Substantial changes were: 1) The objective related to the hyperinsulinaemic-euglycaemic clamp was moved from a secondary to an exploratory objective; 2) The 4-point and 7-point glucose profiles were removed as secondary endpoints, as they were not sensitive enough to detect potential effects; 3) Adequate contraception was required for females of childbearing potential who were sexually active with a non-sterile male partner;4) Discontinuation criteria related to dropping heart rate and systolic blood pressure were clarified to be accompanied by symptoms; 5) Storage condition of study drug was changed for consistency with the study drug label and EU labeling for solid dosage forms; 6) Laboratory tests for FPG and fasting insulin were removed from the Week 4, 8, 16, and 20 visits; and 7) Provision was added to allow the Investigator’s discretion on the performance of the hyperinsulinemic-euglycemic clamp procedure for certain subjects if appropriate.

Substantial changes were: 1) A 36-week Extension Period (EP) was added to capture longer term safety and exploratory efficacy data of PBI-4050 in subjects with ALMS; 2) The time period to collect historical data relevant to the disease course was extended from 3 to 10 years; 3) The Data Safety Monitoring Board reviewed individual safety data during the 36-week EP and determined if the safety data supported an additional 36 weeks of study drug treatment; 4) Glycated hemoglobin was performed at every visit during the initial 24 weeks of study drug treatment to capture more data; 5) Exclusion criterion 10 was added to exclude subjects who had a history of an allergic reaction to PBI-4050 or any of its excipients; 6) Based on the addition of a 36-week EP, the primary analysis was to be conducted after the initial 24 weeks of study drug treatment and a final analysis was to be completed at the end of the EP; 7) Subjects were required to give informed consent in order to enter into the 36-week EP; 8) According to the Investigator's Brochure, organic anion transporter (OAT) inhibition could lead to a clinically relevant drug interaction at efficacious human exposures of PBI-4050 based on in vitro inhibitory potency. Therefore, concomitant use of substrates for OAT1 and OAT3 was to be avoided or Investigators were to closely monitor the subject for possible dose adjustments of concomitant substrates for OAT1 and OAT3; 9) Subjects who had already stopped study drug at Week 24 and completed an End of Study (EoS) visit recommenced capture of concomitant therapy at the Start of Extension Study visit; 10) Subjects who had stopped study drug and completed an EoS visit and wanted to continue treatment in the EP were required to meet inclusion and exclusion criteria in order to be treated during the EP; and 11) Secondary and exploratory biomarkers of glucose metabolism were only analyzed at visits that the subject was required to attend fasted.

Substantial changes were: 1) Added 12 weeks to the 36-week Extension Period (EP) to allow subjects who completed the 36-week EP to continue study drug treatment without a break until the rollover study was open for enrolment (i.e., approved and initiated); 2) A Data Safety Monitoring Board continued to review individual subject safety data through the EP, regardless of whether it was 36- or 48-weeks in duration; 3) Clarified that subjects who entered the EP at Week 24 signed informed consent; 4) Liver and cardiac magnetic resonance imaging scans were removed from the EP Week 12 and EP Week 24 visits to reduce subjects’ burden and radiological exposure in the study; 5) Subjects who completed study drug treatment through the EP Week 48 visit were eligible to enter a rollover study in order to continue ongoing study drug without any break in treatment; 6) Removed Inclusion Criterion #6 restricting subjects who had a body mass index of at least 25 kg/m2 to broaden the subject population; 7) Revised Exclusion Criterion #6 to add use of any moderate/potent inducer or inhibitor of cytochrome P450 (CYP) 2C9 isozyme, based on preclinical data showing that CYP2C9 is the major isoform responsible for the metabolism of PBI-4050 and that co-administration of drugs known to be inducers or inhibitors of CYP2C9 could alter the rate of metabolic clearance of PBI 4050; 8) Added telephone contacts for subjects who could not enroll in the rollover study because it was not open for enrolment and for subjects who completed the 48-week EP but chose not to enter the rollover study; and 9) Since subjects could enroll in a rollover study at either the EP Week 36 or EP Week 48 visit without completing the End of Study visit, the defined end of the study was changed to the final visit of the final subject in the study.