With global amendment 1, exclusion criterion no. 7 was aligned with the parent trial 1368-0016: The timeframe for the history of malignancy was changed from “at screening” to “within 5 years prior to screening in parent trial” to avoid losing patients with an older history of malignancy from the parent trial. Restrictions on previous and concomitant medications were aligned with the parent trial 1368-0016: the use of non-steroidal anti-inflammatory drugs and acetaminophen/paracetamol was changed from “not allowed/restricted use” to “allowed but recommended to be maintained at stable dose and not to change medication”. Phototherapy, previously not allowed, was now allowed if palms and soles were exempted. The benefit-risk assessment of spesolimab in the context of the COVID 19 pandemic was added, with the administration of spesolimab still considered favourable. To mitigate potential risks regarding the COVID-19 pandemic, every patient was to be assessed thoroughly, and individual benefit-risk assessments were made prior to trial entry and during the trial by the investigator in respect of SARSCoV- 2 infection. A suspected or diagnosed COVID-19 infection was to be treated according to the standard of care and trial treatment could be interrupted. In case of a confirmed infection, trial treatment was to be discontinued immediately and appropriate measures for monitoring, treatment and quarantine were to be implemented. A patient could resume trial treatment following recovery from a SARS-CoV-2 infection if he/she was expected to derive clinical benefit, as agreed between the investigator and sponsor.

With global amendment 2, the description of adverse events (AE) collection was corrected so that after the first administration of trial drug in the extension trial 1368-0024 no further AE updates should be done in the parent trial. The rationale for this change was that the first administration of trial drug in the extension trial was defined as end of study (EoS) for the parent trial and after EoS no further updates were to be made for the parent trial. Regarding the assessment of local tolerability, it was added that any observed local tolerability reaction, e.g. “swelling”, “induration”, “heat”, “redness”, “pain”, and other findings were to be reported as an AE.

Global amendment 3, Part 2: Restrictions on previous and concomitant medications were updated: o To align with the parent trial, other systemic immunomodulating treatment was no longer prohibited for other conditions than palmoplantar pustulosis (PPP) o Topical treatment for PPP was now prohibited on all areas affected by PPP (even extended beyond palms/soles) to cover also cases where the topical treatment for PPP extended beyond palms/soles o Topical corticosteroids for other conditions than PPP were now prohibited on all regions affected by PPP to cover cases where topical corticosteroids were applied to regions other than palms/soles and where PPP could have extended to o Topical treatments (other than topical corticosteroids) for other conditions than PPP were now allowed if they did not affect the PPP assessment. This was added to prohibit topical treatments only to regions that could have affected PPP assessment. The terms ‘suspected or diagnosed’ and ‘confirmed’ COVID-19 infection were further differentiated to ‘suspected or diagnosed, non-severe and non-serious’ and ‘confirmed severe (according to Rheumatology Common Toxicity Criteria, RCTC grading) and/or serious’ COVID-19 infection.

Global amendment 3, Part 1: With global amendment 3, the exclusion of patients with acute demyelinating neuropathy (exclusion criterion no. 18) was added as mitigation strategy to account for the newly added potential risk “peripheral neuropathy” which was derived from the three cases reported as Guillain-Barré syndrome by the investigator in spesolimab trials. The cases were considered as peripheral neuropathy by an independent external neurologist expert panel. In addition, “peripheral neuropathy” was added to the table including risks, summary of data, and mitigation strategies, described under implications of specific events, and added as adverse event of special interest. With regard to patients who met the trial treatment discontinuation criteria, it was updated that these patients could not only be discontinued from trial treatment but had to be discontinued if discontinuation criteria were met at 2 consecutive visits. This was to ensure that patients who no longer benefit from the trial drug discontinued the trial and received treatment according to local standard of care. It was clarified that patients who needed to take rescue medication or who took prohibited medication had to be discontinued from the trial.