The timing of the final liver biopsy and corresponding serum HSP47 analysis was changed from Week 5 to Week 6. Screening evaluations were updated to include antibodies for hepatitis C virus (HCV) and human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and to remove testing for hepatitis B virus (HBV) and HCV viral load. A urine drug screen was added to screening. The permitted concomitant treatments were updated to remove permission for stable, suppressive therapies for HBV and to include permission for a list of commonly administered medications. The prohibited concomitant treatments were updated to prohibit ongoing therapies for HBV and HCV, as well as treatment with interferon for any indication. The timing of weekly visits for subjects receiving infusions once per week or twice per week were made more stringent during Weeks 1 to 5 to ensure that treatments and assessments were made at appropriate intervals. The timing of weekly visits was relaxed for Week 7 to 24 to ± 2 days. The weight to be used for dose determination for all doses was corrected from weight taken at screening to weight taken at baseline. A statement indicating that instructions for treating immediate or delayed infusion-related reactions would be provided to the site was removed to allow the Investigator to treat such reactions as medically appropriate at their discretion. procedures/assessments to be completed in the event of early termination from the study were added. The number of subjects screened for the study and protocol deviations was to be included in the data that is reviewed by the Data Safety Monitoring Board (DSMB) before opening the next cohort. An inclusion criterion was added to allow enrollment of active substance abusers at the discretion of the Investigator. The exclusion criterion which excludes subjects with a history of malignancy within the last 5 years was modified to include an exception for basal cell carcinoma.

Provided windows around the timing of blood draws for PK assessments. Provided windows for blood draws for complement determination during and after study drug infusion. Clarified the difference between prior and concomitant medications. Added definition of the METAVIR score system for severity of fibrosis. Included language that the METAVIR activity grading would be collected. Specified treatment days for the twice-weekly treatment regimen and provided treatment windows for treatment days; specified minimum time between infusions during study treatment weeks. Specified a visit window for the Week 6 evaluation and clarified that the window does not apply to the liver biopsy. Changed the requirement for the Week 6 visit to occur on Monday for those dosed twice weekly to occur 1 week after the last infusion. Changed the requirement for blood pressure to be taken from the same extremity each measurement to be taken from the opposite arm from the infusion arm. Allow screening labs to serve also as baseline labs if the screening visit was within 7 days of the baseline visit. Removed collection of samples for serum heat shock protein 47 (HSP47) assessment. Changed the section on pregnancy from gaining informed consent to gaining permission to follow a pregnancy through to outcome. Clarified that temperature is to be taken orally. Removed the exclusion criterion for subjects with carcinoembryonic antigen (CEA) levels above upper limit of normal.

Visit schedule clarified for subjects who receive treatment once weekly. Text made consistent with Section 10.1 Dosing Schedule (ie, subjects randomly assigned to receive treatment once per week should be dosed the same day of the week throughout the treatment period). A breathalyzer was added as an option for ethanol screening at European sites in the event that urine ethanol testing is unavailable. The liver fibrosis scoring system was changed. METAVIR scoring was used to evaluate liver fibrosis. Knodell scoring and Ishak scoring were removed from the protocol. Weight and height discussion moved from physical examination section to vital signs/weight/height section. The requirement to conduct a baseline physical exam and a baseline electrocardiogram (ECG) was removed if these procedures were conducted at screening within 7 days before the baseline visit.

Study days were corrected for Weeks 12, 16, 20, and 24: Week 12 (Day 78 ± 2 days) Week 16 (Day 106 ± 2 days) Week 20 (Day 134 ± 2 days) Week 24 (Day 162 ± 2 days) Additional timepoint was added at Week 12 (Visit 11, ± 2 days). Additional blood samples were added for liver fibrosis marker, Mac-2 binding protein glycosylation isomer (M2BPGi) before the first treatment (Week 1), after the end of infusion (EOI) of the last treatment (Week 5), and during follow-up at the Week 12 and at Week 24 visits (or at early termination). Results were added for long-term pharmacology and toxicology studies conducted with ND-L02-s0201. Modified the language to allow flexibility for the total number of enrolled subjects, to accommodate the potential of replacement subjects, and clarified that subjects who withdraw from the study during the dosing phase may have been replaced and described the procedures for their replacement. Wording revised to indicate that any potential disturbance in bone density was monitored in human subjects by dual-energy X-ray absorptiometry (DEXA) scans. Description of results from the Phase 1a Study ND-L02-s0201-001 was expanded to indicate there was no evidence of drug-related effects on biomarkers of bone turnover. Justification was expanded to include nonclinical study results. Introduced a window of ± 15 minutes to the 2 hours before the start of study drug infusion at which the premedication oral dose of levocetirizine dihydrochloride could be administered. The liver fibrosis scoring system was changed. Ishak and Knodell scoring were used in addition to METAVIR scoring to evaluate liver fibrosis. An evaluation of the analysis of the biopsy samples using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and histology staining was done throughout the study. Slides for all subjects in all cohorts were stained for Sirius Red staining throughout the study not just those in Cohort 3.