The main changes were: The reference to the standard treatment for diabetic nephropathy therapy in the title has been deleted as angiotensin converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) were not registered for this indication by regulatory authorities in every country (this change was also made in the entire document accordingly). There was a change in Trial Clinical Monitor (TCM). Some clarifications regarding Ambulatory blood pressure measurement (ABPM) and biomarkers procedures and update of the flowchart (randomisation visit number changed from Visit 3 to Visit 3.1), as well as clarification regarding the procedure for rescue therapy. Denmark has been added in participating countries. Inclusion criterion 2 has been modified to clarify the use of basal insulin and to prohibit the use of Sulphonylurea (SU) and glinide as antidiabetic background therapy (in order to decrease the risks of hypoglycaemia). Inclusion criterion 4 has been modified to allow the screening of the patients on other criteria than exclusively Urinary albumin creatinine ratio (UACR) as it was not systematically measured in each participating country; to describe albuminuria collection; and to clarify the parameter to consider in order to assess patient’s eligibility.

The main changes were: The flow chart has been updated to reflect some clarifications regarding the procedures. Measurement of beta-2-microglobulin has been deleted because of practical reasons and redundancy. SU and glinide were allowed again during the follow-up period. Clarification that Adverse Event (AE) have to be considered under treatment during the 7 days after last trial drug administration and that AEs have to be declared between Visits 7 and 8. The Estimated glomerular filtration rate (eGFR) formula CDK-EPI has been changed to be in agreement with the central laboratory. It was stated that separate Trial Statistical Analysis Plan (TSAPs) for (other) biomarkers analyses were to be written as biomarkers analyses were to be reported separately.

The main changes were: SU and glinide have been added as potential options for rescue medication as they had been allowed as background therapies; inclusion criteria 2 and 3 and exclusion criterion 13 were modified accordingly in order to facilitate the recruitment. In the inclusion criterion 3, Glycosylated haemoglobin (HbA1c) lower level was decreased from 7% to 6.5% in order to facilitate the recruitment. It was added that pancreatic events will have to be adjudicated in order to better follow up the occurrence of pancreatic events. The use of rescue medication was added as further efficacy endpoint. Clarifications have been added regarding declaration of Serious adverse event (SAEs) and Adverse event of special interest (AESIs) in order to harmonize processes with Boehringer Ingelheim Standard operating procedure (BI SOP). The Full analysis set (FAS) definition has been changed in order to include the Urinary albumin creatinine ratio (UACR) endpoint as an additional requirement. The statistical models have been corrected to include log10 (UACR) instead of UACR, in regards to the normality of the UACR endpoint. The range of baseline categories for UACR endpoint has been changed in order to be compliant with project specifications.

The main changes were: The Estimated creatinine clearance (eCrCl) Cockcroft Gault formula has been replaced by eGFR assessed by CKD-EPI equation as this equation is not influenced by Body mass index (BMI) and would then allow a better assessment of GFR in patients with T2DM. As a consequence of the previous change, the endpoint "change from baseline in eGFR as assessed by CKD-EPI equation after 24 weeks of treatment” has been categorised as a secondary safety endpoint and the endpoint “change from baseline in eCrCl as assessed by Cockcroft Gault formula after 24 weeks of treatment” has been categorised as other safety endpoint. The sample size has been reduced to 350 patients based on new clinical study results and a revised statistical assumption to ensure a power of at least ≥85%. The primary analysis model has been changed from an ANCOVA on the FAS (LOCF) to a MMRM approach on the FAS (OC) based on Food & Drug Administration (FDA) recommendation. The inclusion criterion 2 has been modified to clarify the number of oral antidiabetic therapies allowed in combination with basal insulin. The exclusion criterion 13 has been clarified. ‘Transition from baseline macro- or microalbuminuria to either micro- or normal albuminuria after 24 weeks of treatment’ has been added as efficacy endpoint to identify patients with improvement of the pre-existing renal impairment condition. Safety endpoints related to ABPM measurements (change from baseline in mean 24 h arterial blood pressure and in mean 24 h pulse rate after 24 weeks of treatment) have been added for consistency with the endpoints on vital signs. The endpoint AESI has been removed as AESIs are already included in the AE analysis.