The updates to the CLI 00076 protocol include: -The description of Control RBC component, Input RBC, S-303 treated RBC, Investigational product were modified ("leukocyte-depleted") to conform to standard operating procedures at the study Blood Centers; EDQM uses depleted, not reduced. -The donation and preparation of study RBC was modified to conform to the standard operating procedures at the study Blood Centers. -The information with regards to whole blood collection and processing was modified to allow the blood centers to use their established procedures and available disposables to process leukocyte depleted RBC in additive solution. -Updated Subject Exclusion Criteria: Added definition to splenic enlargement to accurately define splenomegaly by ultrasound. Splenomegaly is important to identify because it can affect the primary efficacy endpoint. Added an exclusion, the purpose of this change is to assure, to the extent possible, that any change in the number of RBC units transfused is due to the performance of the Investigational Product and not simply to growth of the patient. - Updated the Subject Exclusion Criteria to allow for better representation of the patient population currently treated for thalassemia major. - Updated Subject Exclusion Criteria for additional clarification per Investigator’s recommendation. - Updated the verbiage for the methods and timing of Efficacy Parameters for additional clarification and in accordance with the Investigator’s SOPs and requirements. - Additional updates to ensure per Investigator’s recommendations and ensure consistency.

The updates to the CLI 00076 protocol include: - Updated the Medical Monitor. - Modification made to improve the protocol in accordance with Ministry of Health observations: Updates to clarify that the Blood Centers operate according to Italian regulations. Removed reference to “licensed” Blood Centers. Clarified description of Qualified Person (QP). Clarified that the RBC components are collected according to applicable Italian regulation and the Test and Control RBCs will meet the Council of Europe Guidelines (2010). Evaluation and Disposition of Red Blood Cells at the Blood Centers – clarification added that RBCs are tracked by donation number using the existing electronic data management system. Storage and Disposition of Red Blood Cells at Clinical Sites - Added details about the maximum age of RBC components for transfusion to subjects with Thalassemia. Detection and Confirmation of Antibody Specific to S-303 Treated RBC - Added details about secondary screening panel and clarified the scoring and classification of the test results. - Administration of Study Treatments - Text added to provide method for determining amount of hemoglobin transfused. - Subject Participation - Added safety follow-up for 2 non-study transfusions and clarified end of subject participation in the study. - New Inclusion Criteria added and updated exclusion criteria to clarify requirements for Female subjects. Updated the Exclusion Criteria to add information about participation in another study. - Treatment Plan Updated - Added extended safety follow-up period and modified end of subject participation to improve protocol clarity and study conduct. - Study Assessments table updated for consistency with the study requirements.

The updates to the CLI 00076 protocol include: -Increased number of clinical study sites, and updated the Clinical Project Manager. - Updated: Timing of whole blood processing by centrifugation to within 24 hours of collection. - Clarified the non-inferiority margin of the primary efficacy endpoint and deleted the secondary efficacy endpoints. Hgb increment 1hr post-transfusion and % Proportional decline in post transfusion hgb level per day (%/day). Clarified the study randomization scheme and process. - Updated: Subjects will be followed for safety for 2 non-study RBC transfusion episodes after the last study transfusion or 45 days, whichever is greater. Deleted: References to a separate biotin study. - Modified Inclusion Criteria: Subjects ≥4 years old are eligible (previously ≥10 years old), negative DAT modified as an exclusion requirement, requirement for stable iron chelation regimen removed, removed subject available for 1-hr post transfusion blood sample, and added pediatric assent, if applicable. - Updated the Exclusion Criteria: Clarify and modify eligibility of subjects with positive DAT, subjects at risk for cardiac decompensation, subjects with G-6DR deficiency requiring medications known to adversely affect RBC viability, algorithm to exclude some DAT positive subjects, concurrent chemotherapy for cancer, and inability to comply with the protocol. - Clarified withdrawal of subjects treated with medication demonstrated to have caused hemolysis while on study and allow for replacement of subjects who withdraw prior to being transfused. -Updated screening assessments, to allow the inclusion of a subset of DAT positive subjects and improve the current enrollment rate. Added details for evaluation of positive DAT reactions and development of positive DAT during the trial. -Updated Subject Inclusion Criteria: Updated the minimum age to ≥11 years. Response to ANSM letter 16 Jul 2014. Updated withdrawal criteria: added withdrawal of subjects.