The overall reason for the amendment was to include the definitions for suspension of treatment were revised, requiring fewer adverse events to satisfy the criteria, If a dose level was suspended and comprehensive review conducted, the provision to continue treatment at that dose level or repeat that dose level was removed and study drug packaging was revised to allow for the use of amber syringes covered with aluminum foil overlaid with the drug label.

The overall reason for the amendment was to include the viral challenge model to more closely emulate clinical RSV disease, The first modification allowed initiation of treatment up to 3 days after subjects were found to be Polymerase Chain Reaction (PCR) positive by nasopharyngeal wash. This longer time window was more analogous to the time window that will be seen in clinical practice, where patients do not usually present to their doctors until symptoms have occurred, typically around Day 3 of infection, The second modification to the protocol allowed for treatment of subjects for up to 9 days. This revision was considered important in the event that data from study period 1 suggested the 5-day treatment duration was insufficient. This less than or equal (< =) to 9-day treatment duration remains shorter than the 14-day treatment duration previously evaluated in the healthy volunteer SAD/MAD study, which was found to be well tolerated. The safety profile of ALS-008176 was also updated to include adverse events experienced by healthy volunteers treated for 14 days to further support this change, Inclusion of recently available proof-of-concept data from an African Green monkey RSV infection model, Removal of plaque assay analysis at Days 16 and 28, Addition of a provision for dose administration via single use amber glass bottles, Editorial changes for consistency within the document.

The overall reason for the amendment was to include the The rate of infection in the study was anticipated to be < 70 percent (%). An additional study period (study period 4) with a slightly larger size (N = 24) was added because it would provide additional infected subject data which will further enhance the statistical assessment of the efficacy and PK-PD properties of ALS-008176. In the event that a full study period could not be enrolled in a timely fashion, the added language allowed the possibility to enroll the additional 24 subjects across multiple study periods, Additional changes and clarifications included The protocol already provided for once daily treatment after conduct of study period 1. Further editorial changes were made to assure consistency across the document, Existing antiviral parameters were clarified and additional antiviral parameters (as determined by qPCR of nasal wash) including change in viral load over time; change in AUC0-t over different time periods; time to non-detectability of virus from commencement of study medication; peak viral load and time to peak viral load; and proportion of subjects with detectable virus by time following commencement of study medication) were introduced to aid in analysis of efficacy and PK-PD. Similar antiviral endpoints may have been evaluated based on quantitative culture (tissue infectivity plaque assays), Increased the total number of subjects that could be enrolled, clarification that O2 saturation will not be assessed as clinically warranted, at the physician’s discretion, clarification of the timing of Day 1 safety laboratories, clarification of nasal swab tolerability testing, potential analyses of inflammatory markers and added text identifying Triangle Biostatistics as the statistical analysis vendor and provides updates to harmonize the protocol with the SAP.