The following changes were made as per amendment 1: • Addressed comments by Health Authority reviewers which identified items requiring further clarification or precision. • Incorporated suggestions from Investigators based on their experiences with practical implementation of the protocol. • Clarified study procedures. • Clarified ambiguities in the previous version. • Addressed ambiguities regarding safety procedures and safety assessments by clarifying the relevant safety definitions and assessments.

The following changes were made as per amendment 2: • Addressed comments by Ethics Committees in Austria and Germany which proposed modification to the concomitant medication guidance for the study. • Incorporated suggestions from Investigators based on their experiences with practical implementation of the protocol. • Clarified study procedures. • Clarified ambiguities in the previous version. • Incorporated revised statistical methodology for consistency with statistical analysis plan in development based on additional statistical consultation.

The following changes were made as per amendment 3: • Incorporated Administrative Clarification Memo dated 16 July, 2019 • Incorporated Administrative Clarification Memo dated 7 November, 2019 • Clarified the intention and/or execution of various study procedures. • Clarified procedural ambiguities in the previous version.

The following changes were made as per amendment 4: • Updated the target enrolment of study subjects from 240 to 360, based on the DSMB recommendations after reviewing results from the pre-specified Sample Size Re- Estimation (SSRE). In that analysis, the Conditional Power fell within the ‘promising zone’ as defined in the reference Mehta and Pocock33 publication; the increase required in the ‘promising zone’ was pre-specified as 360. • Refined the exclusion criteria related to the ECG assessments of the QTcF based on advice from the consultant Cardiologist who is a recognized arrythmia expert. • Clarified text that washout during screening should be completed prior to the start of the WI- NRS collection. This has been the requirement throughout prior study conduct but the specific language has been confusing to sites. This confusion was primarily introduced by textual changes that inadvertently dropped the phrase ‘WI-NRS collection’ from the longer ‘screening period WI-NRS collection” in earlier protocol revisions. • Clarified study procedures, and ambiguities noted across previous protocol versions, including ambiguity regarding the specifications for medication washout periods in relationship to the screening period and or the screening WI-NRS collection. • Formalized and integrated into the Study Protocol document the actual changes in the Operational implementation of the study that occurred due to the initial imposition of COVID- 19 Pandemic-related limitations on in-person study visits. These were previously documented and submitted to Health Authorities in real time as “COVID-19 Administrative Memorandum” numbers 1 and 2, dated April 1, 2020 and April 23, 2020, respectively.

The following changes were made as per amendment 5: • Deleted exclusion criterion #18 to permit enrollment of subjects who have had prior exposure to dupilumab or nemolizumab. As per Exclusion Criterion #17, eligibility still requires a minimal period of 3 months with no exposure to either dupilumab or nemolizumab immediately prior to enrollment in TR11. • Enabled co-enrollment in TR11 for potential subjects who may also be participating in the long-term safety follow-up period of a COVID-19 vaccine study so long as: 1) they have completed the full vaccine series; 2) that specific vaccine has been approved via an Emergency Use Authorization or comparable relevant Health Authority assessment in the country where enrollment takes place; and 3) the concomitant vaccine safety follow-up study permits co-enrollment. • The additional text updates are all considered to be Operational clarifications in response to key questions from site staff and are described in the table below. • Corrected a typographic error in the body of the protocol for inclusion criterion #5. In the V5 version of the protocol the Synopsis text was updated correctly, but that update was accidentally omitted in Section 9.5.1 in the body of the protocol. The current change provides internal consistency between the Synopsis and Section 9.5.1. • Addition of clarifications regarding the eligibility check prior to randomization, and the specific instruction that the final WINRS score entry for confirming eligibility should be performed on the day of the baseline visit and prior to dosing. • Clarified the specific ‘lesion healing’ criterion to be used for assessing whether a subject is eligible to consider dose reduction at Weeks 28, 32 and 36 by specifically referencing the Prurigo Activity Score Item 5b.

The following changes were made as per amendment 6: • Updated the inclusion criteria 6 to remove “non-sedating” so that it is consistent with the change allowing sedating antidepressants. Duration at stable dose also changes to coincide with allowed changes for sedating antidepressants. • Updated the exclusion criteria to eliminate systemic antihistamines as excluded and add that the subject must be on a stable dose. • Updated the exclusion criteria to eliminate sedating antidepressants as excluded. • Updated Table 3 to revise exclusion information for systemic antihistamines, sedating antidepressants, and for medicines with a known risk for Torsade de Pointes. • Provided clarification on the QTcF values to prevent exclusion of subjects who present with Right Bundle Branch block • Allowed drugs previously not allowed due to known risk for Torsade de Pointes as long as the subject has been on a stable dose for at least 4 weeks prior to screening. Elimination of exclusion criteria #34 as it is no longer required.