The changes made aim to facilitate the recruitment of patients without change the philosophy of the general objective and the main objective of the project. Specifically, the selection criteria have been extended to include patients with a albuminuria/creatininuria (A/C) ratio > 1000 mg/g (instead of > 2000 mg/g). This approach leads to an increase in the pool of potentially eligible patients of around 63%. The model used to estimate the study sample consider the number of expected events in the various treatment groups. The number of expected events depends on the incidence of events over time (influenced by treatment) and the duration of follow-up. Originally it had been hypothesized a median follow-up of 3 years, equal to the duration of the treatment of the last patient randomized. In this amendment we specified that all randomized patients will come maintained in active follow-up until the last patient has completed the three years of treatment. Since the period initially envisaged for recruitment has been extended, it can be to predict that when the last randomized patient has completed three years of treatment provided, the median follow-up of patients will be at least 4.5 years.

The protocol has been modified in order to allow the inclusion in the study of patients who for specific cardiovascular indications cannot suspend treatment with an ACE inhibitor or a sartan and who have an albumin/creatinine ratio in the urine spot of the same or higher morning at 500 mg/g. The changes made aim to facilitate the recruitment of patients without changing the general philosophy and the main objective of the project. The original version of the the protocol expected to be randomized patients who at the end of one month of washout from any previous treatment with ACE inhibitors and/or ARBs had an albumin/creatinine ratio in the urine spot of 1000 or more in the morning mg/g. In clinical practice, however, many of these patients are treated with ACE inhibitors and/or ARB for specific cardiovascular indications such as heart failure and/or ischemic heart disease. In these cases it may be unsafe to discontinue treatment with these drugs even for a month. Therefore, these patients cannot perform the wash-out and therefore cannot enter the study. This represents a significant obstacle to the finalization of the study when the vast majority of patients with type 2 diabetes and nephropathy have at least one cardiovascular indication for treatment with ACE inhibitors and / or sartans. With the proposed amendment also patients with specific cardiovascular indications for treatment with an ACE inhibitor or a sartan could be included. Therefore it was proposed to include in the study patients who have at least one month of treatment with an ACE inhibitor or a sartan and an albumin / creatinine ratio in the morning urine spot equal to or greater than 500 mg/g, without prejudice to the other inclusion and exclusion criteria already provided by the protocol.