Protocol, version 2.0 A secondary objective and endpoint were added to measure the health impact of glucocorticoid use in participants with pemphigus. Training for self-administration and caregiver-supported administration were implemented to allow these types of administration in OLE study ARGX-113-1905. Assessments of vaccine-induced immunity in the context of efgartigimod treatment were added. The upper age limit of participants was removed. Changes to the contraceptive requirements based on new data about the IMP were implemented. Participants with specific cancers were allowed in the study if they were adequately treated before they started the study. It was clarified that dapsone use within 2 months of baseline was not exclusionary. A new criterion was added allowing the withdrawal of a participant from the study for whom a severe AE, SAE, or clinically significant change in a laboratory test parameter was reported. A transition in efgartigimod concentration from 165 mg/mL to 180 mg/mL was implemented to reduce the volume for each 1000-mg SC injection. Information on estimands and sensitivity analyses was added to align with the ICH guidelines. The prednisone dose escalation criteria were clarified.

Protocol, version 3.0 A requirement to assess direct immunofluorescence/histopathology at screening, if not available from medical history, was added. High-density lipoprotein cholesterol, total cholesterol, and triglycerides were added to the blood chemistry profile. Guidance was added that the investigator should not implement any deviation from the concurrent oral prednisone (or equivalent) regimen except for immediate safety concerns of the participant. Specialty tests (ie, apolipoprotein B, lipoprotein A, fibrinogen, von Willebrand factor, D-dimer, and proprotein convertase subtilisin/kexin type 9 serine protease) were added to further investigate the effect of the IMP on lipid metabolism.

Protocol, version 4.0 The sample size was increased due to (1) the geopolitical situation in Ukraine and impacted areas and (2) the additional analyses (including a supplementary landmark analysis of the primary endpoint performed at week 30) to align with feedback from regulatory interactions. The changes implemented in the Japan country-specific amendment (version 3.1 – Japan) were incorporated. Specialty tests (ie, apolipoprotein B, lipoprotein A, fibrinogen, von Willebrand factor, D-dimer, and proprotein convertase subtilisin/kexin type 9 serine protease) were removed because no relevant safety signals were observed in efgartigimod studies to date. Based on nonclinical teratogenicity and reproductive toxicity data, the inclusion and exclusion criteria were updated: 1) Female participants could stop their contraception method at the date of the last IMP dose; 2) Female participants could become pregnant immediately after the study.

Protocol, version 5.0 To limit the risk of unblinding and ensure data integrity in this double-blinded efgartigimod study, study sites were no longer provided with the real-time albumin and total protein results. The inclusion criteria were updated to allow male participants to donate sperm, in alignment with the general guidance for efgartigimod on sperm donation. The use of male contraception was no longer required until the end of the study but until the last dose of IMP. Relevant changes implemented in the Germany and China country-specific protocols, v4.1-Germany and v4.1-China, were included also in this protocol amendment.