The primary reason for Amendment 1 was to include European sites as participants. The secondary reason was to clarify the timing of the interim analysis and to incorporate the Independent Data Monitoring Committee that would monitor safety throughout the study and review safety and efficacy data during the interim analysis. The number of interim analyses was updated from two to one.

Amendment 2 was implemented to add the EU-DRACT number for European sites. This amendment only applied to Europe and was not applicable to Latin America.

Amendment 3: The protocol has been revised to modify certain inclusion and exclusion criteria such as primarily INF-a usage and Bone Marrow testing for confirmation of study inclusion. The changes were implemented following thorough analysis of reasons for screening failure of patients considered for the protocol under previous amendment. These changes will not affect the study endpoints or objectives but merely allow for patient that would otherwise be eligible for this study to be included. Also addressed in this amendment is the change in ELN 2009 recommendations to allow for patients at 3 months of treatment with imatinib to be evaluated for suboptimal response.

Amendment 4 was issued to revise the Case Report Forms (CRFs) and Data Management section as well as to update the language in the IVRS/IWRS section in accordance with Novartis SOPs. In addition, this amendment clarified the Visit Assessment Schedule and OS follow up.

Amendment 5 was issued to update safety information and to clarify patient eligibility criteria. The safety update included pregnancy language, cardiac, death and sudden cardiac death and CYP34a inhibitors/inducers. The pregnancy language was updated since the reproductive-developmental toxicity profiles of nilotinib and imatinib do not indicate genotoxicity, pregnancy outcomes from female partners of male patients participating in this study were collected. The main eligibility criteria clarifications were to prior therapy, definition of intolerance and definition of chronic phase CML. An additional change was made to the secondary endpoints. The rate of CHR was removed as a secondary endpoint. Patients with no CHR at baseline are considered treatment failures and were thus not eligible for the study. All patients were expected to be in CHR at baseline. However, it was possible for patients to have loss of CHR on study. Loss of CHR, which needed to be confirmed, was retained as a study endpoint CHR as it was one of the events included in the definition of EFS.

The major reason for amendment 6 was to ensure alignment and consistency of pregnancy prevention language with the nilotinib program language, nilotinib label, and Novartis internal pregnancy guidelines. These changes have also been incorporated into the consent form. In addition, the risks associated with nilotinib in the consent form have been updated to reflect the current investigators brochure.