A Phase 2A, Double-blind, Placebo-controlled, Randomized
Study to Evaluate the Safety and Efficacy of TRC150094 in Increasing Insulin Sensitivity in Male patients with increased Cardiometabolic Risk

The incidence of visceral adiposity and the related comorbidities are
increasing worldwide, leading to increased burden of cardiovascular risk in
general population. Cardiometabolic risk which is the overall risk of
cardiovascular disease (CVD) and diabetes resulting from the presence of the
non-traditional risk factors and also of traditional risk has been described as
a plausible target for treatment. To date, pharmacological agents for the
management of Cardiometabolic risk have been limited and unsatisfactory.
TRC150094 is a novel thyromimetic analogous to 3.5-diiodothyronine (T2) being
developed by Torrent for the treatment of Cardiometabolic risk associated with
visceral adiposity.
In various preclinical studies conducted in multiple animal models of visceral
adiposity, insulin resistance and metabolic syndrome, it was found that
TRC150094 increases energy expenditure through increase in mitochondrial
metabolic activity and attenuates visceral adiposity, atherogenic dyslipidemia,
blood pressure and improved insulin sensitivity. If these effects are
replicated in clinical setting, this profile will prove invaluable in the
treatment of Cardiometabolic risk associated with visceral adiposity. We
therefore propose to investigate the safety and efficacy of TRC150094 in
increasing insulin sensitivity in male subjects with an increased
cardiometabolic risk

To determine the safety and efficacy (in increasing insulin sensitivity) of TRC
150094 once daily dosing for 4 weeks in male subjects with increased
cardiometabolic risk.
To evaluate the effect of TRC150094 on hepatic fat and metabolic parameters.
To evaluate the ethnic differences for effect of TRC 150094 on Insulin
sensitivity parameters

This will be a Phase 2A, two-centre, double-blind, placebo-controlled,
multiple-dose study to assess the effect of multiple oral doses of TRC150094 on
insulin sensitivity in 40 overweight/obese male subjects.20 Subjects will be
enrolled in India and another 20 subjects at Amsterdam, the Netherlands. The
maximum duration of participation in the study for each subject will be 9.5
weeks including a *4 weeks screening period, 4 weeks of treatment and a 10 days
post treatment follow-up evaluation period .

At each study site 20 subjects will be enrolled. Each subject will attend the
study centre in a fasting state, for a screening visit, 2 study visits (one
baseline and one end of treatment), 1 intermediate safety visit and 1
post-study follow-up visit (Total 5 visits). The subjects at each site will be
randomized to receive TRC150094 or placebo in a ratio of 1:1. The tentative
dose level is 50 mg to be administered OD (morning) under fasting conditions.
Dosing will take place daily on Days 1-*28. Subjects will arrive at the study
centre for screening visit. Physical examination, vital signs, safety
biochemistry and laboratory investigations for verification of inclusion/
exclusion criteria will be performed during screening visit. Subjects meeting
all the inclusion criteria and none of the exclusion criteria and who have
given their informed consent for the study will be asked to come for the study
on Day 0 (or day -1 if required). Baseline investigations (including baseline
clamp procedure and hepatic MRS) will be done on Day 0 (or day -1). Subjects
will receive properly labelled bottle containing either Active treatment or
Placebo as per the randomization number of the subject. Subjects will be asked
to take the dose (tentatively 50mg) OD in the morning on Days 1-28 inclusive,
in fasting conditions, with a glass of water. Drug compliance of at least 90%
will be ensured. Hence the allowable limit of missing the dose should not be
more than 3 days in total. Discontinuation should not be of more than 2
consecutive days at any point of time. Uniformity in timing of intake of
medication will be advised which should be preferably within ± 1 hr of the time
of intake of study medication on Day 1. Each subject will attend the study
centre on Day 14 for safety investigations. A deviation of ± 1 day will be
allowed for these visits. Subjects will attend the study centre again on Day 28
for clamp procedure and hepatic MRS. After 10 days subjects will return to the
study centre for a post treatment follow-up visit. It is planned that the study
will take place over 6 months (including screening and follow-up periods).

Subjects will be treated with either TRC150094 tablets of 50 mg or placebo once
a day for 28 days.
Venapunction will be performed three times
All subjects will undergo a hyperinsulinemic euglycemic clamp twice.

This study does not have specific advantages for the study subjects. The
results of this study may help researchers learn whether TRC150094 may be
beneficial for the treatment of male subjects with increased cardiometabolic
risk. [The most important adverse event of the study drug is headaeche.
6,6-2H2] glucose is glucose labeled with a stable isotope of hydrogen, which
behaves as the natural substrate and has no side effects. [2H5] labelled
glycerol is glycerol labeled with 5 stable isotope of hydrogen, which behaves
as the natural substrate and has no side effects. Actrapid is fast acting
insulin, a hormone that could induce hypoglycemia. However, it is not in the
scope of this protocol to allow hypoglycemia to occur, since plasma glucose
concentration will be fixed at 5 mmol/l by a variable infusion of glucose 20%
guided by frequent bedside glucose measurements. An overview of the blood
samples and blood volumes taken during the study is provided in Table 1. The
total blood volume to be withdrawn from any individual subject will be 391 ml
for subjects at Veeda Clinical Research, India and 361 ml at AMC, Netherlands.
This amount is not considered to be of negative influence to the subject*s
health. MR- spectroscopy of the liver will be made which takes about 30
minutes. This spectroscopy is not considered to be potentially harmful to
subjects. An X-thorax will be performed during the screening visit, to exclude
TB-infection, in patients in India only. The radiation hazard of the X-thorax
is 0.02 milliSievert per X-ray. For comparison: background radiation is 2
milliSievert per year for every person.