Add Glucokinase Activator to Target A1c

Study Overview
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Brief Summary
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This trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, Phase 2 study in subjects with T2DM to evaluate the effect of TTP399 on HbA1c following administration for 6 months.

Official Title
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A Multi-Center, Adaptive Phase 2, Randomized, Double-Blind, Placebo- and Active-Controlled (Sitagliptin), Parallel Group Study to Evaluate the Safety and Efficacy of TTP399 Following 6 Months Administration in Subjects With Type 2 Diabetes Mellitus on A Stable Dose of Metformin

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: TTP399 400 mg
* Drug: TTP399 800 mg
* Drug: Sitagliptin 100 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A historical diagnosis of Type 2 Diabetes in accordance with the American Diabetes Association (ADA) guidelines, with diagnosis at least 6 months prior to Screening. On a stable (for the last 3 months prior to screening) regimen of metformin monotherapy equivalent of at least 1000 mg once daily. Males, females of childbearing potential (must have a negative pregnancy test and be willing to comply with protocol contraception), and females of non-childbearing potential. Age 18 to 75 years, inclusive, at the time of screening. HbA1c ≥7.0% and ≤9.5%. Generally stable health without active infection or history of major surgery or significant injuries within the last year. Exclusion Criteria: Diagnosis of Type 1 diabetes mellitus, maturity-onset diabetes of the young, insulin-requiring Type 2 Diabetes, other unusual or rare forms of diabetes mellitus, or history of diabetic ketoacidosis. Clinically significant abnormal lab values including eGFR <50ml/min/1.73m2, ALT, bilirubin or AST >1.5 X ULN, hypokalemia or other clinically significant electrolyte abnormality. History of myocardial infarction, unstable angina, coronary revascularization, stroke, or transient ischemic attack within 2 years of screening. Presence of symptomatic congestive heart failure. History of cardiac arrhythmias requiring treatment or prophylaxis with drugs or devices during the last 2 years or any history of atrial fibrillation or flutter beyond a single short-term episode (e.g., lasting 1-2 days). History or presence of a 2nd degree or greater atrioventricular block in the absence of a pacemaker. A 12-lead ECG, from screening or baseline demonstrating QTcF interval >450 msec for males or >47 msec for females. A family or personal history of long QT syndrome. History of pancreatitis. Persistent, uncontrolled hypertension. Presence of chronic active hepatitis (hepatitis B, hepatitis C, nonalcoholic steatohepatitis [NASH]) and/or known liver cirrhosis. Participation in any formal weight loss program, or fluctuation of > 5% in body weight, or having received medications approved for weight loss within 3 months prior to screening. A positive pre-study drug screen. Participation in a clinical trial and receipt of an investigational product within 30 days. Have a history of drug abuse within 2 years of screening or a positive pre-screen drug screen. Have a history of hypoglycemic episode requiring glucose, glucagon, or orange juice administered by someone other than the patient within 6 months prior to screening. A history of excessive alcohol consumption within the last 2 years prior to screening Mental or legal incapacitation. Blood donation of approximately 1 pint (500 mL) within 8 weeks. History of MEN-2 or family history of medullary thyroid cancer. History of cancer, other than non-melanoma skin cancer, that required therapy in the 5 years prior study start.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TTP399 400 mg<br>TTP399 once daily | Drug: TTP399 400 mg<br>* once daily<br>|
| Experimental: TTP399 800 mg<br>TTP399 once daily | Drug: TTP399 800 mg<br>* once daily<br>|
| Active Comparator: Sitagliptin 100 mg<br>Sitagliptin once daily | Drug: Sitagliptin 100 mg<br>* once daily<br>|
| Placebo Comparator: Placebo<br>Placebo once daily | Drug: Placebo<br>* once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c (Glycosylated haemoglobin) |  | Day 1 to Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c < 7% at 6 months |  | Day 1 to Day 168 | 
| HbA1c < 6.5% at 6 months |  | Day 1 to Day 168 | 
| Plasma Glucose Levels |  | Day 1 to Day 168 | 
| Lipid Levels |  | Day 1 to Day 168 | 
| Insulin Levels |  | Day 1 to Day 168 | 
| Lactate Levels |  | Day 1 to Day 168 | 
| C-peptide Levels |  | Day 1 to Day 168 | 
| Glucagon Levels |  | Day 1 to Day 168 | 
| Glucagon-like Peptide-1 Levels |  | Day 1 to Day 168 | 
| Change in Body Weight |  | Day 1 to Day 168 | 
| Adverse Events |  | Day 1 to Day 182 | 
| Blood Pressure |  | Day 1 to Day 182 | 
| Electrocardiogram Parameters |  | Day 1 to Day 182 | 
| Hematology |  | Day 1 to Day 182 | 
| Blood Chemistry |  | Day 1 to Day 182 | 
| Urinalysis |  | Day 1 to Day 182 | 
| Pulse |  | Day 1 to Day 182 |