14. Clinically significant cardiovascular disease but not limited to active infections; unstable angina; stroke or transient cerebral ischemia (within 6 months prior to screening); myocardial infarction (within 6 months prior to screening) ; congestive heart-failure (New York Heart Association (NYHA) class≥ II) ; serious cardiac arrhythmia, hepatic, renal or metabolic disease requiring medication during the study.