adverse events (TEAEs) recorded from baseline to Week 14
• Number of confirmed hypoglycemic episodes recorded from baseline to Week 14
• Change in vital signs (temperature, pulse, systolic- and diastolic blood pressure from baselineto Week 12
• Change in electrocardiogram (ECG) from baseline to Week 12
• Change in physical examination from baseline to Week 12
• Change in laboratory safety variables (hematology, biochemistry, hormones, and urinalysis) from baseline to Week 12

Pharmacodynamics
• Change in glycated albumin (GA), fasting plasma glucose (FPG), C-peptide,
fasting insulin, and glucagon from baseline to Week 12
• Change in insulin resistance (homeostasis model assessment index of insulin resistance,
HOMA-IR) and beta-cell function (homeostasis model assessment index of beta-cell function,
HOMA-β) from baseline to week 12
• Change in fasting lipids (total cholesterol, low-density lipoprotein (LDL), high-density
lipoprotein (HDL), non-high-density lipoprotein (Non-HDL), very low-density lipoprotein
(VLDL), triglycerides, and free fatty acids) from baseline to week 12
• Change in body weight from baseline to Week 12
• Change in waist circumference from baseline to Week 12
• Change in body mass index (BMI) from baseline to week 12

Pharmacokinetics:
• AUC 0-24h: Area under the concentration-time curve from time 0 to 24 hours
• C max: Peak concentration
• T max: Time to maximum plasma concentration
• AUC [0-t, ss]: Area under the concentration-time curve from time 0 to the end of the first dosing
interval tau, where tau=24 h for QPM dose administration and tau=10 h for BID dose administration
• AUC 0-last: The area under the plasma concentration versus time curve from time 0 to the last measurable dose
• Apparent clearance CL/F
• Trough plasma concentration (Day 14, Weeks 4, 8, 12)
• TTP273’s metabolites

