SAVOR-TIMI 53: 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 with Type 2 Diabetes

Summary

This is a multicentre, randomized, 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 ischemic 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 enrollment 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 with documented T2DM and with either a history of previous CV events or multiple risk factors for vascular disease will be enrolled from sites throughout the world. To reflect a scenario as close to real life as possible, both patients who are treated with glucose-lowering medication including oral antidiabetics and/or insulin (with the exception of incretin-based therapy) and treatment-naïve patients will be enrolled.

The study will focus on recruiting T2DM patients at elevated risk for CV events according to the two categories below:
and #149; Patients with established CV disease (secondary prevention)
and #149; Patients with multiple risk factors for CV events, but without established CV disease (primary prevention)

Further grouping of the patients will be based on their renal function (estimated GFR):
and #149; Normal renal function and mild renal impairment (estimated GFR and amp;gt;50mL/min)
and #149; Moderate renal impairment (estimated GFR 30 to 50 mL/min)
and #149; Severe renal impairment (estimated GFR and amp;lt;30 mL/min), excluding patients on chronic dialysis

Approximately 12,000 patients meeting all eligibility criteria at approximately 700 study sites will be randomized (1:1) to receive either saxagliptin or placebo. All potentially eligible patients will undergo a combined screening/enrolment/randomization visit. Each patient will sign an Informed Consent Form (ICF) and have screening evaluations performed. Twenty five patients will be enrolled at this site.

At least 800 patients with moderate to severe renal impairment will be randomized into the study, approximately 300 of them with severe renal impairment. No more than approximately 11,200 patients with normal renal function or mild renal impairment will be randomized to ensure that at least 800 patients with moderate to severe renal impairment are included. Once 300 patients with severe renal impairment are randomized, randomization into this group will be stopped. The dose of saxagliptin is 5 mg in patients with normal renal function and mild renal impairment and 2.5 mg in patients with moderate and severe renal impairment.

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.

Participant Eligibility

1. Provision of informed consent prior to any study-specific procedures
2. Age ≥40 years
3. Diagnosed with T2DM based on the current American Diabetes Association guidelines
4. HbA1c ≥6.5% (based on the last measured and documented laboratory measurement in the previous 6 months)
5. High risk for a CV event defined as having either established CV disease and/or multiple risk factors:
Established CV disease:
• Ischemic heart disease, and/or
• Peripheral vascular disease (e.g., intermittent claudication), and/or
• Ischemic stroke
Multiple Risk Factors
Patient must be at least 55 years old (men) and 60 years old (females) and have at least one additional risk factor (treated or non-treated) from the following:
• Dyslipidemia (based on the last measured and documented laboratory measurement in the previous 6 months and defined as at least 1 of the following):
• High level of low-density lipoprotein cholesterol (LDL-C), defined as >130 mg/dL (> 3.36 mmol/L)
• Low level of high-density lipoprotein cholesterol (HDL-C), defined as <40 mg/dL (<1.04 mmol/L) for men or <50 mg/dL (<1.30 mmol/L) for women
• Hypertension, as confirmed at the enrolment visit
• BP >140/90 mm/Hg or on a BP-lowering agent with BP >130/80 mm/Hg
• Currently smoking, as confirmed at the enrolment visit
6. Women of childbearing potential (WOCBP) must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose.
WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 72 hours prior to the start of study medication.
WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥2 consecutive years).