A Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase IV Trial to Evaluate the Effect of Saxagliptin on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischaemic Stroke in Patients whith Type 2 Diabetes

Cardiovascular disease is the leading cause of death in patients with type 2
diabetes mellitus. More than 60% of all patients with type 2 diabetes mellitus
die of cardiovascular disease and an even greater percentage have serious
cardiovascular related complications. There are compelling data in patients
with type 2 diabetes mellitus supporting a reduced risk of microvascular
complications with improved long-term glycaemic control. The ability of glucose
lowering to impact cardiovascular outcome is not clear.

The results from the 8 studies in the saxagliptin Phase IIb/III programmes in
over 4600 patients combined with the results from clinical pharmacology studies
support the oral dose of saxagliptin 5 mg once daily in a wide range of
patients with type 2 diabetes mellitus, as either monotherapy, add-on
combination therapy with metformin, a thiazolidinedione, or a sulphonylurea, or
initial combination therapy with metformin.
Currently none of the available antidiabetic agents are indicated for CV risk
reduction in patients with type 2 diabetes mellitus. The Phase IIb/III
programme has not only established the efficacy and safety of saxagliptin in
lowering glucose levels (as assessed by HbA1c) but also created
hypothesis-generating data suggesting fewer occurrences of MACE (Major adverse
cardiovascular events). This clinical study will test this hypothesis in a
rigorous fashion. The potential results of such a study will be of great
benefit to all patients with type 2 diabetes mellitus.

Primary objectives

Efficacy
The primary efficacy objective is to determine, as a superiority assessment,
whether treatment with saxagliptin compared with placebo when added to current
background therapy will result in a reduction in the composite endpoint of
cardiovascular death, non-fatal myocardial infarction or non-fatal ischaemic
stroke, in patients with type 2 diabetes mellitus.

Safety
The primary safety objective of this trial is to establish that the upper bound
of the 2-sided 95% confidence interval for the estimated risk ratio comparing
the incidence of the composite endpoint of cardiovascular death, non fatal
myocardial infarction or non-fatal ischaemic stroke, in patients with type 2
diabetes mellitus, observed with saxagliptin to that observed in the placebo
group is less than 1.3.

Secondary efficacy objective
The secondary efficacy objective is to determine whether treatment with
saxagliptin compared with placebo when added to current background therapy in
patients with type 2 diabetes mellitus will result in a reduction of the
composite endpoint of cardiovascular death, non fatal myocardial infarction,
non-fatal ischaemic stroke, hospitalisation for heart failure, hospitalisation
for unstable angina pectoris or hospitalisation for coronary revascularisation.

Secondary safety objectives
Safety and tolerability will be evaluated by assessment of overall adverse
events and adverse events of special interest. These will include assessment
of the long-term effects of saxagliptin on decrease in lymphocyte counts,
decrease in thrombocyte counts, severe infections, hypersensitivity reactions,
liver abnormalities, bone fractures, pancreatitis, skin reactions and renal
abnormalities.

This is a multicentre, randomised, double-blind, placebo-controlled Phase IV
study to evaluate whether treatment with saxagliptin can reduce the composite
endpoint of CV death, non-fatal MI or non-fatal ischaemic stroke in patients
with T2DM and to definitively exclude unacceptable CV toxicity. The
anticipated duration of the study is approximately 5 years, including an
anticipated enrolment period of 2 years and follow-up period of 3 years.
However, the duration of the trial will be based on accrual of the
predetermined number of events, and therefore the study may be shorter or
longer.

Patients meeting all eligibility criteria will be randomised (1:1) to receive
either saxagliptin or placebo. Active treatment will comprise the doses of 5
and 2.5 mg based upon a patient*s renal function. Patients with a estimated
GFR >50 mL/min will be randomised to receive 5 mg saxagliptin or placebo and
patients with a estimated GFR *50 mL/min will be randomised to receive 2.5 mg
saxagliptin or placebo. Saxagliptin is administered orally, once daily.
Matching placebo, as described above, will be used as comparator.

Patients will return every 6 months for assessment of events related to the
objectives of the study, tolerability and safety. Assessment of treatment
compliance and provision of study drug will be done at these 6 month visits.
In addition, phone contacts will be performed at a 3 month interval in between
regular visits.

The study medication may cause some side effects. The taking of a blood sample
may cause some discomfort.
It is hoped that saxagliptin treatment will help reducing the risk of
experiencing a cardiovascular event. The information we get from this study may
help to treat future patients with type 2 diabetes better.