The most frequent grade 3-4 toxic effects were neutropenia ( 15 [ 25 % ] patients in placebo group vs 15 [ 25 % ] in metformin group ) , skin rash ( six [ 10 % ] vs four [ 7 % ] ) , diarrhoea ( three [ 5 % ] vs six [ 10 % ] ) , and fatigue ( two [ 3 % ] vs six [ 10 % ] ) .