Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease Patients With Type 2 Diabetes

Ticagrelor has been shown to significantly reduce the rate of cardiovascular disease (CVD)
events and death compared with clopidogrel in patients having prior acute coronary syndrome.
A number of outcome studies have demonstrated the risk of major CVD events increased with
blood viscosity. Stroke patients and those with stroke risk factors were shown to have
chronically elevated blood viscosity relative to healthy controls. Based on prior
observations, the rationale for this study is to demonstrate that both aspirin-ticagrelor and
ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole
blood viscosity at the end of each 4 week treatment period.

The primary objectives for this study is to: (1) Compare the effect of aspirin-ticagrelor
with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10,
and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) shear rates at the
end of each 4-week treatment period; and (2) to compare the effect of ticagrelor mono-therapy
with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10,
and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) at the end of each
4-week treatment.

The secondary objectives for this study include: (1) a determination as to whether there are
differences in low and high shear rate dependent viscosity with treatment by ticagrelor alone
and combination aspirin-ticagrelor. Additionally, investigated will be the effect of the
treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial
index, and toe pressures.

The general approach to evaluation of drug efficacy will be through blood samples collected
with a standard venipuncture for viscosity testing. Blood viscosity will be measured using an
automated scanning capillary tube viscometer across a physiologic range of shear rates of
1-1000 s-1 in increments of 0.1 s-1. Blood viscosity levels at 5 s-1 will be reported as
low-shear viscosity, and blood viscosity measurements at 300 s-1 will be reported as
high-shear viscosity. Additionally, pulse volume recordings will be simultaneously obtained
at the level of the ankle, metatarsal and toe bilaterally according to standard protocol, and
Continuous-wave Doppler will be used to determine ankle-brachial indices or toe-brachial
indices, and flow velocity profiles.

Inclusion Criteria:

- Female or male aged ≥ 35 years

- Type 2 diabetes mellitus

- Symptomatic PAD

- Ankle-brachial index ≤ 0.85 or calcified blood vessels with toe-brachial index ≤ 0.6
and/or abnormal post-exercise ankle-brachial index

- Prior surgical or percutaneous intervention of the peripheral arteries ≥12 months
previously with a residual stenoses of ≥50% in a non-dilated artery.

Exclusion Criteria:

- Subject is pregnant or breast-feeding

- Planned revascularization or amputation

- Known bleeding disorder

- History of intracranial hemorrhag3

- Considered at risk of hemorrhagic events

- Hypersensitivity or allergic reactions to aspirin

- Concomitant use of anticoagulants such as warfarin, dabigatran, factor Xa inhibitors
or antiplatelet drugs such as clopidogrel, dipyridamole and sulfapyridine

- Subject has a condition or circumstance which would prevent them from adhering to
treatment regimens

- Subject has active infection

- Subject has an anemia

- Subject has given blood or received a blood transfusion at any point during the study

- Subject has polycythemia vera or any hyperviscosity syndrome

- Subjects with Waldenstrom's macroglobulinemia who have an increased risk of
hyperviscosity syndrome

- Subject has history of severe liver disease, obstructive liver disease such as primary
biliary cirrhosis or end-stage renal disease (eGFR <30 mL/min/m2)

- Family members or employees of the investigator or study centers involved in the study

- Subject has poor diabetes or hypertension control (systolic blood pressure ≥ 180 mmHg
or diastolic blood pressure ≥ 100 mmHg)