Changes included: increased the number of randomised subjects to 105; for statistical considerations, modifications were made to the population definition and missing data handling descriptions.

Modified the clinical experience safety language to reflect updated blinded safety data from ongoing studies; allowed subjects who screen-failed in ISIS 304801-CS6 to enter ISIS 304801-CS16 (per sponsor approval, in consultation with investigator) if qualified, and for screening and qualification assessments from the ISIS 304801-CS6 study to be used for enrolment into ISIS 304801-CS16; allowed subjects with familial chylomicronaemia syndrome (FCS), as defined in ISIS 304801-CS6 study, and who satisfactorily complete ISIS 304801-CS16, to be considered for eligibility in ISIS 304801-CS7 (i.e., FCS) open-label extension (OLE) study; indicated that, data and safety monitoring board (DSMB) was independent; revised the contraceptive requirements to state that abstinence was only acceptable as true abstinence, i.e., when it was in line with the preferred and usual lifestyle of the subject; increased the frequency of pregnancy testing; added haematology blood draws at Weeks 12, 16, 22 and 25 to more frequently assess platelet counts; allowed blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, and 32 to be conducted by a home healthcare nurse; added language that each time a haematology lab was drawn and sent to the central laboratory for analysis, an additional sample would be collected in parallel and analysed locally, to reduce the occurrence of unreportable haematology results; provided guidance that the length of fasting should preferably not be more than 12 hours; updated platelet monitoring rule language to allow for more frequent monitoring as determined by the sponsor medical monitor in consultation with the investigator; provided guidance on monitoring for insulin, oral antidiabetic medication and glucose; added a safety monitoring rule and guidance for severe hypoglycaemia; clarified guidance on determining relatedness of a suspected unexpected serious adverse event (SUSAR); modified the statistical analyses methods in accordance with regulatory agency requests.

Changes included: added language that any case of a platelet count ≤ 50,000/cubic millimetre (mm^3) should be reported in an expedited fashion to the sponsor; added language regarding the frequency of obtaining platelet counts after a study drug dose pause and subsequent rechallenge; added language that any unreportable platelet count result must have been rechecked and determined not to have met a stopping rule before dosing could continue.

Haematology blood draws so that platelet counts (PCs) were measured every 2 weeks (Ws) during treatment (T) period and every 2 Ws for first 6 Ws after last dose (D) of study drug; updated platelet safety monitoring rules; indicated that if there were no reportable PC within 14 days of last PC, investigator (Iv) would contact subject (S) to hold dosing until a new PC was obtained and reviewed; indicated that all PC results would be promptly reviewed by Iv to ensure that C had not met stopping rule and to determine whether rate of decline was suggestive that S could be approaching D pause rule of 75000/mm3 (M); changed platelet D pause/stopping rule from 50000/M to 75000/M and added that when PC returned to ≥100000/M dosing could be continued but at a reduced D frequency of 300mg every 2 Ws or a reduced D of 150mg/W and only if approved by sponsor medical monitor; indicated that in event of any PC less than 25000/M, or a PC less than 50000/M that occurred while S was on dosing at 300mg every 2 Ws or 150mg/W, then dosing of a S with study drug (volanesorsen or placebo) would be stopped permanently; PC would be monitored daily until 2 successive values showed improvement, then monitored every 2-3days until PC was stable; indicated that administration of steroids was recommended for Ss whose PC was less than 25000/M and provided T guidelines for administration of steroids; added a table summarising actions to be taken in event of a low PC; indicated that all Ss would have D frequency reduced to 300mg every 2 Ws or D reduced to 150mg/W after 13 Ws of T (exemptions were Ss who had completed ≥5 months of dosing as of 27 May 2016); added effect of gender on pharmacokinetics (PK) by separate population PK analysis (A) rather than descriptive statistics for a robust assessment and to estimate half-life by separate population PKA rather than non- compartmental analysis.