inclusion criteria
Subjects must meet all the following inclusion criteria to be eligible for enrollment into this study.
1. Aged 18 to 75 years, inclusive, at the time of screening.
2. Male subjects or female subjects of non-childbearing potential (sterile and/or
postmenopausal). Male subjects, as well as their sexual partners, agree to take medical
accept reliable contraceptive methods (bilateral vasectomy, total abstinence, and in the
case of the use of intrauterine contraceptive device at the same time the use of condoms
and/or contraceptive tools such as vaginal septum) during the study and 1 month after final
administration. Sterile women are defined as receiving bilateral tubal ligation, or bilateral
ovariectomy, or total hysterectomy (with medical records). Postmenopausal female is
defined as menopausal cessation for more than 12 months without alternative medical
treatment and follicle stimulating hormone (FSH) values are within the menopausal range.
3. Body Mass Index (BMI) between 20 and 40 kg/m2, inclusive, and weight ≥ 45 kg.
4. Subjects diagnosed with T2DM treated with diet and exercise (drug naïve subjects) and/or
who have been on a stable dose of metformin (at least 1000 mg/day) for at least 60 days
prior to screening. No anti-diabetic history as drug naïve subjects (in 6 months prior to
screening, anti-diabetic treatment shall be less than 2 weeks).
5. Have an HbA1c value of 7.5% to 10.5%, inclusive, obtained at Screening from a Central
Lab within 10 days prior to Baseline/Randomization.
6. At screening, have a fasting plasma glucose (FPG) between 7.0 mmol/L (126 mg/dL) and
13.9 mmol/L (250 mg/dL), inclusive; C-peptide concentration ≥ 0.8 ng/mL.
7. Generally stable health without a history of major surgery or significant injuries within the
last year and without an active infection. Any chronic diseases shall be stable, i.e. unlikely
to show significant worsening, or require multiple medication changes, hospitalization, or
intensive monitoring during the trial.
8. The subject can give informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Subjects presenting with any of the following will not be included in the study:
1. Diagnosis of Type 1 diabetes mellitus, maturity-onset diabetes of the young, pancreatic surgery, insulin-requiring T2DM, other unusual or rare forms of diabetes mellitus, or history of diabetic ketoacidosis within 1 year to Screening.
2. Have a history of hypoglycemic episode requiring IV glucose, IM glucagon, or oral carbohydrates (e.g. juice) administered by someone other than the subject within 6 months prior to screening.
3. All diabetic agents except metformin are prohibited within 2 months prior to Screening
until the follow-up visit. Examples include, but are not limited to insulin, alpha-glucosidase inhibitor (such as acarbose), thiazolidinediones, GLP-1 analogues, dipeptidyl-peptidase-4 inhibitors, bromocriptine, and sulfonylureas other than metformin.
4. The use of other medications or supplements known to affect glucose metabolism are prohibited within 2 months prior to Screening. Subjects who are expected to use or require these agents during the study are also excluded. Examples of such agents include, but are not limited to:
a) Antipsychotic medication including olanzapine, risperidone, clozapine, quetiapine, and haloperidol.
b)Traditional Chinese herbal medications.
c)Weight loss pill, appetite suppressant, or “metabolism booster” supplements.
d)Chronic use of corticosteroids (e.g. prednisone, dexamethasone, methylprednisolone, or hydrocortisone) at any dose. However:
i. Short course (≤ 7 days) of oral and parenteral corticosteroids (e.g. for allergic signs
or symptoms or intraarticular injections of steroids up to once every 6 months
are allowed, except within 14 days of the last visit).
ii. Inhaled, intranasal and topical corticosteroids are permitted.
5. Previous surgical treatment of obesity or any clinically significant condition possibly
affecting drug absorption (e.g., severe gastroparesis, gastric bypass, gastrectomy, intestinal
resection, active inflammatory bowel disease, or pancreatic insufficiency).
6. Participation in any formal weight loss program, or fluctuation of > 5% in body weight,
within 3 months prior to screening; or having received medications approved for weight
loss within 3 months prior to screening or contemplating such therapy during the trial.
7. Within 6 months prior to screening, suffer an uncontrolled serious cardiocerebrovascular
disease, include but are not limited to: myocardial infarction, unstable angina, coronary
revascularization, stroke, or transient ischemic attack, heart failure (NYHA Functional Classes ≥ 2).
8. Persistent, uncontrolled hypertension at screening, defined as sitting systolic blood
pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg after at
least 5 minutes rest if confirmed by up to 3 repeat assessments on the same or another screen day.
9. A screening 12-lead ECG demonstrating QTcF interval >450 msec for males or >470 msec
for females, if confirmed by a single repeat during the screening period OR the average
QTcF intervals from the three ECGs performed at baseline exceeds the above values and
no single value > 500 msec. This exclusion does not apply to subjects with bundle branch
block or those whose ECG indicates the presence of a pacemaker.
10. A family or personal history of long QT syndrome; History or presence of second degree
or greater atrioventricular block in the absence of a pacemaker.
11. Within 1 year prior to Screening, uncontrolled chronic respiratory diseases, include but are
not limit to: COPD, Severe asthma, severe pneumonia, active tuberculosis.
12. History of pancreatitis or at high risk for acute pancreatitis (for example, with known
history of biliary gallstone[s], or with very high triglyceride level [> 500 mg/dL]) at Screening.
13. Within 1 year prior to Screening, uncontrolled severe digestive system diseases, include
but are not limit to: inflammatory bower disease, peptic ulcer with complications such as
bleeding, perforation, or obstruction; Hemorrhagic colitis and severe biliary tract infection.
14. Presence of active viral hepatitis or any form of cirrhosis, confirmed Alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5X ULN; total bilirubin (TBIL) >1.5X ULN.
15. Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
per Modification of Diet in Renal Disease (MDRD) formula.
16. History of multiple endocrine neoplasia syndrome type 2 (MEN-2) or family history of medullary thyroid cancer.
17. Mental or legal incapacitation.
18. Diagnosis of malignant neoplasm within 5 years prior to screening (except basal cell skin
cancer or squamous cell skin cancer).
19. Current alcoholism or a history of excessive alcohol consumption within 2 years prior to
screening. Excessive alcohol consumption is defined as usual weekly alcohol intake in
excess of 1,050 mL of wine or 2,520 mL of beer or 315 mL of hard liquor for females; or
weekly intake in excess of 2,100 mL of wine or 5,040 mL of beer or 630 mL of hard liquor for males
20. History of drug abuse within 5 years prior to screening or a positive pre-study drug screen,
unless findings are consistent with documented prescribed medications.
21. Known or suspected hypersensitivity to investigational product(s), having a clear history
of drug allergy, especially those who have a history of drug allergy similar to the structure
of the drug in this study, and those who have allergic diseases.
22. Positive pregnancy test; Breastfeeding; Subjects have a parenthood plan from screening to 6 months post last dosing.
23. Participation in a clinical trial and receipt of an investigational product within 30 days
prior to screening or 5 half-lives of the product (whichever is longer) or in the follow-up period.
24. Unwilling or unable to follow the procedures outlined in the protocol.
25. Any other reason that in the opinion of the investigator or licensed physician designee, makes the study participant unsuitable to participate in this clinical trial.