Study schema of the ESTIMATE study. Safety and efficacy analysis were planned after completion of the 1-year fixed-dose extension period. BID, twice daily; D, study visit day of the dose-finding period with D0 at the start; M, study visit month of the prolonged fixed-dose extension period with M0 at the start corresponding to W52 of the fixed-dose extension period; W, study visit week of the fixed-dose extension period with W0 at the start corresponding to D56 of the dose-finding period.