Rationale and Design for Shiga Microalbuminuria Reduction Trial

The Reduction of Microalbuminuria in Japanese Hypertensive Subjects With Type 2 Diabetes Mellitus Treated With Valsartan or Amlodipine: Study Design for the Shiga Microalbuminuria Reduction Trial (SMART)

The purpose of this trial are to evaluate the reduction of urinary albumin excretion by an angiotensin receptor blocker (ARB), valsartan, in comparison with a calcium channel blocker (CCB), amlodipine, in Japanese hypertensive patients with type 2 diabetes mellitus and microalbuminuria under strict blood pressure control, and to compare the additional effects of an ARB or a CCB in combination with angiotensin-converting enzyme (ACE) inhibitor treatment.

Microalbuminuria in diabetic patients is an established risk marker for the progression of diabetic nephropathy and for cardiovascular mortality. Intervention trials have demonstrated that drugs that blockade the renin-angiotensin system can reduce microalbuminuria in Caucasian patients with type 2 diabetes mellitus and microalbuminuria, regardless of blood pressure level. However, it remains uncertain whether angiotensin receptor blockers or calcium channel blockers give a greater reduction of microalbuminuria. The Shiga Microalbuminuria Reduction Trial (SMART) is a prospective, multicentre, randomized, active-controlled, two-arm parallel treatment group comparison study aimed at evaluating reduction of microalbuminuria in 160 Japanese hypertensive patients with type 2 diabetes mellitus and microalbuminuria. The trial consists of an 8-week observation period for screening and washout, and a 24-week intervention period. After the observation period, patients are randomized to either amlodipine 5 mg once daily or valsartan 80 mg once daily as an initial dose. After four weeks, if patients cannot achieve the target blood pressure (<130/80 mmHg) with the initial dose of a study drug, doses are titrated up to amlodipine 10 mg once daily or valsartan 160 mg once daily. The primary endpoints are a change in the rate of urinary albumin excretion from baseline, a normalization of microalbuminuria, and a 50% reduction in urinary albumin excretion from baseline, which are compared between treatment groups. This study will provide additional data for the treatment of hypertension and microalbuminuria and has important health care implications for Japanese patients with type 2 diabetes.

Inclusion Criteria:

• Hypertensive patient with type 2 diabetes
• Microalbuminuria defined as a urinary albumin excretion of 30 to 300 mg/gCr

Exclusion Criteria:

• Type 1 diabetes mellitus
• Pregnant women and women of childbearing potential
• Severe hypertension (> 180/110 mmHg), malignant hypertension, secondary hypertension
• History of cardiovascular diseases in the preceding 6 months (including symptomatic heart failure, unstable angina, myocardial infarction, the performance of percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass graft [CABG], severe arrhythmia, or second or third degree atrioventricular [AV] block)
• History of clinically significant valvular disease (e.g., aortic stenosis, mitral insufficiency)
• History of cerebral infarction, cerebral hemorrhage, or transient ischemic attack
• Serum creatinine level >1.5 mg/dl
• Persistent hematuria
• Serum potassium > 5.6 mEq/L (hyperkalemia)
• Severe hepatic disorder (e.g., hepatic failure, hepatic cirrhosis)
• Complication of an allergy of potential clinical concern
• Hypersensitivity to ARBs or CCBs
• Gastrointestinal surgery or gastrointestinal disorders which could interfere with drug absorption
• Autoimmune disease
• Participation in any intervention trial within 3 months prior to the observation period
• Patients who are unwilling or unable to comply with the trial protocol
• Concomitant use of other ARBs, CCBs, or potassium-retaining diuretics