There were 3 substantial and 2 non-substantial amendments to the original protocol, dated 26 May 2011. In addition, there were 4 country-specific amendments for Israel. The second general protocol amendment, dated 10 January 2012, was considered substantial and was based on feedback from the Health Authorities. A strong correlation between SVR12 and SVR24 was demonstrated in completed SMV Phase 2b studies (C205 and C206), and in telaprevir and boceprevir Phase 3 studies. Health Authorities agreed that the primary efficacy endpoint for ongoing and future SMV Phase 3 studies could be changed from SVR24 to SVR12. SVR24 became a secondary endpoint. It was clarified that the thyroid function of the subjects should be adequately controlled and that subjects with abnormal thyroid-stimulating hormone (TSH) levels would be excluded from the study or should stop treatment. The antinuclear antibody (ANA) titer and TSH levels were added to exclusion criterion 10. Specific management of pancreatic amylase or lipase elevations, gastrointestinal nausea (with or without vomiting) and diarrhea were deleted from the specific toxicities section and general guidelines on management of graded AEs and laboratory abnormalities considered at least possibly related to SMV. The platelet and absolute neutrophil count in exclusion criteria 13 was revised to facilitate enrollment of African American subjects in the study. It was clarified that the Roche Cobas TaqMan HCV Test v2.0, for use with the High Pure System was used as the assay to determine HCV RNA levels. The performance characteristics of the assay reported by the manufacturer as well as the internal assay performance validation document were added to the reference list. A liver biopsy inclusion criterion was added to the protocol. A liver biopsy was the required method for all subjects without a contraindication for this procedure.

The protocol was amended to update the RGT duration criteria and the treatment stopping rules based on the Phase 3 results. Virologic stopping rules were modified so that subjects with HCV RNA ?25 IU/mL at Week 4 discontinued all treatment. Indeed, results from Phase 3 studies showed that the best predictor of achieving SVR with SMV plus PegIFN/RBV therapy is the Week 4 response, which is therefore considered an optimal and early time point for a decision regarding continuing or discontinuing therapy with the objective to terminize unnecessary exposure to treatment in subjects with very low likelihood of achieving SVR. Total treatment duration rules in eligible subjects (ie, subjects with viral relapse or breakthrough during prior PegIFN/RBV therapy in the control arm of SMV Phase 2/3 studies) were modified in line with the observations from Phase 3 studies, so that only subjects with undetectable HCV RNA at Week 4 and 12 could complete all treatment at Week 24, whereas subjects with HCV RNA <25 IU/mL detectable at Week 4 and undetectable at Week 12 were to receive 48 weeks of PegIFN?-2a/RBV treatment. The stopping rule at Week 12 was adapted: Subjects with detectable HCV RNA at Week 12 discontinued all treatment in line with analysis from the Phase 2b C206 study in prior nonresponders and Phase 3 studies in treatment naïve and prior relapse subjects, showing that subjects not achieving undetectable HCV RNA at Week 12 had a very low chance of achieving SVR. This modified stopping rule (ie, confirmed detectable HCV RNA) was also applicable at Week 24 and Week 36. The management of laboratory abnormalities and management of specific toxicities was updated and clarified based on the results from Phase 3 studies. It was determined that it was not necessary to discontinue study medication for isolated grade 4 abnormalities in bilirubin.

It includes phase 1 photosensitivity study C125 had concluded that the photosensitizing potential of SMV is similar to that of placebo. Accordingly, formal recommendations for sun protective measures were removed from the ongoing SMV studies at the time that these results became available, and not included in future SMV study protocols. After analysis of the Phase 3 (C208/C216/HPC3007) studies, in which subjects were dosed with SMV prior to removal of recommendation for sun-protective measures, photosensitivity conditions were nevertheless identified as adverse drug reaction of SMV as detailed in the updated IB edition 7, issued in June 2013.34 As a follow-up to a recommendation by the United States (US) Food and Drug Administration (FDA), it was decided to reintroduce the same recommendations initially included in Phase 3 studies (C208/C216/HPC3007), in SMV studies where subjects were still being dosed with SMV and in any future SMV study. Therefore, the protocol was amended to reintroduce the precautionary language on photosensitivity.