Extended the treatment period from 6 to 12 months; expanded enrolment of subjects with a history of acute pancreatitis to at least 36 of the 50 subjects (72%); incorporated a stratification of subjects by previous history of pancreatitis, replacing the Glybera exposure strata; modified statistical methods for handling missing data and for the primary analysis; added a description of the planned collection and analysis of injection site reactions; removed the exclusion based on screening echocardiogram results; added fundus photography to study procedures to better assess the presence/absence of lipemia retinalis; made minor changes to correct errors and/or to improve the overall clarity of the protocol.

Updated the approximate anticipated number of subjects that could enrol into the study (approximately 60 subjects); updated the time point for the collection of post-heparin samples (from 15 minutes to 10 minutes) to align with the assay validation parameters for the measurement of lipoprotein lipase (LPL) activity; made an addition to the platelet monitoring rule to allow for more frequent monitoring when appropriate; provided guidance to investigators with enrolled FCS subjects who also had T2DM; provided specific glucose monitoring rules for subjects on insulin and oral antidiabetic medications. The definition of documented severe hypoglycemia was included and safety monitoring rules were defined. Also, specific monitoring rules were incorporated into the protocol for hyperglycaemic events; modified the statistical analysis section to preserve the integrity of the randomisation and to clarify the statistical analyses methods in accordance with regulatory agency requests.

Updated the approximate anticipated number of subjects that could enrol into the study (approximately 70 subjects).

Modified the clinical experience safety language to reflect updated blinded safety data from ongoing studies; indicated that the 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 the pregnancy testing; added haematology blood draws at Weeks 12, 16, 22, 25, 29, 35, 41, 47, and 51 to more frequently assess platelet counts; allowed blood sampling at Weeks 4, 8, 12, 16, 19, 22, 25, 29, 32, 35, 41, 44, 47, 51, and 58 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 should 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; added language to the safety monitoring for insulin, oral antidiabetic medication and glucose that all subjects, including those not on insulin, who used a glucometer should also bring their glucometer and/or glucometer log printout to every clinic visit; clarified guidance on determining relatedness of a suspected unexpected serious adverse reaction (SUSAR); added language to justify the increase in the number of subjects in the previous amendment (Amendment 3 dated 01 December 2015).

Added language that any case of a platelet count ≤ 50,000/cubic millimetres (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 be rechecked and determined not to have met a stopping rule before dosing could continue; made minor changes to correct errors and/or to improve the overall clarity of the protocol.

Added haematology blood draws so that platelet counts (PCs) were measured every 2 weeks (Ws) during treatment period and every 2 Ws for first 6 Ws after last dose (D) of study drug; updated platelet safety monitoring rules; added language that if there were no reportable PC within 14 days of last PC, investigator would contact subject to hold dosing until a new PC was obtained and reviewed; added language to indicate that all PC results would be promptly reviewed by investigator to ensure that count had not met stopping rule and to determine whether rate of decline was suggestive that subject could be approaching D pause rule of 75000/mm^3(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 300 mg every 2 Ws or a reduced D of 150 mg/ W and only if approved by sponsor medical monitor; added language to indicate that in event of any PC less than 25000/M, or a PC less than 50000/M that occurred while subject was on dosing at 300 mg every 2 Ws or 150 mg/W, then dosing of a subject with study drug (volanesorsen or placebo) would be stopped permanently. PC would be monitored daily until 2 successive values showed improvement then monitored every 2-3 days until PC was stable; added language to indicate that administration of steroids was recommended for subjects whose PC was less than 25000/M and to provide treatment guidelines for administration of steroids; added a table summarising actions to be taken in event of a low PC; added language to clarify definition of pharmacokinetic (PK) population; added language to evaluate effect of gender on 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 as limited wash-out data were expected; made minor changes to correct errors and/or to improve overall clarity of protocol.