Imatinib changed to investigational agent; clarification of endpoints and procedures; modification of definition of progression-free survival; FISH (peripheral blood) added as alternative to conventional cytogenetic assessments; visit windows slightly lengthened; annual follow-up visit specified; timing of some assessments refined with extra detail such as ECG timing and addition of Morisky Medication Adherence Scale at visit 1; details of some procedures added (eg pill count specified for adherence); minor editorial changes .

This amendment includes changes to the protocol made in compliance with requests from the French Health Authority and the Korean Health Authority related to the monitoring of the safety of patients enrolled in the study and to the specifications of those subjects who are eligible for the study. In addition, the role of the internal data monitoring committee has been specified with respect to the frequency and scope of review, and language to specify that patients will be followed for overall survival post study follow-up has been added. Editorial changes for clarification made throughout the protocol.

Country specific amendment for Austria  Changes to the definition of post-menopausal woman.  For women of childbearing potential (WOCPB) duration of contraceptive use after discontinuation of study drug must be a minimum of five half-lives of the investigational product.  Duration of contraceptive use after discontinuation of study drug must be a minimum of five half-lives of the investigational product plus the addition of one sperm cycle of 60-90 days for sexually active men whose partners are WOCBP.

(CARES) and a revision to an internal BMS directive related to “Women of Childbearing Potential (WOCBP) in clinical trials”, this protocol was amended to adjust the frequency of pregnancy testing for sexually active female patients of childbearing potential to monthly pregnancy testing, Additional changes related to this initiative are:  updated language related to WOCBP to harmonize with the new BMS directive including requiring 2 highly effective forms of birth control  define highly effective forms of birth control  adjust language related to sexually active fertile men with WOCBP partners and adapt the length of birth control to be used after the last dose of investigational product (90 days) In addition, clarifications were added to the exclusion criteria for uncontrolled or significant cardiovascular disease and to the bone marrow assessment. Analyses conducted for safety and efficacy are now categorized under other analysis rather than interim analysis

 Increase in sample size  Secondary and Tertiary objectives and endpoints modified  Inclusion criteria for imatinib dose interruption prior to randomization and tolerance to imatinib further specified  Patients with no evidence of clonal evolution, including those patients without cytogenetic testing at 3 months clarified as eligible for the study  Interim Analyses added  Change in assessment schedule for chest x-ray, echocardiogram, and complete blood count (CBC).  The last on study visit has been clarified to “At study close: 60 months after LPFV” due to a change in the anticipated time for enrollment. Headings in the Table 5.1C have been adjusted accordingly.  Update per BMS template for Destruction of Study Drug.  Pill counts (drug adherence) deleted study assessment. Patient Reported Outcome and MDASI CML Symptom Burden deleted study assessment.  Toxicity rates for CTC grades changed from “Grade 3” to “Grade 3 or above” (synopsis, statistical safety section)  Exclusion from study due to pleural or pericardial effusion is clarified to at randomization rather than at “study entry”;  FISH (peripheral blood) allowed as a substitute for conventional cytogenetics at all time points except screening  For cytogenetic response, the suggested number of metaphases (20) to be examined is no longer specified.  Section 6.6, Potential Drug Induced Liver Injury (DILI) has been updated to reflect standard definitions for no known liver toxicities at baseline.  Appendix 3: Medical Conditions and Drugs Which May Cause QTC Prolongation and Torsade De Pointes (Not All Inclusive): Update to Category Titles.  Appendix 8: ELN 2013 replaces ELN 2009  Updated references  Editorial changes.

 Hepatitis B serology status of all randomized subjects now required and recommendations for subjects with positive serology included.  Pregnancy Log (Appendix 9) has been revised to include method of contraception guidelines.  Methods of contraception have been aligned with the most recent international guidance and are presented in Appendix 10.  Protocol requirements for contraception while on treatment with dasatinib and for protocol-specified periods after the withdrawal or termination of treatment will now be reviewed with subjects as part of study assessments.  The number of enrolled subjects has been increased to approximately 1100 due to enrollment/screen failure rate.

Added clarifications for study assessments and assessment schedule for patients who crossover to treatment with dasatinib after ELN defined failure after treatment with imatinib and for all patients who remain on treatment after 60 months.