Following the receipt of a Direct Healthcare Professional Communication report (dated 21st March 2016) regarding the risk of diabetic ketoacidosis (DKA) during treatment with SGLT2-inhibitors including Canagliflozin, the study team updated the protocol to include additional exclusion criteria, revised the treatment management sub-section, and revised the expected serious adverse events/reactions sub-section. Further, the study team revised timelines throughout the protocol to indicate a study extension of 3-4 months (recruitment phase extended to April 2017 but follow-up period reduced from 12 months to 3 months) to enable the LPLV in September 2017.

Exclusion criteria revised to include 1) Any contraindication to the IMP 2) individuals on loop diuretics. The study team added an ALT blood test at baseline to assess eligibility (12. Impaired liver function (ALT ≥ 2.5 times upper limit of normal)). Further, the study team included some treatment management information about lower limbs and AKI in the treatment section of the protocol (following the recent safety updates) and included AKI in the expected SAE/SAR section of the protocol (in line with updated SmPC).

The study team extended the study timelines to enable an extended recruitment period (proposed recruitment end date: April 2018) to aid the study team to recruit participants to time and target. Further, the inclusion/exclusion criteria were revised to aid recruitment following a high screen failure rate in the previous recruitment phase. HbA1c ranges were widened, the requirement to fast for 10 consecutive days was removed, and participants taking DPP-4 inhibitors were included. The study team revised the wording within the protocol (randomisation & code breaking, study design and statistical methods) about stratification to include DPP-4 inhibitors. Specifically, randomisation was carried out using block design and stratified by site (Leicester and Birmingham) and entry therapy (monotherapy, dual therapy not including DPP-4 inhibitor, and dual therapy including DPP-4 inhibitor). Participants with monotherapy at entry were randomised 1:1 to metformin + Canagliflozin (Invokana™) or to metformin + a sulphonylurea or repaglinide or pioglitazone; whilst participants with dual therapy at entry were randomised 1:1 to metformin + Canagliflozin (Invokana™) or to existing dual therapy combination. Finally the study team included some additional information for Repaglinide under the treatment section of the protocol following the SmPC review. In an interaction study with healthy volunteers, co-administration of clopidogrel (300 mg loading dose), a CYP2C8 inhibitor, increased repaglinide exposure (AUC0–∞) 5.1-fold and continued administration (75 mg daily dose) increased repaglinide exposure (AUC0–∞) 3.9-fold. A small, significant decrease in blood glucose values was observed. Since the safety profile of the co-treatment had not been established in these patients, the concomitant use of clopidogrel and repaglinide were avoided.

Notification to the MHRA from the Chief Investigator about the decision to terminate recruitment of participants into the trial. This decision was made solely due to practical issues/challenges with recruitment. All patients enrolled into the study at that time and receiving treatment were followed-up until September 2018.