Safety and Efficacy Study of TRC150094 to Improve the CV Risk in Subjects With Diabetes, Dyslipidemia and Hypertension

A Phase III Randomized, Double Blind, Parallel Group, Placebo Controlled, Multi-centre, Multinational Study to Evaluate Efficacy and Safety of TRC150094 as an Add On to Standard of Care in Improving Cardiovascular Risk in Subjects With Diabetes, Dyslipidemia and Hypertension

The phase III trial is designed with an aim of determining the efficacy of Investigational Product TRC150094 in concurrently reducing non-traditional risk factors for CV risk i.e., HbA1c, MAP and non-HDL cholesterol. This study will be a randomized, double blind, parallel group, placebo controlled, multi-centre, multinational study in 1250 subjects. All the study subjects will receive once daily dose of TRC150094 45 mg or placebo tablets in addition to their standard of care, for 24 weeks followed by roll over to a safety extension phase of 26 weeks.

TRC150094 is an Investigational Product for the treatment of CV risk associated with non-traditional risk factors ie, diabetes, hypertension and dyslipidemia, which acts by increasing the energy expenditure and restoring mitochondrial flexibility which is deranged in patients with these risk factors. Treatment with TRC150094 has shown clinically meaningful benefits in well-established contributors of CV risk i.e., insulin resistance and hyperglycemia, SBP as well as non-traditional risk factors i.e. non-HDL cholesterol and MAP, over and above standard of care.

The phase III trial is designed with an aim of determining the efficacy of TRC150094 in concurrently reducing non-traditional risk factors for CV risk i.e., HbA1c, MAP and non-HDL cholesterol. This study will be a randomized, double blind, parallel group, placebo controlled, multi-centre, multinational study in 1250 subjects. All the study subjects will receive once daily dose of TRC150094 45 mg or placebo tablets in addition to their standard of care, for 24 weeks followed by roll over to a safety extension phase of 26 weeks.

Primary Objective of the study is, To evaluate the efficacy of TRC150094 in improving cardiovascular (CV) risk in subjects with diabetes, dyslipidemia and hypertension Secondary Objectives of the study are,

1. To evaluate safety of TRC150094 in subjects with diabetes, dyslipidemia and hypertension
2. To evaluate extended safety profile of TRC150094 beyond 24 weeks of treatment in subjects with diabetes, dyslipidemia and hypertension

In this study there will be five visits at week 4, 12, 24, 36 and 50 after enrolment.

Inclusion Criteria:

1. Male and female subjects in the age range 30-70 years (both inclusive)
2. BMI in the range 23-39 (inclusive) kg/m2
3. HbA1C ≥7.5 %
4. Stable therapy of ≤2 oral hypoglycemic agents for at least two months prior to screening at doses that are appropriate for the duration of the study in the judgment of the investigator.
5. Non HDL-cholesterol ≥ 160 mg/dL.
6. Mean Arterial Pressure (MAP) ≥100 mm Hg based on average of 24 hours' ambulatory blood pressure monitoring (ABPM) with or without antihypertensive treatment (subjects will have to be on stable dose of anti-hypertensive treatment for at least two months prior to screening); Dose should be appropriate for the duration of the study in the judgment of the investigator.
7. Willing to give written informed consent
8. Ability to adhere to the study restrictions and assessments schedule

Exclusion Criteria:

1. Uncontrolled hypertension: SBP of ≥ 180 mm Hg and DBP ≥ 110 mmHg based on average of 24 hours' ambulatory blood pressure monitoring.
2. HbA1C > 10 % at screening.
3. Serum triglycerides >400 mg/dL.
4. LDL-cholesterol >300 mg/dL or medical history/clinical evidence of familial hyperlipidemic disorder.
5. Subjects on Insulin or Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors.
6. Acute coronary syndrome (ACS) or stroke or any revascularization within last 6 months.
7. Subjects having untreated thyroid dysfunction (TSH <0.3 or >5.5 µIU/mL) or hormone related obesity disorder.
8. Subjects with liver enzymes (SGOT, SGPT) more than 3X of upper limit of normal value.
9. eGFR <30 mL/min as evaluated by Modification of Diet in Renal Disease (MDRD) method.
10. Seropositive for HIV, Hepatitis B or Hepatitis C.
11. History of alcohol or drug abuse, psychiatric disorder, any bleeding disorder, malignancy in last 3 years.
12. Pregnant or lactating women.
13. Female of childbearing potential, who are neither surgically sterilized nor willing to use reliable contraceptive methods (double barrier methods or intrauterine device).
14. Male subjects with partners of childbearing potential not willing to use reliable contraception methods.
15. Clinically significant abnormal physical findings, laboratory results, ECG findings and/or any other clinical observation or history during the screening examination, which would interfere with the objectives of the study.
16. Intake of any investigational drug within 3 months prior to the first dose of study drug.
17. In the opinion of the investigator, subject is unable to cooperate with any study procedures, unlikely to adhere to the study procedures, keep appointments, or plan to relocate during the study.