Clinical experience with MEDI-524 Section was updated to reflect the current status of enrollment and results from the Phase 1/2 studies of MEDI-524. Updated study objective and overview to reflect increased monitoring for RSV hospitalizations and medically attended outpatient LRI; the addition of monitoring for non-medically attended wheezing episodes in children who have experienced 3 prior medically attended wheezing episodes while on the study. Timing of the screening visit was changed from "within 7 days before Study Day 0" to "within 60 days before Study Day 0". Follow-up/Evaluations of LRI, Wheezing, OM and Respiratory Hospitalizations Section was updated to include collection of nasopharyngeal samples for RSV for all medically-attended wheezing episode. Safety assessment section was modified to reflect change in the point of contact for serious adverse event reporting and as the party responsible for the day-today safety monitoring of the study.

The study title was changed to reflect the fact that the study would be conducted in "Native American Indian Infants in the Southwestern United States" rather than being restricted to "Navajo and White Mountain Apache Infants." Dosing with study drug was changed from two RSV seasons for each child to one RSV season for each child. Sample size was changed from approximately 3000 to a minimum of 2100 up to a maximum of 3000. Time period for enrolment was changed from 3-4 RSV seasons to 3 RSV seasons. A futility assessment was added following study completion through Study Day 150 of the second cohort of subjects (Summer 2006), to assess the minimum RSV attack rate in the placebo group and the conditional power calculation of the primary endpoint. An additional analysis was added to determine if RSV immunoprophylaxis during the first RSV season affects subsequent medically-attended LRI or wheezing episodes, after all children in the study have been followed for 3 years. The secondary objective was changed to indicate that wheezing and LRI events would be compared through 3 years of follow-up. Non-medically-attended wheezing episodes would longer be collected. Time period for collection of RSV hospitalization and medically-attended LRI or wheezing episodes were changed.

Secondary objective was revised to clarify the secondary endpoints and stipulate RSV LRI and wheezing as separate outcomes. Futility assessment to be performed Summer of 2006 would no longer be conducted. Alternatively, an assessment of the blinded events rates was to be conducted after the third season to determine if a fourth season of enrollment was needed to achieve primary and secondary objectives. Respiratory Secretions for RSV detection Section was updated to reflect all future testing of respiratory secretions for RSV be conducted by quantitative polymerase chain reaction.

Routine Visits and Follow-up through Study Day 150 Section was updated to add that cord blood can only be used to obtain Study Day 0 results if the child was enrolled by 7 days of age. Final Visit for Patients who prematurely discontinue from the Study Section was revised to clarify that the investigator, not the sponsor, was responsible for requesting permission to continue follow-up.

The study title was changed by replacing Numax™ with Motavizumab and to reflect the fact that the study would be conducted in Native American Infants in the Southwestern United States vs. Native American Indian infants. Clinical Experience with Motavizumab Section was revised with the most current data from recently completed studies (MI-CP118 and MI-CP110) and information from ongoing blinded trials (MI-CP124 and MI-CP127). Rationale for Study Section was updated to detail the conduct and rationale of an interim analysis and possible unbinding of data. Secondary Objectives Section was modified to add seventh objective of “the incidence of asthma in children at 5 years of age who received motavizumab or placebo". Blinding Section was revised by removing all reference to the data monitoring committee, and adding details of the potential unbinding to analyse primary endpoints and secondary endpoints of medically attended LRI and OM, pharmacokinetics, immunogenicity. Routine Visits and Follow-up through Study Day 150 Section was modified to reflect that pre-dose vital sign measurement was extended to within 60 minutes prior to drug dose. Sample Size Section was revised to reflect the updated protocol strategy of conducting an interim analysis. Pulmonary Function Measures Section was revised by specifying that pulmonary function tests would continue unless the analysis of wheezing through 3 years suggests that evaluating the endpoint would be futile. Safety Management During the Study Section was updated to include the content of the DMC reviews for Season 1 and Season 2 (through 15 February 2006) as the concluding paragraph.

Updated secondary objectives for sample size analysed and for time points. Overview Section was modified. Clarified that the Indian Health Service physician are primary care physicians. Exclusion criteria Section - Exclusion #30 Clarified that for Version 7.0 of the protocol, the follow-up period was being amended to “...through 3 years of age. Blinding Section was updated reflect that interim analysis was performed and data monitoring committee recommended continuation of the study for a fourth season and changed follow-up from “5 years of age” to “3 years of age.” In Schedule of Patient Evaluations Section, follow-up was changed from “up to 5 years” to “through 3 years”. Routine Laboratory Evaluations Section was updated to clarify that blood samples would only be collected in seasons 1, 2, and 3. Medically Attended Acute Respiratory Illnesses Section clarified that patients in seasons 1 and 2 would be followed for 3 years on study. Definition of wheezing episode Section was changed from 5 years to 3 years. General considerations Section updated number of subjects randomized. Updated the definition of Wheezing Episode, Completion of Primary Study, and Loss to Follow-up visits.