Randomization, allocation, and intervention
Patients were randomized on a 1:1:1 ratio to receive metformin, donepezil or placebo using a web-based platform with blinded allocation. The randomization included a pre-stratified according to adjuvant or neoadjuvant status as surgery may affect cardiac troponin level. Randomization was performed by using a permuted block design. The randomization codes and allocation groups were secured at the research unit at the division of cardiology independent of the trial investigators.Metformin, donepezil and placebo were commenced one day prior to chemotherapy. The intervention drugs were administered in a double-dummy technique. In metformin group, we decided to use extended-release metformin to attenuate gastrointestinal side effects. Metformin was initiated as 1000 mg daily (1 tablet) and titrated to 2000 mg (2 tablets once daily) after 1 week, if well-tolerated. Co-administration of sham-donepezil was started at half tablet and increased to one tablet after 1 week. In donepezil group, donepezil was started at 5 mg (half tablet) and increased to 10 mg (1 tablet) after 1 week, if well-tolerated. Co-treatment with sham-metformin was initiated one tablet then increased to two tablets after 1 week. The placebo group was treated with sham-metformin and sham-donepezil with the same titration protocol as in the intervention groups. All drugs were continued until completion of doxorubicin therapy.